Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:29])[CH:10]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[C:20]([Cl:28])[CH:19]=2)[CH2:11][CH:12]2[CH2:16][CH2:15][C:14](=O)[CH2:13]2)=[N:6][CH:7]=1.Cl.[CH3:31][O:32][NH2:33]>CO.N1C=CC=CC=1>[Br:1][C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:29])[CH:10]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:25])=[O:26])=[C:20]([Cl:28])[CH:19]=2)[CH2:11][CH:12]2[CH2:16][CH2:15][C:14](=[N:33][O:32][CH3:31])[CH2:13]2)=[N:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCC(=O)C2)C(=O)Nc2cnc(Br)cn2)cc1Cl
Reactant: CON
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CON=C1CCC(CC(C(=O)Nc2cnc(Br)cn2)c2ccc(S(C)(=O)=O)c(Cl)c2)C1
Temperature: 25 °C
Yield: 30.4 %

Procedure:
A solution of N-(5-bromo-pyrazin-2-yl)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-(3-oxo-cyclopentyl)-propionamide (prepared as in Example 49, 190 mg, 0.38 mmol) and methoxyamine hydrochloride (48 mg, 0.57 mmol) in methanol (0.90 mL) and pyridine (0.90 mL) was heated under reflux for 3 h. The reaction mixture was allowed to cool to 25° C. and then was concentrated in vacuo. The resulting residue was diluted with water (50 mL) and extracted with ethyl acetate (50 mL). The organic layers were washed with a 1N aqueous hydrochloric acid solution (50 mL) and a saturated aqueous sodium chloride solution (50 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 50% ethyl acetate/hexanes) afforded the N-(5-bromo-pyrazin-2-yl)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-(3-methoxyimino-cyclopentyl)-propionamide (61.2 mg, 78%) as a yellow foam: mp 91–97° C.; (ES)+-HRMS m/e calcd for C20H22BrClN4O4S (M+H)+ 529.0307 found 529.0310.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[Cs+].[Cs+].Cl[C:8]1[C:9]2[N:17]=[CH:16][C:15](Cl)=[CH:14][C:10]=2N=C[N:13]=1.[CH2:19]([Si:21]([CH2:26][CH3:27])([CH2:24][CH3:25])[C:22]#[CH:23])[CH3:20]>CC#N.CC#N.Cl[Pd]Cl.C(#N)C>[CH3:1][O:4][C:15]1[CH:14]=[C:10]([C:20]#[C:19][Si:21]([CH2:26][CH3:27])([CH2:24][CH3:25])[CH2:22][CH3:23])[C:9]([C:8]#[N:13])=[N:17][CH:16]=1
Reactant: O=C([O-])[O-]
Reactant: C#C[Si](CC)(CC)CC
Reactant: Clc1cnc2c(Cl)ncnc2c1
Agent: Cl[Pd]Cl
Agent: [Cs+]
Solvent: CC#N
Product: CC[Si](C#Cc1cc(OC)cnc1C#N)(CC)CC
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
A sealable vessel was charged with bis(acetonitrile)palladium (II) chloride (0.154 g, 0.593 mmol), dicyclohexyl(2′,4′,6′-triisopropyl-[1′,1′-biphenyl]-2-yl)phosphine (0.848 g, 1.780 mmol), cesium carbonate (25.1 g, 77 mmol), the product of Intermediate 9, step 1 (5 g, 29.7 mmol), and ACN (60 mL). The vessel was flushed with argon, sealed, and stirred at RT for 25 minutes. To the reaction was added triethyl(ethynyl)silane (5.41 g, 38.6 mmol), and the vessel was resealed and stirred at 90° C. for 3 hours. The solution was concentrated, and the residue was purified via silica gel chromatography, eluting with 0-50% ethyl acetate in heptanes, to afford the title compound (3.8 g, 13.9 mmol). MS m/z=273 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)=O)=[CH:5][C:4]=1[O:22][CH3:23].CN(C)[CH:26]=[O:27].O(Cl)[Cl:30].O>O1CCCC1>[CH3:23][O:22][C:4]1[CH:5]=[C:6]([C:9](=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)[Cl:30])[CH:26]=[O:27])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: CN(C)C=O
Reactant: COc1ccc(CC(=O)c2ccc(OC)c(OC)c2)cc1OC
Reactant: ClOCl
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(Cl)=C(C=O)c2ccc(OC)c(OC)c2)cc1OC
Reaction time: 0.33 h
Yield: 59 %

Procedure:
Desoxyveratroin (2.5 g, 0.0079 moles) was dissolved in a solution of tetrahydrofuran (20 ml) and a preformed solution of dimethylformamide (12 ml) and phophorous oxychloride (7 ml) was added with stirring over a period of 20 minutes to form a reaction mixture. The reaction mixture was kept below 30° by ice bath cooling and stirred for 5 hrs. The resulting slurry was then poured into water (200 ml) and stirred for 18 hrs. The crude product (2.9 g, mp. 162°-166°) was recrystallized from methanol-benzene to yield 1.7 g (59%) of the title compound as yellow needles, mp. 183°-184°. IR(mull): 1665, 1589 cm-1 ; 1H-NMR (CDCl3): δ3.93 (s, 12H), 7.0 (m, 6H), 9.8 (s, 1H); mass spectrum: M+ 364 (100%).
Reaction SMILES: O[CH2:2][C:3]1[N:7]([CH2:8][CH2:9][CH3:10])[CH:6]=[N:5][C:4]=1[CH3:11].S(Cl)([Cl:14])=O>>[ClH:14].[Cl:14][CH2:2][C:3]1[N:7]([CH2:8][CH2:9][CH3:10])[CH:6]=[N:5][C:4]=1[CH3:11]
Reactant: O=S(Cl)Cl
Reactant: CCCn1cnc(C)c1CO
Product: CCCn1cnc(C)c1CCl
Product: Cl
Temperature: 90 °C

Procedure:
To 5-hydroxymethyl-4-methyl-1-propylimidazole (2.4 g) was added thionyl chloride (10 ml) at 0° C., and the mixture was heated for 30 minutes at 90° C. The mixture was allowed to be at room temperature. The solvent was distilled off under reduced pressure and the obtained residue was dissolved in methanol. The solvent was distilled off again under reduced pressure, to give 5-chloromethyl-4-methyl-1-propylimidazole hydrochloride (3.13 g) as brown oil.
Reaction SMILES: [OH:1][CH:2]([CH2:9][NH:10][S:11]([C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[CH3:24][I:25]>CO>[I-:25].[OH:1][CH:2]([CH2:9][NH:10][S:11]([C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH2:3][N+:4]1([CH3:24])[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: O=S(=O)(NCC(O)CN1CCCC1)c1cccc2ccccc12
Reactant: CI
Solvent: CO
Product: C[N+]1(CC(O)CNS(=O)(=O)c2cccc3ccccc23)CCCC1
Product: [I-]
Reaction time: 12 h
Yield: 545.8 %

Procedure:
To a solution of 1-[2-hydroxy-3-(1-naphthalenesulphonamido)propyl]pyrrolidine (2 g; 0.0005 mol) in methanol (50 ml) was added methyl iodide (6.9 g; 0.05 mol). The mixture was left at room temperature 12 hours. The reaction mixture was evaporated to dryness and the residue was recrystallized from ethanol (20 ml) to obtain the product (1.3 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][CH:6]=[C:5]2[CH:12]=O.Cl.[NH2:15]O.C(OC(=O)C)(=O)C.[OH-].[Na+].Cl>O1CCCC1.N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][CH:6]=[C:5]2[C:12]#[N:15]
Reactant: O=Cc1c[nH]c2cc(F)c(F)cc12
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: N#Cc1c[nH]c2cc(F)c(F)cc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 96.6 %

Procedure:
To a solution of 5,6-difluoro-1H-indole-3-carbaldehyde (1.0 g) in tetrahydrofuran (15 ml) were added hydroxylamine hydrochloride (0.81 g) and pyridine (1.9 g), and this mixture was stirred at 80° C. for 8 hours. Acetic anhydride was added to reaction mixture and this mixture was stirred at 80° C. for 8 hours. After cooling to ambient temperature, 2 mol/L aqueous sodium hydroxide solution was added to this mixture and resulting mixture was stirred for 30 minutes. This mixture was poured into 2 mol/L hydrochloric acid and the precipitated solid was collected by filtration, and washed with water and n-hexane. The solid was dissolved in ethyl acetate and this residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate) to give the title compound (0.95 g).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]2[N:4]([N:5]=[C:6]([CH2:10][CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:45])[CH:21]([O:28][C:29]4[CH:34]=[CH:33][C:32]([C:35]([CH2:38][CH3:39])([CH3:37])[CH3:36])=[CH:31][C:30]=4[C:40]([CH2:43][CH3:44])([CH3:42])[CH3:41])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:15][CH:14]=3)[NH:7]2)[N:3]=1.[Br:46]N1C(=O)CCC1=O>O1CCCC1.ClCCl>[Br:46][C:9]1[C:2]([CH3:1])=[N:3][N:4]2[C:8]=1[NH:7][C:6]([CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20](=[O:45])[CH:21]([O:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]([CH2:38][CH3:39])([CH3:36])[CH3:37])=[CH:31][C:30]=3[C:40]([CH2:43][CH3:44])([CH3:42])[CH3:41])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:17][CH:18]=1)=[N:5]2
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCCCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1ccc(CCCc2nn3nc(C)cc3[nH]2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCCCCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1ccc(CCCc2nn3nc(C)c(Br)c3[nH]2)cc1
Reaction time: 0.5 h

Procedure:
In a mixture of 100 ml of tetrahydrofuran and 500 ml of dichloromethane was dissolved 50.0 g of 6-methyl-2-(3-(4-(2-(2,4-di-tert-amylphenoxy)octaneamido)phenyl)propyl)-1H-pyrazolo(1,5-b)(1,2,4)triazole (J). Thereto, 13.8 g of N-bromosuccinimide was added at room temperature, and stirring was continued for 30 minutes. The resulting reaction mixture was washed with 500 ml each of water for three times, and dried over anhydrous magnesium sulfate. An oily substance obtained by removing the solvent from the reaction mixture by distillation under reduced pressure was fractionated by chromatography on a column of silica gel (eluting solvent; hexane-ethyl acetate (3/1) mixture), and the eluate was concentrated and evaporated to dryness. Thus, the desired intermediate (K), 7-bromo-6-methyl-2-(3-(4-(2-(2,4-di-tert-amylphenoxy)octaneamido)phenyl)propyl)-1H-pyrazolo(1,5-b)(1,2,4)triazole, was obtained. Yield: 49.3 g (87%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([OH:9])=[C:4]([CH2:10][CH3:11])[N:3]=1.O.[OH-].[Li+].[Cl:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]=[CH:21][CH:20]=[C:19]2[O:26][CH2:27][CH2:28][CH2:29]Br.ClCCl>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([O:9][CH2:29][CH2:28][CH2:27][O:26][C:19]2[C:18]3[C:23](=[CH:24][CH:25]=[C:16]([Cl:15])[CH:17]=3)[N:22]=[CH:21][CH:20]=2)=[C:4]([CH2:10][CH3:11])[N:3]=1
Reactant: CCc1nc(N)nc(N)c1O
Reactant: Clc1ccc2nccc(OCCCBr)c2c1
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nc(N)nc(N)c1OCCCOc1ccnc2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
2,4-Diamino-6-ethyl-5-hydroxypyrimidine (1.39 g, 9 mmol) was added to a stirred solution of lithium hydroxide monohydrate (1.32 g, 31.50 mmol) in DMF (5 mL) and the reaction mixture was stirred at 25° C. for 1 hour. A solution of 3-(6-chloroquinolin-4-yloxy)propyl bromide (2.71 g, 9 mmol) in DMF (3 mL) was added and the reaction mixture was left stirring at 25° C. overnight. DMF was partially removed under reduced pressure to give residue. The residue was digested with dichloromethane and filtered to give white solid. Recrystallization with aqueous methanol and hot water afforded the desired diaminopyrimidine as white solid (1.85 g, 55%, m.p. 230-231° C. (dec.)). 1H NMR (500 MHz, DMSO-d6): 0.91 (3H, t, J=7.6 Hz), 2.26 (2H, q, J=7.6 Hz), 2.31 (2H, m), 3.86 (2H, t, J=6 Hz), 4.45 (2H, t, J=5.9 Hz), 5.59 (2H, s), 6.17, (2H, s), 7.15 (1H, d, J=5.3 Hz), 7.76 (1H, dd, J=9.0, 2.4 Hz), 7.98 (1H, d, J=9.0 Hz), 8.14 (1H, d, J=2.4 Hz), 8.77 (1H, d, J=5.2 Hz).
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[CH:20]=[CH:19][C:18]2[S:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH:21]([CH3:28])[CH2:22][N:23]3[CH2:27][CH:26]=[CH:25][CH2:24]3)[C:9]=2[CH:8]=1)=[O:6])[CH:2]=[CH2:3].[CH3:29][I:30]>CC(C)=O>[I-:30].[CH2:1]([NH:4][C:5]([C:7]1[CH:20]=[CH:19][C:18]2[S:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH:21]([CH3:28])[CH2:22][N+:23]3([CH3:29])[CH2:27][CH:26]=[CH:25][CH2:24]3)[C:9]=2[CH:8]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: CI
Reactant: C=CCNC(=O)c1ccc2c(c1)N(C(C)CN1CC=CC1)c1ccccc1S2
Solvent: CC(C)=O
Product: C=CCNC(=O)c1ccc2c(c1)N(C(C)C[N+]1(C)CC=CC1)c1ccccc1S2
Product: [I-]
Reaction time: 0.5 h

Procedure:
A solution of N-allyl-10-[1-(2,5-dihydro-1-pyrrolyl)-2-propyl]-2-phenothiazinecarboxamide, L series (1.1 g), and methyl iodide (0.4 g) in acetone (10 cc) is stirred for 3 days at a temperature in the region of 20° C. and then concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 45° C. The residue is purified by chromatography on a column (height: 30 cm; diameter: 3 cm) of silica gel (0.04-0.063 mm) under a slight excess pressure of nitrogen (40 kPa), eluting successively with a mixture (300 cc) of ethyl acetate and methanol (90:10 by volume) and then with a mixture (500 cc) of ethyl acetate and methanol (80:20 by volume) and collecting 40-cc fractions. Fractions 5 to 15 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. and the residue is taken up with stirring for 30 minutes in isopropyl ether (40 cc). The suspension is filtered and the solid is washed with isopropyl ether (2×5 cc), drained and dried under reduced pressure (5 mm Hg; 0.7 kPa) at 40° C. 1-[2-(2-Allylcarbamoyl-10-pheno-thiazinyl)propyl]-1-methyl-2,5-dihydropyrrolium iodide, L series (0.66 g), is thereby obtained in the form of a yellow powder, m.p. about 170° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Cl[C:10](Cl)(Cl)[C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=1.Cl>>[C:14]1([C:15]2[O:16][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=2)[CH:18]=[CH:19][C:11]([C:10]2[O:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=2)=[CH:12][CH:13]=1
Reactant: Nc1ccccc1O
Reactant: O=C(Cl)c1ccc(C(Cl)(Cl)Cl)cc1
Agent: Cl
Product: c1ccc2oc(-c3ccc(-c4nc5ccccc5o4)cc3)nc2c1
Yield: 71.4 %

Procedure:
In the apparatus described under Example 1, 21.8 g of reactant A (0.2 mol), 25.8 g of p-trichloromethyl-benzoyl chloride (0.1 mol) and 3.5 g of B2O3 (0.05 mol) were mixed and slowly heated. Between 190° and 200° C, a vigorous evolution of HCl began. After 2 hours the mixture was cooled and ground in a mortar. After extraction twice with 100 ml of CHCl3 and twice with 100 ml of water, 22.3 g of raw product (71% of the theory) was obtained, melting at 318° to 328° C. Compound XIX can be recrystallized from dimethylformamide, o-dichlorobenzene, nitrobenzene, dimethylsulfoxide or 1,2-dibromoethane. A small specimen recrystallized from o-dichlorobenzene melted at 325° to 329° C. The product can be further purified by chromatography on Al2O3 with 1,2-dibromoethane as the elutant at 120° C, whereupon the melting point becomes 340° to 342° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:11]=2[F:17])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[S:27])=[CH:21][CH:20]=1.C1(C)C=CC=CC=1>C(OCC)C>[F:17][C:11]1[C:12]([CH3:16])=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:26]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=2)=[S:27])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: S=C=Nc1ccc(Cl)cc1
Reactant: Cc1cccc(COc2cccnc2N)c1F
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Cc1cccc(COc2cccnc2NC(=S)Nc2ccc(Cl)cc2)c1F

Procedure:
A mixture of 2-amino-3-(2-fluoro-3-methylbenzyloxy)pyridine (2.00 g, 0.0086 mol), 4chlorophenyl isothiocyanate (1.75 g, 0.0103 mol) and toluene (10 ml) was refluxed for 3 hours, then cooled and treated with diethyl ether to induce crystallisation of the product. Yield 3.21g (93%), m.p. 184°-187 ° C.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:19][C:20]2[CH:21]=[C:22]([CH:28]=[CH:29][C:30]=2[CH3:31])[C:23]([NH:25][O:26][CH3:27])=[O:24])=[N:5][C:6](S(C)=O)=[N:7][C:8]=1[N:9]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH3:10])#[N:2].[CH3:32][N:33]1[CH2:39][CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>C1COCC1>[C:1]([C:3]1[C:4]([NH:19][C:20]2[CH:21]=[C:22]([CH:28]=[CH:29][C:30]=2[CH3:31])[C:23]([NH:25][O:26][CH3:27])=[O:24])=[N:5][C:6]([N:36]2[CH2:37][CH2:38][CH2:39][N:33]([CH3:32])[CH2:34][CH2:35]2)=[N:7][C:8]=1[N:9]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH3:10])#[N:2]
Reactant: CN1CCCNCC1
Reactant: CONC(=O)c1ccc(C)c(Nc2nc(S(C)=O)nc(N(C)CC(C)(C)C)c2C#N)c1
Solvent: C1CCOC1
Product: CONC(=O)c1ccc(C)c(Nc2nc(N3CCCN(C)CC3)nc(N(C)CC(C)(C)C)c2C#N)c1

Procedure:
3-{5-Cyano-6-[(2,2-dimethyl-propyl)-methyl-amino]-2-methanesulfinyl-pyrimidin-4-ylamino}-N-methoxy-4-methyl-benzamide (40 mg) and 1-methyl-homopiperazine (0.05 mL) in THF (0.5 mL) were heated in sealed tube at 75° C. for overnight. After the solvent was removed in vacuo, the residue was purified by silica gel column chromatography to afford the product (6.8 mg). MS (m/z): 495 (M+H).
Reaction SMILES: [CH2:1](OP(CC(C)=CC(OCC)=O)(OCC)=O)C.C([Li])CCC.CCCCCC.[CH2:29]([N:31]1[C:40]2[C:35](=[CH:36][C:37]([CH:47]([CH3:49])[CH3:48])=[CH:38][C:39]=2/[C:41](/[CH3:46])=[C:42](/[F:45])\[CH:43]=[O:44])[C:34]([CH3:51])([CH3:50])[CH2:33][CH2:32]1)[CH3:30]>C1COCC1.CN1CCCN(C)C1=O>[F:45]/[C:42](=[C:41](/[C:39]1[CH:38]=[C:37]([CH:47]([CH3:48])[CH3:49])[CH:36]=[C:35]2[C:40]=1[N:31]([CH2:29][CH2:30][CH3:1])[CH2:32][CH2:33][C:34]2([CH3:50])[CH3:51])\[CH3:46])/[CH:43]=[O:44]
Reactant: CCOC(=O)C=C(C)CP(=O)(OCC)OCC
Reactant: CCN1CCC(C)(C)c2cc(C(C)C)cc(/C(C)=C(/F)C=O)c21
Agent: [Li]CCCC
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCN1CCC(C)(C)c2cc(C(C)C)cc(/C(C)=C(/F)C=O)c21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 4-(diethoxyphosphoryl)-3-methyl-but-2-enoate (210 mg, 0.80 mmol), 10 ml of anhydrous THF, and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (0.12 ml) under argon at −78° C. was slowly added a 1.6 M solution of n-butyl lithium and hexane (0.52 ml, 0.84 mmol). The resulting mixture was stirred at −78° C. for 30 minutes before a solution of (E)-3-(1-ethyl-6-isopropyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-8-yl)-2-fluoro-but-2-enal (Intermediate 21, 87 mg, 0.27 mmol) and 3 ml THF was added by cannula. The resulting mixture was stirred at 0° C. for 1 h. The reaction was quenched with saturated NH4Cl, and the product was extracted with ethyl ether. The extract was washed with water, and brine, and dried over Na2SO4. The solution was filtered and concentrated in vacuo. The residue was purified by column chromatography using 5% ethyl acetate in hexane to yield the title compound as a bright yellow oil.
Reaction SMILES: [F:1][C:2]1[C:11]2[NH:10][CH:9]=[C:8]3[C:12](=[O:24])[N:13]([C:15]4[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=4)[N:14]=[C:7]3[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:28])=O.CN(C)C=O>ClCCl>[F:1][C:2]1[C:11]2[NH:10][CH:9]=[C:8]3[C:12](=[O:24])[N:13]([C:15]4[CH:23]=[CH:22][C:18]([C:19]([Cl:28])=[O:20])=[CH:17][CH:16]=4)[N:14]=[C:7]3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(-n2nc3c4cccc(F)c4[nH]cc-3c2=O)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(-n2nc3c4cccc(F)c4[nH]cc-3c2=O)cc1
Temperature: 45 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
To a suspension of finely ground 4-(6-Fluoro-3-oxo-3,5-dihydro-pyrazolo[4,3-c]quinolin-2-yl]-benzoic acid (1.1 g. 3.4 mmol) in dichloromethane (6 ml) was added oxalyl chloride (2.4 ml, 29 mmol) followed by a drop of dimethyl formamide. The mixture was stirred under nitrogen at 45° C. for 3 h. The solvent was removed in vacuum to yield 4-(6-Fluoro-3-oxo-3,5-dihydro-pyrazolo[4, 3-c]quinolin-2-yl]-benzoyl chloride (1.15 g, quantitative) as a pale yellow solid that was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[C:8]([C:13]#N)=[N:9][CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1.[OH-:17].[K+]>>[Br:1][C:2]1[CH:16]=[CH:15][C:5]2[O:6][C:7]3[C:8](=[N:9][CH:10]=[CH:11][CH:12]=3)[C:13](=[O:17])[C:4]=2[CH:3]=1
Reactant: [OH-]
Reactant: N#Cc1ncccc1Oc1ccc(Br)cc1
Agent: [K+]
Product: O=c1c2cc(Br)ccc2oc2cccnc12
Temperature: 190 °C
Reaction time: 2 h

Procedure:
A mixture of 3-(4-bromophenoxy)-picolinonitrile (57 g, 207 mmol) and 300 g of PPA was stirred at 190° C. for 2 h, followed by 180° C. overnight. After cooling to RT, the reaction mixture was poured into 500 g of ice water. After the PH was adjusted to 7 with KOH, the suspension was filtered. The solid was washed with large excess of water, followed by washing with methanol and acetone. The resulting solid was air dried to give 8-bromo-10H-chromeno[3,2-b]pyridin-10-one as a tan solid with >90% purity. The material was carried on to the next step.
Reaction SMILES: B(Cl)(Cl)Cl.C(OC([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[C:19]([C:23]3[CH:28]=[C:27]([Cl:29])[C:26]([O:30]CC4C=CC=CC=4)=[CH:25][C:24]=3[O:38]CC3C=CC=CC=3)=[N:20][NH:21][CH:22]=2)[CH2:14][CH2:13]1)=O)(C)(C)C.C(=O)(O)[O-].[Na+]>ClCCl>[NH3:12].[Cl:29][C:27]1[CH:28]=[C:23]([C:19]2[C:18]([N:15]3[CH2:16][CH2:17][NH:12][CH2:13][CH2:14]3)=[CH:22][NH:21][N:20]=2)[C:24]([OH:38])=[CH:25][C:26]=1[OH:30]
Reactant: CC(C)(C)OC(=O)N1CCN(c2c[nH]nc2-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)CC1
Agent: ClB(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: N
Product: Oc1cc(O)c(-c2n[nH]cc2N2CCNCC2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.4 %

Procedure:
Boron trichloride (1M solution in dichloromethane; 8 ml, 8 mmol) was added dropwise to a solution of 4-[3-(2,4-Bis-benzyloxy-5-chloro-phenyl)-1H-pyrazol-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (1.5 g, 2.6 mmol) in dichloromethane (15 ml) at 0° C. The resulting mixture was stirred at room temperature for 1 h, then basified with saturated sodium bicarbonate solution. The suspension was concentrated in vacuo, azeotroping with toluene until the residue was dry. The residue was triturated with dichloromethane:ethanol (1:1; 15 ml) and filtered. The filtrate was purified on a bond elute cartridge (20 g) eluting with dichloromethane:ethanol:ammonia, 50:8:1 then 20:8:1 to give 4-chloro-6-(4-piperazin-1-yl-1H-pyrazol-3-yl)-benzene-1,3-diol as a pale yellow solid (400 mg) (Example 2)
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:19])[C:11](=[CH:15][O:16]CC)[C:12]([CH3:14])=O)=[CH:5][CH:4]=1.Cl.[NH2:23]O.[OH-].[Na+]>C(O)C.O>[CH3:14][C:12]1[C:11]([C:10]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:21])([F:20])[F:1])=[CH:4][CH:5]=2)=[O:19])=[CH:15][O:16][N:23]=1
Reactant: CCOC=C(C(C)=O)C(=O)Nc1ccc(C(F)(F)F)cc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1nocc1C(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 8.4 %

Procedure:
N-[4-(Trifluoromethyl)phenyl]-2-(ethoxymethylene)-acetoacetamide (4 g) is suspended in 10 mL of ethanol treated with 1.5 g of hydroxylamine hydrochloride in 10 mL of water which has been adjusted to pH 5 with sodium hydroxide. The mixture is stirred and warmed to 40° C. for 2 hours, then cooled to room temperature and the precipitate collected by vacuum filtration. Sodium hydroxide (1 g) is added to the filtrate which is stirred for 30 minutes. The mixture is acidified to pH 2 with 6 N hydrochloric acid and the precipitate collected by vacuum filtration. The filtrate is then diluted with 100 mL of water and allowed to stand at 4° C. overnight. The precipitate is collected by vacuum filtration, washed with ethanol:water 2:1 and dried to give 300 mg of crude 3-methyl-4-[4-(trifluoromethyl)-phenylaminocarbonyl]isoxazole. The crude is purified on a column of silica gel eluting with ethyl acetate:hexane 1:4 to give 100 mg of 3-methyl-4-[4-(trifluoromethyl)phenylaminocarbonyl]-isoxazole, an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[CH:10]([C:12]1[CH:20]=[C:16]([C:17]([OH:19])=[O:18])[C:15]([OH:21])=[CH:14][CH:13]=1)=O.C([BH3-])#N.[Na+].C(OCC)(=O)C>CO.CN1CCCC1=O>[OH:21][C:15]1[CH:14]=[CH:13][C:12]([CH2:10][NH:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:20][C:16]=1[C:17]([OH:19])=[O:18]
Reactant: O=Cc1ccc(O)c(C(=O)O)c1
Reactant: COc1ccc(N)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(NCc2ccc(O)c(C(=O)O)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
p-Anisidine (1.3 g, 10.6 mmol) was dissolved in methanol (20 mL) and 5-formylsalicylic acid (1.75 g, 10.6 mmol) was added and the resulting mixture was stirred at room temperature for 16 hours. The solid formed was isolated by filtration, re-dissolved in N-methyl pyrrolidone (20 mL) and methanol (2 mL). To the mixture was added sodium cyanoborohydride (1.2 g) and the mixture was heated to 70° C. for 3 hours. To the cooled mixture was added ethyl acetate (100 mL) and the mixture was extracted with water (100 mL) and saturated aqueous ammonium chloride (100 mL). The combined aqueous phases were concentrated in vacuo and a 2 g aliquot was purified by SepPac chromatography eluting with mixtures of aetonitrile and water containing 0.1% trifluoroacetic acid to afford the title compound.