Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:9]1[C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:17]2[C:12]([C:13]3[CH:25]=[CH:24][O:23][C:14]=3[CH2:15][O:16]2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>O1CCOCC1.C(O)(=O)C.[Pd]>[C:29]([O:28][C:26]([N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:9]1[C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:17]2[C:12]([C@H:13]3[CH2:25][CH2:24][O:23][C@H:14]3[CH2:15][O:16]2)=[CH:11][CH:10]=1)=[O:27])([CH3:31])([CH3:32])[CH3:30]
Reactant: COC(=O)c1c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc2c1OCc1occc1-2
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: COC(=O)c1c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc2c1OC[C@@H]1OCC[C@H]21
Yield: 99.1 %

Procedure:
A solution of methyl 7-[bis-(tert-butoxycarbonyl)amino]-4H-furo[2,3-c]-chromene-6-carboxylate (Intermediate 3, 0.15 g) in a mixture of dioxane (15 mL) and acetic acid (1.5 mL) was treated under an atmosphere of nitrogen with palladium on carbon (10%, 0.02 g). The mixture was stirred and the nitrogen was replaced by hydrogen then the mixture was stirred under an atmosphere of hydrogen for 3 hours. The mixture was filtered through Celite, the pad was washed thoroughly with dioxane and the filtrate was evaporated to dryness to give methyl cis-(3aRS,9bRS)-7-[bis-(tert-butoxycarbonyl)amino]-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylate (0.15 g) as a gum.
Reaction SMILES: [CH:1]([S:4](Cl)(=[O:6])=[O:5])([CH3:3])[CH3:2].[CH3:8][C:9]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=2)[N:12]=[CH:11][C:10]=1[C:24]([NH:26][C:27]1[CH:28]=[N:29][C:30]([CH:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[C:31]([CH3:33])[CH:32]=1)=[O:25].C(=O)([O-])[O-].[K+].[K+].C(N(CC)CC)C>CN(C)C=O.O>[CH3:8][C:9]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:16][N:15]=2)[N:12]=[CH:11][C:10]=1[C:24]([NH:26][C:27]1[CH:28]=[N:29][C:30]([CH:34]2[CH2:35][CH2:36][N:37]([S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])[CH2:38][CH2:39]2)=[C:31]([CH3:33])[CH:32]=1)=[O:25]
Reactant: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1C1CCNCC1
Reactant: CC(C)S(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1C1CCN(S(=O)(=O)C(C)C)CC1
Temperature: 25 °C

Procedure:
Isopropylsulfonyl chloride (72 μl) was added to a suspension of 5-methyl-N-[5-methyl-6-(piperidin-4-yl)pyridin-3-yl]-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (222 mg) described in Reference Example 171 and potassium carbonate (138 mg) in N,N-dimethylformamide (1.7 ml) and stirred at room temperature for an hour. Then, isopropylsulfonyl chloride (36 μl) was added and stirred at room temperature for two hours. Triethylamine (350 μl) and water were added and the precipitated solid was washed with ethanol and water. The resulting solid was purified with silica gel chromatography (chloroform/methanol) to give the titled compound (103 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[N:9]([O-])=O.[Na+].[F:13][B-:14]([F:17])([F:16])[F:15].[Na+]>O.Cl>[F:13][B-:14]([F:17])([F:16])[F:15].[Cl:1][C:2]1[CH:3]=[C:4]([N+:5]#[N:9])[CH:6]=[CH:7][CH:8]=1
Reactant: O=N[O-]
Reactant: Nc1cccc(Cl)c1
Agent: Cl
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: O
Product: N#[N+]c1cccc(Cl)c1
Reaction time: 0.17 h
Yield: 74.1 %

Procedure:
3-Chloroaniline (2.0 g) was dissolved in a solvent mixture of water (30 mL) and concentrated HCl (3.5 mL), and sodium nitrite (1.30 g) was added thereto under ice cooling, followed by stirring for 10 minutes. To the resultant mixture were added concentrated HCl (5.3 mL) and sodium tetrafluoroborate (6.90 g), followed by stirring for 30 minutes under ice cooling. The precipitate was collected by filtration, and was washed with water, methanol, and diethyl ether, to thereby give the title compound (2.63 g). The compound was directly used for the next reaction.
Reaction SMILES: Br[C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:23]1[CH:28]=[C:27](B(O)O)[CH:26]=[N:25][CH:24]=1.[C:32]([O-:35])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:35][C@@H:32]1[CH2:2][CH2:3][N:4]([C:3]2[C:2]([C:27]3[CH:28]=[N:23][CH:24]=[N:25][CH:26]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:5]1
Reactant: O=C([O-])[O-]
Reactant: OB(O)c1cncnc1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2cncnc2)c1
Temperature: 80 °C
Reaction time: 3.5 h

Procedure:
5-Bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 35.1, 2 g, 4.48 mmol), pyrimidin-5-ylboronic acid (0.666 g, 5.38 mmol), Pd(PPh3)2Cl2 (0.315 g, 0.448 mmol) and Na2CO3 (1.425 g, 13.45 mmol) were added to a MW vial. The vial was sealed, evacuated/purged with argon, and DME (12.55 mL), water (3.59 mL), EtOH (1.793 mL) were added. The RM was stirred at 80° C. for 3.5 h, diluted with THF (4 mL), treated with Si-Thiol (Silicycle, 1.27 mmol/g, 1.765 g, 2.241 mmol), filtered and the filtrate was evaporated off under reduced pressure to give a residue which was purified by flash chromatography (RediSep® Silica gel column, 120 g, cyclohexane/EtOAc-EtOH+0.1% NH4OH (9:1), from 60% to 90% EtOAc-EtOH+0.1% NH4OH (9:1)). Crystallization from a toluene/EtOH mixture yielded the title compound as a white amorphous solid. HPLC Chiral (CHIRALPAK® AD-H, 250×4.6 mm, eluent: EtOH, 0.5 mL/min, UV 210 nm) tR=18.58 min, UPLC-MS (condition 1) tR=2.07 min, m/z=446.1 [M+H]+, m/z=444.2 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.70-1.80 (m, 1H) 1.81-1.92 (m, 1H) 2.89 (d, J=11.25 Hz, 1H) 3.18-3.28 (m, 2H) 3.35-3.44 (m, 1H) 4.22 (br. s, br. s, 1H) 4.89 (d, J=3.42 Hz, 1H) 7.35 (d, J=9.05 Hz, 2H) 7.85 (d, J=9.05 Hz, 2H) 8.10 (d, J=2.45 Hz, 1H) 8.80 (d, J=2.20 Hz, 1H) 8.89 (s, 2H) 9.20 (s, 1H) 10.17 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]3[N:14]([CH:15]=2)[N:13]=[CH:12][N:11]=[C:10]3[N:16]2[CH2:21][CH2:20][N:19]([C:22]3[N:27]=[CH:26][C:25]([C@H:28]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)N)=[CH:24][N:23]=3)[CH2:18][CH2:17]2)[CH:4]=[N:3]1.C=O.[C:38]([BH3-])#[N:39].[Na+].[C:42](O)(=O)C.C([O-])(O)=O.[Na+]>CC#N>[CH3:42][N:39]([CH3:38])[C@H:28]([C:25]1[CH:24]=[N:23][C:22]([N:19]2[CH2:20][CH2:21][N:16]([C:10]3[C:9]4=[CH:8][C:7]([C:5]5[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=5)=[CH:15][N:14]4[N:13]=[CH:12][N:11]=3)[CH2:17][CH2:18]2)=[N:27][CH:26]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(=O)O
Reactant: [BH3-]C#N
Reactant: Cn1cc(-c2cc3c(N4CCN(c5ncc([C@@H](N)c6ccccc6)cn5)CC4)ncnn3c2)cn1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CN(C)[C@@H](c1ccccc1)c1cnc(N2CCN(c3ncnn4cc(-c5cnn(C)c5)cc34)CC2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 19.5 %

Procedure:
(S)-(2-(4-(6-(1-Methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)(phenyl)methanamine (72 mg, 0.154 mmol) and formaldehyde (125 mg, 1.543 mmol) were taken up in MeCN (1.5 mL). Sodium cyanoborohydride (25 mg, 0.398 mmol) was added, followed by acetic acid (0.02 mL, 0.349 mmol) and the resulting mixture was stirred at room temperature for 3 hours. Saturated NaHCO3 was added and the products extracted into DCM (×2). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the residue by MPLC (0-10% MeOH-DCM), followed by MPLC (0-10% MeOH-EtOAc), followed by MPLC (0-8% MeOH-EtOAc) gave (S)—N,N-dimethyl-1-(2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)-1-phenylmethanamine (15 mg, 0.030 mmol, 19.65% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:15])=[C:5]([C:9]([N+:12]([O-:14])=[O:13])=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].[C:16]([O-])([O-])=O.[Cs+].[Cs+].IC.O>CO>[CH3:16][O:7][C:6](=[O:8])[C:5]1[C:9]([N+:12]([O-:14])=[O:13])=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[C:4]=1[CH3:15]
Reactant: COc1ccc([N+](=O)[O-])c(C(=O)O)c1C
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: O
Solvent: CI
Product: COC(=O)c1c([N+](=O)[O-])ccc(OC)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-Methoxy-2-methyl-6-nitro-benzoic acid in 45 mL of methanol, Cs2CO3 (7.8 g, 24 mmol) is added and stirred at the room temperature for 1 hour. The solution is concentrated under reduced pressure then the resulting yellow solid is suspended in 45 ml of DMF. Iodomethane (1.5 ml 24 mol) is added at 0° C. and stirred at the room temperature for 21 hours. Water is added to the solution and the precipitates are collected and washed by water to give 3-Methoxy-2-methyl-6-nitro-benzoic acid methyl ester (4.0 g) as orange solid in 81% yields. 1H-NMR (400 MHz, δ, ppm) CDCl3: 2.2 (s, 3H), 3.93 (s, 3H), 3.98 (s, 3H), 6.91 (d, 1H), 8.11 (d, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:15]2[N:14]3[CH2:18][CH2:19][C:20](=O)[C:13]3=[CH:12][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([O:26][C:27](=[O:48])[CH:28]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([CH3:25])([CH3:24])[CH3:23]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:15]2[N:14]3[CH2:18][CH2:19]/[C:20](=[CH:28]\[C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:48])/[C:13]3=[CH:12][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCn2c1cc1cc(OCc3ccccc3)ccc12
Reactant: CC(C)(C)OC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)/C=C1\CCn2c1cc1cc(OCc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 7-(benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-one (20.0 g, 72.1 mmol) and tert-Butyl(triphenylphosphoranylidene)acetate (136 g, 361 mmol) in THF (700 mL) was heated at reflux for 4 days. Additional and tert-Butyl(triphenylphosphoranylidene)acetate (27.1 g, 72.1 mmol) was added and stiffing at reflux was continued for an additional 24 h. The mixture was cooled to room temperature and the solvent was removed under reduced pressure. Recrystallization from hot IPA gave (E)-tert-butyl 2-(7-(benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-ylidene)acetate as a white solid. Exact mass calculated for C24H25NO3: 375.2, found: LCMS m/z=376.2, (M+H+); 1H NMR (400 MHz, CDCl3) δ ppm 1.53 (s, 9 H), 3.75 (td, J1=6.4, J2=2.4 Hz, 2 H), 4.20 (t, J=6.4 Hz, 2 H), 5.11 (s, 2 H), 6.23 (t, J=2.4 Hz, 1 H), 6.58 (s, 1 H), 6.98 (dd, J1=8.9, J2=2.3 Hz, 1 H), 7.13 (d, J=2.3 Hz, 1 H), 7.21 (d, J=8.9 Hz, 1 H), 7.33 (m, 1 H), 7.39 (m, 2 H), 7.48 (m, 2 H).
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]([OH:13])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[O:14].[C:15]([O:19][CH3:20])(=[O:18])[CH2:16][SH:17]>>[CH3:20][O:19][C:15](=[O:18])[CH2:16][S:17][CH2:2][C:3]1[C:4]2[CH2:5][CH2:6][CH2:7][C:8](=[O:14])[C:9]=2[CH:10]=[CH:11][C:12]=1[OH:13]
Reactant: O=C1CCCc2c1ccc(O)c2CCl
Reactant: COC(=O)CS
Product: COC(=O)CSCc1c(O)ccc2c1CCCC2=O
Temperature: 40 °C
Yield: 52.1 %

Procedure:
5-Chloromethyl-6-hydroxy-1-tetralone (315 mg, 1.5 mmol) and methyl thioglycolate (2.0 mL, 22 mmol) were combined in a septum capped round bottomed flask and heated to 40° C. overnight. The excess methyl thioglycolate was removed in vacuo and the pot residue was purified by silica gel chromatography (Rf=0.18, hexanes/ethyl acetate/acetic acid, 58:40:2) to give 219 mg (52%) of the desired compound as a colorless glass: 1H NMR (CDCl3) δ 2.02 (p, 2H, J=6.01 Hz); 2.50 (t, 2H, J=6.01 Hz); 2.89 (t, 2H, J=6.01 Hz); 3.19 (s, 2H); 3.64 (s, 3H); 3.85 (s, 2H); 6.79 (d, 1H, J=8.7 Hz); 7.83 (d, 1H, J=8.7 Hz); 8.59 (br s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH2:17])[C:5]2[O:12][C:9]3([CH2:11][CH2:10]3)[CH2:8][C:7]([CH3:14])([CH3:13])[C:6]=2[CH:15]=1.[N+](=[CH2:20])=[N-].CCCCCC>C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:16]2[CH2:20][CH2:17]2)[C:5]2[O:12][C:9]3([CH2:10][CH2:11]3)[CH2:8][C:7]([CH3:13])([CH3:14])[C:6]=2[CH:15]=1
Reactant: C=Cc1cc(Br)cc2c1OC1(CC1)CC2(C)C
Reactant: C=[N+]=[N-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCCCCC
Solvent: CCOCC
Product: CC1(C)CC2(CC2)Oc2c(C3CC3)cc(Br)cc21

Procedure:
Following general procedure O and, using A 6-bromo-3,4-dihydro-4,4-dimethyl-8-vinylspiro[2H-1-benzopyran-2,1′-cyclopropane] (Intermediate 41, 1.36 g, 4.6 mmol), a solution of diazomethane in diethyl ether and palladium(II)acetate (˜30 mg) followed by flash column chromatography over silica gel (230-400 mesh) using hexane as the eluent, the title compound was obtained as a clear oil (1.38 g, 100%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:43][C:44]1[CH:45]=[C:46]([C:54]2[CH:63]=[CH:62][C:61]3[C:56](=[C:57]([NH2:64])[CH:58]=[CH:59][CH:60]=3)[N:55]=2)[CH:47]=[C:48]([C:50]([F:53])([F:52])[F:51])[CH:49]=1>CN(C=O)C.O>[F:43][C:44]1[CH:45]=[C:46]([C:54]2[CH:63]=[CH:62][C:61]3[C:56](=[C:57]([NH:64][C:7]([C:2]4[CH:3]=[N:4][CH:5]=[CH:6][N:1]=4)=[O:9])[CH:58]=[CH:59][CH:60]=3)[N:55]=2)[CH:47]=[C:48]([C:50]([F:52])([F:53])[F:51])[CH:49]=1
Reactant: O=C(O)c1cnccn1
Reactant: Nc1cccc2ccc(-c3cc(F)cc(C(F)(F)F)c3)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccc2ccc(-c3cc(F)cc(C(F)(F)F)c3)nc12)c1cnccn1
Yield: 40.3 %

Procedure:
2-pyrazine carboxylic acid (0.065 g, 0.51 mmol) was combined with DIPEA (0.140 mL, 0.811 mmol) and HATU (0.200 g, 0.51 mmol) in 5 mL DMF. The mixture was stirred at room temperature for ten minutes, at which time 2-(3-fluoro-5-(trifluoromethyl)phenyl)quinolin-8-amine (0.12 g, 0.391 mmol) was added. The mixture was stirred at room temperature for 18 hours before 10 mL water was added. The resulting precipitate was collected by filtration, and the solids were triturated in methanol to yield N-(2-(3-fluoro-5-(trifluoromethyl)phenyl)quinolin-8-yl)pyrazine-2-carboxamide as a beige solid (0.065 g, 31% yield). MS (ESI) calcd for C21H12F4N4O (m/z): 412.09. found: 413 [M+1].
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH2:9][C:8](=[O:10])[NH:7][C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[N:4]=1.[H-].[Na+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O.O>[CH2:19]([N:7]1[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[N:4]=[C:3]([C:2]([F:1])([F:15])[F:16])[CH:9]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]1=[O:10])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CC(C(F)(F)F)=Nc2ccccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1C(Cc2ccccc2)C(C(F)(F)F)=Nc2ccccc2N1Cc1ccccc1
Reaction time: 0.25 h
Yield: 61.7 %

Procedure:
To a solution of 4-trifluoromethyl-1,3-dihydro-1,5-benzodiazepin-2(2H)-one(3.0 g, 13.1 mmol) in N,N-dimethylformamide(20 mL) was added sodium hydride (content 60%, 1.1 g, 27.5 mmol), and the mixture was stirred for 15 minutes. To the mixture was added benzyl bromide (4.7 g, 27.5 mmol), which was stirred for further 30 minutes. The reaction mixture was diluted with water, which was extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The concentrate was crystallized from ethyl acetate-hexane to give 3.3 g of the titled compound. Yield 61%. m.p. 150°-151° C.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:12]([CH3:13])=[CH:11][C:8]([CH:9]=O)=[CH:7][C:6]=1[CH3:14])([CH3:3])[CH3:2].Cl.[NH2:16][OH:17].C([O-])([O-])=O.[Na+].[Na+]>CCO.CCOC(C)=O>[CH:1]([O:4][C:5]1[C:12]([CH3:13])=[CH:11][C:8]([CH:9]=[N:16][OH:17])=[CH:7][C:6]=1[CH3:14])([CH3:3])[CH3:2]
Reactant: NO
Reactant: Cc1cc(C=O)cc(C)c1OC(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cc(C=NO)cc(C)c1OC(C)C

Procedure:
4-(Isopropoxy)-3,5-dimethylbenzaldehyde (1.98 g, 10.3 mmol) in EtOH (60 mL) was heated to 60° C. with hydroxylamine hydrochloride (2.4 M aq. solution, 5.2 mL, 1.2 eq.) and Na2CO3 (1.2 M solution, 5.2 mL, 0.6 eq.) at room temperature for 2 hours. The reaction was transferred to a separatory funnel, diluted with EtOAc; the organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated to yield 710 mg (3.24 mmol) of 4-(isopropoxy)-3,5-dimethylbenzaldehyde oxime as a light yellow oil. 1H-NMR (500 MHz, CDCl3): 8.10 (s, 1H), 7.23 (s, 2H), 4.29-4.18 (m, 1H), 2.29 (s, 6H), 1.29 (d, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][C:3]=1[N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].[O:24]=[C:25]1[NH:29][C:28](=[O:30])[CH:27]([CH2:31][C:32]2[CH:42]=[CH:41][C:35]([O:36][CH2:37][C:38](O)=[O:39])=[CH:34][CH:33]=2)[S:26]1.C(N(CC)CC)C>O1CCCC1>[O:24]=[C:25]1[NH:29][C:28](=[O:30])[CH:27]([CH2:31][C:32]2[CH:33]=[CH:34][C:35]([O:36][CH2:37][C:38]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][C:9]4[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=4)=[CH:4][C:3]=3[N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:39])=[CH:41][CH:42]=2)[S:26]1
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2cccnc2)ccc1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2cccnc2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 76.1 %

Procedure:
In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(pyridin-3-yloxy)phenyl]-N-methylcarbamate (0.63 g), 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (0.62 g), diethyl cyanophsphonate (0.36 g), triethylamine (0.22 g) and anhydrous tetrahydrofuran (15 ml) and the reaction mixture was purified to give the desired product (0.88 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14](OC(C)(C)C)=[O:15])[C@:11]([CH3:27])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:10]=1.O[C@@H]1[CH2:33][N:32](C(OC(C)(C)C)=O)[C@:31](C)(C2C=CC=CC=2)C1.FC(F)(F)C(O)=O.C(N(CC)CC)C.CN(C)C(Cl)=O>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14]([N:32]([CH3:33])[CH3:31])=[O:15])[C@:11]([CH3:27])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CC(c2cc(F)ccc2F)=C[C@@]1(C)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)C[C@@]1(C)c1ccccc1
Agent: CN(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)N1CC(c2cc(F)ccc2F)=C[C@@]1(C)c1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl(2S)-4-(2,5-difluorophenyl)-2-methyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxylate (21-3, prepared from tert-butyl(2S,4S)-4-hydroxy-2-methyl-2-phenylpyrrolidine-1-carboxylate (21-2) by the procedures of Scheme 20, 24 mg, 0.065 mmol, 1 equiv) in a 1:1 mixture of trifluoroacetic acid and dichloromethane (10 mL) was stirred for 30 minutes, then concentrated. The residue was dried via toluene azeotrope (2×10 mL), then dissolved in dichloromethane (10 mL). Triethylamine (0.090 mL, 0.65 mmol, 10 equiv) and dimethylcarbamoyl chloride (0.030 mL, 0.33 mmol, 5.0 equiv) were added, and the resulting mixture was stirred at 40° C. for 6 hours, then 23° C. for 2 days. The reaction mixture was partitioned between aqueous saturated sodium bicarbonate solution (30 mL) and ethyl acetate (2×25 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (hexanes initially, grading to 40% ethyl acetate in hexanes) to provide (2S)-4-(2,5-difluorophenyl)-N,N,2-trimethyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide (21-4) as an off-white solid. 1H NMR (500 MD, CDCl3) δ 7.40 (br d, 2H, J=7.7 Hz), 7.32 (br t, 2H, J=7.8 Hz), 7.22 (t, 1H, J=7.5 Hz), 7.08-6.91 (m, 3H), 6.24 (m, 1H), 4.82 (dd, 1H, J=13.9, 1.5 Hz), 4.77 (dd, 1H, J=13.9, 1.5 Hz), 2.77 (s, 6H), 2.02 (s, 3H). LRMS m/z (M+H) 343.0 found, 343.2 required.
Reaction SMILES: [OH:1]S(O)(=O)=O.[O-]O.[C:8]1([CH:14]([CH3:16])[CH3:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1([OH:23])C=CC=CC=1.[C:24]1([CH:30]([CH3:32])[CH3:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CC(C)=O>[C:8]1([CH:14]([CH3:16])[CH3:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:31][C:30]([CH3:32])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[OH:23].[C:14]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:1])[CH3:16]
Reactant: Oc1ccccc1
Reactant: O=S(=O)(O)O
Agent: [O-]O
Solvent: CC(C)=O
Solvent: CC(C)c1ccccc1
Product: CC(=O)c1ccccc1
Product: CC(C)(O)c1ccccc1

Procedure:
The current process of choice for commercial phenol production utilizes the autocatalytic cumene/air oxidation to cumene hydroperoxide (CHP) route for over 50% of the world's production of phenol. A key step in this process is the decomposition (cleavage) of CHP produced in the oxidation section of the plant to phenol and acetone using dilute mineral acid (H2SO4) as an acid catalyst. Use of the liquid acid requires subsequent neutralization and purification of the phenol at substantial cost, and a waste stream generation that could be avoided if an effective solid acid catalyst could be used. CHP decomposition is a very exothermic reaction which is normally carried out on a commercial scale in continuous stirred or back-mixed reactors. In such reactors only a small fraction of CHP is unreacted at any given time and the reaction medium consists essentially of the products of decomposition of CHP, i.e., phenol and acetone, plus any solvent (e.g., cumene and/or recycle acetone) and other materials added with CHP to the reactor. During cumene oxidation small amounts of dimethylphenylcarbinol (DMPC) and acetophenone are also formed. In the presence of acid catalyst, DMPC dehydrates to alpha-methylstyrene (AMS), a useful by-product. Very high yields of AMS can be obtained from pure DMPC, e.g., 98% yield upon dehydration over acidic silica at 300° C. In the presence of phenol, however, and more specifically in a phenol/acetone/cumene mixture which is a solvent in the decomposition of CHP/DMPC mixtures, the ultimate AMS yield is normally about 50-60 mol % of the DMPC. Main by-products are AMS dimers and cumylphenol which have no commercial value. Formation of cumylphenol also reduces the phenol yield.