Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:21][CH2:22][C:23]([O:25]C)=[O:24])[C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][C:13]=3[C:27](=[O:29])[NH2:28])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[OH-].Cl>C1COCC1.CO>[CH:1]1([CH2:7][N:8]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:21][CH2:22][C:23]([OH:25])=[O:24])[C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][C:13]=3[C:27](=[O:29])[NH2:28])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2CC1CCCCC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: NC(=O)c1cccc2c1c1c(OCC(=O)O)cccc1n2CC1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A slurry of [9-[(cyclohexyl)methyl]-5-carbamoylcarbazol-4-yl]oxyacetic acid, methyl ester (20 mg, 0.051 mmol) in 0.3 mL of THF and 0.1 mL of MeOH was treated with 0.1 mL of 1 N aq LiOH (0.1 mmol), and the mixture stirred at room temperature for 2 h. The reaction was acidified with 0.2 N HCl, and the organics were removed in vacuo. The white precipitate was filtered away from the aqueous layer and rinsed with Et2O to afford 16 mg (0.042 mmol; 83%) the title acid as a white powder. MS (ES) m/e 381 (M+1), 364 (M+H—NH3), 379 (M−1).
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[C:12]([CH3:14])[C:11](/[CH:15]=[CH:16]/[CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)=[C:10]([CH3:30])[CH:9]=1)=[O:7])CCC.O1CCCC1>C(O)C.[OH-].[Na+]>[C:26]([O:25][C:23]([N:20]1[CH2:19][CH2:18][CH:17](/[CH:16]=[CH:15]/[C:11]2[C:10]([CH3:30])=[CH:9][C:8]([C:6]([OH:7])=[O:5])=[CH:13][C:12]=2[CH3:14])[CH2:22][CH2:21]1)=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: CCCCOC(=O)c1cc(C)c(/C=C/C2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)cc(C)c1/C=C/C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 99 %

Procedure:
To a solution of 209 mg of tert-butyl 4-{(E)-2-[4-(butoxycarbonyl)-2,6-dimethylphenyl]vinyl}piperidine-1-carboxylate in 5 ml of ethanol, 1.5 ml of 1N aqueous sodium hydroxide solution was added, followed by stirring at ambient temperature for 3.5 hours. After 1 ml of tetrahydrofuran was added to the reaction mixture, the mixture was stirred at 50° C. overnight. The solvent was evaporated under reduced pressure, water and 1.6 ml of 1N hydrochloric acid were added thereto. The formed precipitates were collected by filtration and dried to give 179 mg of 4-{(E)-2-[1-(tert-butoxycarbonyl)piperidin-4-yl]vinyl}-3,5-dimethylbenzoic acid.
Reaction SMILES: [CH:1]1([NH:7][N:8]=[C:9]([CH3:11])[CH3:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:12]=[O:13]>CCCCCCC>[CH:1]1([N:7]=[N:8][C:9]([O:12][OH:13])([CH3:11])[CH3:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=O
Reactant: CC(C)=NNC1CCCCC1
Agent: *CC*
Solvent: CCCCCCC
Product: CC(C)(N=NC1CCCCC1)OO
Reaction time: 0.58 h
Yield: 85 %

Procedure:
A solution of 5.0 grams (0.0324 moles) of acetone cyclohexylhydrazone in 70 grams of heptane was oxidized by passing oxygen through the solution as in Example II. The oxidation was initiated at 35° C. The reaction was followed by gas chromatography, following the disappearance of the cyclohexylhydrazone peak. The reaction was complete in 35 minutes at 35° C. The solution was cooled to 0° and drained into a tared, cooled, polyethylene bottle, weighed and stored at -30° C. The solution weighed 75.1 grams (85% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:15](=[O:16])[C:14]3=[CH:17][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:19][CH:20]=[C:13]3[C:12]2=[O:25])[CH:5]=1)([O-])=O.CN(C)C=O.[H][H]>[Pd].C(OCC)(=O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:15](=[O:16])[C:14]3=[CH:17][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:19][CH:20]=[C:13]3[C:12]2=[O:25])[CH:5]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1N1C(=O)c2ccc(S(C)(=O)=O)cc2C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(N)cc1N1C(=O)c2ccc(S(C)(=O)=O)cc2C1=O

Procedure:
The mixture of 2.5 g of N-(4- nitro-o-tolyl)-4-methylsulfonylphthalimide, 0.1 g of palladium on carbon, 80 ml of dimethylformamide and 200 ml of ethyl acetate is hydrogenated at 2.7 atm. and room temperature until the hydrogen uptake ceases. It is filtered, the filtrate extracted with hydrochloric acid, washed with ethyl acetate, basified with sodium carbonate, reextracted with ethyl acetate, the organic solution washed with water, dried filtered and evaporated. The residue is triturated with ethyl acetate-diethyl ether, to yield the N-(4-amino-o-tolyl)-4-methylsulfonylphthalimide melting at 214°-220°.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[CH3:20][O:21][C:22]([CH:24]1[CH2:28][CH:27]([OH:29])[CH2:26][NH:25]1)=[O:23]>>[CH3:20][O:21][C:22]([CH:24]1[CH2:28][CH:27]([OH:29])[CH2:26][N:25]1[C:17]([C:15]1[CH:16]=[C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])[CH:12]=[N:13][CH:14]=1)=[O:19])=[O:23]
Reactant: COC(=O)C1CC(O)CN1
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Product: CCc1cc(-c2cncc(C(=O)N3CC(O)CC3C(=O)OC)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and 4-hydroxy-pyrrolidine-2-carboxylic acid methyl ester to afford the title compound. MS: m/e=386 (M+H).
Reaction SMILES: C([Li])CCC.[C:6]([O:10][CH2:11][CH3:12])(=[O:9])[C:7]#[CH:8].[O:13]=[C:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.C(O)(=O)C>O1CCCC1>[CH2:11]([O:10][C:6](=[O:9])[C:7]#[C:8][C:14]1([OH:13])[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:18][CH2:19]1)[CH3:12]
Reactant: C#CC(=O)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)C#CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -70 °C
Reaction time: 0.17 h
Yield: 105.6 %

Procedure:
n-Butyllithium (175 mL, 0.28 mol) was added dropwise over 45 minutes to a stirred, cooled (−70° C.) solution of ethyl propiolate (32 mL, 0.32 mol) in tetrahydrofuran (250 mL). The mixture was stirred at −70° C. for 10 minutes, then a solution of 1,1-dimethylethyl 4-oxo-1-piperidinecarboxylate (18.6 g, 0.093 mol) in tetrahydrofuran (250 mL) was added dropwise over 1 hour maintaining the internal temperature below −70° C. The mixture was stirred at −70° C. for 1 hour, acetic acid (21 mL) in tetrahydrofuran (50 mL) was added. The mixture was warmed to room temperature and the solvent was evaporated under reduced pressure. Saturated aqueous sodium hydrogen carbonate (300 mL) and ethyl acetate (650 mL) were added and the layers were separated. The aqueous fraction was extracted with ethyl acetate (2×650 mL) and the combined organic fractions were washed with brine, dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on a short silica gel column, eluting with 1:1 isohexane:ethyl acetate, to give the title compound (29.2 g, contains trace impurity). m/z (ES+) 298 (M+1).
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH:5]([CH3:8])[CH2:4][CH2:3]1.[Mg].[C:10]([O:17][CH2:18][CH3:19])(=[O:16])[C:11]([O:13]CC)=O.[NH4+].[Cl-]>C1COCC1>[CH3:8][CH:5]1[CH2:6][CH2:7][CH:2]([C:11](=[O:13])[C:10]([O:17][CH2:18][CH3:19])=[O:16])[CH2:3][CH2:4]1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC1CCC(Br)CC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)C1CCC(C)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 35.5 %

Procedure:
A Grignard reagent prepared from 1-bromo-4-methylcyclohexane (20.0 g, 0.11 mol) and magnesium (2.9 g, 0.12 mol) in THF (110 ml) was added dropwise (during a period of 80 min) to a mechanically stirred solution of diethyl oxalate (16.0 g, 0.11 mol) in THF (250 ml) at −78° C. The mixture was left stirring for 2 h and then slowly warmed up to 0° C. A saturated solution of NH4Cl (100 ml) was added and the formation of a white precipitate was observed. Extraction with diethyl ether (2×), washing with water, drying (Na2SO4) and concentrating afforded 22.6 g of the crude compound. Kugelrohr distillation of 10 g (100° C./2 mbar) gave 7.74 g (76%) of ethyl 2-(4-methylcyclohexyl)-2-oxoacetate as a slightly yellow oil (mixture of cis/trans isomers ca. 1:3).
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22](=[O:24])[CH3:23])=[C:9]([CH3:25])[C:8]([O:26][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:7]([O:44][CH3:45])[C:6]=1[O:46][CH3:47])(=[O:3])[CH3:2].O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:1]([O:4][C:5]1[C:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22](=[O:24])[CH3:23])=[C:9]([CH3:25])[C:8]([OH:26])=[C:7]([O:44][CH3:45])[C:6]=1[O:46][CH3:47])(=[O:3])[CH3:2]
Reactant: COc1c(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(C)c(CCCCCCCCCCOC(C)=O)c(OC(C)=O)c1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COc1c(O)c(C)c(CCCCCCCCCCOC(C)=O)c(OC(C)=O)c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.6 %

Procedure:
1-Acetoxy-6-(10-acetoxydecyl)-4-tert-butyldiphenylsilyloxy-2,3-dimethoxy-5-methylbenzene (0.483 g) was dissolved in tetrahydrofuran (5 ml), and tetrabutylammonium fluoride trihydrate (0.5 g) was added. The mixture was stirred at room temperature for 30 minutes. After concentration under reduced pressure, the residue was subjected to column chromatography on silica gel and eluted with hexane/ethyl acetate (7:3) to obtain the desired compound (0.24 g).
Reaction SMILES: [NH2:1][C:2]1[CH:35]=[CH:34][C:5]([C:6]([N:8]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25](=[O:33])[C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH2:21][CH2:20]2)[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>>[F:32][C:29]1[CH:28]=[CH:27][C:26]([C:25]([CH:22]2[CH2:23][CH2:24][N:19]([CH2:18][CH2:17][N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=3)[C:6](=[O:7])[C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:37]([CH3:36])(=[O:39])=[O:38])=[CH:35][CH:34]=3)[CH2:20][CH2:21]2)=[O:33])=[CH:31][CH:30]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cccc(N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)C(=O)c2ccc(N)cc2)c1
Product: COc1cccc(N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)C(=O)c2ccc(NS(C)(=O)=O)cc2)c1
Yield: 95.3 %

Procedure:
Using 4-amino-N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-N-(3-methoxyphenyl)benzamide (475.0mg, 1.00 mmol) and methanesulfonyl chloride (0.12 ml, 1.50 mmol), the procedure of inventive Example 94 was repeated to obtain 527.8 mg (95.4%) of the title compound in a colorless amorphous form.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][C:3]=1[N:12]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=1)[S:13]([C:16]1[CH:24]=[CH:23][C:19]([C:20]([O-:22])=O)=[CH:18][CH:17]=1)(=[O:15])=[O:14].[Na+].[Cl-].[NH4+].C([N:43](CC)C(C)C)(C)C.C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.C(=O)([O-])O.[Na+]>CN(C)C(=O)C>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][C:3]=1[N:12]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33]([F:35])([F:36])[F:34])=[CH:28][CH:27]=1)[S:13]([C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH2:43])=[O:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14]
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1c(N(Cc2ccc(OC(F)(F)F)cc2)S(=O)(=O)c2ccc(C(=O)[O-])cc2)ncc2ccccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[NH3+]
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Product: Cc1c(N(Cc2ccc(OC(F)(F)F)cc2)S(=O)(=O)c2ccc(C(N)=O)cc2)ncc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.1 %

Procedure:
To a solution of sodium 4-({(4-methylisoquinolin-3-yl)[4-(trifluoromethoxy)-benzyl]amino}sulfonyl)benzoate (100 mg, 0.186 mmol) prepared in Example 2, ammonium chloride (50 mg, 0.929 mmol) and N,N-diisopropylethylamine (162 μL, 0.929 mmol) in N,N-dimethylacetamide (1.8 mL) was added 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate methanaminium (85 mg, 0.223 mmol) at 0° C., and the mixture was stirred at room temperature overnight. To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate three times. The organic layer was combined, washed with water twice, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:0→91:9) to give 4-({(4-methylisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl]amino}sulfonyl)benzamide (26 mg, 27%) as a colorless powder.
Reaction SMILES: CN(C)C=[O:4].[Mn]([O-])(=O)(=O)=O.[K+].[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH:23]=[CH:22][C:21]([CH:24]=[O:25])=[CH:20]2)=[CH:15][CH:14]=1.[OH-].[Na+]>O>[F:12][C:13]1[CH:14]=[CH:15][C:16]([N:19]2[CH:23]=[CH:22][C:21]([C:24]([OH:4])=[O:25])=[CH:20]2)=[CH:17][CH:18]=1
Reactant: O=Cc1ccn(-c2ccc(F)cc2)c1
Reactant: CN(C)C=O
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccn(-c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N,N-Dimethylformamide (300 ml) and water (100 ml) were added to potassium permanganate (28.7 g), and 1-(4-fluorophenyl)-3-formylpyrrole (34.4 g) was added under ice cooling. Potassium permanganate (14.4 g) was further added and the mixture was warmed up to room temperature and stirred for two hours. 1N Aqueous solution of sodium hydroxide (300 ml) was added to the reaction solution and stirred at room temperature for 0.5 hour. The reaction solution was washed with ethyl acetate, neutralized by the addition of hydrochloric acid and extracted with ethyl acetate. The organic layer was concentrated, isopropylether was added to the residue and the precipitated solid was collected by filtration to give the titled compound (15.2 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]#[C:7][C:8]1([OH:19])[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]1)=[O:5])[CH3:2].[H][H].OCC1(OC[C@@H](O)[C@@H](O)[C@H]1O)O>[Pd].C(O)C>[CH2:1]([O:3][C:4]([CH2:6][CH2:7][C:8]1([OH:19])[CH2:9][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C#CC1(O)CN(C(=O)OC(C)(C)C)C1
Reactant: [H][H]
Agent: [Pd]
Agent: OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O
Solvent: CCO
Product: CCOC(=O)CCC1(O)CN(C(=O)OC(C)(C)C)C1
Yield: 54.4 %

Procedure:
To palladium on carbon (10%, 75 mg) under a nitrogen atmosphere was added a solution of tert-butyl 3-(2-(ethoxycarbonyl)ethynyl)-3-hydroxyazetidine-1-carboxylate (0.20 g, 0.74 mmol) in ethanol (10 ml). The suspension was subjected to hydrogen (Parr hydrogenation apparatus) at 45 Psi for 3 hrs. The reaction was filtered and concentrated to give an oil. The oil was purified by flash column chromatography eluting with 30 to 50% ethyl acetate/hexanes to give the title compound as a colorless oil 0.11 g, 50%. 1H NMR (CDCl3, 400 MHz) 1.28 (3H, t), 1.43 (9H, s), 2.15 (2H, t), 2.50 (2H, t), 3.32 (1H, s), 3.83 (4H, dd), 4.18 (2H, q).
Reaction SMILES: [CH2:1]([N:3]([CH2:35][CH3:36])[CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[CH:27]=[CH:26][C:25]2[N:24]3[CH2:28][CH2:29][CH2:30][CH:23]3[CH2:22][CH2:21][C:20]=2[C:19]=1[C:31]([O:33]C)=[O:32])(=[O:16])=[O:15])[CH3:2].O.[OH-].[Li+].C(O)=O>O1CCOCC1.O.CO>[CH2:35]([N:3]([CH2:1][CH3:2])[CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[CH:27]=[CH:26][C:25]2[N:24]3[CH2:28][CH2:29][CH2:30][CH:23]3[CH2:22][CH2:21][C:20]=2[C:19]=1[C:31]([OH:33])=[O:32])(=[O:15])=[O:16])[CH3:36]
Reactant: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)CCC1CCCN21
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O=CO
Solvent: O
Product: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)CCC1CCCN21
Yield: 30 %

Procedure:
A mixture of methyl 7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]quinoline-6-carboxylate (Intermediate 31, 0.48 g) and lithium hydroxide monohydrate (0.526 g) in dioxane (10 mL) and water (2.5 mL) was irradiated in the microwave at 135° C. for a total of 75 minutes. After cooling, the mixture was diluted with methanol, acidified with formic acid and evaporated in vacuo. The residue was triturated with 10% methanol in DCM and filtered. The filtrate was evaporated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 0-15%. The resultant solid was triturated with acetone and filtered off to give 7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,2,3,3a,4,5-hexahydro-pyrrolo[1,2-a]quinoline-6-carboxylic acid (0.14 g) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:21](=[O:22])[N:20]([CH3:23])[C:11]3[N:12]([CH3:19])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][CH:16]=[CH:15][CH:14]=4)=[CH:4][CH:3]=1.[C:24](Cl)(=[O:26])[CH3:25]>>[C:24]([C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:19])[C:11]1[N:20]([CH3:23])[C:21](=[O:22])[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:9][C:10]2=1)(=[O:26])[CH3:25]
Reactant: Cn1c(=O)c(-c2ccc(F)cc2)cc2c3ccccc3n(C)c21
Reactant: CC(=O)Cl
Product: CC(=O)c1ccc2c(c1)c1cc(-c3ccc(F)cc3)c(=O)n(C)c1n2C

Procedure:
The process is carried out as in preparation 1.9B above, using 3-(4-fluorophenyl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one from Example 63A above and acetyl chloride.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:12][NH2:13]>C(#N)C.[Cl-].[Na+].O>[CH3:12][NH:13][CH2:8][C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CN
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CNCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.25 h
Yield: 97.2 %

Procedure:
A solution of p-nitrobenzylbromide (5.40 g, 25 mmol) in acetonitrile (60 ml) is added dropwise to a stirred solution of aqueous methylamine (65 mL, 40 wt. %, 0.75 mol) in acetonitrile (50 mL) at 0°. After stirring an additional 15 minutes, the solution is poured into brine and extracted 2× with dichloromethane. The combined organic layers are washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give 4-(methylaminomethyl)nitrobenzene (4.04g).
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[CH2:17](OC(OCC)OCC)C>C(O)C>[CH3:1][C:2]1[N:6]=[C:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:4]2[C:3]=1[C:13](=[O:14])[NH:15][N:16]=[CH:17]2
Reactant: Cc1[nH]c(-c2cccnc2)nc1C(=O)NN
Reactant: CCOC(OCC)OCC
Solvent: CCO
Product: Cc1nc(-c2cccnc2)n2cn[nH]c(=O)c12
Temperature: 220 °C
Reaction time: 0.5 h

Procedure:
A 5 g portion of 5-methyl-2-(3-pyridinyl)-1H-imidazole-4-carboxylic acid, hydrazide in 100 ml of triethoxymethane was stirred at reflux for 18 hours in an oil bath at 220° C. The volatiles were boiled off as the temperature of the oil bath rose to 250°-260° C. The residue in the flask melted, then solidified, was kept at 250°-260° C. for 30 minutes and then cooled to room temperature. The solid was boiled in 200 ml of ethanol, the solid collected, dissolved in 100 ml of boiling methyl cellosolve, treated with charcoal and clarified. The filtrate was cooled at -5° C., the solid collected washed with ethanol and dried, giving 600 mg of the desired product, mp 292°-295° C. (dec.).
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)C(C)C)C.[C:27](OC(=O)C)(=[O:29])[CH3:28].ClCCl>O1CCOCC1>[C:1]1([N:7]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][CH:9]=2)[C:27](=[O:29])[CH3:28])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)OC(C)=O
Reactant: c1ccc(Nc2ccnc3ccccc23)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(=O)N(c1ccccc1)c1ccnc2ccccc12

Procedure:
To a solution of phenyl-quinolin-4-yl-amine (13 g) and N-ethyl-N,N-diisopropylamine (1.5 eq) in dioxane (105 ml) was added acetic anhydride (28.1 ml, 5 eq). The solution was warmed to reflux of dioxane for 5 days. After cooling, dichloromethane was added and the solution was washed by water and sodium hydroxide 1N. The organic layer was separated and dried over sodium sulfate. The solvent was removed and the mixture was purified by chromatography on silica gel (dichloromethane/ethanol (95:5)) to afford N-phenyl-N-quinolin-4-yl-acetamide (10 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:14]([C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](Cl)=[O:20])([O-:16])=[O:15]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:19](=[O:20])[C:18]2[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=2[N+:14]([O-:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccccc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.5 %

Procedure:
To a mixture of 1-(tert-butoxycarbonyl)piperazine (11.18 g, 60 mmol) in CH2Cl2 (120 mL) at 0° C. was added 2-nitrobenzoyl chloride (8.0 mL, 60.6 mmol). The reaction was warmed to room temperature and stirred for 2 hours. A solution of 50% satd Na2 CO3 was added and the mixture was extracted with CH2Cl2. The organic layer was washed with satd citric acid and water, dried over MgSO4, and concentrated to a slurry. Ether was added to the mixture and it was filtered to give the desired product as a white solid (16.0 g, 79%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@:9]2([C:14]#N)[CH2:11][CH:10]2[CH2:12][OH:13])[CH:5]=[CH:6][C:7]=1[Cl:8].C([OH:18])C.[OH-].[Na+].Cl>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C@:9]23[CH2:11][C@H:10]2[CH2:12][O:13][C:14]3=[O:18])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: N#C[C@@]1(c2ccc(Cl)c(Cl)c2)CC1CO
Reactant: CCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C1OC[C@@H]2C[C@]12c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
(1S)-1-(3,4-dichloro-phenyl)-2-hydroxymethyl cyclopropanecarbonitrile (10 g, 4.13 mmol), ethanol (20 mL) and 25N sodium hydroxide solution (10 mL) were heated under reflux for 18 hours. The reaction is monitored by TLC (dichloromethane (100%)). The reaction mixture was cooled to room temperature and ice cold water (10 mL) was added to the reaction mass followed by concentrated hydrochloric acid drop wise to adjust the pH of the reaction mass to 1-2 and stirred for overnight at room temperature. The aqueous layer was extracted with dichloromethane (100 mL). The organic layer was washed with 3% sodium bicarbonate solution, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to yield 4.5 g (45%) of product. 1H NMR δ(300 MHz,CDCl3): 1.41-1.43 (1H,t, J=4.9 Hz), 1.58-1.63 (1H,dd, J=7.79,4.94 Hz), 2.56-2.62 (1H,m), 4.28-4.31 (1H,d, J=9.3 Hz), 4.44-4.48 (1H,dd, J=9.34,4.58 Hz), 7.26-7.30 (1H,dd, J=8.2,2.0 Hz), 7.40-7.43 (1H,d, J=8.2 Hz), 7.52-7.53 (1H,d, J=2 Hz).