Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9](O)[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[N:7]=1)=[O:5])[CH3:2].P(Br)(Br)([Br:21])=O.CN(C)[CH:26]=[O:27].ClCCl>ClCCCl>[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH:26]=[O:27])=[C:9]([Br:21])[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[N:7]=1)=[O:5])[CH3:2]
Reactant: CN(C)C=O
Reactant: O=P(Br)(Br)Br
Reactant: CCOC(=O)c1cc(O)n(-c2ccccc2Cl)n1
Solvent: ClCCCl
Solvent: ClCCl
Product: CCOC(=O)c1nn(-c2ccccc2Cl)c(Br)c1C=O
Temperature: 0 °C
Reaction time: 20 h

Procedure:
To a stirred solution of 1-(2-chloro-phenyl)-5-hydroxy-1H-pyrazole-3-carboxylic acid ethyl ester I-1a (18.2 g) and phosphorus oxybromide (39 g) in 1,2-dichloroethane (200 ml) was added dimethylformamide (10.5 ml) over a 15-min period. The resulting mixture was heated at reflux for 3 hours, cooled, then an additional portion of phosphorus oxybromide (98 g) was added and refluxing was continued for 20 hours. The black reaction mixture was cooled, poured over ice (150 g) and stirred for 30 minutes. The mixture was extracted with dichloromethane (2×), the combined organic layers dried over magnesium sulfate and concentrated in vacuo to afford a dark oil. The oil was passed through a 200 g plug of silica gel, elueting with 30% hexanes:dichloromethane to afford the title compound (I-1b) as a yellow solid, 8.3 g.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][CH2:4][CH:5]([NH:8][CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10])[C:6]#[N:7].[OH:19]S(O)(=O)=O.[NH4+].[OH-].C(Cl)[Cl:27]>>[ClH:27].[F:1][C:2]([F:17])([F:18])[CH2:3][CH2:4][C@@H:5]([NH:8][C@@H:9]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH3:10])[C:6]([NH2:7])=[O:19]
Reactant: ClCCl
Reactant: O=S(=O)(O)O
Reactant: CC(NC(C#N)CCC(F)(F)F)c1ccccc1
Agent: [NH4+]
Agent: [OH-]
Product: C[C@@H](N[C@H](CCC(F)(F)F)C(N)=O)c1ccccc1
Product: Cl
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a solution of 5,5,5-trifluoro-2-(1-phenylethylamino)pentanenitrile (18.0 g, 70.31 mmol, 4:1 mixture of diastereomers) in CH2Cl2 (100 mL) was added H2SO4 (100 mL). The reaction was stirred at room temperature for 22 h, poured onto crushed ice and neutralized with NH4OH. The mixture was extracted with EtOAc (3×500 mL). The combined organic layer was dried over Na2SO4 and concentrated under vacuum to provide the free base of the title compound as a mixture of diastereomers (18.94 g, 98%) as an orange oil: 1H NMR (300 MHz, CDCl3) δ 7.40-7.18 (m, 5H), 6.78 (br s, 0.23H), 6.50 (br s, 0.77H), 6.00 (br s, 0.77H), 5.81 (br s, 0.23H), 3.82 (q, J=6.5 Hz, 0.23H), 3.70 (q, J=6.5 Hz, 0.77H), 3.14 (t, J=6.0 Hz, 0.23H), 2.86 (t, J=7.0 Hz, 0.77H), 2.35-1.86 (m, 2H), 1.84-1.64 (m, 2H), 1.39 (d, J=6.5 Hz, 0.69H), 1.35 (d, J=6.5 Hz, 2.31H); ESI MS m/z 275 [C13H17F3N2O+H].
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:17]([OH:45])([C:21]3[N:22]=[CH:23][N:24](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:25]=3)[CH:18]([CH3:20])[CH3:19])[CH:13]=2)[C:8]=1[C:46]([NH:48][CH3:49])=[O:47])(=O)=O.C(O)=O.C(N(CCCC)CCCC)CCC.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:45][C:17]([C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:46]([NH:48][CH3:49])=[O:47])=[CH:7][CH:16]=[CH:15]2)([C:21]1[N:22]=[CH:23][NH:24][CH:25]=1)[CH:18]([CH3:20])[CH3:19]
Reactant: CNC(=O)c1c(OS(=O)(=O)C(F)(F)F)ccc2cc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)ccc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: O=CO
Solvent: CN(C)C=O
Solvent: CCCCN(CCCC)CCCC
Product: CNC(=O)c1cccc2cc(C(O)(c3c[nH]cn3)C(C)C)ccc12
Temperature: 80 °C
Yield: 121.1 %

Procedure:
A mixture of 6-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]-1-(methylaminocarbonyl)-2-naphthyl trifluoromethanesulfonate (700 mg), formic acid (0.1 mL), tributylamine (1.0 mL), dichlorobis(triphenylphosphine)palladium (70 mg), and 1,3-bis-(diphenylphosphino)propane (103 mg) in anhydrous DMF (5 mL) was heated at 80° C. for 4 h. After dilution with water, the yellow precipitate was filtered and washed with water. The precipitate was purified by flash column chromatography on silica gel (hexane:AcOEt=3:2→1:1) to give the title compound (384 mg) as a colorless amorphous powder.
Reaction SMILES: [OH:1][CH:2]([CH2:10][OH:11])[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[CH2:12]([O:14][C:15]([C:17]1[CH:22]=[CH:21][N:20]=[N:19][C:18]=1Cl)=[O:16])[CH3:13]>O1CCOCC1>[CH2:12]([O:14][C:15]([C:17]1[CH:22]=[CH:21][N:20]=[N:19][C:18]=1[N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH:2]([OH:1])[CH2:10][OH:11])[CH2:5][CH2:6]1)=[O:16])[CH3:13]
Reactant: OCC(O)CN1CCNCC1
Reactant: CCOC(=O)c1ccnnc1Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1ccnnc1N1CCN(CC(O)CO)CC1

Procedure:
Grams 10.2 of 1-(2,3-dihydroxypropyl)piperazine and 5.9 g of 3-chloropyridazine-4-carboxylic acid ethyl ester in 100 ml dioxane were refluxed for one hour. Then it was settled, the solvent evaporated till dryness, and the residue dissolved in chloroform and washed with a small amount of water. The organic phase was made anhydrous, evaporated to dryness and the residue, purified on a column eluting with chloroform:methanol (9:1), gave 2.4 g of 3-[4-(2,3-dihydroxypropyl)piperazin-1-yl]pyridazine-4-carboxylic acid ethyl ester as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2=[O:13])=[CH:5][CH:4]=1.C(O[CH:17](OCC)[N:18]([CH3:20])[CH3:19])C>>[CH3:17][N:18]([CH:20]=[C:9]1[CH2:8][CH2:7][C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:10]1=[O:13])[CH3:19]
Reactant: CCOC(OCC)N(C)C
Reactant: COc1ccc2c(c1)C(=O)CCC2
Product: COc1ccc2c(c1)C(=O)C(=CN(C)C)CC2

Procedure:
The 3,4-dihydro-2-(dimethylaminomethylene)-7-methoxy-1(2H)-naphthalenone starting material was prepared from 7-methoxy-1-tetralone (5.0 g, 28.4 mmol) and N,N-dimethylformamide diethyl acetal (10 ml, 58.3 mmol) ito give the desired product as a yellow solid (1.28 g). m.p. 95.1°. MS (ES+) 232 (MH+, 100%).
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)(=O)=O.[N:19]1[C:27]2[N:22]3[C:23](=[N:28][CH:29]=[C:21]3[C:20]=1[SH:30])[CH:24]=[CH:25][CH:26]=2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[N:19]1[C:27]2[N:22]3[C:23](=[N:28][CH:29]=[C:21]3[C:20]=1[S:30][CH:6]1[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:10][CH2:11]1)[CH:24]=[CH:25][CH:26]=2
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: Sc1nc2cccc3ncc1n32
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Sc2nc3cccc4ncc2n43)CC1
Yield: 56 %

Procedure:
To a solution of tert-butyl 4-[(methylsulfonyl)oxy]-1-piperidinecarboxylate (3.5 g, 12.5 mmol) in DMF (60 ml) were added 1,4,7b-triazacyclopenta[cd]inden-2-thiol (3.7 g, 21.3 mmol). and DBU (3.7 ml, 25 mmol), and the mixture was stirred at 80° C. for 11 hours. The reaction mixture was concentrated under reduced pressure, and to the concentrate was added water (200 ml). The mixture was extracted with a mixed solution of THF and ethyl acetate (3/2, 500 ml). The organic layer was washed with saturated aqueous solution of sodium chloride (200 ml), successively, and dried over anhydrous sodium sulfate, concentrated under reduced pressure. The concentrate was subjected to flash column chromatography (silica gel 30 g,: ethyl acetate/hexane=1/2 to 1/0), and the desired fraction was concentrated under reduced pressure. To the concentrate was added diisopropyl ether and the precipitates were collected by filtration to give the titled compound (2.5 g, 7 mmol) as yellowish powdery crystals.
Reaction SMILES: [C:1]([C:5]1[CH:18]=[C:17]([CH3:19])[C:8]([CH2:9][CH:10](C(O)=O)[C:11]([OH:13])=[O:12])=[C:7]([CH3:20])[C:6]=1[OH:21])([CH3:4])([CH3:3])[CH3:2].C(=O)=O.C(=O)(O)[O-].[Na+]>O.CCCCCC>[C:1]([C:5]1[CH:18]=[C:17]([CH3:19])[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[C:7]([CH3:20])[C:6]=1[OH:21])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C)c1CC(C(=O)O)C(=O)O
Agent: O=C([O-])O
Agent: O=C=O
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Product: Cc1cc(C(C)(C)C)c(O)c(C)c1CCC(=O)O

Procedure:
17.9 grams of the compound of Example 16 was stirred together with white oil at 165° to 180° for 2 hours until little CO2 evolution could be detected. The reaction mixture was cooled to 50° and stirred thoroughly together with 5.2 grams of sodium bicarbonate dissolved in 100 ml of water until no foaming took place and all solids had dissolved. The reaction mixture was diluted with 50 ml of n-hexane and the upper organic phase separated from the lower aqueous phase. The organic phase was washed with water, the wash water being combined with the aqueous phase. The combined aqueous phase was then washed with n-hexane, clarified by filtration through filtercel, and added dropwise to about 150 ml of cold 6N aqueous hydrochloric acid so that a granular off-white precipitate was obtained. The produce was used as such after drying in the vacuum oven at 60° and 3mm Hg. overnight.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[N:10]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:8]([C:7]1[C:2]([N:13]2[CH2:12][CH2:11][N:10]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]2)=[N:3][CH:4]=[CH:5][CH:6]=1)#[N:9]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: N#Cc1cccnc1Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ncccc2C#N)CC1

Procedure:
A mixture of 2-chloro-3-cyanopyridine (15.2 g, 0.11 mol), tert-butyl 1-piperazinecarboxylate (25 g, 0.13 mol) and triethylamine (18 ml, 0.13 mol) in toluene (200 ml), was heated under reflux for 24 hours. The cooled mixture was concentrated under reduced pressure and the residue suspended in ethyl acetate (250 ml), and washed with water (3×). The organic solution was dried (MgSO4), and concentrated under reduced pressure. The residue was triturated with pentane, filtered and dried in vacuo, at 60° C., to afford the title compound as a cream coloured solid, 24.2 g.
Reaction SMILES: [Cl:1][CH:2]1[N:11]=[C:10](Cl)[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[NH:3]1.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([NH:19][CH3:20])=[CH:17][CH:16]=1.Cl>C(O)(C)C>[Cl:1][C:2]1[N:11]=[C:10]([N:19]([C:18]2[CH:21]=[CH:22][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)[CH3:20])[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: CNc1ccc(OC)cc1
Reactant: ClC1=NC(Cl)NC2=C1CCCC2
Agent: Cl
Solvent: CC(C)O
Product: COc1ccc(N(C)c2nc(Cl)nc3c2CCCC3)cc1
Yield: 50 %

Procedure:
A mixture of 2-methoxylcarbonyl cyclohexanone 5.00 g (455 mmol) and urea 6.00 g (100.0 mmol) with 2 mL of ethanol was stirred for 48 h under reflux. After cooling, the formed crude product was washed with water and dried in vacuo to give ca.4 g of 5,6,7,8-tetrahydro-1H-quinazoline-2,4-dione. A mixture of 5,6,7,8-tetrahydro-1H-quinazoline-2,4-dione 2.00 g (12.0 mmol) and POCl3 10 mL was stirred under reflux for 3 h. After cooling, excess of POCl3 was removed under reduced pressure, and the crude product was diluted with CHCl3, which was poured into ice-water, washed with water, and dried on anhydrous MgSO4. Removal of CHCl3 gave 2,4-dichloro-5,6,7,8-tetrahydro-1H-quinazoline in 95% yield. A solution of 2,4-dichloro-5,6,7,8-tetrahydro-1H-quinazoline 0.615 g (3.0 mmol) and 4-methoxy-N-methylaniline 0.411 g (1.0 mmol) with conc. HCl 0.5 mL in iso-propanol 30 mL was stirred at 23° C. for 16 h. The solution was concentrated under reduced pressure, diluted with CH2Cl2 30 mL, washed with sat. Na2CO3 aqueous solution, and dried on anhydrous MgSO4. After removal of solvents, the crude product was purified with gradient column chromatography (EtOAc/hexanes, 0% to 60%) to give titled product in 50% yield, which was further purified with preparative HPLC to give the corresponding TFA salt. 1H NMR (CDCl3, 400 MHz): δ 7.02 (d, 2H, J=9.0 Hz), 6.86 (d, 2H, J=9.0 Hz), 3.83 (s, 3H), 3.40 (s, 3H), 2.73 (t, 2H, J=6.7 Hz), 1.62-1.68 (m, 4H), 1.44-1.49 (m, 2H). m/z: 304.1236 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9](Cl)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[CH:28]([NH2:30])[CH3:29].C(N(CC)CC)C>>[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[CH:28]([NH:30][S:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:11])=[O:10])[CH3:29]
Reactant: CC(N)c1ccc(F)cc1-c1ccc(F)cc1F
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Solvent: CCN(CC)CC
Product: COc1cccc(S(=O)(=O)NC(C)c2ccc(F)cc2-c2ccc(F)cc2F)c1
Yield: 83.2 %

Procedure:
The title compound was prepared from 3-methoxybenzenesulfonyl chloride (146 mg, 0.7 mmol), 1-(-2′,4′,5-trifluoro-1,1′-biphenyl-2-yl)ethylamine (169 mg, 0.67 mmol), and triethylamine (187 μL, 1.3 mmol) according to the procedure and in the same manner as described in Example 105, step c. The product was purified by preparative liquid chromatography on a Biotage® 40 Mi column of prepacked silica gel (90 g), eluting with a gradient of 30%-50% methyl tert-butyl ether in hexane (35 min), to afford the desired compound (235 mg, 83%) as a white solid;
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1)=[O:5].[CH3:25][Mg]Br.CCOCC>O1CCCC1>[C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:22])[CH3:20])[CH2:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1)(=[O:5])[CH3:25]
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1ccc(C2(NC(=O)OC(C)(C)C)CCC2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)c1ccc(C2(NC(=O)OC(C)(C)C)CCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl (1-(4-(methoxy(methyl)carbamoyl)phenyl)cyclobutyl)carbamate (0.5 g, 1 eq.) in tetrahydrofuran (THF) (5 mL) cooled to 0° C. was slowly added a 1 M solution of methylmagnesium bromide in ether (4.5 mL, 3 eq.). The reaction mixture was stirred at room temperature overnight then quenched by the addition of saturated aqueous ammonium chloride (15 mL). The mixture was extracted with dichloromethane (2×25 mL). The combined extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was purified by column chromatography (15% ethyl acetate in dichloromethane), giving tert-butyl (1-(4-acetylphenyl)cyclobutyl)carbamate as a colorless oil which solidified upon standing (261 mg, 60%). 1H NMR (DMSO-d6) 400 MHz δ 7.91 (d, J=8.0 Hz, 2H), 7.74 (br. s, 1 H), 7.50 (d, J=8.4 Hz, 2H), 2.56 (s, 3H), 2.45-2.32 (m, 4H), 2.06-1.94 (m, 1H), 1.86-1.75 (m, 1H), 1.33 (s, 9H).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[NH:4][C:3]1=[O:14].O=[C:16]1N(C(OCC2C=CC=CC=2)=O)[C@H](C(O)=O)CN1.CI.[H-].[Na+]>CN(C)C=O>[CH3:1][N:2]1[CH2:6][CH:5]([C:7]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:8])[N:4]([CH3:16])[C:3]1=[O:14]
Reactant: CN1CC(C(=O)OC(C)(C)C)NC1=O
Reactant: O=C(O)[C@@H]1CNC(=O)N1C(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1CC(C(=O)OC(C)(C)C)N(C)C1=O
Temperature: -10 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
A stirred solution of 1,1-dimethylethyl 1-methyl-2-oxo-4-imidazolidinecarboxylate (1.75 g, 8.74 mmol) (prepared as described in step (i) of Example 49 from 5-(1,1-dimethylethyl)1-(phenylmethyl)3-methyl-2-oxo-1,5-imidazolidinedicarboxylate, itself prepared as described in step (ii) of Example 13, starting originally from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) in N,N-dimethylformamide (22 ml) was cooled to −10° C. under argon, and then the methyl iodide (2.186 ml, 35.0 mmol) was added. Sodium hydride (60% dispersion in oil) (0.329 g, 8.22 mmol) was then added portion wise. The reaction mixture was allowed to warm to RT while stirring under argon overnight. The solvent was evaporated in vacuo and then the residue partitioned between ethyl acetate (40 ml) and brine (30 ml). The aqueous layer was re-extracted with ethyl acetate (×2) and then the combined organic extracts were washed with water (×2, 50 ml), brine (50 ml) and dried over magnesium sulphate. The solvent was evaporated in vacuo. The crude product was purified by flash-silica gel chromatography, eluting with 25-100% ethyl acetate/iso-hexane. The fractions containing product were combined and solvent evaporated in vacuo to give a yellow oil, 1,1-dimethylethyl 1,3-dimethyl-2-oxo-4-imidazolidinecarboxylate (1.48 g, 79% yield). (ii) A solution of 1,1-dimethylethyl 1,3-dimethyl-2-oxo-4-imidazolidinecarboxylate (1.92 g, 8.96 mmol) in dichloromethane (12 ml)/trifluoroacetic acid (6.00 ml) was stirred at room temperature for 24 hours. The solution was evaporated and the residue was co-evaporated with toluene (×3) and then dichloromethane (×2). The product was then dried to give crude 1,3-dimethyl-2-oxo-4-imidazolidinecarboxylic acid (1.65 g) which was dissolved in dichloromethane (90 ml) to give a ˜0.1M solution in dichloromethane which was used in subsequent reactions. LC/MS [M+H]+=159.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[F:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)=[CH:4][CH:3]=1.[Br:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[CH2:31][NH:30][CH2:29]2>CN(C=O)C>[Br:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[CH2:31][N:30]([C:15]1[C:16]([F:18])=[C:17]3[C:12]([C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9][N:8]3[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:13][C:14]=1[F:20])[CH2:29]2
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)c2c(F)c(F)c(F)cc2c1=O
Reactant: Brc1ccc2c(c1)CNC2
Solvent: CN(C)C=O
Product: O=C(O)c1cn(-c2ccc(F)cc2)c2c(F)c(N3Cc4ccc(Br)cc4C3)c(F)cc2c1=O
Yield: 55.4 %

Procedure:
170 mg of 1-(4-fluorophenyl)-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 300 mg of 5- bromoisoindoline, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 144 mg of the target compound.
Reaction SMILES: [OH-:1].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[N:13]=[C:12]3[CH:24]=[O:25])[CH:4]=1>O.O1CCOCC1.[N+]([O-])([O-])=O.[Ag+]>[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[N:13]=[C:12]3[C:24]([OH:1])=[O:25])[CH:4]=1
Reactant: O=Cc1nn(C2CCCCO2)c2ccc(-c3cccnc3)cc12
Reactant: [OH-]
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1nn(C2CCCCO2)c2ccc(-c3cccnc3)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.5 %

Procedure:
To a solution of silver nitrate (0.55 g, 3.25 mmol) in water (10 mL) was added a solution of sodium hydroxide (0.26 g, 6.50 mmol) in water (5 mL) to give a brown precipitate. 5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde (CXXXII) (0.40 g, 1.30 mmol) dissolved in 1,4-dioxane (3 mL) was added to the reaction which was stirred at room temperature for 2 h. The reaction was then extracted with diethyl ether. The aqueous layer was separated and carefully brought to pH=3 with 10% aqueous HCl. The aqueous layer was then extracted five times with iPrOH/chloroform (1/9). The combined organic layers were then dried (MgSO4) and concentrated to afford 5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxylic acid (CXXXIII) (0.30 g, 0.93 mmol, 70% yield) as a white solid. 1H NMR (DMSO-d6) δ ppm 13.28 (br, 1H), 8.93 (s, 1H), 8.60 (d, J=4.1 Hz, 1H), 8.32 (d, J=0.83 Hz, 1H), 8.14-8.12 (m, 1H), 8.00 (d, J=8.8 Hz, 1H), 7.86 (dd, J=8.8, 1.7 Hz, 1H), 7.52 (dd, J=7.8, 4.7 Hz, 1H), 6.04 (dd, J=9.3, 2.3 Hz, 1H), 3.92-3.90 (m, 1H), 3.83-3.78 (m, 1H), 2.44-2.37 (m, 1H), 2.08-2.02 (m, 2H), 1.79-1.76 (m, 1H), 1.63-1.61 (m, 2H).
Reaction SMILES: [CH:1]1([CH:4]([OH:16])[C:5]2[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=2[OH:15])[C:8]([O:10][CH3:11])=[O:9])[CH2:3][CH2:2]1>[O-2].[Mn+4].[O-2].O1CCOCC1>[CH:1]1([C:4]([C:5]2[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=2[OH:15])[C:8]([O:10][CH3:11])=[O:9])=[O:16])[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(O)c(C(O)C2CC2)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(O)c(C(=O)C2CC2)c1

Procedure:
To a flask with methyl 3-(cyclopropyl(hydroxy)methyl)-4-hydroxybenzoate (T20.2) (845 mg, 0.38 mmol) was added manganese (IV) oxide (1.65 g, 1.9 mmol). Then dioxane 3.5 mL was added and the reaction was heated at reflux for 4 hours. The reaction was filtered and concentrated and silica gel chromatography afforded 693 mg of T20.3 (83%).
Reaction SMILES: C(OC([N:8]([CH2:29][CH:30]1[CH2:32][CH2:31]1)/[N:9]=[C:10](\[S:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])/[C:11]([O:13][CH2:14][CH3:15])=[O:12])=O)(C)(C)C.Cl.C(=O)([O-])O.[Na+]>O1CCOCC1>[CH:30]1([CH2:29][NH:8]/[N:9]=[C:10](/[S:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])\[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:32][CH2:31]1.[CH:30]1([CH2:29][NH:8]/[N:9]=[C:10](\[S:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:32][CH2:31]1
Reactant: CCCCCCCCCCCCS/C(=N\N(CC1CC1)C(=O)OC(C)(C)C)C(=O)OCC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CCCCCCCCCCCCS/C(=N/NCC1CC1)C(=O)OCC
Product: CCCCCCCCCCCCS/C(=N\NCC1CC1)C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 17 %
Yield: 16 %

Procedure:
To a solution of Z-ethyl 2-(2-t-butoxycarbonyl-2-(cyclopropylmethyl)hydrazono)-2-(dodecylthio)acetate (10.0 g, 21.3 mmol) in dioxane (10 ml) was added a 4M solution of hydrogen chloride in dioxane (10 ml), and stirred at room temperature for 2 hours. The reaction solution was added to saturated aqueous sodium hydrogen carbonate solution, and extracted with tert-butyl methyl ether 2 times. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 1.26 g of E-ethyl 2-(2-(cyclopropylmethyl)hydrazono)-2-(dodecylthio)acetate (yield: 16%) and 1.34 g of Z-ethyl 2-(2-(cyclopropylmethyl)hydrazono)-2-(dodecylthio)acetate (yield: 17%).
Reaction SMILES: [CH2:1]([N:5]1[C:9]2=[C:10](Cl)[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH3:15])=[C:6]1[CH3:16])[CH:2]=[CH:3][CH3:4].[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[CH2:25][SH:26]>>[CH2:1]([N:5]1[C:9]2=[C:10]([S:26][CH2:25][C:19]3[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:18]=3[Cl:17])[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH3:15])=[C:6]1[CH3:16])[CH:2]=[CH:3][CH3:4]
Reactant: CC=CCn1c(C)c(C)c2cnnc(Cl)c21
Reactant: SCc1ccc(Cl)cc1Cl
Product: CC=CCn1c(C)c(C)c2cnnc(SCc3ccc(Cl)cc3Cl)c21
Yield: 63.2 %

Procedure:
The title compound (cis/trans=16:84) was prepared as pale brown crystals in 63.2% yield in a similar procedure to that described in Example 1 by using 1-(2-butenyl)-7-chloro-2,3-dimethylpyrrolo[2,3-d]pyridazine (cis/trans=22/78) and 2,4-dichlorophenylmethanethiol.