Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:18]=[C:17]2[C:8]([N:9]3[CH:14]([C:15](=[O:19])[NH:16]2)[CH2:13][N:12]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:11][CH2:10]3)=[N:7][CH:6]=1)=O.[H-].[Na+].[H-].[Al+3].[Li+].[H-].[H-].[H-].CO>O1CCCC1.O.C(OCC)(=O)C>[C:23]([O:22][C:20]([N:12]1[CH2:11][CH2:10][N:9]2[CH:14]([C:15](=[O:19])[NH:16][C:17]3[C:8]2=[N:7][CH:6]=[C:5]([CH2:3][OH:2])[CH:18]=3)[CH2:13]1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: COC(=O)c1cnc2c(c1)NC(=O)C1CN(C(=O)OC(C)(C)C)CCN21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN2c3ncc(CO)cc3NC(=O)C2C1
Temperature: -45 °C
Reaction time: 0.5 h

Procedure:
10-Oxo-1,3,4,9,10,10a-hexahydro-2,4a,5,9-tetraaza-phenanthrene-2,7-dicarboxylic acid 2-tert-butyl ester 7-methyl ester (545 mg, 1.504 mmol) was taken up in tetrahydrofuran (18 mL) in an inert environment. To the stirred suspension at room temperature was added NaH (90 mg, 2.26 mmol, 60% dispersion in mineral oil) and stirred 30 minutes. The reaction was then cooled to −45° C. and lithium aluminum hydride (2.26 ml, 2M in THF) was added. The reaction was stirred at a temperature between −20 and −10° C. for 1 hour. The reaction was then cooled back to −60° C. and MeOH (5 ml) followed by water (1 ml) was added. The reaction was allowed to stir at ambient temperature for 2 hours and then poured into ethyl acetate (400 ml) and water (100 ml). The biphasic mixture was stirred vigorously and then filtered through a medium frit. The filtrate was collected. The layers were separated and the aqueous phase was extracted with ethyl acetate (1×100 ml). The organic layers were combined, washed with brine (100 ml), and concentrated to 429.4 mg (96%) of the title compound as an off-white solid. [M+H] calc'd for C16H22N4O4, 335. found, 335
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][NH:21][C:22](=[O:29])[CH2:23][O:24][CH2:25][C:26]([OH:28])=[O:27])=[N+]=[N-]>O>[NH2:1][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][NH:21][C:22](=[O:29])[CH2:23][O:24][CH2:25][C:26]([OH:28])=[O:27]
Reactant: [N-]=[N+]=NCCOCCOCCOCCOCCOCCNC(=O)COCC(=O)O
Solvent: O
Product: NCCOCCOCCOCCOCCOCCNC(=O)COCC(=O)O

Procedure:
23-Azido-5-oxo-6-aza-3,9,12,15,18,21-hexaoxatricosanoic acid (9.0 g, 21 mmol) was dissolved in water (50 mL) and reduced using H2(g)-Pd/C (10%). The reaction was run until ESI-MS analysis showed complete conversion to the desired product (MH+ calculated: 397.2; found 397.6). The crude product was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9](=O)[CH3:10])=[C:4]([N+:19]([O-])=O)[CH:3]=1.[Sn](Cl)Cl>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[C:9]([CH3:10])=[N:19][C:4]=2[CH:3]=1
Reactant: CC(=O)N(c1ccc(F)cc1)c1ccc(Br)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Cc1nc2cc(Br)ccc2n1-c1ccc(F)cc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 25.2 %

Procedure:
To a stirred room temperature solution of N-(4-bromo-2-nitrophenyl)-N-(4-fluorophenyl)acetamide (3.7 g, 10.8 mmol) in ethanol (75 mL) was added tin (II) chloride (6 g, 31.4 mmol) and the mixture was warmed at 90° C. After 3 hours, the mixture was cooled, concentrated in vacuo, diluted with cold water, made basic with 2 N NaOH (pH 11), and extracted with three 75 mL portions of methylene chloride. The combined organic layers were washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo to afford a reddish brown oil. The residue was purified by column chromatography over silica gel eluting with 0-50% ethyl acetate in methylene chloride to afford 830 mg of 5-bromo-1-(4-fluorophenyl)-2-methyl-1H-benzimidazole as an off-white solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]2[C:5]3[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]=3[CH:13]=[CH:14][CH:15]=2.ClC1C=CC=C(C(OO)=[O:24])C=1.[OH-].[Na+]>C(O)C>[CH3:1][S:2]([C:3]1[C:4]2[C:5]3[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]=3[CH:13]=[CH:14][CH:15]=2)=[O:24]
Reactant: CSc1ccc2c3c(cccc13)C(=O)N2
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CS(=O)c1ccc2c3c(cccc13)C(=O)N2
Temperature: 0 °C
Reaction time: 1.25 h
Yield: 46.5 %

Procedure:
To an ice water cooled stirred suspension of 1.3 g of 6-(methylthio)-benz[cd]indol-2(1H)-one (Example 2) in 25 ml of ethanol is added portionwise over 12 minutes 1.2 g of 85% m-chloroperbenzoic acid at a rate so the temperature is kept below 7° C. Stirring is continued over 1.25 hours. The reaction mixture is poured over crushed ice and 8 ml of 1N sodium hydroxide with stirring. After 15 minutes of additional stirring, the reaction mixture is filtered. The filtrate is extracted with methylene chloride, dried with magnesium sulfate and evaporated to afford 0.65 g of the desired product as a yellow solid, m.p. 178°-185° C.
Reaction SMILES: O=[C:2]1[CH:6]([C:7]([O:9][CH3:10])=[O:8])[CH2:5][S:4][CH2:3]1.[CH:11]1([NH:17][C:18]([NH2:20])=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C(C)=CC=CC=1>O>[CH:11]1([NH:17][C:18]([NH:20][C:2]2[CH2:3][S:4][CH2:5][C:6]=2[C:7]([O:9][CH3:10])=[O:8])=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: COC(=O)C1CSCC1=O
Reactant: NC(=O)NC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: COC(=O)C1=C(NC(=O)NC2CCCCC2)CSC1

Procedure:
15.1 parts by weight of methyl 3-keto-1,5-dihydrothiophene-4-carboxylate, 14.2 parts by weight of cyclohexylurea and 0.5 part by weight of p-toluenesulfonic acid in 100 parts by weight of xylene were refluxed for 4 hours in an apparatus equipped with a water separator. The mixture was cooled, and the residue was then filtered off under suction and recrystallized from toluene. 20.3 parts by weight of N-cyclohexyl-N'-(3-methoxycarbonyl-2,5-dihydrothien-4-yl)-urea of melting point 154°-155° C. were obtained.
Reaction SMILES: [N:1]1([CH2:6][C:7]#[CH:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([Li])CCC.[CH3:14][C:15]([CH3:17])=[O:16]>O1CCCC1>[CH3:14][C:15]([OH:16])([C:8]#[C:7][CH2:6][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[CH3:17]
Reactant: CC(C)=O
Reactant: C#CCN1CCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(O)C#CCN1CCCC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-(pyrrolidin-1-yl)-prop-2-yne (prepared by the method of Biel and DiPierro J. Am. Chem. Soc. 1958, 80, 4609) (0.545 g) in dry tetrahydrofuran (15 ml) was treated at -78° C. with a solution of n-butyl lithium in hexanes (2.5 M, 2.2 ml) and the mixture was allowed to stir at -78° C. for 30 minutes and them permitted to warm to room temperature over the course of one hour. Upon recooling to -78° C. this mixture was treated with a solution of acetone (1 ml) in tetrahydrofuran (1 ml). The reaction was permitted to warm to room temperature over the course of two hours, and was then partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate, and the pooled organic phase was washed with water, brine, and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo to give a crude product, which was purified by column chromatography over silica gel (5% methanol in dichloromethane was used as the eluant) to afford the product as an oil. MS(+ES), m/z: 168 (M+H)+.
Reaction SMILES: C[Si](C)(C)[C:3]1[S:4][CH:5]=[CH:6][N:7]=1.[Li]CCCC.[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1.[Cl-].[NH4+]>C1COCC1.CCOC(C)=O>[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]([C:5]2[S:4][CH:3]=[N:7][CH:6]=2)[OH:21])=[CH:18][CH:17]=1
Reactant: C[Si](C)(C)c1nccs1
Reactant: O=Cc1ccc(F)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OC(c1ccc(F)cc1)c1cncs1
Temperature: 25 °C
Yield: 50.1 %

Procedure:
A solution of 2-(trimethylsilyl)thiazole (6.12 g, 38.9 mmol) in THF (80 mL) was cooled to −78° C. and treated with a dropwise addition of nBuLi (2.5 M in hexanes, 15.6 mL, 39.0 mmol). The reaction mixture was stirred at −78° C. for 1 h before 4-fluorobenzaldehyde (4.59 mL, 42.8 mmol) was added dropwise. The stirred suspension was allowed to warm gradually to room temperature over 16 h, then treated with 100 mL of saturated aqueous ammonium chloride and 100 mL of EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography, eluting with a gradient of 10-50% EtOAc/hexanes to afford the product as a white solid (4.09 g, 19.5 mmol, 50% yield). MS (M+H)+ 210.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH:2]([CH:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3].NC1C2C(C3C=CC(NC(NC4C=CC=C(F)C=4)=O)=CC=3)=CSC=2C(C2C=NN(CCO)C=2)=CN=1>C1COCC1.O>[C:1]([OH:10])(=[O:9])[C@@H:2]([C@H:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3]
Reactant: O=C(O)C(O)C(O)C(=O)O
Agent: Nc1ncc(-c2cnn(CCO)c2)c2scc(-c3ccc(NC(=O)Nc4cccc(F)c4)cc3)c12
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Reaction time: 8 h

Procedure:
A saturated solution of l-tartaric acid was prepared at 25 C by dissolving tartaric acid in a 85/15 v/v THF/water mixture. This solution (2 mL) was heated 2 to 65 C. Approximately 200 mg of N-(4-{4-amino-7-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]thieno[3,2-c]pyridin-3-yl}phenyl)-N′-(3-fluorophenyl)urea free base solid was then added, which readily dissolved. N-(4-{4-amino-7-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]thieno[3,2-c]pyridin-3-yl}phenyl)-N′-(3-fluorophenyl)urea L-bitartrate crystallized within 30 minutes from this clear solution. The slurry was then diluted with the saturated solution (at 25° C.) of l-tartaric acid and cooled to ambient temperatures. The slurry was continue to be stirred overnight and the solids were isolated via filtration. The filtered solids were washed with 85/15 v/v mixture of THF/water to remove excess l-tartaric acid and then dried in the oven at 45° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](/[CH:14]=[C:15]3/[C:16](=[O:22])[N:17]=[C:18](SC)[S:19]/3)[CH:12]=2)[N:7]=[CH:6][C:5]=1[C:23]#[N:24])[CH3:2].[N:25]1([CH2:30][CH2:31][NH2:32])[CH:29]=[CH:28][N:27]=[CH:26]1.CCN(C(C)C)C(C)C>>[CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](/[CH:14]=[C:15]3/[C:16](=[O:22])[N:17]=[C:18]([NH:32][CH2:31][CH2:30][N:25]4[CH:29]=[CH:28][N:27]=[CH:26]4)[S:19]/3)[CH:12]=2)[N:7]=[CH:6][C:5]=1[C:23]#[N:24])[CH3:2]
Reactant: NCCn1ccnc1
Reactant: CCOc1c(C#N)cnc2ccc(/C=C3\SC(SC)=NC3=O)cc12
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1c(C#N)cnc2ccc(/C=C3\SC(NCCn4ccnc4)=NC3=O)cc12

Procedure:
Similar procedure as described in example 14h was used, starting from 4-ethoxy-6-[2-methylsulfanyl-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-quinoline-3-carbonitrile (example 14g), 2-imidazol-1-yl-ethylamine and DIEA to give 4-ethoxy-6-[2-(2-imidazol-1-yl-ethylamino)-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-quinoline-3-carbonitrile. LC-MS m/e 417 (MH+).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C@@H:15]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[I:29]I.CCOC(C)=O>C(Cl)(Cl)Cl.[O-]S(C(F)(F)F)(=O)=O.[Ag+]>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C@@H:15]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[C:10]([I:29])=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: II
Reactant: COc1ccc([C@H](Cc2ccncc2)c2ccccc2)cc1OC1CCCC1
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: COc1cc(I)c([C@H](Cc2ccncc2)c2ccccc2)cc1OC1CCCC1
Yield: 90.3 %

Procedure:
From (R)-(+)-4-[2-(3-cyclopentyloxy-4-methoxyphenyl)-2-phenylethyl] pyridine (made as described in International Patent Specification No. WO 94/14742) (1.82 g, 4.88 mmol) in CHCl3 (50 ml)m, silver triflate (1.26 g, 4.88 mmol) and iodine (1.24 g, 4.88 mmol). Chromatography (SiO2 ;EtOAc) afforded the title compound (2.2 g) as a colourless gum. (Found C, 59.23; H, 5.32; N, 2.67. C23H26NO2 l requires C, 60.13; H, 5.25; N, 2.81) δH (CDCl3) 1.5-1.9 (8H, m,CH2)4), 3.25 (1H, d, J 5 Hz, CH2 pyridine), 3.27 (1H, d, J 5 Hz, CH2 pyridine), 3.74 (3H, s, OCH3), 4.6-4.7 (1H, m, OCH), 4.64 (1H, t, J 8 Hz, CH phenyl), 6.74 (1H, s, C6H2), 7.01 (2H, d, J 5 Hz, H3, H5 pyridine), 7.24 (1H, s, C6 H2), 7.25-7.4 (5H, m, C6H5), and 8.39 (2H, d, J 5 Hz, H2, H6 pyridine). m/z 500 (M+, 100%), 406 (25) and 212 (14).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([OH:13])=O)=[C:4]2[CH:3]=1.[CH3:14][O:15][C:16]1[CH:32]=[CH:31][C:19]([CH2:20][NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[CH:18][CH:17]=1.CCN=C=NCCCN(C)C.CN(C=O)C>CN(C1C=CN=CC=1)C.O>[I:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([N:21]([CH2:20][C:19]3[CH:18]=[CH:17][C:16]([O:15][CH3:14])=[CH:32][CH:31]=3)[CH2:22][C:23]3[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)=[O:13])=[C:4]2[CH:3]=1
Reactant: COc1ccc(CNCc2ccc(OC)cc2)cc1
Reactant: O=C(O)c1cnn2ccc(I)cc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)C(=O)c2cnn3ccc(I)cc23)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 22 L round bottom flask was charged with 5-iodopyrazolo[1,5-a]pyridine-3-carboxylic acid (I-42) (200 g, 694.3 mmol), bis(4-methoxybenzyl)amine (182.2 g, 708.3 mmol), DMAP (42.4 g, 347.2 mmol), EDCI (146.4 g, 763.8 mmol) and DMF (3500 mL). The suspension was stirred at room temperature over 16 hours and a dark solution was obtained. HPLC showed no (I-42) remaining. 2-MethylTHF (4 L) and water (7 L) were added to the reaction mixture while keeping the batch temperature <25° C. The aqueous layer was separated and extracted with 2-methylTHF (4 L). The combined 2-methylTHF layers were washed with 0.25 N HCl (2×4 L), aqueous saturated NaHCO3 (4 L) and 10% brine (4 L). The 2-methylTHF layer was treated with carbon (20 g) and Na2SO4 (80 g). The solution was passed through a silica gel pad (400 g of silica gel 240-400 mesh) and the pad was washed with 2-MeTHF (3 L). The filtrate was concentrated under vacuum to give 5-iodo-N,N-bis(4-methoxybenzyl)pyrazolo[1,5-a]pyridine-3-carboxamide (I-43) as a solid. 1H NMR (500 MHz, CDCl3) δ 8.73 (d, 1 H), 8.17 (d, 1H), 7.86 (s, 1H), 7.22 (d, 4 H), 7.14 (dd, 1 H), 6.92 (d, 4 H), 4.68 (s, 4 H), 3.83 (s, 6 H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:12][CH:11]([NH2:13])[CH2:10]2)=[N:7][CH:8]=1.[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]=[C:24]=[O:25]>ClCCl>[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][C:24]([NH:13][CH:11]1[CH2:10][N:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:14])[F:15])=[CH:8][N:7]=2)[CH2:12]1)=[O:25]
Reactant: O=C=Nc1ccccc1Br
Reactant: NC1CN(c2ccc(C(F)(F)F)cn2)C1
Solvent: ClCCl
Product: O=C(Nc1ccccc1Br)NC1CN(c2ccc(C(F)(F)F)cn2)C1
Temperature: 25 °C
Yield: 83.8 %

Procedure:
D7 (100 mg, 0.46 mmol) in dichloromethane (2 ml) at ambient temperature was treated with 2-bromophenyl isocyanate (91 mg, 0.46 mmol) in dichloromethane (1 ml). The reaction mixture was maintained at ambient temperature overnight. The white solid was removed by centrifugation and washed with diethyl ether, and dried in vacuo, to give the title compound, (160 mg). MH+ 415, 417.
Reaction SMILES: [O:1]=[CH:2][CH2:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:9][C:10]([C:14]#[N:15])=[N:11]2)=[CH:6][CH:5]=1.[BH4-].[Na+]>C1COCC1.CO>[OH:1][CH2:2][CH2:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:9][C:10]([C:14]#[N:15])=[N:11]2)=[CH:6][CH:5]=1
Reactant: N#Cc1cc(-c2ccccc2)c2ccc(CC=O)cc2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1cc(-c2ccccc2)c2ccc(CCO)cc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 7-(2-oxoethyl)-4-phenylquinoline-2-carbonitrile (1.5 g, 5.5 mmol) in THF (30 mL) and MeOH (10 mL) was added portionwise at 0° C. sodium borohydride (320 mg, 8.4 mmol). The mixture was stirred overnight at rt. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 concentrated under reduced pressure and purified on silica gel (eluting with ethyl acetate/hexanes, 1:1) to give the title compound. MS (+ESI): 275 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.Cl[CH2:31][C:32]1[O:36][N:35]=[C:34]([OH:37])[CH:33]=1>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:31][C:32]5[O:36][N:35]=[C:34]([OH:37])[CH:33]=5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:27])([F:29])[F:28])[CH:3]=1
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: Oc1cc(CCl)on1
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1Cc1cc(O)no1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(3-hydroxyisoxazol-5-yl)methyl]-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and 5-chloromethyl-3-hydroxyisoxazole following General Procedure H.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4](F)[CH:3]=1.[CH3:11][O-:12].[Na+]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:12][CH3:11])[CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1F
Reactant: C[O-]
Agent: [Na+]
Product: COc1cc(Cl)ccc1C=O
Temperature: 50 °C
Reaction time: 3 h
Yield: 77.8 %

Procedure:
4-Chloro-2-Fluorobenzaldehyde (300 mg, 1.89 mmol) was diluted with NaOMe (3784 μL, 1.89 mmol) (solution in methanol), heated to 50° C. and stirred for 3 hours. The reaction was concentrated in half and loaded directly onto a biotage 25 cartridge eluting with 5% ethyl acetate/hexanes to yield 4-chloro-2-methoxybenzaldehyde (250 mg, 1.47 mmol, 77.5% yield).
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:58]1[CH:67]=[CH:66][C:65]([OH:68])=[C:64]2[C:59]=1[CH:60]=[CH:61][C:62](=[O:69])[NH:63]2)[CH2:10][NH:11]CCCC#CC1C=C(NC(C2C=C(S(C3C=C4C(=C(C)C=3)N=CC(C(N)=O)=C4NC3C=CC=C(OC)C=3)(=O)=O)C=CC=2)=O)C=CC=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][O:77][CH2:78][CH2:79][CH2:80][CH2:81][C:82]1[CH:87]=[CH:86][C:85]([N:88]([CH3:123])[C:89]([C:91]2[CH:92]=[C:93]([S:97]([C:100]3[CH:101]=[C:102]4[C:107](=[C:108]([CH3:110])[CH:109]=3)[N:106]=[CH:105][C:104]([C:111]([NH2:113])=[O:112])=[C:103]4[NH:114][C:115]3[CH:120]=[CH:119][CH:118]=[C:117]([O:121][CH3:122])[CH:116]=3)(=[O:99])=[O:98])[CH:94]=[CH:95][CH:96]=2)=[O:90])=[CH:84][CH:83]=1>>[OH:68][C:65]1[CH:66]=[CH:67][C:58]([C@H:9]([CH2:10][NH:11][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][O:77][CH2:78][CH2:79][CH2:80][CH2:81][C:82]2[CH:87]=[CH:86][C:85]([N:88]([CH3:123])[C:89]([C:91]3[CH:92]=[C:93]([S:97]([C:100]4[CH:101]=[C:102]5[C:107](=[C:108]([CH3:110])[CH:109]=4)[N:106]=[CH:105][C:104]([C:111]([NH2:113])=[O:112])=[C:103]5[NH:114][C:115]4[CH:120]=[CH:119][CH:118]=[C:117]([O:121][CH3:122])[CH:116]=4)(=[O:99])=[O:98])[CH:94]=[CH:95][CH:96]=3)=[O:90])=[CH:84][CH:83]=2)[O:8][Si:1]([CH3:2])([CH3:3])[C:4]([CH3:5])([CH3:6])[CH3:7])=[C:59]2[C:64]=1[NH:63][C:62](=[O:69])[CH:61]=[CH:60]2
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)N(C)c5ccc(CCCCOCCCCCCBr)cc5)c4)cc23)c1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5cccc(C#CCCCNC[C@H](O[Si](C)(C)C(C)(C)C)c6ccc(O)c7[nH]c(=O)ccc67)c5)c4)cc23)c1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)N(C)c5ccc(CCCCOCCCCCCNC[C@H](O[Si](C)(C)C(C)(C)C)c6ccc(O)c7[nH]c(=O)ccc67)cc5)c4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 157, using Intermediate 99 in place of Intermediate 98. ES/MS calcd. for C54H73BrN6O9SSi+ 1069.5. Found m/z=1069.7 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:13]=2)[O:8][C:7]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[N:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][C:29]=1[CH2:38][N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1.C(=O)([O-])O.[Na+].[I-].[Na+]>CC(=O)CC>[CH2:20]([O:19][C:17]([C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:42]1[CH2:43][CH2:44][N:39]([CH2:38][C:29]3[CH:30]=[CH:31][C:32]4[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=4)[N:28]=3)[CH2:40][CH2:41]1)[C:15]2=[O:16])=[O:18])[CH3:21]
Reactant: CCOC(=O)c1ccc2oc(-c3ccccc3)c(OCCCCl)c(=O)c2c1
Reactant: c1ccc2nc(CN3CCNCC3)ccc2c1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCOC(=O)c1ccc2oc(-c3ccccc3)c(OCCCN3CCN(Cc4ccc5ccccc5n4)CC3)c(=O)c2c1
Reaction time: 8 h
Yield: 75 %

Procedure:
3-(3-Chloropropoxy)-6-ethoxycarbonylflavone (1.2 mmol), 1-(2-quinolinylmethyl)piperazine (0.32 g, 1.2 mmol), sodium hydrogencarbonate (0.31 g, 2.9 mmol) and sodium iodide (0.43 g, 2.9 mmol) were dissolved in 25 ml of 2-butanone, followed by overnight refluxing. The reaction mixture was concentrated under reduced pressure. Chloroform was added to the residue, and an insoluble matter was removed. The filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (ethyl acetate:methanol=5:1), whereby the title compound represented by the following formula was obtained as a brown oil (yield: 75%). ##STR64##
Reaction SMILES: [C:1]([C:3]1[C:4](F)=[CH:5][C:6](F)=[C:7]([NH:9][C:10]2[N:15]=[C:14]([NH:16][CH:17]3[CH2:19][CH2:18]3)[C:13]3=[N:20][CH:21]=[C:22]([C:23]#[N:24])[N:12]3[N:11]=2)[CH:8]=1)#[N:2].[O:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][OH:35])[CH2:29][CH2:28]1>>[C:1]([C:3]1[C:4]([O:35][CH2:34][CH2:33][N:30]2[CH2:31][CH2:32][O:27][CH2:28][CH2:29]2)=[CH:5][C:6]([O:35][CH2:34][CH2:33][N:30]2[CH2:31][CH2:32][O:27][CH2:28][CH2:29]2)=[C:7]([NH:9][C:10]2[N:15]=[C:14]([NH:16][CH:17]3[CH2:19][CH2:18]3)[C:13]3=[N:20][CH:21]=[C:22]([C:23]#[N:24])[N:12]3[N:11]=2)[CH:8]=1)#[N:2]
Reactant: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(F)cc1F
Reactant: OCCN1CCOCC1
Product: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(OCCN2CCOCC2)cc1OCCN1CCOCC1

Procedure:
The title compound was obtained as the minor product (33% yield) from the reaction between 2-((5-cyano-2,4-difluorophenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 414) and 2-morpholinoethanol according to the procedure described in Example 419.
Reaction SMILES: C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.COC1C=CC(C[O:22][CH:23]([C:29]2[CH:34]=[CH:33][C:32]([C:35]3[C@@H:36]([CH2:46][CH2:47][CH2:48][C:49]4[S:53][C:52]([C:54]([O:56][CH3:57])=[O:55])=[CH:51][CH:50]=4)[CH2:37][CH2:38][C:39]=3[C:40]#[C:41][Si:42]([CH3:45])([CH3:44])[CH3:43])=[CH:31][CH:30]=2)[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=CC=1.O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:22][CH:23]([C:29]1[CH:34]=[CH:33][C:32]([C:35]2[C@@H:36]([CH2:46][CH2:47][CH2:48][C:49]3[S:53][C:52]([C:54]([O:56][CH3:57])=[O:55])=[CH:51][CH:50]=3)[CH2:37][CH2:38][C:39]=2[C:40]#[C:41][Si:42]([CH3:43])([CH3:44])[CH3:45])=[CH:31][CH:30]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCC(OCc1ccc(OC)cc1)c1ccc(C2=C(C#C[Si](C)(C)C)CC[C@@H]2CCCc2ccc(C(=O)OC)s2)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCCCCC(O)c1ccc(C2=C(C#C[Si](C)(C)C)CC[C@@H]2CCCc2ccc(C(=O)OC)s2)cc1
Reaction time: 0.5 h
Yield: 20.7 %

Procedure:
DDQ (160 mg, 0.71 mmol) was added to a solution of 1-2 (392 mg, 0.61 mmol) and H2O (0.9 mL) in CH2Cl2 (18 mL). After 30 minutes, saturated NaHCO3 solution (40 mL) was added and the resulting mixture was extracted with CH2Cl2 (3×25 mL). The combined CH2Cl2 solution was washed with brine and then was dried (Na2SO4), filtered and evaporated. The residue was purified by flash chromatography using a Combiflash unit from Teledyne Isco (0% ethyl acetate/hexanes→40%) to give the title compound (66 mg, 21%).