Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].[F:13][CH:14]1[C:19](=O)[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]1.N>C(O)(=O)C.OP(O)(O)=O>[F:13][CH:14]1[C:19]([C:7]2[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[NH:9][CH:8]=2)=[CH:18][CH2:17][NH:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(F)C1
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Agent: N
Agent: O=P(O)(O)O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc2[nH]cc(C3=CCNCC3F)c2c1
Reaction time: 16 h
Yield: 46.6 %

Procedure:
A solution of 5-nitroindole (38) (1.0 g, 6.167 mmol) in glacial acetic acid (10 mL) at 90° C. was treated with compound 130 (1.33 g, 6.167 mmol) in glacial AcOH (5 mL), 1 M H3PO4 in glacial AcOH (5 mL) and the resulting solution was stirred at same temperature for 16 h. The reaction was brought to room temperature, poured into 15% cold aqueous ammonia solution (100 mL) and product was extracted into ethyl acetate (2 50 mL). The combined ethyl acetate layer was washed with brine (25 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2 M NH3 in methanol: CH2Cl2, 1:99 to 5:95) to obtain compound 131 (0.75 g, 47%) as a yellow solid. mp 205-207° C.; 1H NMR (DMSO-d6) δ 2.35 (brs, 1H), 2.86-3.06 (m, 1H), 3.19-3.26 (m, 1H), 3.35-3.58 (m, 2H), 5.28 (d, 1H, J=49.5 Hz), 6.53-6.56 (m, 1H), 7.58 (d, 1H, J=8.7 Hz), 7.74 (s, 1H), 8.02 (dd, 1H, J=2.4, 9.0 Hz), 8.68 (d, 1H, J=2.4 Hz), 11.94 (s, 1H); ESI-MS m/z (%): 262 (MH+, 100), 233 (50).
Reaction SMILES: [C:1](OCC1C=CC=CC=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([OH:25])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O=O>C1(C)C=CC=CC=1>[CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([OH:25])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(OCc1ccccc1)c1ccccc1
Agent: O=C(O)c1ccccc1
Agent: O=O
Solvent: Cc1ccccc1
Product: O=Cc1ccccc1

Procedure:
In a preferred embodiment of the invention, the feedstock that is subjected to liquid phase oxidation to convert benzyl benzoate to benzoic acid is obtained from a tar or other residue resulting from a process in which toluene is oxidized with an oxygen-containing gas in the liquid phase in the presence of a heavy metal oxidation catalyst to produce an oxidation product mixture, and benzaldehyde and/or benzoic acid is recovered from the oxidation product mixture.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH2:17][CH:18]1[CH:23]([OH:24])[C:22]([CH3:26])([CH3:25])[O:21][C:20]2[CH:27]=[CH:28][S:29][C:19]1=2>ClCCl>[C:1]([NH:17][CH:18]1[CH:23]([OH:24])[C:22]([CH3:25])([CH3:26])[O:21][C:20]2[CH:27]=[CH:28][S:29][C:19]1=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC1(C)Oc2ccsc2C(N)C1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)Oc2ccsc2C(NC(=O)c2ccccc2)C1O

Procedure:
The title compound was prepared as described in Example 34 starting with benzoyl chloride (0.95 ml), triethylamine (3.3 ml, 23 mmol) and 7-amino-5,6-dihydro-6-hydroxy-5,5-dimethyl-7H-thieno[3,2-b]pyran (1.55 g, 7.78 mmol) in dichloromethane (35 ml) to give the product 1.07 g (45%) as a colorless solid; mp 219°-220° C.; IR(KBr):3398, 1657, 1526 and 1490 cm-1 ; MS:m/z 304 (MH+); 1H NMR (DMSO-d6):δ1.21(5,3H), 1.39(5,3H), 3.81(m,1H, simplifies to d, J=8.8 Hz, with D2O), 5.00(m,1H simplifies to d, 5=8.8 Hz, with D2O), 5.61(d,J=6.0 Hz, 1H, exchanges with D2O), 6.58(d,J=5.3 Hz,1H), 7.29(d,J=5.3 Hz,1H), 7.47(m,3H), 7.92(dd,J=1.3 Hz, J=8.2 Hz,2H) and 8.79(d,J=8.3 Hz, 1H, exchanges with D2O).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[N:6][CH:7]=1.[NH:9]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:10]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:18])[CH3:20])[CH2:10]2)=[N:6][CH:7]=1
Reactant: Fc1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(Br)cn2)C1
Temperature: 100 °C
Reaction time: 6 h
Yield: 35.9 %

Procedure:
5-Bromo-2-fluoropyridine (1.76 mg, 10 mmol) and 3.62 g (10 mmol) of tert-butyl pyrrolidin-3-ylcarbamate were dissolved in 20 ml of N,N-dimethylformamide. Potassium carbonate (1.38 g, 10 mmol) was added to the solution, and the mixture was stirred at 100° C. for 6 hr. Ethyl acetate (60 ml) and 8.5 ml of water were added to the reaction solution, and the organic layer was washed five times with 30 ml of water. The organic layer was dried over anhydrous sodium sulfate and was filtered. The solvent was then removed by distillation, and the residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=4:1) to give 1.23 g (yield 36%) of the title compound.
Reaction SMILES: NC1C=CC(C(N2C3C(=CC=CC=3)[C@H](N(C3C=CC=CC=3)C(=O)CC)C[C@@H]2C)=O)=CC=1.[CH2:32]([CH:34](CC)[CH2:35][NH:36][C:37]1[CH:66]=[CH:65][C:40]([C:41]([N:43]2[C:52]3[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=3)[C@H:46]([N:53]([C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)[C:54](=[O:57])[CH2:55][CH3:56])[CH2:45][C@@H:44]2[CH3:64])=[O:42])=[CH:39][CH:38]=1)C.C(=O)CC.C(C(CC)C=O)C>>[CH3:64][C@H:44]1[CH2:45][C@@H:46]([N:53]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[C:54](=[O:57])[CH2:55][CH3:56])[C:47]2[C:52](=[CH:51][CH:50]=[CH:49][CH:48]=2)[N:43]1[C:41](=[O:42])[C:40]1[CH:65]=[CH:66][C:37]([NH:36][CH2:35][CH2:34][CH3:32])=[CH:38][CH:39]=1
Reactant: CCC(=O)N(c1ccccc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(NCC(CC)CC)cc2)c2ccccc21
Agent: CCC(=O)N(c1ccccc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(N)cc2)c2ccccc21
Agent: CCC(C=O)CC
Solvent: CCC=O
Product: CCCNc1ccc(C(=O)N2c3ccccc3[C@H](N(C(=O)CC)c3ccccc3)C[C@@H]2C)cc1

Procedure:
(±)-Cis-N-[2-methyl-1-(4-propylamino-benzoyl)-1,2,3,4-tetrahydro-quinolin-4-yl]-N-phenyl-propionamide was prepared from (±)-cis-N-[1-(4-amino-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-N-phenyl-propionamide utilizing the reductive amination conditions described for the synthesis of (±)-cis-N-{1-[4-(2-ethyl-butylamino)-benzoyl]-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl}-N-phenyl-propionamide. Propionaldehyde was substituted for 2-ethylbutyraldehyde. The reaction was poorly selective and afforded approximately equivalent amounts of mono- and di-alkylated products (i.e., (±)-cis-N-[1-(4-dipropylamino-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-N-phenyl propionamidel see below).
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:34])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=3)[N:18]([CH2:29][C:30]([F:33])([F:32])[F:31])[N:17]=2)[CH2:9]1.[CH2:35]([C:37]1[S:38][C:39]([C:42]2([OH:49])[CH2:47][CH2:46][C:45](=O)[CH2:44][CH2:43]2)=[CH:40][N:41]=1)[CH3:36]>>[CH2:35]([C:37]1[S:38][C:39]([C:42]2([OH:49])[CH2:43][CH2:44][CH:45]([N:8]3[CH2:11][CH:10]([NH:12][C:13](=[O:34])[CH2:14][NH:15][C:16]4[C:24]5[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:27])([F:28])[F:26])[CH:23]=5)[N:18]([CH2:29][C:30]([F:31])([F:32])[F:33])[N:17]=4)[CH2:9]3)[CH2:46][CH2:47]2)=[CH:40][N:41]=1)[CH3:36]
Reactant: O=C(CNc1nn(CC(F)(F)F)c2ccc(C(F)(F)F)cc12)NC1CNC1
Reactant: CCc1ncc(C2(O)CCC(=O)CC2)s1
Solvent: O=C(O)C(F)(F)F
Product: CCc1ncc(C2(O)CCC(N3CC(NC(=O)CNc4nn(CC(F)(F)F)c5ccc(C(F)(F)F)cc45)C3)CC2)s1

Procedure:
The title compound was prepared as a white solid from reaction of N-(azetidin-3-yl)-2-((1-(2,2,2-trifluoroethyl)-5-(trifluoromethyl)-1H-indazol-3-yl)amino)acetamide TFA salt (as prepared in Example 72, Step A) and 4-(2-ethyl-thiazol-5-yl)-4-hydroxy-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][C:6]1[N:7]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:8]([CH3:27])=[CH:9][C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19].ClCCl.C([O-])(O)=O.[Na+]>C(#N)C>[C:1]([C:9]1[C:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[S:18]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)(=[O:20])=[O:19])=[C:6]([CH3:5])[N:7]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:8]=1[CH3:27])(=[O:3])[CH3:2]
Reactant: CCOC(=O)Cn1c(C)cc(Cc2ccccc2S(=O)(=O)c2ccccc2)c1C
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: CCOC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)c2ccccc2)c(C(C)=O)c1C
Reaction time: 0.08 h
Yield: 73.5 %

Procedure:
In a round-bottomed flask equipped with a magnetic stir bar, acetyl chloride (1.7 μL, 0.024 mmol) was added to a solution of ethyl 2-(2,5-dimethyl-3-(2-(phenylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetate (10 mg, 0.024 mmol) in acetonitrile (0.5 mL) at room temperature. The reaction was stirred for 5 minutes, then dichloromethane (10 mL) and NaHCO3 (sat. aq. 10 mL) were added. The dichloromethane layer was separated and dried over Na2SO4, filtered and concentrated to yield ethyl 2-(3-acetyl-2,5-dimethyl-4-(2-(phenylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetate (8 mgs, 72%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][C:14]([C:20]([CH:22]2[CH2:24][CH2:23]2)=[O:21])=[C:13]3[NH:25][C@H:26]2[CH2:31][CH2:30][C@H:29]([CH2:32][NH:33]C(=O)OC(C)(C)C)[CH2:28][CH2:27]2)[CH:5]=[C:6]([F:9])[C:7]=1[OH:8].C(O)(C(F)(F)F)=O>>[NH2:33][CH2:32][C@H:29]1[CH2:30][CH2:31][C@H:26]([NH:25][C:13]2[C:12]3[C:17](=[CH:18][CH:19]=[C:10]([C:4]4[CH:5]=[C:6]([F:9])[C:7]([OH:8])=[C:2]([Cl:1])[CH:3]=4)[CH:11]=3)[N:16]=[CH:15][C:14]=2[C:20]([CH:22]2[CH2:23][CH2:24]2)=[O:21])[CH2:27][CH2:28]1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(F)c(O)c(Cl)c4)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: NC[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(F)c(O)c(Cl)c4)cc23)CC1

Procedure:
Following general procedure A-2, tert-butyl {trans-4-[6-(3-chloro-5-fluoro-4-hydroxyphenyl)-3-(cyclopropanecarbonyl)quinolin-4-ylamino]cyclohexyl}methylcarbamate (0.123 mmol) was reacted with TFA (2 mL) to afford the desired product (23 mg, 40% over two steps) as a yellow solid: 1H NMR (300 MHz, CD3OD+TFA-d) δ 9.37 (s, 1H), 8.45 (s, 1H), 8.26 (d, J=8.7 Hz, 1H), 7.98 (d, J=8.7 Hz, 1H), 7.63-7.47 (m, 2H), 4.51 (s, 1H), 2.92-2.83 (m, 3H), 2.46-2.40 (m, 2H), 2.11-1.98 (m, 2H), 1.83-1.63 (m, 3H), 1.32-1.14 (m, 6H); ESI MS m/z 468 [C26H27ClFN3O2+H]+; HPLC 98.6% (AUC), tR=11.33 min.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.[CH3:24][O:25][C:26](=[O:65])[CH2:27][C:28]1[CH:29]=[N:30][CH:31]=[C:32]([C:34]2[CH:39]=[CH:38][C:37]([C:40]([CH2:62][CH3:63])([C:43]3[CH:48]=[CH:47][C:46]([C:49]#[C:50][C:51]4([O:56][Si](C)(C)C)[CH2:55][CH2:54][CH2:53][CH2:52]4)=[C:45]([CH3:61])[CH:44]=3)[CH2:41][CH3:42])=[CH:36][C:35]=2[CH3:64])[CH:33]=1>>[CH3:24][O:25][C:26](=[O:65])[CH2:27][C:28]1[CH:29]=[N:30][CH:31]=[C:32]([C:34]2[CH:39]=[CH:38][C:37]([C:40]([CH2:41][CH3:42])([C:43]3[CH:48]=[CH:47][C:46]([C:49]#[C:50][C:51]4([OH:56])[CH2:52][CH2:53][CH2:54][CH2:55]4)=[C:45]([CH3:61])[CH:44]=3)[CH2:62][CH3:63])=[CH:36][C:35]=2[CH3:64])[CH:33]=1
Reactant: CCC(CC)(c1ccc(C#CC2(O[Si](C)(C)C)CCCC2)c(C)c1)c1ccc(-c2cncc(CC(=O)OC)c2)c(C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(C#CC2(O)CCCC2)c(C)c1)c1ccc(-c2cncc(CC(=O)OC)c2)c(C)c1
Reaction time: 2 h
Yield: 39.2 %

Procedure:
A 1.0 M solution of tetrabutylammonium fluoride in tetrahydrofuran (0.079 mL, 0.079 mmol) was added to [5-(4-{1-ethyl-1-[3-methyl-4-(1-trimethylsilanyloxy-cyclopentylethynyl)-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid methyl ester (Example 94-(1); 38.2 mg, 0.0656 mmol), and the mixture was stirred for two hours. The reaction mixture was purified by silica gel chromatography (35 to 50% ethyl acetate/hexane) to give the title compound (13.1 mg, 39%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([F:15])[C:12]([N+:16]([O-])=O)=[CH:11][C:10]=1[F:19])C1C=CC=CC=1>CO.[Pd]>[NH2:16][C:12]1[C:13]([F:15])=[CH:14][C:9]([OH:8])=[C:10]([F:19])[CH:11]=1
Reactant: O=[N+]([O-])c1cc(F)c(OCc2ccccc2)cc1F
Agent: [Pd]
Solvent: CO
Product: Nc1cc(F)c(O)cc1F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 98.4 %

Procedure:
To a solution of 1-(benzyloxy)-2,5-difluoro-4-nitrobenzene (9.21 g) in methanol (300 ml) was added 10% palladium on carbon (921 mg), and the mixture was stirred at room temperature for 24 hours and 20 minutes under a hydrogen atmosphere. After terminating the reaction by substituting the atmosphere in the flask with nitrogen, the catalyst was filtered using Celite. The filtrate was distilled off under reduced pressure to give the title compound (4.96 g, 99%) as a brown solid.
Reaction SMILES: P(C)(C)C.[C:5]([O:9][C:10](=[O:28])[N:11]([CH2:15][C:16]1[CH:21]=[C:20]([CH2:22][CH2:23][N:24]=[N+]=[N-])[CH:19]=[CH:18][C:17]=1[Cl:27])[CH:12]1[CH2:14][CH2:13]1)([CH3:8])([CH3:7])[CH3:6].P([O-])([O-])([O-])=O>C1COCC1>[C:5]([O:9][C:10](=[O:28])[N:11]([CH2:15][C:16]1[CH:21]=[C:20]([CH2:22][CH2:23][NH2:24])[CH:19]=[CH:18][C:17]=1[Cl:27])[CH:12]1[CH2:13][CH2:14]1)([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N(Cc1cc(CCN=[N+]=[N-])ccc1Cl)C1CC1
Agent: CP(C)C
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(Cc1cc(CCN)ccc1Cl)C1CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.1 %

Procedure:
Me3P (1M in toluene, 4.20 mL, 4.20 mmol) was added to a sol. of [5-(2-azido-ethyl)-2-chloro-benzyl]-cyclopropyl-carbamic acid tert-butyl ester (1.49 g, 4.25 mmol) in THF (13.0 mL), and the mixture was stirred at rt for 5 h. Phosphate buffer (pH 7.4, DPBS Gibco 14200, diluted 10×) was added, and the mixture was extracted with CH2Cl2 several times. The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Drying the residue under high vacuum yielded the crude title compound (1.34 g, 97%) that was used further without purification. LC-MS: tR=0.81 min; ES+: 325.18.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]([C:21]([F:24])([F:23])[F:22])=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[N:14]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].C(OCC)(=O)C>[N:18]1[CH:19]=[CH:20][C:15]([C:13]2[N:14]=[C:10]([C:7]3[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=3)[O:11][C:12]=2[C:21]([F:24])([F:22])[F:23])=[CH:16][CH:17]=1
Reactant: O=[N+]([O-])c1ccc(-c2nc(-c3ccncc3)c(C(F)(F)F)o2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(-c2nc(-c3ccncc3)c(C(F)(F)F)o2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
to a nitrogen purged flask charged with palladium on carbon (0.032 g, 0.30 mmol) and 4-(2-(4-nitrophenyl)-5-(trifluoromethyl)oxazol-4-yl)pyridine (1.015 g, 3.0 mmol) in 40 mL ethyl acetate was introduced hydrogen (0.0061 g, 3.0 mmol) by balloon. The reaction mixture was stirred at room temperature under an atmosphere of hydrogen for 18 h then purged with nitrogen and filtered through a pad of Celite. The filtrate was concentrated under reduced pressure to afford a yellow solid. The desired product was isolated by chromatography on silica, eluting with 100% ethyl acetate, affording product as a colorless solid (0.52 g, 56%). ESI+ m/z=306.1 [MH]+.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:9][CH:10]=2)[N:6]=1.[CH3:15][C@H:16]1[CH2:21][O:20][CH2:19][C@H:18]([CH3:22])[NH:17]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:15][C@@H:16]1[N:17]([C:2]2[O:3][C:4]3[C:5](=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:9][CH:10]=3)[N:6]=2)[C@@H:18]([CH3:22])[CH2:19][O:20][CH2:21]1
Reactant: COC(=O)c1cccc2oc(Cl)nc12
Reactant: C[C@H]1COC[C@H](C)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc2oc(N3[C@@H](C)COC[C@@H]3C)nc12
Temperature: 25 °C
Reaction time: 17 h
Yield: 89.6 %

Procedure:
A mixture of methyl 2-chlorobenzoxazole-4-carboxylate (620 mg, 2.96 mmol) and (3S,5S)-3,5-dimethylmorpholine (341 mg, 2.96 mmol) and potassium carbonate (1.0 g, 7.4 mmol), in DMF (15 mL), was stirred in a 35° C. oil bath. After 17 h, the reaction mixture was cooled to ambient temperature, diluted with H2O (50 mL) and extracted with EtOAc (2×30 mL). The combined organic layers were washed with H2O (3×20 mL), brine (20 mL), dried (Na2SO4), and concentrated under reduced pressure. Methyl 2-((3 S,5S)-3,5-dimethylmorpholino)benzoxazole-4-carboxylate (770 mg, 89%) was obtained as an amber oil. 1H NMR consistent.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([OH:16])=O)=[N:10][N:11]([CH3:13])[CH:12]=2)=[CH:4][CH:3]=1.[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[CH2:23][C:24]1[O:32][C:31]2[C:26](=[N:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:14]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]3[CH2:23][C:24]3[O:32][C:31]4[C:26](=[N:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=3)=[O:16])=[N:10][N:11]([CH3:13])[CH:12]=2)=[CH:6][CH:7]=1
Reactant: c1cnc2cc(CC3CCCCN3)oc2c1
Reactant: Cn1cc(-c2ccc(F)cc2)c(C(=O)O)n1
Product: Cn1cc(-c2ccc(F)cc2)c(C(=O)N2CCCCC2Cc2cc3ncccc3o2)n1

Procedure:
The title compound was prepared using the method of Example 4, from 4-(4-fluoro-phenyl)-1-methyl-1H-pyrazole-3-carboxylic acid (110 mg, 0.5 mmol) and (RS)-2-Piperidin-2-ylmethyl-furo[3,2-b]pyridine, D47 (108 mg, 0.5 mmol), as a colourless solid (130 mg, 62%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([N:8]1[CH2:12][CH:11]([N:13]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[C:18]([F:26])[CH:17]=2)[CH3:14])[CH:10]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=2)[CH2:9]1)=[O:7].[C-:35]#[N:36].[K+]>CN(C=O)C>[Cl:34][C:29]1[CH:28]=[C:27]([CH:10]2[CH:11]([N:13]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[C:18]([F:26])[CH:17]=3)[CH3:14])[CH2:12][N:8]([C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][C:35]#[N:36])[CH2:9]2)[CH:32]=[CH:31][C:30]=1[Cl:33]
Reactant: CN(Cc1ccc(C(F)(F)F)c(F)c1)C1CN(C(=O)CCCCBr)CC1c1ccc(Cl)c(Cl)c1
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(Cc1ccc(C(F)(F)F)c(F)c1)C1CN(C(=O)CCCCC#N)CC1c1ccc(Cl)c(Cl)c1
Temperature: 40 °C
Reaction time: 8 h
Yield: 8.9 %

Procedure:
To a stirred solution of 5-bromo-1-{(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-[(3-fluoro-4-trifluoromethyl-benzyl)-methyl-amino]-pyrrolidin-1-yl}-pentan-1-one (XV-1) (40 mg, 0.068 mmol) in DMF (2 ml) was added potassium cyanide (5.0 mg, 0.077 mmol) and 18 crown 6-ether (18 mg, 0.068 mmol). The reaction mixture was stirred at 40° C. overnight, concentrated under vacuo. The product was purified by preparation HPLC to yield 3.2 mg (9%) of the title product as a colorless oil. ES-MS m/e: 530.1 (M+H+).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl:7][C:8]1[C:17]([Cl:18])=[CH:16][C:11]([C:12](OC)=[O:13])=[C:10]([O:19][CH3:20])[CH:9]=1.O.[OH-].[Na+]>C1COCC1>[Cl:7][C:8]1[C:17]([Cl:18])=[CH:16][C:11]([CH2:12][OH:13])=[C:10]([O:19][CH3:20])[CH:9]=1
Reactant: COC(=O)c1cc(Cl)c(Cl)cc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(Cl)c(Cl)cc1CO
Temperature: -20 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
To a mixture of LiAlH4 (2.42 g, 64 mmol) in THF (40 mL) at −40° C. under argon, a solution of methyl 4,5-dichloro-2-methoxybenzoate (6 g, 26 mmol) in THF (50 mL) was added dropwise. The reaction mixture was stirred at −5° C. to 5° C. for 1 h. The mixture was cooled to −20° C. and then water (2 mL) and NaOH (15%) aqueous were added. The resulting mixture was stirred for 15 min. The solid was filtered, and the cake rinsed with ethyl acetate. The combined filtrate was dried over Na2SO4 and concentrated in vacuo to afford the crude product (4.6 g).
Reaction SMILES: [Si]([O:18][CH2:19][C@@H:20]([N:23]1[C@H:28]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[C@@H:27]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[CH2:26][CH:25]([CH2:43][CH3:44])[C:24]1=[O:45])[CH2:21][CH3:22])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[CH:46]([N-]C(C)C)([CH3:48])[CH3:47].[Li+].C(Br)C=C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C1(C)C=CC=CC=1>[CH2:48]([C:25]1([CH2:43][CH3:44])[CH2:26][C@H:27]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[C@@H:28]([C:29]2[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=2)[N:23]([C@@H:20]([CH2:21][CH3:22])[CH2:19][OH:18])[C:24]1=[O:45])[CH:46]=[CH2:47]
Reactant: CCC1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1=O
Reactant: CC(C)[N-]C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: C=CCBr
Product: C=CCC1(CC)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CO)C1=O
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
(5R,6S)-1-((S)-1-(Tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethylpiperidin-2-one (421 mg, 0.639 mmol; Example 202, Step A) was azeotroped with toluene (3×). THF (1.6 mL) was added. The mixture was sparged with argon for 5 minutes and then cooled to 0° C. 1.0 M lithium diisopropylamide solution in THF (1.246 mL, 1.246 mmol) was added dropwise. After 25 minutes, allyl bromide (0.166 mL, 1.917 mmol) was added dropwise. After 20 minutes, the mixture was quenched with sat. aq. NH4Cl solution. The mixture was extracted with ethyl acetate. The organic layer was washed with sat. aq. NaCl solution, dried over Na2SO4, and concentrated. The residue was dissolved in THF (3 mL) and 1.0M tetrabutylammonium fluoride solution in THF (2.335 mL, 2.335 mmol) was added. After stirring overnight, the mixture was partitioned between 5% aq. HCl and ethyl acetate. The organic layer was washed with sat. aq. NaCl solution, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography on silica gel (eluent: 20 to 50% ethyl acetate/hexanes) to afford the title compound as the more polar major diastereomer.
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([CH3:10])[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:3]=1[C:4]#[N:5].[O-:14][CH2:15][CH3:16].[Na+]>C(O)C.O.C(OCC)(=O)C>[CH2:15]([O:14][C:2]1[N:9]=[C:8]([CH3:10])[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:3]=1[C:4]#[N:5])[CH3:16]
Reactant: CC[O-]
Reactant: Cc1nc(Cl)c(C#N)cc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: CCOc1nc(C)c([N+](=O)[O-])cc1C#N
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a stirred solution of the compound prepared in Example 443 (2.04 g) in ethanol (50 mL) at ambient temperature was added a 21% solution of sodium ethoxide in denatured ethanol (4.24 mL). The reaction mixture immediately turned dark purple and was stirred at ambient temperature for 2.5 hours, then diluted with water (250 mL), and the resulting mixture was stirred at ambient temperature for 3 days. The mixture was poured into a separatory funnel and diluted with water (250 mL) and ethyl acetate (500 mL). The organic layer was dried over sodium sulfate and concentrated to give about 9 g of a dark semisolid. This material was partitioned between dichloromethane (200 mL) and water (100 mL). The organic layer was dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel, eluting with 4/1 hexanes/ethyl acetate, to provide the title compound (0.87 g) with the following physical data.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[CH2:4][N:5]([C:11]1[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][C:14]([C:21]#[N:22])=[CH:13][C:12]=1[N+:23]([O-])=O)[C:6](=[O:10])[O:7][CH2:8][CH3:9].C(=O)(O)[O-].[Na+]>CO.[Cl-].[Ti+3].[Cl-].[Cl-]>[NH2:23][C:12]1[CH:13]=[C:14]([C:21]#[N:22])[CH:15]=[C:16]([C:17]([F:19])([F:20])[F:18])[C:11]=1[N:5]([CH2:4][C:3]1[CH:26]=[CH:27][CH:28]=[CH:29][C:2]=1[Cl:1])[C:6](=[O:10])[O:7][CH2:8][CH3:9]
Reactant: CCOC(=O)N(Cc1ccccc1Cl)c1c([N+](=O)[O-])cc(C#N)cc1C(F)(F)F
Agent: [Ti+3]
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CO
Product: CCOC(=O)N(Cc1ccccc1Cl)c1c(N)cc(C#N)cc1C(F)(F)F
Reaction time: 0.33 h
Yield: 113.7 %

Procedure:
Ethyl 2-chlorobenzyl[4-cyano-2-nitro-6-(trifluoromethyl)phenyl]carbamate (298.4 mg) was dissolved in methanol (30 ml), and to the solution were added titanium(III) chloride solution (6.672 g) under ice-cooling. After stirring for 20 minutes, to the reaction mixture was added saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the title compound (315.4 mg, quantitative yield).