Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]=[C:7]=[S:8])=[O:5])[CH3:2].[NH3:9]>C(O)C>[CH2:1]([O:3][C:4]([NH:6][C:7]([NH2:9])=[S:8])=[O:5])[CH3:2]
Reactant: CCOC(=O)N=C=S
Reactant: N
Solvent: CCO
Product: CCOC(=O)NC(N)=S
Reaction time: 2 h

Procedure:
To 0.1 mole of ethoxycarbonyl isothiocyanate in ethanol (50 ml) is added 50 ml of a 2M ethanolic solution of ammonia. After 2 hours at room temperature, the precipitated product is collected by filtration and used in the next step.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:13]=[CH:12][C:11]([Mg]Br)=[CH:10][CH:9]=1.[CH3:16][N:17]1[CH:21]=[CH:20][N:19]=[C:18]1[CH:22]=[O:23]>C1COCC1>[CH3:16][N:17]1[CH:21]=[CH:20][N:19]=[C:18]1[CH:22]([C:11]1[CH:12]=[CH:13][C:8]([O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)=[CH:9][CH:10]=1)[OH:23]
Reactant: Cn1ccnc1C=O
Reactant: Br[Mg]c1ccc(OC2CCCCO2)cc1
Solvent: C1CCOC1
Product: Cn1ccnc1C(O)c1ccc(OC2CCCCO2)cc1
Reaction time: 3 h
Yield: 100.2 %

Procedure:
4-(2-Tetrahydro-2H-pyranoxy)phenylmagnesium bromide (0.5M in THF, 160 mL, 80 mmol) was added slowly to a solution of 1-methyl-2-imidazolecarboxaldehyde (8 g, 72.7 mmol) in THF (100 mL) via syringe at −78° C. The reaction mixture was stirred at this temperature for 3 hours and quenched with saturated NH4Cl (aq). The mixture was extracted with EtOAc (2×100 mL), and the combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 9.1 as a colorless oil (21 g), which was used directly in the next step.
Reaction SMILES: [OH:1][CH:2]([CH2:8][C:9](=[O:11])[O-:10])[CH2:3][N+:4]([CH3:7])([CH3:6])[CH3:5].[ClH:12].O[C@H](CC(=O)[O-])C[N+](C)(C)C>>[CH3:5][N+:4]([CH2:3][C:2]([CH2:8][C:9]([OH:11])=[O:10])=[O:1])([CH3:6])[CH3:7].[Cl-:12]
Reactant: Cl
Reactant: C[N+](C)(C)CC(O)CC(=O)[O-]
Agent: C[N+](C)(C)C[C@H](O)CC(=O)[O-]
Product: C[N+](C)(C)CC(=O)CC(=O)O
Product: [Cl-]
Yield: 57 %

Procedure:
The reaction product was passed through a column of cation exchange resin Dowex AG 50W-X8 of 20×200 mm. This column had been previously brought to the H+ form by washing with 350 ml of 10% HCl and then with 500 ml of water. After introduction of the sample, the column was washed with 400 ml of water and then eluted with a 1-normal ammonia solution. The fraction discharged from the column between 150 ml and 225 ml, after the beginning of the elution with ammonia, was collected. By carnitine acetyltransferase titration, it was found to contain 1.48 g of carnitine. The sample was then evaporated in vacuo, re-dissolved into water (15 ml) and evaporated again. The carnitine base was converted to the hydrochloride by addition of 8 ml of a 1-normal HCl solution and evaporated again. The deliquescent product was dissolved into 75 ml of an anhydrous mixture of 3 parts of acetone with 2 parts of ethanol. 210 ml of acetone at 0° C. was added and the solution was stored at -9° C. for 12 hours. The crystals were collected, washed with ether and dried under vacuum. 0.91 g of carnitine was obtained. The final product was titrated with carnitine acetyltransferase and found to contain 89.5% of L-carnitine hydrochloride. It was obtained with an aggregate yield of 57% with respect to dehydrocarnitine hydrochloride.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[Cl:27][C:28]1[C:29]([F:54])=[C:30]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][C:41]([O:47][CH:48]4[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]4)=[C:42]([O:45][CH3:46])[CH:43]=3)[N:38]=[CH:37][N:36]=2)[CH:31]=[CH:32][CH:33]=1.C(N(C(C)C)CC)(C)C.[CH3:64][O:65][CH2:66][C:67](O)=[O:68]>C(Cl)Cl>[Cl:27][C:28]1[C:29]([F:54])=[C:30]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][C:41]([O:47][CH:48]4[CH2:53][CH2:52][N:51]([C:67](=[O:68])[CH2:66][O:65][CH3:64])[CH2:50][CH2:49]4)=[C:42]([O:45][CH3:46])[CH:43]=3)[N:38]=[CH:37][N:36]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: COCC(=O)O
Reactant: COc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCC(=O)N1CCC(Oc2cc3ncnc(Nc4cccc(Cl)c4F)c3cc2OC)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 80.1 %

Procedure:
HATU (0.24 g) was added to a solution of N-(3-chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine dihydrochloride (250 mg), diisopropylethylamine (0.37 ml) and methoxyacetic acid (0.054 g) in methylene chloride (9 ml) and the mixture was stirred at room temperature for 2.5 hours. Methylene chloride (20 ml) was added and the organic layer was washed with aqueous sodium hydroxide (2M, 30 ml) and water (30 ml). The resulting product was purified by flash column chromatography eluting with methanol (3%) and methylene chloride (97%) to give a foam. This was re-precipitated by stirring in diethyl ether (20 ml) to give the title product as a white solid (0.200 g); 1H N Spectrum: (DMSO d6 373K) 1.73 (m, 2H), 2.02 (m, 2H), 3.37 (s, 3H), 3.41 (m, 2H), 3.77 (m, 2H), 3.98 (s, 3H), 4.09 (s, 2H), 4.85 (m, 1H), 7.26 (m, 1H), 7.30 (s, 1H), 7.39 (m, 1H), 7.59 (m, 1H), 7.81 (s, 1H), 8.38 (s, 1H), 9.34 (br s, 1H); Mass Spectrum: (M+H)+ 475.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C@@H:13]([C:55]([CH3:58])([CH3:57])[CH3:56])[C:14]([NH:16][C@@H:17]([CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C@@H:18]([OH:47])[CH2:19][C@@H:20]([NH:34][C:35]([C@@H:37]([NH:42][C:43](=[O:46])[O:44][CH3:45])[C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[CH:24][CH:23]=2)=[O:15])[C:9]1=[O:59])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:60]([S:62][CH2:63][CH3:64])[CH3:61].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(#N)C.C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C@@H:13]([C:55]([CH3:58])([CH3:57])[CH3:56])[C:14]([NH:16][C@@H:17]([CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C@@H:18]([O:47][CH:60]([S:62][CH2:63][CH3:64])[CH3:61])[CH2:19][C@@H:20]([NH:34][C:35](=[O:36])[C@H:37]([C:38]([CH3:41])([CH3:40])[CH3:39])[NH:42][C:43]([O:44][CH3:45])=[O:46])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[CH:24][CH:23]=2)=[O:15])[C:9]1=[O:59])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCSCC
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2ccccc2)C1=O)C(C)(C)C)C(C)(C)C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCSC(C)O[C@@H](C[C@H](Cc1ccc(-c2ccccn2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2ccccc2)C1=O)C(C)(C)C
Yield: 94.8 %

Procedure:
To a solution of the compound of Example 111 (0.200 g, 0.248 mmol) and ethyl sulfide (0.70 mL, 6.48 mmol) in acetonitrile (2.0 mL) at 0° C. was added benzoyl peroxide (0.38 g, 1.57 mmol) in three portions over 2 hours. The reaction was diluted with ethyl acetate and washed with 10% Na2CO3 and brine. The organic was dried over MgSO4, filtered and evaporated. The residue was chromatographed on silica gel eluting with a gradient starting with dichloromethane and ending with ethyl acetate to give the title compound (0.210 g, 95% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[SH:9].Br[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-])=O)[CH:13]=1.[C:21]1([S:27](Cl)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[NH2:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[CH2:11][S:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[NH:1][S:27]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:29])=[O:28]
Reactant: Nc1cc(Cl)ccc1S
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Product: Nc1cccc(CSc2ccc(Cl)cc2NS(=O)(=O)c2ccccc2)c1

Procedure:
Following General Procedure A, B, and K, the title compound was prepared from 2-amino-4-chloro-benzenethiol, 1-bromomethyl-3-nitro-benzene, and benzenesulfonyl chloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([OH:19])=[O:18])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.Cl[CH2:21]Cl.C[Si](C=[N+]=[N-])(C)C>CO.C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([O:19][CH3:21])=[O:18])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reactant: ClCCl
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
To a stirred suspension of the 1-(4-fluorophenyl)-1H-indazole-5-carboxylic acid (0.22 g, 0.81 mmol) in methanol (5 mL), THF (5 mL), and dichloromethane (5 mL) was added (trimethylsilyl)diazomethane solution (2M in diethyl ether, 1 mL, 2 mmol) dropwise at rt. The reaction mixture was stirred at rt for 1 hr and carefully quenched by the slow addition of acetic acid. Concentration under reduced pressure and titration with methanol gave methyl 1-(4-fluorophenyl)-1H-indazole-5-carboxylate (0.16 g, 0.59 mmol, 73% yield) as a white solid.
Reaction SMILES: O=[C:2]1[CH2:8][C@H:7]2[N:4]([C:5](=[O:26])[C@@H:6]2[C:9]([CH3:25])([O:11][C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[O:13])[CH3:10])[C@H:3]1[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=1)=[O:28].C(N(C(C)C)CC)(C)C.C1(OP(Cl)(OC2C=CC=CC=2)=O)C=CC=CC=1.[SH:66][C:67]1[CH:72]=[CH:71][N:70]=[CH:69][CH:68]=1>CN(C1C=CN=CC=1)C.C(#N)C.C(OCC)(=O)C>[N:70]1[CH:71]=[CH:72][C:67]([S:66][C:2]2[CH2:8][C@H:7]3[N:4]([C:5](=[O:26])[C@@H:6]3[C:9]([CH3:25])([O:11][C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=3)=[O:13])[CH3:10])[C:3]=2[C:27]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][C:34]([N+:37]([O-:39])=[O:38])=[CH:35][CH:36]=2)=[O:28])=[CH:68][CH:69]=1
Reactant: Sc1ccncc1
Reactant: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)C[C@H]12
Agent: CN(C)c1ccncc1
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Sc3ccncc3)C[C@H]12
Temperature: 0 °C
Reaction time: 8 h
Yield: 81.8 %

Procedure:
To a solution of 4-nitrobenzyl(2R,5R,6S)-3,7-dioxo-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-1-azabicyclo[3.2.0]heptane-2-carboxylate (145.1 mg) and 4-(N,N-dimethylamino)pyridine (3.27 mg) in acetonitrile (7.3 ml) was added dropwise a solution of N,N-diisopropyl-N-ethylamine (56.0 μl) in acetonitrile (0.504 μl), followed by a solution of diphenyl-chlorophosphate (58.3 μl) in acetonitrile (0.525 ml) at 0° C. After stirring for an hour at 0° C., thereto was added a solution of N,N-diisopropyl-N-ethylamine (186.4 μl) in acetonitrile (1.68 ml), followed by 4-mercaptopyridine (31.3 mg) at -15° C. The mixture was allowed to stand overnight at -15° C. The resultant solution was diluted with ethyl acetate (15 ml) and then washed in turn with water and saturated aqueous sodium chloride. After drying over magnesium sulfate, the solution was filtered and evaporated in vacuo. The residue was chromatographed on silica gel (4 g) eluting with a mixture of benzene and acetone (30:1 to 6:1) to give 4-nitrobenzyl(5R,6S)-3-(4-pyridylthio)-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (139.1 mg).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].[Br:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([CH2:14]Br)[CH:8]=1.O.CCOCC>CN(C=O)C>[C:1]([O:4][CH2:14][C:9]1[CH:8]=[C:7]([Br:6])[CH:12]=[CH:11][C:10]=1[F:13])(=[O:3])[CH3:2]
Reactant: Fc1ccc(Br)cc1CBr
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(=O)OCc1cc(Br)ccc1F
Reaction time: 11 h

Procedure:
Anhydrous sodium acetate (1.65 g, 20 mmol) was added to a solution of the compound (1a) (3 g, 14.6 mmol) in DMF (25 mL) and the reaction mixture was stirred under N2 on a steam bath for 11 hours. The reaction mixture was cooled and distributed between H2O (200 mL) and Et2O (100 mL). The organic layer was separated and washed with H2O (3×100 mL), dried, filtered and evaporated, leaving the compound (1b) as a nearly colorless oil; NMR 2.08 (3H, s), 5.08 (2H, s), 6.7-7.9 (3H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:18]=[CH:17][C:10]([C:11]([N:13]([CH2:15][CH3:16])[CH3:14])=[O:12])=[CH:9][CH:8]=2)=[C:4]([N+:21]([O-])=O)[CH:3]=1.Cl[Sn]Cl>>[NH2:21][C:4]1[CH:3]=[C:2]([Cl:1])[CH:20]=[CH:19][C:5]=1[O:6][C:7]1[CH:18]=[CH:17][C:10]([C:11]([N:13]([CH2:15][CH3:16])[CH3:14])=[O:12])=[CH:9][CH:8]=1
Reactant: CCN(C)C(=O)c1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])cc1
Agent: Cl[Sn]Cl
Product: CCN(C)C(=O)c1ccc(Oc2ccc(Cl)cc2N)cc1
Yield: 82.4 %

Procedure:
The product from Example 133a (1.0 g, 2.99 mmol) was reduced with SnCl2 following the procedure from Example 1f giving the title compound as a clear oil (751 mg, 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:9][CH2:10][CH2:11]Cl.[CH3:13][CH:14]([CH3:30])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:19]=1)=[O:16]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:9][CH2:10][CH2:11][N:27]1[CH2:28][CH2:29][CH:24]([C:20]2[CH:19]=[C:18]([NH:17][C:15](=[O:16])[CH:14]([CH3:13])[CH3:30])[CH:23]=[CH:22][CH:21]=2)[CH2:25][CH2:26]1
Reactant: ClCCCOc1ccccc1Cl
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCOc3ccccc3Cl)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 1-chloro-2-(3-chloropropoxy)benzene and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 415.2 (M+H)+.
Reaction SMILES: O.[C:2]1([CH3:12])[CH:7]=[CH:6][C:5](S(O)(=O)=O)=[CH:4][CH:3]=1.O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH:6]1[C:7]2[CH:7]=[CH:2][CH2:3][CH2:4][CH2:12][C:2]=2[CH:3]=[CH:4][CH:5]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: C1=Cc2ccccc2CCC1
Yield: 1773.9 %

Procedure:
A suspension of this compound (7.00 g, 43.2 mmol) and para-toluenesulfonic acid monohydrate (0.82 g, 4.3 mmol) in toluene (100 ml) was refluxed for 1 hour with the azeotropic removal of water. The resulting solution was diluted with ethyl acetate, then washed with saturated sodium hydrogen carbonate solution, dried over MgSO4, filtered and evaporated to give 6,7-dihydro-5H-benzocycloheptene as a brown liquid (5.5 g, 88% yield).
Reaction SMILES: [Cl:1][C:2](Cl)([C:13]([F:16])([F:15])[F:14])[CH2:3][CH:4]1[CH:6]([C:7]([O:9]C)=[O:8])[C:5]1([CH3:12])[CH3:11].O.Cl.ClCCl>[OH-].[K+]>[Cl:1]/[C:2](/[C:13]([F:14])([F:15])[F:16])=[CH:3]\[C@@H:4]1[C@H:6]([C:7]([OH:9])=[O:8])[C:5]1([CH3:12])[CH3:11]
Reactant: COC(=O)C1C(CC(Cl)(Cl)C(F)(F)F)C1(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC1(C)[C@H](/C=C(\Cl)C(F)(F)F)[C@@H]1C(=O)O
Temperature: 60 °C
Reaction time: 8 h

Procedure:
(+) Methyl 3-(2,2-dichloro-3,3,3-trifluoropropyl)-2,2-dimethyl-cyclopropane carboxylate cyclopropanecarboxylic (9.1 gm) was dissolved in methanolic potassium hydroxide (3.44 gm @100%) and heated to 60° C. in a clean dry 25 ml flask fitted with condenser, thermometer, nitrogen purge and magnetic stirrer. Heat was applied from an external oil bath. After 1 hour on temperature sodium carbonate (1.59 gm) was charged followed by ethanol (10 ml) and the reaction temperature increased to 90° C. and held for 8 hours to complete as judged by GLC. The product was obtained by topping off the solvent from the reaction, adding water (50 ml) and concentrated hydrochloric acid to adjust the pH to <2, followed by dichloromethane (50 ml). After separation a second similar dichloromethane wash of the aqueous phase was applied, separated and combined with the first wash. The combined organic layer was washed with water, brine and then topped to give a yellow paste (5.83 gm). The product obtained was analysed by HPLC, GCMS and NMR to confirm the material was consistent with that of structure (IIIa). HPLC revealed that the product was a mixture of Cis and Trans isomers in the ratio of ˜85:15 respectively.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:18])[C:14]([F:17])([F:16])[F:15])[C:6]([OH:8])=[O:7])=[O:2].[C:19]([O-])([O-])=O.[K+].[K+].IC>CC(C)=O.O>[CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:18])[C:14]([F:16])([F:15])[F:17])[C:6]([O:8][CH3:19])=[O:7])=[O:2]
Reactant: O=C([O-])[O-]
Reactant: CC(Oc1ccc(C(=O)O)cc1C=O)C(F)(F)F
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Solvent: O
Product: COC(=O)c1ccc(OC(C)C(F)(F)F)c(C=O)c1
Reaction time: 2 h
Yield: 23.6 %

Procedure:
To a solution of 3-formyl-4-(2,2,2-trifluoro-1-methylethoxy)benzoic acid (490 mg) and K2CO3 (387 mg) in acetone (10 ml) was added iodomethane (350 μl) at room temperature, followed by stirring for 2 hours. The reaction mixture was diluted with water (15 ml), and extracted with EtOAc (30 ml). The organic layer was dried over anhydrous MgSO4, and filtered to remove the desiccant, and the solvent was concentrated. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=95:5 to 80:20) to obtain methyl 3-formyl-4-(2,2,2-trifluoro-1-methylethoxy)benzoate (122 mg) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:30]=[CH:29][C:6]([O:7][C:8]([CH3:28])([CH3:27])[C:9]#[C:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])=[CH:13][N:12]=2)=[CH:5][CH:4]=1)#[N:2]>ClC1C=CC=CC=1Cl>[C:1]([C:3]1[CH:30]=[CH:29][C:6]2[O:7][C:8]([CH3:28])([CH3:27])[CH:9]=[C:10]([C:11]3[N:12]=[CH:13][C:14]([C:17]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[O:18])=[CH:15][CH:16]=3)[C:5]=2[CH:4]=1)#[N:2]
Reactant: CC(C)(C#Cc1ccc(C(=O)OCc2ccccc2)cn1)Oc1ccc(C#N)cc1
Solvent: Clc1ccccc1Cl
Product: CC1(C)C=C(c2ccc(C(=O)OCc3ccccc3)cn2)c2cc(C#N)ccc2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.1 %

Procedure:
9 g of benzyl 2-[3-(4-cyanophenoxy)-3-methyl-1-butyn-1-yl]pyridine-5-carboxylate were dissolved in 300 ml of 1,2-dichlorobenzene and the solution was added dropwise over a period of 5 hours to 10% ml of 1,2-dichlorobenzene heated at reflux. After a further 2 hours the mixture was allowed to cool to room temperature and was then evaporated. The residue was chromatographed on silica gel using ethyl acetate/petroleum ether (1:9), (1:6) and (1:4) for the elution. There were obtained 5.5 g of benzyl 6-(6-cyano-2,2-dimethyl-2H-1-benzopyran-4-yl)- 3-pyridinecarboxylate which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([OH:32])=O)[C:25]=1[CH3:33])(=[O:12])=[O:11].[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(#N)C.CN(C=O)C>[CH3:33][C:25]1[C:26]([C:30]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[O:32])=[C:27]([CH3:29])[NH:28][C:24]=1/[CH:23]=[C:16]1\[C:17](=[O:22])[NH:18][C:19]2[C:15]\1=[CH:14][C:13]([S:10]([CH2:9][C:3]1[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])(=[O:12])=[O:11])=[CH:21][CH:20]=2
Reactant: C1COCCN1
Reactant: Cc1cccc(C)c1CS(=O)(=O)c1ccc2c(c1)/C(=C/c1[nH]c(C)c(C(=O)O)c1C)C(=O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CC#N
Product: Cc1cccc(C)c1CS(=O)(=O)c1ccc2c(c1)/C(=C/c1[nH]c(C)c(C(=O)N3CCOCC3)c1C)C(=O)N2
Reaction time: 8 h

Procedure:
A mixture of 5-[5-(2,6-dimethyl-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (120 mg, 0.26 mmol), morpholine (30 mg, 0.34 mmol), HOBt (42 mg, 1.2 eq.), EDAC.HCl (60 mg, 1.2 eq.) and TEA (80 mg, 3 eq.) in 0.2 M concentration of acetonitrile: DMF (3:1) was stirred at for overnight. The reaction was and purified on a silica gel column to give the titled compound.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C@@H:13]3[CH2:16][C@H:15]([CH2:17]OS(C4C=CC(C)=CC=4)(=O)=O)[CH2:14]3)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>CC(N(C)C)=O>[N:1]1([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([C@@H:13]3[CH2:14][C@H:15]([CH2:17][N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)[CH2:16]3)=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C[C@@H](c3ccc(CN4CCCC4)cc3)C2)cc1
Reactant: C1COCCN1
Solvent: CC(=O)N(C)C
Product: c1cc([C@H]2C[C@@H](CN3CCOCC3)C2)ccc1CN1CCCC1
Temperature: 100 °C

Procedure:
To a stirring cis-toluene-4-sulfonic acid 3-(4-pyrrolidin-1-ylmethyl-phenyl)-cyclobutylmethyl ester (example 47) (0.41 g, 1.0 mmol) in DMA (5 mL) was added an amine for example morpholine (0.18 g, 2 mmo). The reaction was then heated to 100° C. (oil bath). After 4 hr the reaction was cooled to rt and concentrated under reduced pressure. Purification of this material was accomplished by flash column chromatography, using a 45 g ISCO column, eluting with a gradient of 5%, 10%, 20%, 60% MeOH/CH2Cl2 with 0.1% NH4OH. The product containing fractions were collected and concentrated to yield the title compound (214 mg) as the TsOH salt. This material was free based by stirring in solid K2CO3 and MeOH for 2 hours. After 2 hr the methanolic solution was concentrated, diluted with CH2Cl2, filtered, and concentrated under reduced pressure to give the free base. The HCl salt was made by taken the freebase up in EtOAc and then adding a solution of HCl (2 eq, 1 M HCl, THF) to give a colorless solid.
Reaction SMILES: [OH-].[Na+].[O:3]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]3[C:22]([N:23]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[CH2:26][CH2:25][CH2:24]4)=[N:21][C:20]4[C:15](=[CH:16][CH:17]=[C:18]([C:33]([O:35]C)=[O:34])[CH:19]=4)[N:14]=3)=[CH:12][C:7]=2[O:6][CH2:5][CH2:4]1>CO.O>[O:3]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]3[C:22]([N:23]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[CH2:26][CH2:25][CH2:24]4)=[N:21][C:20]4[C:15](=[CH:16][CH:17]=[C:18]([C:33]([OH:35])=[O:34])[CH:19]=4)[N:14]=3)=[CH:12][C:7]=2[O:6][CH2:5][CH2:4]1
Reactant: COC(=O)c1ccc2nc(-c3ccc4c(c3)OCCO4)c(N3CCCc4ccccc43)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2nc(-c3ccc4c(c3)OCCO4)c(N3CCCc4ccccc43)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.5 %

Procedure:
Sodium hydroxide (21.6 mg, 0.54 mmol) was added to a solution of methyl 2-(2,3-dihydro-1,4-benzodioxin-6-yl)-3-(1,2,3,4-tetrahydroquinolin-1-yl)quinoxaline-6-carboxylate (65 mg, crude) in methanol (5 ml) and water (1 ml) and the reaction was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, the residue was dissolved in water (30 ml), adjusted to pH=5 with hydrochloric acid (3 N), and the precipitate was collected by filtration to afford 2-(2,3-dihydro-1,4-benzodioxin-6-yl)-3-(1,2,3,4-tetrahydroquinolin-1-yl)quinoxaline-6-carboxylic acid as a light yellow solid (31.8 mg).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH2:14]O)[C:9]=1[O:16][CH3:17].[Cl:18]C1C=C[N+]([O-])=C(C)C=1OC.S(Cl)([Cl:31])=O>>[ClH:18].[Cl:31][CH2:14][C:10]1[C:9]([O:16][CH3:17])=[C:8]([S:7][CH2:6][C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[CH:13]=[CH:12][N:11]=1
Reactant: COc1c(Cl)cc[n+]([O-])c1C
Reactant: O=S(Cl)Cl
Reactant: COc1c(SCc2ccco2)ccnc1CO
Product: COc1c(SCc2ccco2)ccnc1CCl
Product: Cl

Procedure:
By the procedure described in Aa) to Ac), the intermediate product 4-(2-furylmethylthio)-2-hydroxymethyl-3-methoxypyridine is obtained starting from 4-chloro-3-methoxy-2-methylpyridine N-oxide; m.p. 56-58° C. Chlorination with thionyl chloride by the procedure described in Example Ad) gives the title compound as a beige powder; m.p. 135° C. (decomp.).