Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[O:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][C:16]#[N:17])[CH2:9][CH2:8]1>C1COCC1.O>[O:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])[CH2:9][CH2:8]1
Reactant: N#CCCCN1CCOCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: NCCCCN1CCOCC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To anhydrous THF (70 mL) was added LiAlH4 (5.37 g, 142 mmol) in one portion. The mixture was stirred at 0° C. for 20 min, and a solution of 4-morpholinobutanenitrile (7.26 g, 47 mmol) in anhydrous THF (40 mL) was added dropwise. Upon the end of addition the mixture was refluxed for 4 h, then cooled to 0° C., diluted with water (20 mL) and filtered. The filtrate was concentrated in vacuo to give the crude product for the next step without further purification.
Reaction SMILES: C([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11]([C:17]1[CH:22]=[N:21][CH:20]=[CH:19][N:18]=1)([OH:16])[CH2:12]2)C1C=CC=CC=1.C([O-])=O.[NH4+]>O.[Pd]>[N:18]1[CH:19]=[CH:20][N:21]=[CH:22][C:17]=1[C:11]1([OH:16])[CH2:12][CH:13]2[NH:8][CH:9]([CH2:15][CH2:14]2)[CH2:10]1
Reactant: OC1(c2cnccn2)CC2CCC(C1)N2Cc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Product: OC1(c2cnccn2)CC2CCC(C1)N2
Yield: 63 %

Procedure:
8-Benzyl-3-pyrazin-2-yl-8-aza-bicyclo[3.2.1]octan-3-ol (0.25 g, 0.85 mmol) was dissolved in IMS (10 mL) and water (1 mL). Palladium on carbon (10%; 0.1 g) was added under nitrogen. Ammonium formate (0.58 g, 9.2 mmol) was added and the mixture heated at reflux for 1 hour. The mixture was allowed to cool, filtered and the solvent removed by evaporation under vacuum. The residues were passed through an SCX cartridge, eluting with 2 M ammonia in methanol to give the title compound as a colourless oil (0.11 g). LCMS m/z 206.2 [M+H]+. R.T.=0.34 min (Analytical Method 3).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[CH2:6]([N:10]=[C:11]=[O:12])[CH2:7][CH2:8][CH3:9]>[N+](C1C=CC=CC=1)([O-])=O.C(Cl)(Cl)(Cl)Cl>[CH2:6]([NH:10][C:11]([C:2]1[NH:1][CH:5]=[CH:4][N:3]=1)=[O:12])[CH2:7][CH2:8][CH3:9]
Reactant: c1c[nH]cn1
Reactant: CCCCN=C=O
Solvent: O=[N+]([O-])c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCNC(=O)c1ncc[nH]1
Yield: 18 %

Procedure:
A solution of 0.10 mol of imidazole and 0.10 mol of n-butyl isocyanate in 40 ml of nitrobenzene was heated under reflux for 8 hours. After cooling the reaction mixture, it was diluted with carbon tetrachloride and the solid was filtered off and washed with carbon tetrachloride until the carbon tetrachloride runnings were colourless. After drying, imidazole-2-carboxylic acid n-butylamide was obtained in 18% yield. Melting point: 188°-190° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][O:8]/[N:9]=[C:10](/[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)\[C:11]#[N:12])[N:6]=1.Cl.[NH2:20][OH:21].C(=O)([O-])[O-].[K+].[K+]>CC(O)C.O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][O:8]/[N:9]=[C:10](/[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)\[C:11](=[N:20]\[OH:21])\[NH2:12])[N:6]=1
Reactant: NO
Reactant: N#C/C(=N\OCc1csc(N)n1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: NC(=N\O)/C(=N\OCc1csc(N)n1)c1ccccc1
Temperature: 80 °C
Yield: 115.5 %

Procedure:
To a suspension of (2Z)-{[(2-amino-1,3-thiazol-4-yl)methoxy]imino}(phenyl)acetonitrile (4.5 g, 17.42 mmol, 1 eq.) in iPrOH/H2O (10/1, 110 ml) were added hydroxylamine hydrochloride (3.63 g, 52.26 mmol, 3 eq.) and potassium carbonate (7.22 g, 52.2 mmol, 3 eq.). The reaction was heated to 80° C. for 6 h and the solvent was evaporated to ¾th. The residue was extracted with EtOAc (3×50 ml) and washed with aq. sat. NaCl. The organics were combined, dried over MgSO4 and concentrated to give (1Z,2Z)-2-{[(2-amino-1,3-thiazol-4-yl)methoxy]imino}-N′-hydroxy-2-phenylethanimidamide (5.86 g) as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:48])[CH2:5][N:6]([CH2:42][C:43]([O:45]CC)=[O:44])[C:7](=[O:41])[C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:11]=[CH:10][C:9]=1[O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)C.[OH-].[Na+]>CO>[C:43]([CH2:42][N:6]([C:7](=[O:41])[C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:11]=[CH:10][C:9]=1[O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[CH2:5][C:4]([OH:48])=[O:3])([OH:45])=[O:44]
Reactant: CCCCCCCCCCCCCCCCCCOc1ccc(OCc2ccccc2)c(C(=O)N(CC(=O)OCC)CC(=O)OCC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCOc1ccc(OCc2ccccc2)c(C(=O)N(CC(=O)O)CC(=O)O)c1
Yield: 95.8 %

Procedure:
A mixture of 6.6 g (9.9 mmol) of N-(2-ethoxy-2-oxoethyl)-N-[5-(octadecyloxy)-2-(phenylmethoxy)benzoyl]glycine ethyl ester and 25 ml (50 mmol) of 2N NaOH in 300 ml of methanol was stirred at reflux for 2 hours. The solvent was removed at reduced pressure, the residue was acidified and the product was extracted with ethyl acetate. The dried extract was concentrated to an oil which was treated with water and cooled in the refrigerator. The resultant solid was filtered, triturated with ether-hexane and filtered again to give 5.8 g (96% yield, mp 81°-83°) of N-(carboxymethyl)-N-[5-(octadecyloxy)-2-(phenylmethoxy)benzoyl]glycine.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[CH3:13][N:14]([CH3:21])[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([N:18]2[CH2:19][CH2:20][CH:15]([N:14]([CH3:21])[CH3:13])[CH2:16][CH2:17]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: CN(C)C1CCNCC1
Product: COc1cc(N2CCC(N(C)C)CC2)ccc1[N+](=O)[O-]

Procedure:
Starting materials: 4-fluoro-2-methoxy-1-nitrobenzene and N,N-dimethylpiperidin-4-amine. m/z 280.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:20])[CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:6]=[CH:7][CH:8]=1)#[CH:2].C(N(CC)CC)C.[Cl:28][C:29]1[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:30]=1[C:31](Cl)=[N:32][OH:33]>O1CCCC1.C(OCC)(=O)C>[Cl:28][C:29]1[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:30]=1[C:31]1[CH:2]=[C:1]([C:3]2[CH:4]=[C:5]([NH:9][C:10](=[O:20])[CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:17])[CH3:18])[CH:6]=[CH:7][CH:8]=2)[O:33][N:32]=1
Reactant: C#Cc1cccc(NC(=O)CNC(=O)OC(C)(C)C)c1
Reactant: ON=C(Cl)c1c(Cl)cccc1Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC(=O)Nc1cccc(-c2cc(-c3c(Cl)cccc3Cl)no2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
tert-Butyl 2-(3-ethynylphenylamino)-2-oxoethylcarbamate (1.6 g, 5.83 mmol) was dissolved in anhydrous tetrahydrofuran (25 mL) and treated with triethylamine (0.82 g, 8.1 mmol) and then 2,6-dichloro-N-hydroxybenzimidoyl chloride (1.4 g, 6.3 mmol). After stirring 15 min at room temperature the mixture was heated at reflux for 4 h. The mixture was diluted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl 2-(3-(3-(2,6-dichlorophenyl)isoxazol-5-yl)phenylamino)-2-oxoethylcarbamate. 1H NMR (CDCl3): 8.51 (br s, 1H), 8.01 (s, 1H), 7.51-7.45 (m, 2H), 7.40-7.28 (m, 4H), 6.63 (m, 1H), 5.28 (br s, 2H), 3.95 (d, 2H), 1.45 ppm (s, 9H).
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])[CH3:3].C(N(CC)CC)C.[CH2:21]([O:23][C:24](=[O:35])[C:25](=O)[CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH3:22].Cl>C(O)C.[Ni]>[CH2:21]([O:23][C:24]([C@@H:25]([NH:1][C@H:2]([C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])[CH3:3])[CH2:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:35])[CH3:22]
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Agent: [Ni]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 2 h

Procedure:
50 mmoles (9.3 g) Ala-Pro were suspended in 100 ml ethanol, mixed with 10 moles (1 g) triethylamine, 75 mmoles (15.5 g) 2-oxo-4-phenyl-butyric acid ethyl ester and 18 g molecular sieve 3 A and agitated for 2 hours under anhydrous conditions. One teaspoon of dehydrated Raney nickel and 15 g molecular sieve 3 A were now added, briefly reacted and subsequently hydrogenated for 22 hours under an atmosphere of 4 bars of H2. The reaction mixture was filtered and evaporated to concentrate it to a small volume. Conversion (according to HPLC) relative to Ala-Pro used: 95.6%, product yield (according to HPLC): 95%. The residue was taken up in 250 ml ethanol and adjusted to pH 4.25 with conc. HCl (an aliquot was removed for this purpose, diluted with water and the pH adjusted, then the entire amount of HCl required was calculated). The solution was evaporated to low bulk under reduced pressure at 40° C. to 50 g, filtered with Celite and diluted to 100 ml total volume with ethyl acetate. 5.2 g maleic acid dissolved in ethyl acetate+ethanol were added and the mixture was seeded with enalapril maleate. The crystallizate formed was separated off and dried.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([O:11][CH3:12])[C:7]=1[C:8]([NH2:10])=[O:9].[H-].[Na+].[CH3:15]I>CN(C)C=O>[NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([O:11][CH3:12])[C:7]=1[C:8]([NH:10][CH3:15])=[O:9]
Reactant: CI
Reactant: COc1cccc(N)c1C(N)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNC(=O)c1c(N)cccc1OC
Temperature: 3 °C
Reaction time: 2 h
Yield: 8.3 %

Procedure:
Slow addition of 4.98 g. (0.03 mole) of 6-amino-o-anisamide to a mixture of 57% NaH (1.32 g., 0.0315 mole) in 50 ml. dimethylformamide was carried out at room temperature. After the evolution of H2 ceased, the mixture was cooled to 3° C. and 2.06 ml. (0.033 mole) of methyliodide was slowly added at 3°-5° C. The temperature was allowed to go up to room temperature and stir for 2 hours. The mixture was concentrated, the residue extracted into ethyl acetate-water, the mixture was basified, and the ethyl acetate layer was washed with water, brine and dried. Concentration gave a tan solid that was crystallized (ethanol), giving 0.45 g (8%) Of 6-amino-N-methyl-o-anisamide m.p. 186°-189° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH2:9])[CH:4]=1)[CH3:2].Cl[CH2:11][CH:12]=O>CCO>[CH2:1]([C:3]1[CH:8]=[CH:7][N:6]2[CH:11]=[CH:12][N:9]=[C:5]2[CH:4]=1)[CH3:2]
Reactant: CCc1ccnc(N)c1
Reactant: O=CCCl
Solvent: CCO
Product: CCc1ccn2ccnc2c1
Yield: 98.6 %

Procedure:
A mixture of 4-ethylpyridin-2-amine (3.21 g, 8.19 mmol), and chloroacetaldehyde (50% aqueous solution, 2.6 ml, 10.5 mmol) in EtOH (10 ml) was refluxed vigorously for 12 hours. The reaction mixture was concentrated, and the residue was suspended in saturated aqueous sodium bicarbonate solution. The aqueous mixture was extracted with CH2Cl2 and EtOAc, and the combined organic extracts were dried over Na2SO4, filtered and concentrated to afford the desired product (1.18 g, 98% yield) as a viscous oil. MS APCI (+) m/z 147.2 (M+1) detected.
Reaction SMILES: I[C:2]1[CH:7]=[N:6][N:5](C2CCCCO2)[C:4](=[O:14])[CH:3]=1.[Cl:15][C:16]1[CH:21]=[C:20]([O:22][C:23]([F:26])([F:25])[F:24])[CH:19]=[CH:18][C:17]=1[OH:27]>>[Cl:15][C:16]1[CH:21]=[C:20]([O:22][C:23]([F:24])([F:25])[F:26])[CH:19]=[CH:18][C:17]=1[O:27][C:2]1[CH:7]=[N:6][NH:5][C:4](=[O:14])[CH:3]=1
Reactant: Oc1ccc(OC(F)(F)F)cc1Cl
Reactant: O=c1cc(I)cnn1C1CCCCO1
Product: O=c1cc(Oc2ccc(OC(F)(F)F)cc2Cl)cn[nH]1

Procedure:
In an analogous manner to the stepwise sequence outlined in Intermediate 18, starting from 5-iodo-2-(tetrahydro-pyran-2-yl)-2H-pyridazin-3-one (Intermediate 18, step 2) and 2-chloro-4-trifluoromethoxy-phenol afforded 5-(2-chloro-4-trifluoromethoxy-phenoxy)-2H-pyridazin-3-one which was then reacted in an analogous manner to that outlined in the synthesis of Intermediate 19 (steps 4 and 5) alkylating with 2-bromo-3-cyclohexyl-propionic acid methyl ester (Intermediate 12) afforded 2-[4-(2-chloro-4-trifluoromethoxy-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-cyclohexyl-propionic acid as a white solid (190 mg, 72% for the final step); ES+-HRMS m/e calcd for C20H20N2O5F3Cl [M+H+] 461.1086, found 461.1085. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.74-1.28 (m, 5H), 1.35-1.80 (m, 6H), 1.80-1.96 (m, 1H), 1.98-2.11 (m, 1H), 5.40 (dd, J=10.9, 4.2 Hz, 1H), 5.95 (d, J=2.7 Hz, 1H), 7.54 (dd, J=9.0, 2.0 Hz, 1H), 7.68 (d, J=9.0 Hz, 1H), 7.87 (d, J=2.0 Hz, 1H), 8.21 (d, J=2.7 Hz, 1H), 13.03 (br. s., 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C@@H:16]([N:18]2[CH2:23][CH2:22][C@H:21]([O:24]C(=O)C(C)(C)C)[C@@H:20]([CH3:31])[CH2:19]2)[CH3:17])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+]>>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C@@H:16]([N:18]2[CH2:23][CH2:22][C@H:21]([OH:24])[C@@H:20]([CH3:31])[CH2:19]2)[CH3:17])[CH2:11][CH2:10]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H]1CN([C@@H](C)CN2CCC(NC(=O)OC(C)(C)C)CC2)CC[C@@H]1OC(=O)C(C)(C)C
Agent: C[O-]
Agent: [Na+]
Product: C[C@H]1CN([C@@H](C)CN2CCC(NC(=O)OC(C)(C)C)CC2)CC[C@@H]1O

Procedure:
Ester 58 from above (1.7 g, 3.52 mmol) is treated with NaOMe (0.5M in methanol, 21 ml, 10.5 mmol) and heated under reflux for 24 hours. The solvent is then evaporated, the residue taken up in DCM and extracted with 1N—NaOH and brine. After drying and evaporation the crued is purified by chromatography on silicagel using DCM (saturated with ammonia) and MeOH (from 1% to 3%) to give a white powder.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([OH:13])=[O:12])[CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[CH3:15]O>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH3:15])=[O:12])[CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccc2cccnc2c1
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc2cccnc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of quinoline-7-carboxylic acid (1.00 g, 5.77 mmol) in MeOH (10 mL) was added hydrogen chloride (2.00 mL, 8.00 mmol) (4.0M in 1,4-dioxane). The reaction was stirred for 18 h at rt (LCMS showed <10% conversion to the desired product). Additional hydrogen chloride (2.00 mL, 8.00 mmol) was added, and the reaction mixture was heated to 50° C. in an oil bath for 36 h. The reaction was cooled to rt, and concentrated in vacuo. The solid was dissolved in DCM, and washed with saturated aqueous NaHCO3 (2×50 mL). The organic layer was dried (MgSO4) and concentrated to give the product, which was used without further purification in the next step.
Reaction SMILES: [H-].[Na+].[O-:3][CH2:4][CH3:5].[Na+].[Cl:7][C:8]1[C:9]([C:40]([NH2:42])=[O:41])=[N:10][CH:11]=[CH:12][C:13]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]2[C:25](=[O:38])[N:26]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH:27]=[CH:28][C:29]=2I)=[O:23])=[CH:17][C:16]=1[F:39].ClC1C(C(N)=O)=NC=CC=1OC1C=CC(NC(C2C(=O)N(C3C=CC(F)=CC=3)C=CC=2Cl)=O)=CC=1F>C1COCC1.C(O)C>[Cl:7][C:8]1[C:9]([C:40]([NH2:42])=[O:41])=[N:10][CH:11]=[CH:12][C:13]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]2[C:25](=[O:38])[N:26]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH:27]=[CH:28][C:29]=2[O:3][CH2:4][CH3:5])=[O:23])=[CH:17][C:16]=1[F:39]
Reactant: CC[O-]
Reactant: NC(=O)c1nccc(Oc2ccc(NC(=O)c3c(I)ccn(-c4ccc(F)cc4)c3=O)cc2F)c1Cl
Agent: NC(=O)c1nccc(Oc2ccc(NC(=O)c3c(Cl)ccn(-c4ccc(F)cc4)c3=O)cc2F)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1ccc(Oc2ccnc(C(N)=O)c2Cl)c(F)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 88 %

Procedure:
Sodium hydride (1.89 g, 47.2 mmol, 60% dispersion in mineral oil, Aldrich) was added slowly to a solution of ethanol (77 mL, Aldrich >99.5% 200 proof) and THF (77 mL) under N2 and the resulting mixture was stirred at rt for 5 min. The sodium ethoxide solution was then added to a mixture of 3-chloro-4-(2-fluoro-4-(1-(4-fluorophenyl)-4-iodo-2-oxo-1,2-dihydropyridine-3-carboxamido)phenoxy)-picolinamide and 3-chloro-4-(4-(4-chloro-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamido)-2-fluorophenoxy)picolinamide (22.6 g, ˜36.3 mmol) and stirred for 1 h at rt. The reaction mixture was concentrated in vacuo. The resulting crude solid was suspended in ethyl acetate, saturated aqueous sodium bicarbonate solution, and water (to dissolve any precipitated salts). This mixture was sonicated and stirred until the remaining solid became a filterable powder. This powder was filtered off to yield 17.2 g (88%) of the desired product as a pale yellow solid. The layers of the remaining filtrate were separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting solid was triturated with ethyl acetate, sonicated, and filtered to give an additional 3.02 g of the desired product as a pale brown solid. 1H NMR (CD3OD) δ 8.34 (d, 1H, J=5.6 Hz), 7.94 (dd, 1H, J=12.4, 2.4 Hz), 7.80 (d, 1H, J=8 Hz), 7.48-7.46 (m, 3H), 7.31-7.28 (m, 3H), 6.86 (d, 1H, J=5.6 Hz), 6.61 (d, 1H, J=7.2 Hz), 4.34 (q, 2H, J=7.2 Hz), 1.45 (t, 3H, J=7.2 Hz); MS (ESI+) m/z 541.11 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1(Cl)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](Cl)=[CH:3]1.CC(=[O:16])C>O>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:16])[CH:3]=1
Reactant: ClC1=CC(Cl)(Cl)c2ccccc21
Reactant: CC(C)=O
Solvent: O
Product: O=C1C=C(Cl)c2ccccc21

Procedure:
A mixture of 35 parts of 1,1,3-trichloro-1H-indene, 295 parts of 2-propanone, and 375 parts of water is heated at the boiling point under reflux in a nitrogen atmosphere overnight. The resultant dark brown solution is stripped of solvent by vacuum distillation under nitrogen at 35°. The distilland is extracted with 1,1'-oxybisethane. The extract is consecutively washed with water, 10% sodium chloride, and water, then dried over anhydrous magnesium sulfate and thereupon stripped of solvent by vacuum distillation. The oily residue is crystallized from pentane to give 3-chloro-1H-inden-1-one as a red-orange solid, the formula of which is ##STR4##
Reaction SMILES: [CH2:1]([S:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[CH2:17][CH2:16]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:24]O>>[CH2:1]([S:8]([CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[CH2:17][CH2:16]2)=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OO
Reactant: O=C1CCc2cc(OCCCSCc3ccccc3)ccc2N1
Product: O=C1CCc2cc(OCCCS(=O)Cc3ccccc3)ccc2N1

Procedure:
Prepared analogous to Example 123 from 6-(3-benzylmercapto-propoxy)-3,4-dihydro-carbostyril and hydrogen peroxide.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6](=O)[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=1)C.O.[NH2:20][NH2:21]>C(O)C>[CH3:16][O:15][C:9]1[CH:8]=[C:7]([C:6]2[CH2:5][C:4](=[O:3])[NH:21][N:20]=2)[CH:12]=[CH:11][C:10]=1[O:13][CH3:14]
Reactant: CCOC(=O)CC(=O)c1ccc(OC)c(OC)c1
Reactant: NN
Solvent: O
Solvent: CCO
Product: COc1ccc(C2=NNC(=O)C2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.1 %

Procedure:
To a solution of ethyl-3,4-dimethoxybenzoylacetate (1 g, 4 mmol), (Heterocycles 1979, 13, 239), in ethanol (5 ml) containing hydrazine hydrate (192 μl, 4 mmol) was stirred for 30 minutes at ambient temperature followed by 40 minutes being heated at reflux. After cooling at ambient temperature, the mixture was concentrated to half the volume and ether (10 ml) was added. After trituration, the solid was collected by filtration, washed with ether and dried under vacuum to give 3-(3,4-dimethoxyphenyl)-4,5-dihydro-1H-pyrazol-5-one (521 mg, 60%).
Reaction SMILES: [CH3:1][C:2]([NH2:13])([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([CH3:12])=[CH2:11])[CH:5]=1)[CH3:3]>C(O)C.[Pt]=O>[CH3:3][C:2]([NH2:13])([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:11])[CH3:12])[CH:5]=1)[CH3:1]
Reactant: C=C(C)c1cccc(C(C)(C)N)c1
Agent: O=[Pt]
Solvent: CCO
Product: CC(C)c1cccc(C(C)(C)N)c1
Reaction time: 7 h
Yield: 97.7 %

Procedure:
First, 0.5 g of platinum oxide was added to a solution formed by dissolving 25.3 g of 1-methyl-1-[3-(1-methylethenyl)phenyl]ethylamine in 100 ml of ethyl alcohol, and a hydrogenation reaction was then carried out at a temperature of 15° to 35° C. for 7 hours under atmospheric pressure under a hydrogen gas stream. Afterward, reaction residues were removed by filtration, and the resultant filtrate was then concentrated to obtain 25.0 g of 1-methyl-1-[3-(1-methylethyl)phenyl]ethylamine.
Reaction SMILES: [Cl-].[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH3+:10])=[CH:5][CH:4]=1.[OH-].[Na+].Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>O1CCCC1.O.[Cl-].[Na+].O>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:14](=[O:15])[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:5][CH:4]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: [NH3+]Cc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(NCc1ccc(Br)cc1)OCc1ccccc1
Reaction time: 1 h
Yield: 102.9 %

Procedure:
In a 500 mL round bottomed flask, equipped with a magnetic stir bar, (4-bromophenyl)methanaminium chloride (10.0 g, 44.9 mmol) and sodium hydroxide (4.00 g, 100 mmol) were dissolved in tetrahydrofuran (80 mL) and water (80 mL). The solution was cooled in an ice water bath, and benzyl chloroformate (7.06 mL, 49.4 mmol) was added dropwise. The reaction was allowed to stir for 1 hour. The reaction was poured into a brine solution and extracted with ethyl acetate (2×200 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated to afford the title compound as a white solid (14.8 g, 102%): 1H NMR (400 MHz, DMSO-d6) δ 7.92 (t, J=6.0 Hz, 1H), 7.64-7.53 (m, 2H), 7.47-7.33 (m, 5H), 7.32-7.20 (m, 2H), 5.10 (s, 2H), 4.23 (d, J=6.2 Hz, 2H); 13C NMR (101 MHz, DMSO-d6) δ 156.33, 139.20, 137.05, 131.10, 129.22, 128.33, 127.72, 119.77, 65.42, 43.19; ESIMS m/z 320, 322 ([M+H]+).
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[C:51]([C:58]5[CH:59]=[N:60][N:61]([CH3:64])[C:62]=5[CH3:63])[CH:52]=[CH:53][CH:54]=4)[O:49][C:48]=3[C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C.C(O)(C(F)(F)F)=O.[ClH:79]>CO.O>[ClH:79].[NH2:36][C:37]1([C:41]2[CH:42]=[CH:43][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[C:51]([C:58]5[CH:59]=[N:60][N:61]([CH3:64])[C:62]=5[CH3:63])[CH:52]=[CH:53][CH:54]=4)[O:49][C:48]=3[C:65]3[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=3)=[CH:45][CH:46]=2)[CH2:38][CH2:39][CH2:40]1
Reactant: Cc1c(-c2cccc3c(=O)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(-c4ccccc4)oc23)cnn1C
Agent: Cl
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Solvent: CO
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(-c2cccc3c(=O)c(-c4ccc(C5(N)CCC5)cc4)c(-c4ccccc4)oc23)cnn1C
Yield: 65 %

Procedure:
Following the procedure of 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, (1-{4-[8-(1,5-dimethyl-1H-pyrazol-4-yl)-4-oxo-2-phenyl-4H-chromen-3-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester was treated with TFA. The resultant free base was dissolved in a mixture of MeOH (7 mL), water (7 mL) and 1 M HCl (0.6 mL) and chromatographed on a 5 g C18 cartridge {gradient 10 to 50% MeOH in water+1 M HCl (60 μL in each 10 mL of eluent)} to give the title compound as a white solid (23 mg, 65%). 1H NMR (400 MHz, DMSO-d6): δ 8.61 (s, 3H), 8.01 (dd, J=7.9 and 1.7 Hz, 1H), 7.71 (dd, J=7.3 and 1.6 Hz, 1H), 7.67 (s, 1H), 7.53 (t, J=7.6 Hz, 1H), 7.42 (d, J=8.4 Hz, 2H), 7.37-7.22 (m, 7H), 3.74 (s, 3H), 2.57-2.43 (m, 4H), 2.22 (s, 3H), 2.19-2.05 (m, 1H), 1.81-1.69 (m, 1H). LCMS (Method E): RT=3.29 min, [M+H]+=462.