Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:20])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[NH:11][S:12]([C:15]1[N:19]=[CH:18][NH:17][N:16]=1)(=[O:14])=[O:13].C(=O)([O-])[O-].[K+].[K+].[Cl:27][C:28]1[CH:33]=[C:32]([O:34][CH3:35])[N:31]=[C:30](S(C)(=O)=O)[N:29]=1.S(=O)(=O)(O)O>CN(C)C=O>[F:20][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[NH:11][S:12]([C:15]1[N:19]=[CH:18][N:17]([C:30]2[N:29]=[C:28]([Cl:27])[CH:33]=[C:32]([O:34][CH3:35])[N:31]=2)[N:16]=1)(=[O:14])=[O:13]
Reactant: Cc1cccc(OC(F)F)c1NS(=O)(=O)c1nc[nH]n1
Reactant: COc1cc(Cl)nc(S(C)(=O)=O)n1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(Cl)nc(-n2cnc(S(=O)(=O)Nc3c(C)cccc3OC(F)F)n2)n1
Temperature: 10 °C
Reaction time: 0.75 h

Procedure:
1.8 g (6 mmol) N-(2-Difluoromethoxy-6-methylphenyl)-1H-1,2,4-triazole-3-sulphonamide in 10 ml dimethylformamide was stirred with 1.68 g (12 mmol) potassium carbonate for 10 minutes at 50° C. It was then cooled to 10° C. and treated with 1.33 g (6 mmol) 4-chloro-6-methoxy-2-methylsulphonylpyrimidine and the mixture stirred for 45 minutes at 10° C. It was then added to ice-water, acidified to pH 4 with sulphuric acid and the solid collected and purified by silica gel chromatography using a mixture of methylene chloride and methanol (95/5).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][CH2:8][CH3:9])[C:5]2[CH:10]=[CH:11][C:12]([CH2:14]O)=[CH:13][C:4]=2[N:3]=1.[ClH:16].S(Cl)([Cl:19])=O>ClC(Cl)Cl>[ClH:19].[Cl:16][CH2:14][C:12]1[CH:11]=[CH:10][C:5]2[N:6]([CH2:7][CH2:8][CH3:9])[C:2]([CH3:1])=[N:3][C:4]=2[CH:13]=1
Reactant: CCCn1c(C)nc2cc(CO)ccc21
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCCn1c(C)nc2cc(CCl)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 36 parts of 2-methyl-1-propyl-1H-benzimidazole-5-methanol in 150 parts of trichloromethane is acidified with an excess of gaseous hydrogen chloride. Then there are added dropwise 32 parts of thionyl chloride. Upon completion, the whole is stirred for one hour at room temperature. The reaction mixture is evaporated and the residue is crystallized from 2-propanone. The product is filtered off, washed with 2-propanone and dried, yielding 40.9 parts of 5-(chloromethyl)-2-methyl-1-propyl-1H-benzimidazole monohydrochloride; mp. 180° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH:15]([F:17])[F:16])=[CH:10][CH:9]=2)=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=1.CC1C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>[F:16][CH:15]([F:17])[O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:4]=[N:3][C:2]([NH:18][C:19]3[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=3)=[N:7][CH:6]=2)=[CH:9][CH:10]=1
Reactant: FC(F)Oc1ccc(-c2cnc(Cl)nc2)cc1
Reactant: Nc1cccc(O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Oc1cccc(Nc2ncc(-c3ccc(OC(F)F)cc3)cn2)c1
Temperature: 100 °C

Procedure:
To a mixture of 2-chloro-5-(4-(difluoromethoxy)phenyl)pyrimidine 30 (3.2 mmol) and 3-aminophenol (6.42 mmol) in 1,4-dioxane (5 mL) is added p-TSA (5.4 mmol). The reaction mixture is heated at 100° C. for 12 h. After this time, the reaction is diluted with a 2M solution of Na2CO3 and extracted with DCM (3×50 mL). The organic layer is washed with brine, dried over Na2SO4, and concentrated. Purification by short SiO2 chromatography using a DCM:EtOAc=7:3 as eluant affords (3-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenol 39. MS (m/z) (M+1)+: 330.1.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH:7]([OH:9])[CH3:8].C(N(CC)C(C)C)(C)C.[CH3:19][O:20][CH2:21][CH2:22][O:23][CH2:24]Cl>C(Cl)Cl>[Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH:7]([O:9][CH2:19][O:20][CH2:21][CH2:22][O:23][CH3:24])[CH3:8]
Reactant: COCCOCCl
Reactant: CC(O)c1ccsc1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCOCOC(C)c1ccsc1Br
Temperature: 25 °C
Yield: 65.7 %

Procedure:
A solution of 2-bromo-3-(l-hydroxyethyl)thiophene (97.5 g, 0.47 mol) in dry methylene chloride (400 ml) was cooled in ice and N,N-diisopropylethylamine (68.2 g, 0.517 mol) was added followed by methoxyethoxymethYl chloride (64.4 g, 0.517 mol). The solution was stirred at room temperature over night. The dark solution was washed with water, 3N HCl, saturated NaHCO3 and finally with water. The solution was dried over anhydrous Na2SO4 filtered and concentrated in vacuo at room temperature. A dark amber oil was obtained (123.1 g). The impure product was distilled and the product was collected at 108-116° C. at 0.7 mm Hg. to give 91.1 g (66%) of colorless liquid. NMR supported the structure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][C:10](=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:6][CH:7]=1.[NH2:18][NH2:19]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:19][N:18]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NN
Reactant: CCOC(=O)C(=O)CC(=O)c1cccc(F)c1
Solvent: CCO
Product: CCOC(=O)c1cc(-c2cccc(F)c2)n[nH]1
Temperature: 80 °C
Reaction time: 2 h
Yield: 86.4 %

Procedure:
To a solution of Intermediate 4A (100 g, 420 mmol) in ethanol (250 mL) was added hydrazine (13.83 mL, 441 mmol) in ethanol (250 mL) to give a brown solution. The reaction mixture was stirred at 80° C. for 2 h. Ethanol was removed under reduced pressure and the residue was diluted with water and extracted with ethyl acetate (3×100 mL). The combined organic layer was washed with water (2×100 mL), brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The brown solid thus obtained was purified by ISCO using 20% ethyl acetate in hexane as eluent. The combined fractions were concentrated to afford Intermediate 4B (85 g, 86%) MS(ES): m/z=233 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 14.06 (bs, 1H), 7.68-7.75 (m, 2H), 7.45-7.55 (m, 1H), 7.36 (s, 1H), 7.20 (t, J=7.53 Hz, 1H), 4.34 (q, J=7.03 Hz, 2H), 1.34 (t, J=7.03 Hz, 3H).
Reaction SMILES: [S:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([OH:10])=[N:2]1.[F:11][C:12]([F:23])([F:22])[CH:13]1[CH2:18][CH2:17][N:16]([C:19](Cl)=[O:20])[CH2:15][CH2:14]1>>[F:22][C:12]([F:11])([F:23])[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:10][C:3]2[C:4]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[S:1][N:2]=2)=[O:20])[CH2:15][CH2:14]1
Reactant: Oc1nsc2ncccc12
Reactant: O=C(Cl)N1CCC(C(F)(F)F)CC1
Product: O=C(Oc1nsc2ncccc12)N1CCC(C(F)(F)F)CC1

Procedure:
In analogy to example 1, 2.99 g (9.82 mmol) of isothiazolo[5,4-b]pyridin-3-ol were reacted with 2.33 g (10.81 mmol) of 4-trifluoromethylpiperidine-1-carbonyl chloride. Yield: 1.3 g (40%), M+H+: 332.09.
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][C@H:8]([C:16]([OH:18])=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6])[CH:2]=[CH2:3].Cl.[C:20](=O)(O)[O-].[Na+]>CO>[CH3:20][O:17][C:16](=[O:18])[C@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[NH:7][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6]
Reactant: C=CCOC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C=CCOC(=O)N[C@@H](Cc1ccccc1)C(=O)OC

Procedure:
A solution of 0.06 mol of N-(allyloxycarbonyl)phenylalanine, prepared as described by H. Kunz and C. Unverzagt in Angew. Chem. Int. Ed. Engl., 1984, 23, 436-437, and 0.066 mol of HCl in 100 mL of CH3OH is stirred at reflux for 8 hours. The solution is then cooled and treated with 0.066 mol of sodium bicarbonate. The solvent is removed by rotary evaporator, and the residue is dissolved in diethyl ether, filtered, dried over MgSO4, and filtered. The solvent is removed by rotary evaporator to give N-(allyloxycarbonyl)phenylalanine methyl ester.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:14][CH:13]([C:15]2[C:16]([C:21]3[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=3)[C:24]([O:26]C)=[O:25])=[N:17][CH:18]=[CH:19][N:20]=2)[CH2:12]1.O.[OH-].[Li+:33].O>C1COCC1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:12][CH:13]([C:15]2[C:16]([C:21]3[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=3)[C:24]([O-:26])=[O:25])=[N:17][CH:18]=[CH:19][N:20]=2)[CH2:14]1.[Li+:33]
Reactant: COC(=O)c1cccc(-c2nccnc2C2CN(c3ccc4ccccc4n3)C2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C([O-])c1cccc(-c2nccnc2C2CN(c3ccc4ccccc4n3)C2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 107.9 %

Procedure:
A mixture of methyl 3-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)benzoate (0.079 g, 0.198 mmol, SCHEME 5), lithium hydroxide hydrate (0.017 g, 0.397 mmol), water (0.4 mL) and THF (1.2 mL) was stirred at RT overnight. The mixture was concentrated in vacuo. The product was obtained as an off-white solid (83 mg, 108%).
Reaction SMILES: C1(O[C:8]([NH:10][C@H:11]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:12][CH:13]([CH3:15])[CH3:14])=[O:9])C=CC=CC=1.[CH:26]([NH:29]C(C)C)([CH3:28])[CH3:27]>C(Cl)(Cl)Cl.C(OCC)(=O)C>[NH:29]([CH:26]([CH3:28])[CH3:27])[C@:11]([N:10]=[C:8]=[O:9])([C:16]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:17])[CH2:12][CH:13]([CH3:14])[CH3:15]
Reactant: CC(C)C[C@H](NC(=O)Oc1ccccc1)C(=O)OCc1ccccc1
Reactant: CC(C)NC(C)C
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(C)C[C@](N=C=O)(NC(C)C)C(=O)OCc1ccccc1
Temperature: 55 °C
Reaction time: 17 h

Procedure:
To a solution of PhOCO-Leu-OBzl (70 mg, prepared in (1)) in chloroform (2 ml) were added diisopropylamine (575 μl) and TEA (286 μl) at room temperature under argon atmosphere. The mixture was stirred at 55° C. for 17 h and cooled to room temperature. The mixture was diluted with ethyl acetate, washed with 1N-hydrochloric acid, sat. aq. NaHCO3 and brine successively, dried over MgSO4 and evaporated in vacuo. The residue was purified by preparative TLC (Merck, Kieselgel 60 F254) with ethyl acetate/hexane=1/4 for development to give the product (32 mg).
Reaction SMILES: Cl[CH:2]([C:6](=[O:8])[CH3:7])[C:3](=O)[CH3:4].[C:9]([NH2:13])(=[O:12])[CH2:10][CH3:11].C(O)(=O)CC.[OH-].[Na+]>>[C:6]([C:2]1[O:12][C:9]([CH2:10][CH3:11])=[N:13][C:3]=1[CH3:4])(=[O:8])[CH3:7]
Reactant: CCC(N)=O
Reactant: CC(=O)C(Cl)C(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCC(=O)O
Product: CCc1nc(C)c(C(C)=O)o1
Temperature: 25 °C

Procedure:
3-Chloropentane-2,4-dione (46.5 g), propionamide (50 g) and propionic acid (151 g) were heated at 145° C. for 5 hours. The mixture was cooled to room temperature, then basified to pH 10 using 10M aqueous sodium hydroxide, and extracted with dichloromethane. The combined extracts were washed with brine, dried and the solvent removed to leave a brown oil which was purified by vacuum distillation, b.p. 70° C. at 2 mbar.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH3:23])[C:13](=[O:22])[C:14]([CH3:21])([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].[Cl-].[NH4+]>CO>[CH2:1]([O:8][C:9]([NH:11][CH:12]([CH3:23])[CH:13]([OH:22])[C:14]([CH3:21])([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)(C)C(=O)C(C)NC(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CCOC(=O)C(C)(C)C(O)C(C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 73.5 %

Procedure:
To a solution of ethyl 4-{[(benzyloxy)carbonyl]amino}-2,2-dimethyl-3-oxopentanoate (5.76 g) in methanol (100 mL) was added sodium borohydride (940 mg) at 0° C., and the mixture was stirred at room temperature for 17 hr. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=50/1→1/3) to give the title compound as a colorless solid (yield: 4.26 g, 74%).
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:14]([NH:16][C@H:17]([C:19](C1CCCC1(N)C(OCC)=O)=[O:20])[CH3:18])=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)(=[O:3])[CH3:2].C([O:34]C(C1(N)CCCC1)=O)C>CO>[C:1]([NH:4][C@H:5]([C:14]([NH:16][C@H:17]([C:19]([OH:20])=[O:34])[CH3:18])=[O:15])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)C1(N)CCCC1C(=O)[C@H](C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(C)=O
Reactant: CCOC(=O)C1(N)CCCC1
Solvent: CO
Product: CC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@@H](C)C(=O)O

Procedure:
Ethyl N-acetyltyrosyl-alanyl-1-amino-1-cyclopentanecarboxylate, by the procedure of Example 1 from the preceding compound and ethyl-1-amino-1-cyclopentanecarboxylate, yield 88%, m.p. 168° to 171° C., [α]D20 -3.1° (c 0.2, MeOH).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])OCC(Cl)(Cl)Cl)=[CH:4][CH:3]=1.[C:17]1([C:23]2[N:27]=[C:26]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[S:25][N:24]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([N:31]2[CH2:32][CH2:33][N:28]([C:26]3[S:25][N:24]=[C:23]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:27]=3)[CH2:29][CH2:30]2)=[O:16])=[CH:4][CH:3]=1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: O=C(Nc1ccc(Cl)nc1)OCC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: O=C(Nc1ccc(Cl)nc1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 70 °C
Reaction time: 15 h
Yield: 50.7 %

Procedure:
A mixture of 2,2,2-trichloroethyl (6-chloropyridin-3-yl)carbamate (272 mg, 0.893 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and diisopropylethylamine (0.156 ml, 0.893 mmol) in dimethylsulfoxide (2.7 ml) was stirred at 70° C. for 15 hours. Water was poured into the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and tetrahydrofuran to obtain the desired product (165 mg, 50.7%) as a solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:41]=[CH:42][C:43]=1F)[C:5]1[C:10]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]4[N:25]([CH:26]5[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]5)[C:24]5[CH:32]=[CH:33][C:34]([C:36]([OH:38])=[O:37])=[CH:35][C:23]=5[N:22]=4)[CH:17]=3)[N:12]=2)=[CH:9][C:8]([O:39][CH3:40])=[CH:7][CH:6]=1.C[O:46]C(C1C=CC2N(C3CCCCC3)C(C3C=C4C(=CC=3)N=C(C3C=C(OC)C=CC=3Br)C=C4)=NC=2C=1)=O>>[CH:26]1([N:25]2[C:24]3[CH:32]=[CH:33][C:34]([C:36]([OH:38])=[O:37])=[CH:35][C:23]=3[N:22]=[C:21]2[C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]=[C:11]([C:10]2[C:5]([C:4]4[CH:3]=[CH:2][C:43]([OH:46])=[CH:42][CH:41]=4)=[CH:6][CH:7]=[C:8]([O:39][CH3:40])[CH:9]=2)[CH:20]=[CH:19]3)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: COC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(OC)ccc4Br)ccc3c1)n2C1CCCCC1
Reactant: COc1ccc(-c2ccc(F)c(Cl)c2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Product: COc1ccc(-c2ccc(O)cc2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Yield: 8 %

Procedure:
Following the full procedure and workup for Compound 366, Compound 365b (100 mg, 0.175 mmol) was reacted with 4-phenolboronic acid (36 mg, 0.2625 mmol) to produce the title compound (10 mg, 8% yield).
Reaction SMILES: C([O:4][C@H:5]1[C@H:11]([O:12]C(=O)C)[C@@H:10]([O:16]C(=O)C)[C@:9]2([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28][C:29]4[CH:34]=[CH:33][C:32]([O:35][C:36]5[CH:41]=[CH:40][C:39]([C:42](=[N:44][O:45][CH2:46][CH3:47])[CH3:43])=[CH:38][CH:37]=5)=[CH:31][CH:30]=4)[CH:22]=3)[O:20][C@@:6]1([CH2:48][O:49]C(=O)C)[CH2:7][O:8]2)(=O)C.CO.O.O.[OH-].[Li+]>C1COCC1>[CH2:46]([O:45][N:44]=[C:42]([C:39]1[CH:38]=[CH:37][C:36]([O:35][C:32]2[CH:31]=[CH:30][C:29]([CH2:28][C:23]3[CH:22]=[C:21]([C@@:9]45[O:20][C@@:6]([CH2:48][OH:49])([CH2:7][O:8]4)[C@@H:5]([OH:4])[C@H:11]([OH:12])[C@H:10]5[OH:16])[CH:26]=[CH:25][C:24]=3[Cl:27])=[CH:34][CH:33]=2)=[CH:41][CH:40]=1)[CH3:43])[CH3:47]
Reactant: CCON=C(C)c1ccc(Oc2ccc(Cc3cc([C@]45OC[C@](COC(C)=O)(O4)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]5OC(C)=O)ccc3Cl)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCON=C(C)c1ccc(Oc2ccc(Cc3cc([C@]45OC[C@](CO)(O4)[C@@H](O)[C@H](O)[C@H]5O)ccc3Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
To a solution of (1R,2S,3S,4R,5S)-1-(acetoxymethyl)-5-(4-chloro-3-(4-(4-(1-(ethoxyimino)ethyl)phenoxy)benzyl)phenyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triyl triacetate (210.0 mg, 0.28 mmol), in THF (1.6 mL), methanol (2.4 mL) and water (0.8 mL) was added lithium hydroxide monohydrate (14.0 mg, 0.34 mmol) at 0° C. The reaction mixture was stirred at r.t. for 1 h. After the completion of reaction as confirmed by TLC, volatiles were evaporated in vacuo and the compound was diluted with ethyl acetate (50 mL). The organic layer was washed with water (2×10 mL), dried over Na2SO4 and concentrated to afford title compound (160.0 mg, 98%) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:12][CH2:11][CH2:10][CH2:9][CH:8](O)[C:7]=2[CH:14]=1)#[N:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:12][CH2:11][CH2:10][CH:9]=[CH:8][C:7]=2[CH:14]=1)#[N:2]
Reactant: N#Cc1ccc2c(c1)C(O)CCCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1ccc2c(c1)C=CCCO2
Yield: 95.2 %

Procedure:
18.9 g (0.1 mole) of 7-cyano-5-hydroxy-2,3,4,5-tetrahydro-1-benzoxepin are heated with 0.3 g of p-toluenesulfonic acid monohydrate in toluene with a water trap for 1.5 hours. After the solution has cooled it is washed with 1N potassium bicarbonate solution, water and saturated sodium chloride solution and, after drying over sodium sulfate, the solvent is evaporated off in vacuo. 16.3 g of solid of melting point 69°-71° C. are obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][NH:6][C:5]2=[O:12].[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:15]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)(O)[O-]>CN(C)C(=O)C.C(O)C.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(Cl)Cl>[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:15]=1[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][NH:6][C:5]2=[O:12]
Reactant: Cc1cccc(C)c1B(O)O
Reactant: O=c1[nH]cnc2ccc(Br)cc12
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])O
Solvent: CCO
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1cccc(C)c1-c1ccc2nc[nH]c(=O)c2c1
Yield: 40.1 %

Procedure:
To a solution of 6-bromo-3H-quinazolin-4-one (43.1 mg, 0.1915 mmol) dissolved in 2 ml N,N-dimethylacetamide in a 20 ml vial, 2,6-dimethylphenylboronic acid (114.9 mg, 0.76 mmol) dissolved in 1 ml ethanol and potassium carbonate (26.7 mg, 0.193 mmol) dissolved in 1 ml water were added. Triphenylphosphine (5 mg, 0.019 mmol) and tris(dibenzylideneacetone)dipalladium(0) (3.5 mg, 3.8 umol) were added to the mixture which refluxed overnight. The crude product was poured into 50 ml saturated bicarbonate solution and methylene chloride was used to extract the product. Solvent in the organic phase was removed under vacuum. The resulted residue was purified by preparative HPLC. 19.2 mg product was obtained. Yield: 40%; 1H NMR (500 MHz, DMSO-d6): δ 1.96741(s, 6H), 7.114769–7.16307(d, J=7.69 Hz, 2H), 7.19260–7.22248(dd, J1=8.62 Hz, J2=6.31 Hz 1H), 7.60434–7.62503(dd, J1=8.335 Hz, J2=1.97 Hz, 1H), 7.75179–7.76829(d, J=8.25 Hz, 1H), 7.81882–7.82258(d, J=1.88 Hz, 1H), 8.17882 (s, 1H); ESI-MS: m/z 251 (M++1)
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:15])=[C:4]([Cl:14])[C:5]([Cl:13])=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]=12.[CH2:16]([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21]1[CH3:29])[CH2:17][CH2:18][CH3:19].[Cl-].[Al+3].[Cl-].[Cl-]>C1C=CC=CC=1.Cl>[CH2:16]([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([C:11]([C:6]2[C:5]([Cl:13])=[C:4]([Cl:14])[C:3]([Cl:15])=[C:2]([Cl:1])[C:7]=2[C:8]([OH:10])=[O:9])=[O:12])=[C:21]1[CH3:29])[CH2:17][CH2:18][CH3:19]
Reactant: O=C1OC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Reactant: CCCCn1c(C)cc2ccccc21
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: CCCCn1c(C)c(C(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)O)c2ccccc21

Procedure:
Proceeding in a manner similar to that described in part A of Example 2, 14.3 g (0.05 mole) of tetrachlorophthalic anhydride, 16.0 g (0.07 mole) of 76 percent active 1-n-butyl-2-methylindole and 13.3 g (0.10 mole) of aluminum chloride were interacted in 100 ml of benzene. The reaction mixture was drowned in 200 ml of five percent hydrochloric acid with stirring. The solid which formed was collected by filtration, washed with water and dried to obtain 2-[(1-n-butyl-2-methyl-3-indolyl)carbonyl]-3,4,5,6-tetrachlorobenzoic acid (Formula VIII: Ro =R1 =R2 =R3 =Y1 =H; R5 =CH3 ; R6 =(CH2)3CH3), a pale yellow solid melting at 162°-164° C. The nuclear magnetic resonance spectrum was in accord with the structure.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([C:16]([OH:18])=O)[CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([NH2:24])=[O:23].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.CCN(CC)CC>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH:14]([C:16](=[O:18])[NH:19][C:20]2[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=2[C:22](=[O:23])[NH2:24])[CH3:15])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C(=O)O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: NC(=O)c1ccccc1N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C(=O)Nc1ccccc1C(N)=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 48 h
Yield: 53.3 %

Procedure:
A mixture of 4-(1-carboxy-ethyl)-piperidine-1-carboxylic acid tert-butyl ester (28.6 g, 0.11 mol), 2-aminobenzamide (13.7 g, 0.1 mol), EDCI (21.3 g, 0.11 mol), HOBT (15 g, 0.11 mol) and Et3N (25 mL) in CH2Cl2 (500 mL) was stirred for 48 hr. The reaction mixture was diluted with CH2Cl2 (1000 mL) and washed with NaHCO3 (aq), the organic layer was dried with Na2SO4 and concentrated in vacuo to give the product a yellow solid (20 g, 48%) which was used directly for the next step.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3]1.[N+:9]([CH3:12])([O-:11])=[O:10].C(N)C1C=CC=CC=1.C(O)(=O)C>C(O)C>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([CH:7]=[CH:12][N+:9]([O-:11])=[O:10])=[CH:3]1
Reactant: Cn1ccc(C=O)c1
Reactant: C[N+](=O)[O-]
Solvent: CC(=O)O
Solvent: NCc1ccccc1
Solvent: CCO
Product: Cn1ccc(C=C[N+](=O)[O-])c1
Reaction time: 6 h

Procedure:
A solution of 14.9g (0.137 mole) of 1-methylpyrrole-3-carboxaldehyde, 7.3 ml (0.137 mole) of nitromethane, 2.3 ml (.021 mole) of benzyl amine and 1.2 ml (.021 mole) of acetic acid in 20 ml of absolute ethanol is warmed briefly and stirred for 6 hours. It is then cooled and the precipitated solid is collected, giving as a yellow solid, 1-methyl-3-(2-nitrovinyl)pyrrole; m.p. 90°-92° C.
Reaction SMILES: [C:1]1([C:7]2([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)[CH2:20][C:21](=[O:23])C.C1OC1>C(O)C>[OH:23][CH2:21][CH2:20][N:10]1[CH2:9][CH2:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:12][CH2:11]1
Reactant: CC(=O)CC(C)C
Reactant: CCOC(=O)C1(c2ccccc2)CCNCC1
Solvent: C1CO1
Solvent: CCO
Product: CCOC(=O)C1(c2ccccc2)CCN(CCO)CC1
Temperature: 60 °C

Procedure:
A mixture of 9.9 parts of ethyl 4-phenyl-4-piperidinecarboxylate, 41.8 parts of 4-methyl-2-pentanone, 4.3 parts of ethylene oxide and 79.2 parts of ethanol is heated in a sealed citric bottle at about 60° C for 7 days. The resulting solution is cooled, the solvent is evaporated under reduced pressure and the residual material is partitioned between diluted NaOH and ether. The ether layer is then separated and extracted with diluted HCl. The acid layer is then made alkaline with aqueous sodium hydroxide and the resulting mixture is extracted with ether. The ether layer is dried over sodium sulfate and potassium carbonate and evaporated in vacuum. The residue is crystallized from ether-n-pentane to give ethyl 1-(2-hydroxyethyl)-4-phenyl-4-piperidinecarboxylate, melting at about 91.5°-93° C.