Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH:18]1(Br)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>CN(C)C=O>[CH:18]1([O:1][N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: BrC1CCCCC1
Reactant: CCOC(=O)C(=NO)C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(=NOC1CCCCC1)C(C)=O
Yield: 91.9 %

Procedure:
Ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer, 30 g.), N,N-dimethylformamide (100 ml.), potassium carbonate (39.5 g.) and cyclohexyl bromide (31.1 g.) were treated in a similar manner to that of Example F-(1) to give ethyl 2-cyclohexyloxyimino-3-oxobutyrate (syn isomer, 41.8 g.), oil.
Reaction SMILES: C(N1C=CN=C1)([N:3]1C=CN=C1)=O.[Br:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[C:16]([F:23])[CH:15]=1.[OH-].[NH4+]>ClCCl>[Br:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH2:3])=[O:19])=[C:16]([F:23])[CH:15]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1ccc(Br)cc1F
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: NC(=O)c1ccc(Br)cc1F
Reaction time: 0.33 h

Procedure:
At 0° C., 1,1′-carbonyldiimidazole (8.8 g, 54.3 mmol) was added in portions to a stirred mixture of 4-bromo-2-fluorobenzoic acid (6 g, 27.3 mmol) in dichloromethane (100 ml). After 20 minutes, a clear solution was obtained. Ammonium hydroxide (28%, 30 ml) was added and the mixture was stirred overnight. Aqueous layer was isolated, extracted with dichloromethane twice. Combined organic extracts were washed with water, 1 N HCl twice, water, brine and dried (MgSO4). Solvent was removed under vacuum, and the solid was washed with hexane to afford 4-bromo-2-fluoro-benzamide 2BL (5.56 g).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)=[O:6].[C:14]([NH:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].O>Cl.CCOCC>[C:14]([NH:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:2][CH2:3][CH2:4][C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)=[O:6])[CH2:25][CH2:24]1)(=[O:21])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1.[ClH:1]
Reactant: O=C(CCCCl)c1ccc(Cl)cc1
Reactant: O=C(NC1CCNCC1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: O=C(CCCN1CCC(NC(=O)c2ccccc2)CC1)c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
4-Chloro-4'-chlorobutyrophenone (2.17 g.) was added to a well-ground mixtue of 4-benzamidopiperidine (2.04 g.) and anhydrous potassium carbonate (1.38 g.) and the mixture heated to 100° C. for 1 hour. The solid residue was slurried with hot water (100 ml.) for 3 hours, filtered, washed with ether and dried to give a cream coloured solid. This solid was dissolved in ethanolic hydrogen chloride, treated with ether and then cooled to 0° C. to give the title compound as its hydrochloride (1.9 g.) m.p. 242°-243° C. (Found: C, 62.8; H, 6.2; N, 6.55. C22H25ClN2O2. HCl requires C, 62.7; H, 6.0; N, 6.65%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH:5]=[O:6].[CH3:11][Mg]Br>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:5]([OH:6])[CH3:11])[CH:7]=[C:8]([F:10])[CH:9]=1
Reactant: O=Cc1cc(F)cc(F)c1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)c1cc(F)cc(F)c1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 90.4 %

Procedure:
To a solution of 3,5-difluorobenzaldehyde (3.00 g, 21.1 mmol) in THF (30 mL) at 0-5° C. was added methylmagnesium bromide in THF (3.0 M; 8.44 mL, 25.3 mmol) dropwise. The mixture was stirred at 0-5° C. for 1 h, quenched with brine, and then extracted with EtOAc (2 times). The combined organic phases were washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure to give the sub-title compound as a colorless oil (3.02 g, 90.4%). 1H NMR (300 MHz, CDCl3) δ 6.89 (m, 2H), 6.69 (m, 1H), 4.88 (q, J=6.3 Hz, 1H), 1.47 (d, J=6.3 Hz, 3H) ppm.
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[H-].[Na+].F[C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17].Cl.N#N>CN(C=O)C.[Cl-].[Na+].O>[F:15][C:13]1[CH:12]=[CH:11][C:10]([N+:16]([O-:18])=[O:17])=[C:9]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH:14]=1
Reactant: CS(N)(=O)=O
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: Cl
Agent: N#N
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)Nc1cc(F)ccc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 22 %

Procedure:
Methylsulfonamide (2.421 g, 25.4 mmol) was dissolved in DMF (100 mL) and NaH (60% in oil, 1.00 g, 25 mmol) was added. The reaction stirred for 1 h and added to a stirred solution of 2,4-difluoronitrobenzene (4.372 g, 27.5 mmol) in DMF (20 mL). The reaction mixture was stirred for 2 h, poured into a mixture (1:1) of brine and 1M HCl, and extracted with toluene. The organic phase was dried (MgSO4), and concentrated to give a solid that was crystallized from toluene/petroleum ether. The flask tipped over and some material was lost, to give 1.32 g, 5.64 mmol in 22% yield. MS (posES-FIA) m/z=found: 234; Calcd: 234.01; Anal (C7 H7 F N2 O4 S), C, H, N, S.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[O:11]1[C:15]2([CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]2)[O:14][CH2:13][CH2:12]1>CCOCC>[CH3:9][O:8][C:5]1[N:6]=[CH:7][C:2]([C:18]2([OH:21])[CH2:19][CH2:20][C:15]3([O:14][CH2:13][CH2:12][O:11]3)[CH2:16][CH2:17]2)=[CH:3][C:4]=1[CH3:10]
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: COc1ncc(Br)cc1C
Solvent: CCOCC
Product: COc1ncc(C2(O)CCC3(CC2)OCCO3)cc1C

Procedure:
The title compound was prepared as a white solid from 5-bromo-2-methoxy-3-methyl-pyridine (Alfa Aesar) and 1,4-dioxa-spiro[4.5]decan-8-one in ether using the procedure described in Step A of Example 1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:15]([CH3:17])(O)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([I:18])[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:15](=[CH2:17])[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([I:18])[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1
Reactant: CC1(O)c2cc(I)ccc2Oc2ncc(Br)cc21
Solvent: ClCCl
Product: C=C1c2cc(I)ccc2Oc2ncc(Br)cc21
Temperature: 55 °C
Reaction time: 2 h

Procedure:
3-bromo-7-iodo-5-methyl-5H-chromeno[2,3-b]pyridin-5-ol (12.09 g, 28.9 mmol) was taken up in CH2Cl2 (116 mL) and ppts (0.100 g, 0.578 mmol) was added. The reaction was heated to 55° C. and stirred for two hours. The reaction was concentrated to afford crude 3-bromo-7-iodo-5-methylene-5H-chromeno[2,3-b]pyridine as an orange solid. The material was used immediately in the next step.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:11]([N:13]([O:15][CH3:16])[CH3:14])=[O:12].[O:17]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18]1.C([O-])(O)=O.[Na+]>C(Cl)Cl.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][O:17]1)[N:6]=[C:5]2[C:11]([N:13]([O:15][CH3:16])[CH3:14])=[O:12]
Reactant: CON(C)C(=O)c1n[nH]c2ccc(I)cc12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CON(C)C(=O)c1nn(C2CCCCO2)c2ccc(I)cc12
Yield: 92 %

Procedure:
A mixture of 5-iodo-N-methoxy-N-methyl-1H-indazole-3-carboxamide (X) (16.5 g, 50 mmol), 3,4-dihydro-2H-pyran (10.3 mL, 113 mmol) and PPTS (0.12 g, 0.6 mmol) in DCM was heated to reflux for 5 hours. The solution was poured into a saturated NaHCO3 solution, the layers were separated, and the aqueous layer was extracted with DCM. The combined organic layers were washed with 5% aqueous citric acid and brine, dried over MgSO4, and concentrated. The crude product was purified on a silica gel column (100% EtOAc→3:97 MeOH:DCM) to provide 5-iodo-N-methoxy-N-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxamide (XI) as a white viscous oil (19.1 g, 46 mmol, 92% yield). 1H NMR (DMSO-d6) δ ppm 1.28-1.84 (m, 6H), 3.43 (s, 3H), 3.60-4.04 (s, 5H), 5.86-6.08 (m, 1H), 7.45-7.87 (m, 2H), 8.39 (s, 1H); ESIMS found for C15H18IN3O3 m/z 416 (M+H).
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].CN(C=[N:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[C:21]([C:27]3[S:31][C:30]([C:32](N(OC)C)=[O:33])=[C:29]([CH3:38])[C:28]=3[CH3:39])[CH:20]=2)=[CH:15][CH:14]=1)(=[O:12])=[O:11])C>C1COCC1>[CH3:39][C:28]1[C:29]([CH3:38])=[C:30]([C:32](=[O:33])[CH2:1][CH3:2])[S:31][C:27]=1[C:21]1[CH:22]=[CH:23][C:24]([O:25][CH3:26])=[C:19]([C:16]2[CH:15]=[CH:14][C:13]([S:10]([NH2:9])(=[O:12])=[O:11])=[CH:18][CH:17]=2)[CH:20]=1
Reactant: CC[Mg]Br
Reactant: COc1ccc(-c2sc(C(=O)N(C)OC)c(C)c2C)cc1-c1ccc(S(=O)(=O)N=CN(C)C)cc1
Solvent: C1CCOC1
Product: CCC(=O)c1sc(-c2ccc(OC)c(-c3ccc(S(N)(=O)=O)cc3)c2)c(C)c1C
Temperature: 72.5 °C

Procedure:
Ethyl magnesium bromide (0.14 g, 1.1 ml, 1.06 mmol) was added drop wise to a solution of 5-(4′-(N-((dimethylamino)methylene)sulfamoyl)-6-methoxy-[1,1′-biphenyl]-3-yl)-N-methoxy-N,3,4-trimethylthiophene-2-carboxamide (Step 7, 0.11 g, 0.21 mmol) in anhydrous THF (10 ml) at 25° C. under stirring. The reaction mixture was then heated to 70-75° C. for 1 hour. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to 0° C. The cooled reaction mixture was then quenched with a saturated solution of ammonium chloride (10 ml). The resultant mixture was then extracted with ethyl acetate (3×20 ml). The combined organic layer was dried over anhydrous Na2SO4. The solvent was evaporated from the organic layer under reduced pressure to obtain a crude product, which was then purified by column chromatography using 35% ethyl acetate in hexane as an eluent to obtain the title compound 9 (0.03 g, 33.0%).
Reaction SMILES: [O:1]1[CH:5]2[CH:6]([C:12](OC)=[O:13])[CH:7]([C:8](OC)=[O:9])[C:2]1(OCC)[C:3]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[N:4]2.O.[NH2:26][NH2:27].O>C(O)(=O)C>[OH:1][C:2]1[C:7]2[C:8](=[O:9])[NH:27][NH:26][C:12](=[O:13])[C:6]=2[CH:5]=[N:4][C:3]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NN
Reactant: CCOC12OC(N=C1c1ccccc1)C(C(=O)OC)C2C(=O)OC
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH][nH]c(=O)c2c(O)c(-c3ccccc3)ncc12
Temperature: 100 °C

Procedure:
3,6-Epoxy-3-ethoxy-4,5-dimethoxycarbonyl-2-phenyl-3,4,5,6-tetrahydropyridine (500 mg; 1.5 mmol) was added to hydrazine monohydrate (5 ml), and the mixture was heated in a stream of nitrogen at 100° C. for 1 hour. Under ice-cooling, water was added to reaction mixture, and the mixture was neutralized with acetic acid. The resulting yellow crystalline precipitate was recovered by filtration. Yield: 210 mg (55.0%).
Reaction SMILES: C([NH:4][C:5]1[CH:19]=[CH:18][C:8]2[C:9](=[O:17])[C:10]3[S:16][CH:15]=[CH:14][C:11]=3[CH2:12][O:13][C:7]=2[CH:6]=1)(=O)C.C(=O)(O)[O-].[Na+]>Cl>[NH2:4][C:5]1[CH:19]=[CH:18][C:8]2[C:9](=[O:17])[C:10]3[S:16][CH:15]=[CH:14][C:11]=3[CH2:12][O:13][C:7]=2[CH:6]=1
Reactant: CC(=O)Nc1ccc2c(c1)OCc1ccsc1C2=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Nc1ccc2c(c1)OCc1ccsc1C2=O
Yield: 78 %

Procedure:
In concentrated hydrochloric acid (15 ml), 7-acetamido-4,10-dihydrothieno[3,2-c][1]benzoxepin-10-one obtained in Reference Example 9(0.41 g, 1.51 mmol) was heated under reflux for 2 hours. The reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate, followed by extraction with ethyl acetate (25 ml). The organic layer was washed with a saturated aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the organic layer was concentrated under reduced pressure to give 7-amino-4,10-dihydrothieno[3,2-c][1]benzoxepin-10-one as a yellow solid (0.28 g, 78%).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[CH2:33]([N:40]1[CH2:44][CH2:43][C@@H:42]([NH2:45])[CH2:41]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C1COCC1.CC#N>[CH2:33]([N:40]1[CH2:44][CH2:43][C@@H:42]([NH:45][C:10](=[O:12])[CH2:9][NH:8][C:6](=[O:7])[C:5]2[CH:13]=[CH:14][CH:15]=[C:3]([C:2]([F:1])([F:17])[F:16])[CH:4]=2)[CH2:41]1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: N[C@@H]1CCN(Cc2ccccc2)C1
Reactant: O=C(O)CNC(=O)c1cccc(C(F)(F)F)c1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CN1CCOCC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (3-Trifluoromethyl-benzoylamino)acetic acid (4.2 g, 17 mmol) and NMM (2.8 mL, 25.5 mmol) in dry THF (30 mL) at −10 to −15° C. under N2, was slowly added isobutylchloroformate (2.4 mL, 17.85 mmol) via syringe. The reaction mixture gradually became pink. 15 min later, a solution of (3R)-1-benzylpyrrolidin-3-amine (3.0 g, 17 mmol) in THF (15 mL) was dropwise added to the above mixed anhydride over 20 min, maintaining reaction temperature <−10° C. The reaction mixture became a dark red color. 1 h later, the reaction mixture was allowed to warm to rt, and quenched with water (25 mL), extracted with EtOAc×3, dried, filtered and concentrated to give an orange solid. MeCN was added and concentrated to remove EtOAc. Then MeCN (15-20 mL) was added to afford a slurry, which was chilled in ice bath and stirred for 30 min. After filtration, the solid product was rinsed with cold MeCN (10-15 mL) until the filtrate was colorless After dried under high vacuum overnight, a pale yellow solid product: 5.0 g (73%) was afforded. MS (M+H+)=406.2; 1H NMR (CDCl3) δ 8.16 (s, 1H), 8.00 (dd, 1H), 7.78 (dd, 1H), 7.57 (m, 1H), 7.25 (m, 6H), 7.06 (m, 1H), 6.39 (m, 1H), 4.48 (m, 1H), 4.04 (d, 2H), 3.62 (d, 2H), 2.86 (m, 1H), 2.63 (m, 1H), 2.57 (m, 1H), 2.36 (m, 2H).
Reaction SMILES: C(N(CC)CC)C.[NH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][S:23][CH2:22][CH:21]1[C:26](O)=[O:27])=[O:19])([CH3:16])([CH3:15])[CH3:14].P(C#N)([O-])(OCC)=O>O1CCCC1.O>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][S:23][CH2:22][CH:21]1[C:26]([N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:27])=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCSCC1C(=O)O
Reactant: C1CCNC1
Agent: CCOP(=O)([O-])C#N
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCSCC1C(=O)N1CCCC1
Reaction time: 1 h
Yield: 74 %

Procedure:
Triethylamine (3.1 ml), followed by a solution of pyrrolidine (2.0 ml) in 10 ml of tetrahydrofuran, was added at 0° C. under a stream of nitrogen to a solution of 5.0 g of 4-(t-butoxycarbonyl)thiomorpholine3-carboxylic acid in 100 ml of tetrahydrofuran. After the mixture had been stirred for 1 hour, a solution of 3.6 g of ethyl cyanophosphate in 10 ml of tetrahydrofuran was added to the mixture and the mixture was stirred for 5 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/hexane to yield 4.61 g (74%) of 4-(t-butoxycarbonyl)-3-(pyrrolidine-1-carbonyl)thiomorpholine.
Reaction SMILES: C(=O)([O-])[O-].[Ca+2:5].[C:6]([OH:9])(=[O:8])[CH3:7]>>[C:6]([O-:9])(=[O:8])[CH3:7].[Ca+2:5].[C:6]([O-:9])(=[O:8])[CH3:7]
Reactant: CC(=O)O
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Product: CC(=O)[O-]
Reaction time: 8 h

Procedure:
(EXAMPLE 17) 200 g of the ash was mixed with 1.8 L of 20% (v/v) or 21% (w/w) acetic acid. That amount of acetic acid corresponded to 2.5 times the stoichiometric proportion of calcium carbonate in the ash. The slurry was agitated and left overnight at room temperature. The liquid collected contained 14.0% solids, as shown by evaporation of a 10-mL sample at 105° C. The theoretical amount of calcium acetate, formed in the reaction mixture, would have been 10.9% solids. The elemental calcium content in the dried extract was determined to be 19.6±0.8% (based on four independent measurements), translating into 77% Ca(CH3COO)2, or 86% Ca(CH3COO)2.H2O.
Reaction SMILES: [CH3:1][CH:2]([CH:6]([CH3:10])[C:7](O)=[O:8])[C:3](O)=[O:4].[NH4+:11].Cl>C(OCC)(=O)C>[CH3:1][CH:2]1[CH:6]([CH3:10])[C:7](=[O:8])[NH:11][C:3]1=[O:4]
Reactant: [NH4+]
Reactant: CC(C(=O)O)C(C)C(=O)O
Agent: Cl
Solvent: CCOC(C)=O
Product: CC1C(=O)NC(=O)C1C
Temperature: 60 °C
Reaction time: 1 h

Procedure:
1 g of 2,3-dimethylsuccinic acid (a mixture of D-, L-, and meso-isomers) was added to 10 ml of 28% aqueous ammonium solution. The mixture was heated and stirred at about 60° C. for 1 hour. After cooling, to the reaction mixture was added aqueous hydrochloric acid solution so as to neutralize, and then the mixture was extrated twice with 10 ml of ethyl acetate. The extract was concentrated to obtain 0.73 g of 2,3-dimethylsuccinimide (a mixture of D-, L, and meso-isomers).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[C:11]([CH3:17])=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=1>>[OH:16][C:12]1[C:11]([CH3:17])=[C:10]([NH:9][C:2]2[CH:7]=[C:6]([NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[C:11]=3[CH3:17])[N:5]=[CH:4][N:3]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: Cc1c(N)cccc1O
Reactant: Clc1cc(Cl)ncn1
Product: Cc1c(O)cccc1Nc1cc(Nc2cccc(O)c2C)ncn1
Yield: 40 %

Procedure:
This compound was obtained (yield 40%) based on the method described in Production Example 2B using 4,6-dichloropyrimidine instead of the 4,6-dichloro-2-ethylpyrimidine, and using 3-amino-2-methylphenol instead of the 3-aminophenol.
Reaction SMILES: [C:1](O)([C:3](F)(F)F)=O.Br[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH2:15][C@H:14]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:13][CH2:12]2>C(Cl)Cl>[CH:1]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH2:15][C@H:14]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:13][CH2:12]2)=[CH2:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCc2cc(Br)ccc2C1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=Cc1ccc2c(c1)CC[C@@H](NC(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
TFA (0.7 mL, 9.07 mmol) was added dropwise to a solution of the product from step A (620 mg, 2.27 mmol) in DCM (10 mL). After stirring at room temperature for 4 h, the reaction mixture was evaporated to dryness. NEt3 (1 mL) was added to the residue and evaporated again to give the crude product, which was directly used in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14]([CH:16]=O)=[CH:15][C:10]=3[N:9]=[N:8]2)=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1.[NH:24]1[C:28]([CH2:29][N:30]2[C:34](=[O:35])[CH2:33][S:32][C:31]2=[O:36])=[N:27][N:26]=[N:25]1>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14](/[CH:16]=[C:33]4/[C:34](=[O:35])[N:30]([CH2:29][C:28]5[NH:24][N:25]=[N:26][N:27]=5)[C:31](=[O:36])[S:32]/4)=[CH:15][C:10]=3[N:9]=[N:8]2)=[C:4]([C:20]([F:23])([F:21])[F:22])[CH:3]=1
Reactant: O=Cc1ccc2c(c1)nnn2Cc1ccc(Cl)cc1C(F)(F)F
Reactant: O=C1CSC(=O)N1Cc1nnn[nH]1
Product: O=C1S/C(=C\c2ccc3c(c2)nnn3Cc2ccc(Cl)cc2C(F)(F)F)C(=O)N1Cc1nnn[nH]1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-benzotriazol-5-yl}methylidene)-3-(1H-tetrazol-5-ylmethyl)-1,3-thiazolidine-2,4-dione was prepared from 1-(4-chloro-2-trifluoromethylbenzyl)-1H-benzotriazole-5-carbaldehyde (from Example 258) and 3-(1H-tetrazol-5-ylmethyl)-1,3-thiazolidine-2,4-dione (from Example 72) following General Procedure F.
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH3:12])([CH3:11])[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[Na]>C1COCC1>[Cl:1][CH2:2][C:3]([CH3:12])([CH3:11])[CH2:4][N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CC(C)(CCl)C(=O)N1CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(CCl)CN1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Chloro-2,2-dimethyl-propionyl chloride (0.5 g, 3.2 mmol) was stirred in dichloromethane (20 mL) at RT with triethylamine (0.9 mL, 6.4 mmol). The reaction mixture was cooled to 5° C. and then pyrrolidine (0.32 mL, 3.9 mmol), was added drop wise. After addition the reaction was stirred at RT for 1 hr, and then the reaction mixture was washed with saturated sodium hydrogen carbonate solution (2×50 mL), brine (50 ml), dried (Na2SO4) and concentrated in vacuo to afford 3-chloro-2,2-dimethyl-1-pyrrolidin-1-yl-propan-1-one as a yellow solid, 0.576 g, 94%. To this intermediate, 3-chloro-2,2-dimethyl-1-pyrrolidin-1-yl-propan-1-one (0.57 g, 3 mmol) in anhydrous THF (20 mL) was slowly added a 1M anhydrous THF solution of lithium aluminium hydride (7.5 mL, 7.5 mmol) at room temperature. The resulting clear solution was stirred overnight at room temperature under nitrogen to give a cloudy suspension. Water (0.3 mL) was carefully added to the reaction mixture followed by 15% w/v aqueous sodium hydroxyde solution (0.3 mL) and water (0.9 mL). The reaction was filtered and the filtrate evaporated to dryness to give the title compound which was used without further purification.
Reaction SMILES: C([C@](C(O)=O)(O)[C@](C(=O)C1C=CC(OC)=CC=1)(O)C(O)=O)(=O)C1C=CC(OC)=CC=1.[C:31]1([C:37]2([CH2:42][CH2:43][OH:44])[CH2:41][CH2:40][NH:39][CH2:38]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)(O)[O-].[Na+].[CH3:50][O:51][C:52]1[CH:60]=[CH:59][C:58]([N:61]2[CH:65]=[N:64][N:63]=[N:62]2)=[CH:57][C:53]=1[C:54](Cl)=[O:55].C(OCC)(=O)C>CC(C)=O.O.CC(C)=O.CO.C(OCC)(=O)C>[CH3:50][O:51][C:52]1[CH:60]=[CH:59][C:58]([N:61]2[CH:65]=[N:64][N:63]=[N:62]2)=[CH:57][C:53]=1[C:54]([N:39]1[CH2:40][CH2:41][C:37]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)([CH2:42][CH2:43][OH:44])[CH2:38]1)=[O:55]
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)Cl
Reactant: OCCC1(c2ccccc2)CCNC1
Agent: COc1ccc(C(=O)[C@@](O)(C(=O)O)[C@](O)(C(=O)O)C(=O)c2ccc(OC)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(-n2cnnn2)cc1C(=O)N1CCC(CCO)(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Add (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt (6.72 g, 11.0 mmol) and sodium bicarbonate (4.87 g, 58 mmol) in acetone/water (50 mL/50 mL). Cool in an ice bath. Add a solution of 2-methoxy-5-(1H-tetrazol-1-yl)benzoyl chloride (1.66 g, 9.9 mmol) in acetone (100 mL). After 30 minutes, warm to ambient temperature. After 60 hours, filter the reaction mixture and dilute the filtrate with ethyl acetate. Extract the filtrate with a saturated aqueous sodium bicarbonate solution and then brine. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give residue. Chromatograph the residue on silica gel eluting sequentially with ethyl acetate, 3% methanol/ethyl acetate, and then 5% methanol/ethyl acetate to give the title compound: Rf=0.48 (5% methanol/dichloromethane).
Reaction SMILES: C([O:3][C:4]([C:6]1([S:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:11][CH2:10][N:9]([CH2:12][CH3:13])[CH2:8][CH2:7]1)=[O:5])C>CO.[OH-].[Na+]>[CH2:12]([N:9]1[CH2:8][CH2:7][C:6]([S:14]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)(=[O:16])=[O:15])([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]1)[CH3:13]
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(CC)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCN1CCC(C(=O)O)(S(=O)(=O)c2ccc(OC)cc2)CC1

Procedure:
1-Ethyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid was prepared starting from 1-ethyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl ester (2.42 g, 6.8 mmol) dissolved in methanol (100 ml) and 10 N NaOH (15 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 1.29 g (58%); white solid; mp 209° C.; MS: 328 (M+H)+.