Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[Al+3].[Br-].[Br-].C(S)C.[CH2:8]([C:12]1([CH2:33][CH3:34])[CH2:18][N:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]2[CH:25]=[CH:26][C:27]([O:29]C)=[CH:28][C:15]=2[S:14](=[O:32])(=[O:31])[CH2:13]1)[CH2:9][CH2:10][CH3:11].O>C(Cl)Cl>[CH2:8]([C:12]1([CH2:33][CH3:34])[CH2:18][N:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]2[CH:25]=[CH:26][C:27]([OH:29])=[CH:28][C:15]=2[S:14](=[O:31])(=[O:32])[CH2:13]1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCC1(CC)CN(c2ccccc2)c2ccc(OC)cc2S(=O)(=O)C1
Agent: [Al+3]
Agent: [Br-]
Solvent: ClCCl
Solvent: CCS
Solvent: O
Product: CCCCC1(CC)CN(c2ccccc2)c2ccc(O)cc2S(=O)(=O)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of aluminum bromide (1M in CH2Cl2, 16 mmol) and ethanethiol (7.4 ml, 100 mmol) at 0° C. was added the compound of Example 17 (0.78 g, 2.01 mmol) in 30 ml CH2Cl2. The mixture was stirred for 1 h at 0° C. and then 25 ml water was added and the product extracted with 3×20 ml CH2Cl2. The organic layer was dried and the solvents evaporated. The residue was applied to a silica gel column and the product eluted with 35% ethyl acetate/petroleum ether (0.74 g, 98%). 1H NMR (DMSO-d6) δ 10.00 (s, 1H), 7.28-6.74 (m, 8H); 3.6 (br s, 2H); 3.21 (s, 2H); 1.55-1.02 (m, 8H); 0.73 (m, 6H). MS Da/e=374 (MH+). Calcd for C21H27NSO3 ×0.4 H2O: C, 66.25; H, 7.36; N, 3.68; S, 8.42. Found: C, 66.12; H. 7.37; N, 3.61; S, 8.30.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=1)=[O:7])([CH3:4])(C)C.C(Cl)Cl.C(O)(C(F)(F)F)=O.C(Cl)(OCC1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:44]2[C:39]1=[CH:40][CH:41]=[CH:42][CH:43]=2)=O>CCOCC>[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[CH:22][CH:23]=1)([O:5][CH2:1][CH:4]1[C:43]2[C:44](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:45]2[C:50]1=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:7]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccc(C(=O)O)cc1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Solvent: CCOCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(OC[C@@H]2CCCN2C(=O)OCC2c3ccccc3-c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 91 %

Procedure:
To the above (S)-4-(1-tert-butoxycarbonyl-2-pyrrolidinyl)methoxybenzoic acid was added CH2Cl2 (10 mL) and TFA (10 mL). The mixture was stirred at room temp for 1 hr Et2O was added to the mixture and resulting solid was collected. The solid was dissolved in water (100 mL), dioxane (50 mL) and NaHCO3 (4.4 g). Fmoc-Cl (3.34 g, 12.9 mmol) was added to the solution, and the resulting mixture was stirred for 20 hr at room temp. The mixture was washed with Et2O (×2) and aqueous layer was separated. The layer was acidified by the addition of 1 N HCl. The mixture was extracted with EtOAc. The extract was washed with water, brine, dried over MgSO4 and evaporated in vacuo to afford 5.36 g (91%) (S)-4-(1-Fmoc-2-pyrrolidinyl)methoxybenzoic acid as a viscous oil, which was crystallized on standing.
Reaction SMILES: C(O[C:4](=[O:37])[C:5]1[CH:10]=CC(OC2C=CC=CC=2)=[CH:7][C:6]=1[CH2:18][N:19]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=1[O:35][CH3:36])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl-].[NH4+].[CH2:50]1[CH2:54][O:53][CH2:52][CH2:51]1>>[CH2:24]([O:23][C:21]([C:20]1[N:19]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=2[O:35][CH3:36])[CH2:18][C:6]2[C:5]([C:4]=1[OH:37])=[CH:10][CH:50]=[C:54]([O:53][C:52]1[CH:51]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH:7]=2)=[O:22])[CH3:25]
Reactant: C1CCOC1
Reactant: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1cc(Oc2ccccc2)ccc1C(=O)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Product: CCOC(=O)C1=C(O)c2ccc(Oc3ccccc3)cc2CN1Cc1ccc(OC)cc1OC
Reaction time: 1.5 h

Procedure:
460 mg of 2-{[(2,4-Dimethoxy-benzyl)-ethoxycarbonylmethyl-amino]-methyl}-4-phenoxy-benzoic acid ethyl ester was dissolved in 16 mL of anhydrous THF and the resultant solution cooled to −78 deg C. under a nitrogen atmosphere. To the solution was added 1.95 mL of 1.0 M lithium bis(trimethylsilyl) amide in THF. The reaction was stirred at −78 deg C. for 1.5 h, and at room temperature for 4.5 hours. The resultant solution was poured into a solution of saturated aqueous ammonium chloride and extracted three times with ethyl acetate. The organic fractions were washed with brine, dried over anhydrous sodium sulfate and concentrated to yellow oil. The oil was flash columned on silica gel, eluting with a gradient of 20-75% ethyl acetate in hexanes. The eluted fractions were concentrated under reduced pressure to 373 mg of a yellow oil, which was determined to be a mixture of the enol and keto tautomers of the desired product; MS (+) m/z 484.20 (m+23).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[O:8][C:9]3[C:10](=[C:12]([C:16]([OH:18])=O)[CH:13]=[CH:14][CH:15]=3)[N:11]=2)=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl.Cl.[NH2:43][C@H:44]1[CH:49]2[CH2:50][CH2:51][N:46]([CH2:47][CH2:48]2)[CH2:45]1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[N:46]12[CH2:51][CH2:50][CH:49]([CH2:48][CH2:47]1)[C@H:44]([NH:43][C:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:9]3[O:8][C:7]([C:5]4[S:6][C:2]([Cl:1])=[CH:3][CH:4]=4)=[N:11][C:10]=13)=[O:18])[CH2:45]2
Reactant: O=C(O)c1cccc2oc(-c3ccc(Cl)s3)nc12
Reactant: N[C@@H]1CN2CCC1CC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(N[C@@H]1CN2CCC1CC2)c1cccc2oc(-c3ccc(Cl)s3)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 14.5 %

Procedure:
A mixture of 2-(5-chlorothiophen-2-yl)benzoxazole-4-carboxylic acid (110 mg, 0.39 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (149 mg, 0.78 mmol), 1-hydroxybenzotriazole (106 mg, 0.78 mmol) and (S)-(−)-3-aminoquinuclidine dihydrochloride (135 mg, 0.49 mmol) in DMF (3 mL) was stirred at room temperature for 10 min, then triethylamine (0.22 mL, 1.4 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with dichloromethane (2×50 mL). The combined organic layers were washed with brine (50 mL), dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 dichloromethane/methanol/concentrated ammonium hydroxide) to afford (S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(5-chloro-thiophen-2-yl)benzoxazole-4-carboxamide (22 mg, 17%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 9.41 (d, J=7.3 Hz, 1H), 8.17 (dd, J=7.8, 1.0 Hz, 1H), 7.73 (d, J=4.1 Hz, 1H), 7.69 (dd, J=8.2, 1.0 Hz, 1H), 7.48 (t, J=8.0 Hz, 1H), 7.06 (d, J=4.0 Hz, 1H), 4.50-4.45 (m, 1H), 3.65-3.60 (m, 1H), 3.30-3.20 (m, 2H), 3.15-3.05 (m, 2H), 3.02-2.95 (m, 1H), 2.30-2.55 (m, 2H), 1.95-1.78 (m, 3H); MS (ESI+) m/z 388 (M+H); HPLC>99% (AUC), tR=12.59 min.
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=CC=CC=1.[C:8]([OH:13])(=[O:12])[C:9]([CH3:11])=[O:10].C(O)CC>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[C:8]([O:13][CH2:6][CH2:1][CH3:7])(=[O:12])[C:9]([CH3:11])=[O:10]
Reactant: Cc1ccccc1
Reactant: CC(=O)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCO
Solvent: O
Product: CCCOC(=O)C(C)=O
Temperature: 25 °C
Yield: 62 %

Procedure:
A toluene solution (1 L) containing pyruvic acid (440 g, 5.0 mol), n-propanol (300 g, 5.0 mol) and p-toluenesulfonic acid monohydrate (2.5 g) was heated and refluxed for 16 hours under nitrogen flow. The reaction led to generation of water in the system. However, the water was removed using Dean-Stark trap. The resultant reaction solution was cooled down to room temperature, followed by removal of toluene using an evaporator under a reduced pressure. The residual was then purified using reduced pressure distillation (40 mmHg, 85 to 90° C.) to give propyl pyruvate (400 g, yield: 62%).
Reaction SMILES: [ClH:1].[CH2:2]1[CH2:6][O:5][C:4]2[CH:7]=[CH:8][C:9]3[CH2:10][CH2:11]/[C:12](=[CH:14]\[CH2:15][NH2:16])/[C:13]=3[C:3]1=2.[OH-].[Na+]>C1(C)C=CC=CC=1>[ClH:1].[CH2:2]1[CH2:6][O:5][C:4]2[CH:7]=[CH:8][C:9]3[CH2:10][CH2:11][C@@H:12]([CH2:14][CH2:15][NH2:16])[C:13]=3[C:3]1=2
Reactant: NC/C=C1\CCc2ccc3c(c21)CCO3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: NCC[C@@H]1CCc2ccc3c(c21)CCO3
Yield: 73 %

Procedure:
To an aqueous solution of (E)-2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-ylidene)ethylamine hydrochloride (1979 kg, Net 122 kg, 513 mol) were added toluene (532 L) and 5% aqueous solution of sodium hydroxide (456 L), and stirred. The layers were separated, and to the organic layer were added methanol (155 kg) and [RuCl(benzene)(R)-BINAP]Cl (894 g) under nitrogen atmosphere, followed by stirring at 80° C. for 15 hrs under hydrogen atmosphere (4.9 MPa). The reaction solution was cooled, and water (330 L) and concentrated hydrochloric acid (52.3 kg) were added at below 30° C., followed by stirring for 30 minutes, then the layers were separated. The aqueous layer was washed with toluene (195 L), and pH was adjusted to about 6.0 by adding 5% aqueous solution of NaOH to the aqueous layer. (containing 5.0% of compound III′). 5% Pd—C (50% wet, 9.7 kg) was added thereto, and stirred at 60° C. for 6 hrs under hydrogen atmosphere (4.9 MPa). The reaction mixture was filtered, and the filtrate was adjusted to around pH 6.0 with 5% aqueous solution of NaOH or dilute hydrochloric acid, followed by concentration under reduced pressure. The residue was recrystallized from mixed solution of n-butanol and water to give title compound (88.6 kg, yield 73.0%, compound (III′) is not detected, compound (IV′) is not detected).
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:24])[NH:6][C:7]1[N:8]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][OH:23])=[CH:18][CH:17]=2)[N:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1.[CH3:27][N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C:33]1[N:37]2[CH:38]=[C:39]([O:42][C@@H:43]3[C:51]4[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=4)[C@@H:45]([NH2:52])[CH2:44]3)[CH:40]=[CH:41][C:36]2=[N:35][N:34]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:12]([C:10]1[CH:11]=[C:7]([NH:6][C:5]([NH:52][C@@H:45]2[C:46]3[C:51](=[CH:50][CH:49]=[CH:48][CH:47]=3)[C@@H:43]([O:42][C:39]3[CH:40]=[CH:41][C:36]4[N:37]([C:33]([C@@H:29]5[CH2:30][CH2:31][CH2:32][N:28]5[CH3:27])=[N:34][N:35]=4)[CH:38]=3)[CH2:44]2)=[O:24])[N:8]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][OH:23])=[CH:18][CH:17]=2)[N:9]=1)([CH3:14])([CH3:15])[CH3:13]
Reactant: CN1CCC[C@H]1c1nnc2ccc(O[C@H]3C[C@H](N)c4ccccc43)cn12
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2ccc(CO)cc2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCC[C@H]1c1nnc2ccc(O[C@H]3C[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(CO)cc4)c4ccccc43)cn12

Procedure:
A solution of Intermediate 33a (190 mg, 0.454 mmol), Intermediate 37a (132 mg, 0.378 mmol) and DIPEA (132 μL, 0.756 mmol) in anhydrous DMF (3 mL) was stirred at 100° C. for 3 h. After cooling, the mixture was partitioned between EtOAc (50 mL) and water (50 mL), and then extracted into EtOAc (3×50 mL). The combined organics were washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by FCC, using 0-10% MeOH in DCM, to give the title compound as give an off-white solid after freeze-drying (143 mg, 61%). LCMS (Method 5): Rt 3.23, m/z 621 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.22 (9H, s), 1.95-1.97 (3H, m), 2.07 (3H, s), 2.20-2.23 (3H, m), 2.52-2.53 (1H, m), 3.10 (1H, m), 3.92 (1H, t, J 8.1), 4.51 (2H, d, J 5.6), 5.25-5.27 (2H, m), 5.83 (1H, d, J 5.8), 6.25 (1H, s), 6.99 (1H, d, J 7.9), 7.18 (1H, dd, J 9.9, 2.2), 7.24-7.32 (2H, m), 7.35-7.41 (6H, m), 7.67 (1H, d, J 9.9), 8.10 (1H, s), 8.20 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4](O)=[O:5].C1C=CC2N(O)N=[N:18]C=2C=1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[Cl-].[NH4+].CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[N:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([NH2:18])=[O:5]
Reactant: O=C(O)c1cc(F)cnc1Cl
Reactant: On1nnc2ccccc21
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: NC(=O)c1cc(F)cnc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 43 %

Procedure:
A suspension of 2-chloro-5-fluoro-nicotinic acid (2.0 g, 11.39 mmol), HOBt (2.31 g, 17.13 mmol), BOP—Cl (4.37 g, 17.15 mmol), ammonium chloride (1.22 g, 22.86 mmol), DIPEA (12 ml, 66.74 mmol) in DMF (75 ml) was stirred at ambient temperature for 18 hours. The reaction mixture was diluted with EtOAc and washed with water and brine. The organic phases were dried over MgSO4, filtrated and evaporated. The crude product was purified by column chromatography (silica gel, EtOAc) to obtain 2-chloro-5-fluoro-nicotinamide (850 mg, 4.9 mmol; 43%) as white solid. MS (m/e): 175.1 [M+H+].
Reaction SMILES: [C-:1]#[N:2].[K+].CN(C)[CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[N+:16]([O-:18])=[O:17])[NH:9][CH:8]=1>O.CN(C=O)C>[N+:16]([C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[C:7]([CH2:6][C:1]#[N:2])=[CH:8][NH:9]2)([O-:18])=[O:17]
Reactant: [C-]#N
Reactant: CN(C)Cc1c[nH]c2cccc([N+](=O)[O-])c12
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCc1c[nH]c2cccc([N+](=O)[O-])c12
Temperature: 25 °C

Procedure:
Potassium cyanide (9.20 g, 141 mmol) in H2O (80 mL) was added to a solution of N,N-dimethyl-1-(4-nitro-1H-indol-3-yl)methanamine from Step A (3.10 g, 14.1 mmol) in DMF (80 mL) and the mixture was heated at reflux for 1 h, then cooled to ambient temperature and partitioned between H2O (200 mL) and EtOAc (400 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 0:100, to give the title compound. MS: m/z=265 (M+Na+CH3CN).
Reaction SMILES: [C:1]([O:9][C@H:10]([C@@H:13]1[CH2:17][C@@H:16]([CH3:18])[C:15](=[O:19])[O:14]1)[CH2:11][CH3:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C>C1COCC1>[C:1]([O:9][C@H:10]([C@@H:13]1[CH2:17][C@@H:16]([CH3:18])[CH:15]([OH:19])[O:14]1)[CH2:11][CH3:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[C@H](OC(=O)c1ccccc1)[C@@H]1C[C@@H](C)C(=O)O1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: CC[C@H](OC(=O)c1ccccc1)[C@@H]1C[C@@H](C)C(O)O1
Temperature: -78 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
To a solution of [(1S)-1-[(2S,4R)-4-methyl-5-oxo-tetrahydrofuran-2-yl]propyl] benzoate (compound 28h, 1.3 g, 5.0 mmol) in THF (100 mL) was added diisobutyl aluminium hydride (11 mL, 11 mmol) dropwise at −78° C. and the mixture was stirred at −78° C. for 2 hours. The mixture was quenched by saturated NH4Cl solution (5 mL) and extracted with EtOAc (100 mL) twice. The organic layers were combined, washed with brine (50 ml), dried over Na2SO4 and concentrated in vacuo to afford 1.2 g crude product of [(1S)-1-[(2S,4R)-5-hydroxy-4-methyl-tetrahydrofuran-2-yl]propyl] benzoate (compound 28i), which was used in next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][CH:14]([O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH:20]=[CH:19]3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)[CH3:2].[H][H]>CO.[Pd]>[CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:12][CH2:13][CH:14]([O:17][CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]3)[CH2:15][CH2:16]2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(N2CCC(OC3C=CCCC3)CC2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1ccc(N2CCC(OC3CCCCC3)CC2)cc1
Yield: 61.9 %

Procedure:
To a solution of 4-[4-(2-cyclohexenyloxy)piperidin-1-yl]benzoic acid ethyl ester (3.82 g) in methanol (80 ml) was added 10% palladium on carbon (1.0 g), and hydrogen gas at atmosphere pressure for 5 hours. The reaction mixture was filtered, and the filtrate was concentrated by evaporation under reduced pressure to give 4-(4-cyclohexyloxypiperidin-1-yl)benzoic acid ethyl ester (2.38 g).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([CH:19]3[CH2:21][CH2:20]3)=[O:18])[CH2:13][CH2:12]2)=[O:10])[CH2:5][CH2:4]1.CN(C=O)C.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[C:30](F)[CH:29]=1>>[Cl:27][C:28]1[CH:29]=[CH:30][C:31]([N+:34]([O-:36])=[O:35])=[C:32]([NH:1][CH2:2][C@H:3]2[CH2:8][CH2:7][C@H:6]([C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([CH:19]4[CH2:20][CH2:21]4)=[O:18])[CH2:13][CH2:12]3)=[O:10])[CH2:5][CH2:4]2)[CH:33]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Reactant: NC[C@H]1CC[C@H](C(=O)N2CCN(C(=O)C3CC3)CC2)CC1
Solvent: CN(C)C=O
Product: O=C(C1CC1)N1CCN(C(=O)[C@H]2CC[C@H](CNc3cc(Cl)ccc3[N+](=O)[O-])CC2)CC1
Temperature: 90 °C

Procedure:
To a solution of (trans-4-aminomethyl-cyclohexyl)-(4-cyclopropanecarbonyl-piperazin-1-yl)-methanone (600 mg, 2.1 mmol) in DMF (5 mL) K2CO3 (565 mg, 4.1 mmol) and 4-chloro-2-fluoronitrobenzene (360 mg, 2.1 mmol) were added and the mixture was heated at 90° C. for 4 hours. Then the solvent was removed under reduced pressure and the residue was washed with 7 mL of H2O and the precipitate was filtered affording 788 mg of the titled compound (78% yield).
Reaction SMILES: OO.NC(N)=[O:5].[CH3:7][O:8][C:9](=[O:19])[C:10]1[C:15]([Cl:16])=[CH:14][C:13]([CH3:17])=[N:12][C:11]=1[Cl:18].S([O-])([O-])(=O)=S.[Na+].[Na+].[OH-].[Na+]>FC(F)(F)C(O)=O>[CH3:17][C:13]1[CH:14]=[C:15]([Cl:16])[C:10]([C:9]([O:8][CH3:7])=[O:19])=[C:11]([Cl:18])[N+:12]=1[O-:5]
Reactant: COC(=O)c1c(Cl)cc(C)nc1Cl
Reactant: NC(N)=O
Agent: O=S([O-])([O-])=S
Agent: OO
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1c(Cl)cc(C)[n+]([O-])c1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 93 %

Procedure:
Urea hydrogen peroxide addition compound (98% pure) (3.860 g, 40.9 mmol) was added to a stirring solution of 2,4-dichloro-6-methyl-nicotinic acid methyl ester (3.000 g, 13.6 mmol) in trifluoroacetic acid (15 ml) under nitrogen. The reaction mixture was stirred at room temperature for 18 hr. Additional urea-hydrogen peroxide addition compound (0.640 g, 6.8 mmol) was added and the reaction stirred for an additional 3 hr. Reaction mixture was poured over ice-water and stirred rapidly. The mixture was treated with sodium thiosulfate, adjusted to pH 11 with 2N aqueous NaOH and extracted 3 times with chloroform. The combined chloroform extracts were washed with water, brine, dried over sodium sulfate and concentrated to give 2.98 g (93%) of the title compound of Preparation C. 1H NMR (CDCl3) δ 7.26 (s,1H), 3.98(s,3H), 2.54(s,3H) ppm.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[C:12]1([CH3:19])[C:13]([CH3:18])=[CH:14][CH:15]=[CH:16][CH:17]=1>>[C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH:18]1[C:13]2[C:12](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:19]=[CH:2][CH:1]=1
Reactant: Cc1ccccc1C
Agent: O=C1OC(=O)c2ccccc21
Product: c1ccc2ccccc2c1

Procedure:
A process for the treatment and combustion of byproducts containing some residual phthalic anhydride, obtained in the preparation of phthalic anhydride by the partial oxidation of orthoxylene or naphthalene which consists essentially of the steps of:
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:6]([O:21][CH2:22][CH2:23][CH3:24])[CH2:5]1)(=[O:3])[NH2:2].Br[CH:26]([CH3:36])[C:27](=O)[C:28]([O:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:29].C(=O)(O)[O-].[Na+]>C1COCC1>[CH2:13]([O:12][C:11]([NH:10][C@H:7]1[CH2:8][CH2:9][N:4]([C:1]2[O:3][C:26]([CH3:36])=[C:27]([C:28]([O:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:29])[N:2]=2)[CH2:5][C@H:6]1[O:21][CH2:22][CH2:23][CH3:24])=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCCO[C@@H]1CN(C(N)=O)CC[C@@H]1NC(=O)OCc1ccccc1
Reactant: CCCCOC(=O)C(=O)C(C)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCOC(=O)c1nc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OCCC)C2)oc1C
Yield: 86.6 %

Procedure:
The same operation as in Example (103c) was performed using cis(±)-benzyl (1-carbamoyl-3-propoxypiperidin-4-yl)carbamate obtained in Example (113f) (0.80 g, 2.39 mmol), butyl 3-bromo-2-oxobutanoate obtained in Example (106a) (4 g, 16.9 mmol), sodium bicarbonate (0.7 g, 8.33 mmol) and THF (15 mL). The resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/10, 1/2, 1/1, 2/1, 4/1) to obtain 0.98 g of the title compound as a light brown oily substance (98%).
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([N:7]2[C:15]3[CH:14]=[C:13]([C:16](=[O:22])[NH:17][CH2:18][CH2:19][O:20][CH3:21])[N:12]=[CH:11][C:10]=3[N:9]=[CH:8]2)[S:4][C:3]=1[C:23]([O:25][CH3:26])=[O:24].C([O-])([O-])=O.[K+].[K+].Br[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41]([F:44])([F:43])[F:42]>CN(C)C=O>[CH3:21][O:20][CH2:19][CH2:18][NH:17][C:16]([C:13]1[N:12]=[CH:11][C:10]2[N:9]=[CH:8][N:7]([C:5]3[S:4][C:3]([C:23]([O:25][CH3:26])=[O:24])=[C:2]([O:1][CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[C:41]([F:42])([F:43])[F:44])[CH:6]=3)[C:15]=2[CH:14]=1)=[O:22]
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: COCCNC(=O)c1cc2c(cn1)ncn2-c1cc(O)c(C(=O)OC)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCNC(=O)c1cc2c(cn1)ncn2-c1cc(OCc2ccccc2C(F)(F)F)c(C(=O)OC)s1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 1.5 g of methyl 3-hydroxy-5-{6-[(2-methoxyethyl)carbamoyl]-1H-imidazo[4,5-c]pyridin-1-yl}thiophene-2-carboxylate (compound C5) in 10 ml anhydrous N,N-dimethylformamide were added 610 mg K2CO3 and 1.14 g 1-(bromomethyl)-2-(trifluoromethyl)benzene under a nitrogen atmosphere. The reaction mixture was stirred for 12 h at room temperature, poured into 400 ml of ice water and the resulting precipitate was filtered. The filter cake was washed with water, dissolved in 300 ml ethyl acetate and washed with 50 ml saturated aqueous KCl solution. The organic layer was separated, dried with MgSO4 and concentrated under vacuum. The residue was crystallized from methanol to yield the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([OH:3])=O.CN(C)C=O.S(Cl)(Cl)=O.[CH2:21]([NH:23][CH2:24][CH3:25])[CH3:22]>C1(C)C=CC=CC=1>[CH:8]([C:7]1[CH:10]=[CH:11][C:4]([C:1]([N:23]([CH2:24][CH3:25])[CH2:21][CH3:22])=[O:3])=[CH:5][CH:6]=1)=[O:9]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CCNCC
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CCN(CC)C(=O)c1ccc(C=O)cc1
Reaction time: 2 h
Yield: 84.1 %

Procedure:
4-Carboxybenzaldehyde (100.3 g, 0.67 mol) was dissolved/suspended in toluene (1200 mL), dimethylformamide (0.15 mL) was added and the suspension was stirred during the dropwise addition of thionyl chloride (53.5 mL, 87.2 g, 0.73 mol). The reaction mixture was heated to reflux under nitrogen and stirred for 2 h, during which time much, but not all of the aldehydo-acid passed into solution. A further quantity of thionyl chloride (20 mL, 32.6 g, 0.27 mol) was added and reflux continued overnight. The clear reaction mixture was evaporated, and the residue dissolved in anhydrous tetrahydrofuran (1500 mL). The solution was cooled in an ice/water bath and diethylamine (173 mL, 122 g, 1.67 mol (2.5 equivalents)) was added dropwise to the stirred solution. The ice-bath was removed and stirring continued for 2.5 h. The reaction mixture was filtered to remove the white crystalline diethylamine hydrochloride by-product. The crystals were washed with ethyl acetate (2×600 mL), and the washings set aside. The tetrahydrofuran filtrate was evaporated, and the residue dissolved in the ethyl acetate washings. The solution was washed sequentially with 1 M-hydrochloric acid (2×600 mL), water (2×300 mL), dilute sodium carbonate solution (saturated Na2CO3:H2O, 1:1, 2×600 mL), water (2×300 mL) and saturated sodium chloride solution (300 mL). The organic layer was separated, dried over anhydrous sodium sulfate and evaporated to yield 4-formyl-N,N-diethylbenzamide as a pale brown oil (115.7 g, 84%) which was used without further purification.