Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[NH:11][C:10]([C:15]3[O:19][N:18]=[C:17]([O:20][CH2:21][C:22](O)=[O:23])[CH:16]=3)=[N:9][C:8]=2[N:7]([CH2:25][CH2:26][CH3:27])[C:5]1=[O:6])[CH2:2][CH3:3].[CH2:28]1[O:37][C:36]2[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][C:30]=2[O:29]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[CH3:27][CH2:26][CH2:25][N:7]1[C:5](=[O:6])[N:4]([CH2:1][CH2:2][CH3:3])[C:13](=[O:14])[C:12]2[C:8]1=[N:9]/[C:10](/[N:11]=2)=[C:15]1/[CH:16]=[C:17]([O:20][CH2:21][C:22]([NH:33][C:32]2[CH:34]=[CH:35][C:36]3[O:37][CH2:28][O:29][C:30]=3[CH:31]=2)=[O:23])[NH:18][O:19]/1
Reactant: Nc1ccc2c(c1)OCO2
Reactant: CCCn1c(=O)c2[nH]c(-c3cc(OCC(=O)O)no3)nc2n(CCC)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCCn1c(=O)c2c(n(CCC)c1=O)=N/C(=C1/C=C(OCC(=O)Nc3ccc4c(c3)OCO4)NO1)N=2

Procedure:
Condensation of 2-[5-(1,3-dipropyl-xanthin-8-yl)-isoxazol-3-yl)oxyacetic acid (0.5 mmol) and 3,4-methylenedioxyaniline (1.3 mmol) in the presence of EDCl (1.12 mmol) and HOBt (1.14 mmol) in anhydrous dimethylformamide afforded the desired product.
Reaction SMILES: COC1C=CC(C[N:8]2[N:12]=[N:11][C:10]([C:13]3[C:18](=[O:19])[N:17]4[CH:20]=[CH:21][C:22]([C:24]([OH:26])=O)=[CH:23][C:16]4=[N:15][CH:14]=3)=[N:9]2)=CC=1.[C:29]([C:33]1[N:34]=[C:35]([NH2:38])[S:36][CH:37]=1)([CH3:32])([CH3:31])[CH3:30].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl>CN(C)C1C=CN=CC=1.CN(C)C=O>[C:29]([C:33]1[N:34]=[C:35]([NH:38][C:24]([C:22]2[CH:21]=[CH:20][N:17]3[C:18](=[O:19])[C:13]([C:10]4[N:11]=[N:12][NH:8][N:9]=4)=[CH:14][N:15]=[C:16]3[CH:23]=2)=[O:26])[S:36][CH:37]=1)([CH3:32])([CH3:31])[CH3:30]
Reactant: COc1ccc(Cn2nnc(-c3cnc4cc(C(=O)O)ccn4c3=O)n2)cc1
Reactant: CC(C)(C)c1csc(N)n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)(C)c1csc(NC(=O)c2ccn3c(=O)c(-c4nn[nH]n4)cnc3c2)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3-[2-(4-Methoxybenzyl)-2H-1,2,3,4-tetrazol-5-yl]-4-oxo-4H-pyrido[1,2-a]-pyrimidine-8-carboxylic acid (40 mg, 0.114 mmol) was added with dimethylformamide (2 ml), 4-(tert-butyl)-1,3-thiazol-2-amine (20 mg, 0.125 mmol), 1-hydroxybenzotriazole (20 mg, 0.136 mmol) and 4-dimethylaminopyridine (21 mg, 0.170 mmol) at room temperature, then added with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (35 mg, 0.170 mmol) at room temperature, and stirred at room temperature for 24 hours. The reaction solution was added dropwise with 1 N hydrochloric acid (3 ml) at room temperature, and the deposited yellow crystals were taken by filtration and washed with water. The crystals were dissolved in chloroform and ethanol, concentrated under reduced pressure, and dried to obtain the title compound as yellow crystals without purification. The product was dissolved in anisole (0.2 ml) and trifluoroacetic acid (5 ml), stirred at room temperature for 5 hours, and added with water. The deposited yellow crystals were collected by filtration and washed with water, and the resulting crystals were dissolved in chloroform and ethanol and concentrated under reduced pressure. The crude crystals was added with ethanol, taken by filtration and washed with diethyl ether to obtain 28 mg (67% for the two steps) of the title compound as yellow crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[NH:8][N:7]=1)[CH3:2].[H-].[Na+].Br[CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1.Cl>CN(C)C=O>[N:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:30]=[CH:31][C:22]=1[CH2:21][N:8]1[C:9](=[O:16])[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:17])=[N:7]1
Reactant: CCOC(=O)Cc1n[nH]c(=O)c2ccccc12
Reactant: BrCc1ccc2ccccc2n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1nn(Cc2ccc3ccccc3n2)c(=O)c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.8 %

Procedure:
To a solution of ethyl-4-oxo-3H-phthalazin-1-ylacetate (1.0 g) and sodium hydride (60% w/w dispersion in mineral oil) in dimethylformamide (30 ml) was added 2-bromomethylquinoline (1.05 g). The resulting solution was stirred at room temperature for 30 minutes, poured onto water (100 ml) containing 1N HCl (5 ml), and extracted with ethyl acetate. The organic extract was washed with water (3×50 ml), dried and evaporated to obtain ethyl 3-(quinolin-2ylmethyl)-4-oxo-phthalazin-1-ylacetate (1.54 g). This substance was dissolved in a water/dioxane mixture (70 ml/70 ml). To the solution was added 5N potassium hydroxide (5 ml). The solution was allowed to stir at room temperature for 15 minutes, concentrated to remove excess dioxane, diluted with water (150 ml) and extracted with ethyl acetate (3×70 ml). The aqueous layer was adjusted to pH 2 with concentrated HCl. The precipitated solid was triturated with hot ethyl acetate and then filtered to obtain the title compound (0.54 g; m.p. 193°-194° C.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([N:10]1[CH2:14][CH2:13][N:12]=[CH:11]1)[OH:9]>CC(C)=O.O>[N:10]1([C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Br:1])=[O:9])[CH2:14][CH2:13][N:12]=[CH:11]1
Reactant: OC(c1ccccc1Br)N1C=NCC1
Solvent: O
Solvent: CC(C)=O
Product: O=C(c1ccccc1Br)N1C=NCC1
Reaction time: 1 h
Yield: 72.4 %

Procedure:
A solution of α-(o-bromophenyl)-2-imidazoline-methanol (16.0 g.) in acetone (600 ml.) and water (150 ml.) was stirred with deactivated precipitated manganese dioxide (100 g.) for 24 hours. [The commerical precipitated manganese dioxide was deactivated by stirring with water for 1 hour. and drying in a vacuum oven at ca.65°-70°C for 5 hours]. After filtering and washing the manganese dioxide with acetone, the solution was evaporated to a small volume under reduced pressure, diluted with water and extracted with chloroform. The combined extracts were dried (MgSO4), the solvent removed and the residue allowed to crystallise from a small volume of ether to yield crude o-bromophenyl 2-imidazolinyl ketone (11.5 g.). A sample recrystallised from benzene petroleum (b.p. 60°-80°) had m.p. 149°-151°. [Found: C, 47.9; H, 3.7; N, 11.1%; C10H9BrN2O requires C, 47.5; H, 3.6; N, 11.1%] .
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][CH:10]=1.C[N+]1([O-])CCOCC1>C(Cl)Cl.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]=[O:16])=[CH:13][N:14]=1
Reactant: OCc1ccc(COC2CCCCO2)nc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: O=Cc1ccc(COC2CCCCO2)nc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 42.2 %

Procedure:
(6-((tetrahydro-2H-pyran-2-yloxy)methyl)pyridin-3-yl)methanol (1.3 g, 6.0 mmol) was dissolved in CH2Cl2 (80 mL) and NMO (0.846 g, 7.2 mmol) and TPAP (0.210 g, 0.6 mmol) were added. After stirring at room temperature for 20 minutes, the reaction mixture was filtered through Celite®, and the filtrate was concentrated. Purification of the residue by flash chromatography on silica gel, eluting with 30% ethyl acetate/heptane to 75% ethyl acetate/heptane, afforded 6-((tetrahydro-2H-pyran-2-yloxy)methyl)nicotinaldehyde as a yellow oil (0.560 g, 42%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])[NH2:6].[C:14]([CH2:16][C:17](O)=[O:18])#[N:15].C(N=C=NC(C)C)(C)C>O1CCCC1>[C:14]([CH2:16][C:17]([NH:6][C:5]1[CH:7]=[C:8]([O:12][CH3:13])[C:9]([O:10][CH3:11])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:18])#[N:15]
Reactant: N#CCC(=O)O
Reactant: COc1cc(N)cc(OC)c1OC
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Product: COc1cc(NC(=O)CC#N)cc(OC)c1OC
Reaction time: 0.5 h
Yield: 18.9 %

Procedure:
3,4,5-Trimethoxyaniline (10.00 g, 54.6 mmol) and cyanoacetic acid (4.78 g, 56.19 mmol) were mixed in 100 mL of tetrahydrofuran and heated to reflux. To the resultant solution 1,3-diisopropylcarbodiimide (8.8 mL, 56.29 mmol) was added dropwise. The mixture was cooled in an ice-bath and the solid was collected by filtration washing with tetrahydrofuran. The filtrate was slowly poured into water and stirred for 30 minutes. The white solid was collected by filtration, washed with water and dried to give 2.58 g of 2-cyano-N-(3,4,5-trimethoxyphenyl)acetamide as a white solid, mp 146-147° C.; 1H NMR (400 MHz, DMSO-d6) δ 3.61 (s, 3H), 3.74 (s, 6H), 3.86 (s, 2H), 6.90 (s, 2H), 10.23 (s, 1H); MS (ES) m/z251.1 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[CH:5][C:4]=1/[CH:13]=[CH:14]/[C:15](=[O:17])[CH3:16].O.[C:19]([OH:23])(=[O:22])[CH:20]=O>C(O)(=O)C.O>[O:17]=[C:15](/[CH:14]=[CH:13]/[C:4]1[CH:5]=[CH:6][C:7]([O:11][CH3:12])=[C:8]([O:9][CH3:10])[C:3]=1[O:2][CH3:1])/[CH:16]=[CH:20]/[C:19]([OH:23])=[O:22]
Reactant: O=CC(=O)O
Reactant: COc1ccc(/C=C/C(C)=O)c(OC)c1OC
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(/C=C/C(=O)/C=C/C(=O)O)c(OC)c1OC

Procedure:
A solution of 18 g (76 mmol) of (E)-4-(2,3,4-trimethoxyphenyl)but-3-en-2-one and 7 g (76 mmol) of glyoxylic acid monohydrate in 19 ml of acetic acid was heated at reflux for 20 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was extracted twice with 3N sodium hydroxide solution. The combined aqueous phases were treated with 3N hydrochloric acid to produce a strongly acidic reaction and extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulphate and concentrated. Crystallization of the residue from ether/methylene chloride yielded (E,E)-4-oxo-6-(2,3,4-trimethoxyphenyl)-2,5-hexadienoic acid of melting point 125°-127°.
Reaction SMILES: O[CH:2]([CH2:15][O:16][CH:17]([CH3:19])[CH3:18])[CH2:3][NH:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[O:25]=[C:23]1[C:22]2[C:21](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20](=[O:30])[N:24]1[CH:2]([CH2:15][O:16][CH:17]([CH3:19])[CH3:18])[CH2:3][NH:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)OCC(O)CNC(=O)OCc1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)OCC(CNC(=O)OCc1ccccc1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At RT, 1.28 g of racemic benzyl (2-hydroxy-3-isopropoxypropyl)carbamate (4.79 mmol, 1 equivalent), 0.85 g of phthalimide (5.75 mmol, 1.2 equivalents) and 1.88 g of triphenylphosphine (7.2 mmol, 1.5 equivalent) were initially charged in 20 ml of dry tetrahydrofuran. 1.42 ml of diisopropyl azodicarboxylate (7.2 mmol, 1.5 equivalent) were added dropwise, and the mixture was stirred at RT for 2 h. The reaction mixture was concentrated under reduced pressure and purified by chromatography on silica gel (Biotage Isolera; cyclohexane/ethyl acetate gradient as mobile phase). This gave 2.3 g (66% pure; 78% of theory) of the title compound (contaminated with diisopropyl hydrazine-1,2-dicarboxylate).
Reaction SMILES: Br.Br[CH2:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.[O:10]([C:17]1[C:26]2[N:27]=[CH:28][N:29]([CH2:30][CH2:31][OH:32])[C:25]=2[C:24]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[Na+].CO>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.ClCCl.O>[O:10]([C:17]1[C:26]2[N:27]=[CH:28][N:29]([CH2:30][CH2:31][O:32][CH2:3][C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[C:25]=2[C:24]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N:18]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: BrCc1cccnc1
Reactant: OCCn1cnc2c(Oc3ccccc3)nc3ccccc3c21
Agent: Br
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: c1ccc(Oc2nc3ccccc3c3c2ncn3CCOCc2cccnc2)cc1
Yield: 81.5 %

Procedure:
3-(Bromomethyl)pyridine hydrobromide (0.638 g, 2.52 mmol) was added in a single portion with stirring to a solution containing 2-(4-phenoxy-1H-imidazo[4,5-c]quinolin-1-yl)ethanol (0.7 g, 2.29 mmol), benzyltrimethylammonium chloride (0.03 g), sodium hydroxide (28 mL of 50%) and dichloromethane (28 mL). After 3 hours analysis by TLC (5% methanol in dichloromethane) indicated that the reaction was complete. The reaction mixture was diluted with water (100 mL) and dichloromethane (100 mL). The layers were separated and the aqueous fraction was extracted with dichloromethane (100 mL). The organic fractions were combined, washed with brine, dried over magnesium sulfate and then concentrated under reduced pressure to provide a dark yellow solid. This material was purified by flash chromatography (silica gel eluting with 5% methanol in dichloromethane) to provide 0.74 g of 4-phenoxy-1-[2-(pyridin-3-ylmethoxy)ethyl]-1H-imidazo[4,5-c]quinoline as a bright yellow solid.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[BH4-].[Na+]>CO>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.6 %

Procedure:
To a solution of 1,4-dioxaspiro[4.5]decan-8-one (10.0 g) in methanol (120 ml) was added sodium borohydride (4.84 g) at 0° C. over a period of 15 min, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated in vacuo, and the residue was diluted with ethyl acetate. The mixture was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give the title compound as a pale yellow oil (6.24 g, 62%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([OH:12])=O.S(Cl)(Cl)=O.[OH:17][CH2:18][CH2:19][NH2:20]>C(Cl)(Cl)Cl>[OH:17][CH2:18][CH2:19][NH:20][C:10]([C:2]1[NH:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1)=[O:12]
Reactant: NCCO
Reactant: O=C(O)c1nc2ccccc2[nH]1
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=C(NCCO)c1nc2ccccc2[nH]1
Temperature: 25 °C
Yield: 74.9 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was purged with nitrogen and charged with 1H-benzo[d]imidazole-2-carboxylic acid (1.50 g, 9.26 mmol) and thionyl chloride (10 mL). After heating at reflux for 16 h, the suspension was cooled to room temperature and filtered. The filter cake was washed with toluene (10 mL) and dried under vacuum at room temperature for 5 h. The resulting solid was charged into a 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser, followed by chloroform (10 mL) and 2-hydroxyethylamine (559 mg, 9.17 mmol). After stirring at reflux for 16 h, the reaction mixture was concentrated under reduced pressure, and the resulting residue was triturated with water (20 mL) and dried in a vacuum oven at 45° C. to afford a 73% yield (1.41 g) of 152a as a white solid: mp 194-195° C.; 1H NMR (500 MHz, DMSO-d6) d 13.13 (s, 1H), 8.74 (s, 1H), 7.71-7.29 (m, 4H), 4.80 (s, 1H), 3.55 (dd, 2H, J=10.5, 5.5 Hz), 3.38 (dd, 2H, J=10.5, 5.5 Hz); MS (APCI+) m/z 206.6 (M+H).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([OH:19])=[C:11]([C:20](OCC)=[O:21])[C:10]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].CCN(C(C)C)C(C)C>O1CCOCC1>[CH2:1]([O:8][N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([OH:19])=[C:11]([C:20]([NH:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:21])[C:10]1=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(O)c2ccccc2n(OCc2ccccc2)c1=O
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCOC(=O)CNC(=O)c1c(O)c2ccccc2n(OCc2ccccc2)c1=O
Temperature: 100 °C
Yield: 37 %

Procedure:
To a stirring suspension of ethyl 1-(benzyloxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate (700 mg, 2.063 mmol), ethyl 2-aminoacetate hydrochloride (387 mg, 2.77 mmol) in dioxane (5 mL) was added DIPEA (0.660 ml, 3.78 mmol). Reaction mixture was heated at 100° C. for 12 h. Solvent from reaction mixture was distilled out to get crude product which was then column purified using 15% EtOAC in hexane to get titled product in 37% yield.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:6]2[N:5]=1)=O.[N:21]1([CH2:27][CH2:28][O:29][C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.COCC(O)C.C(N(CC)C(C)C)(C)C>>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[N:6]2[C:7]([CH:8]=[N:9][C:4]([NH:36][C:33]3[CH:34]=[CH:35][C:30]([O:29][CH2:28][CH2:27][N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)=[CH:31][CH:32]=3)=[N:5]2)=[CH:10][CH:11]=1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Reactant: Nc1ccc(OCCN2CCOCC2)cc1
Solvent: COCC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1ccc2cnc(Nc3ccc(OCCN4CCOCC4)cc3)nn12
Yield: 28.2 %

Procedure:
Into a microwave vial, 2-Methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (128 mg, 0.445 mmol), 4-(2-Morpholin-4-yl-ethoxy)-phenylamine (198 mg, 0.891 mmol), 1-Methoxy-2-propanol (1.50 mL, 15.3 mmol) and N,N-Diisopropylethylamine (0.171 mL, 0.980 mmol) were added. The reaction was microwaved on 300 watts, 180° C. for 3 hours. The reaction was monitored by HPLC. The reaction was partitioned with water and DCM. The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The Solvent was removed under vacuum. The desired product was purified via ISCO column chromatography with DCM and methanol as eluant (0 to 10% methano). The collected fractions afforded a yellow solid (56 mg, 28%). LCMS (E/I+) 446.8 (M+H). MP 133-135° C. NMR 1H (DMSO-d6)-9.20 (s, 1H), 8.91 (s, 1H), 7.82 (m, 1H), 7.60 (d, 2H, 8.84 Hz), 7.45 (t, 1H, J=7.88 Hz), 6.92 (d, 1H, J=5.45 Hz), 6.80 (d, 1H, J=5.45 Hz), 6.79 (d, 2H, J=9.09 Hz), 4.02 (t, 2H, J=5.45 Hz), 3.82 (s, 3H), 3.58 (t, 4H, J=4.24 Hz), 2.65 (t, 2H, J=6.06 Hz), 2.46 (m, 4H).
Reaction SMILES: C([NH:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]1[CH:21]=[CH:20][NH:19][N:18]=1)=[S:11])(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>>[NH:19]1[CH:20]=[CH:21][C:17]([NH:16][CH2:15][CH2:14][CH2:13][NH:12][C:10]([NH2:9])=[S:11])=[N:18]1
Reactant: O=C(NC(=S)NCCCNc1cc[nH]n1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: NC(=S)NCCCNc1cc[nH]n1

Procedure:
Treating the benzoyl thiourea with potassium carbonate by the procedure of Example 46 gives N-[3-(3-pyrazolylamino)propyl]thiourea.
Reaction SMILES: [NH2:1][S:2]([C:5]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]([CH3:13])[C:6]=1[NH:14][C:15]([C:17]1[C:18](=[O:35])[N:19]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:20]2[C:25]([C:26]=1[OH:27])=[CH:24][CH:23]=[CH:22][N:21]=2)=O)(=[O:4])=[O:3].NS(C1C=C(Br)C=CC=1NC(C1C(=O)N(CC2C=CC=CC=2)C2C(C=1O)=CC=CN=2)=O)(=O)=O>Cl>[CH2:28]([N:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][N:21]=2)[C:26]([OH:27])=[C:17]([C:15]2[NH:14][C:6]3[C:7]([CH3:13])=[CH:8][CH:9]=[C:10]([O:11][CH3:12])[C:5]=3[S:2](=[O:3])(=[O:4])[N:1]=2)[C:18]1=[O:35])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COc1ccc(C)c(NC(=O)c2c(O)c3cccnc3n(Cc3ccccc3)c2=O)c1S(N)(=O)=O
Agent: Cl
Agent: NS(=O)(=O)c1cc(Br)ccc1NC(=O)c1c(O)c2cccnc2n(Cc2ccccc2)c1=O
Product: COc1ccc(C)c2c1S(=O)(=O)N=C(c1c(O)c3cccnc3n(Cc3ccccc3)c1=O)N2
Yield: 56 %

Procedure:
The title compound was prepared according to the procedure of Example 84D substituting the product of Example 209B for the product of Example 84C. The solution was then acidified with 6N aqueous HCl (10 mL), filtered and the solid washed with methanol (10 mL) to give the title compound as a white solid, (0.12 g, 56% yield). MS (ESI−) m/z 477 (M−H)+. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ 2.37 (s, 3 H) 3.83 (s, 3 H) 5.52 (s, 2 H) 6.76 (d, J=8.5 Hz, 1 H) 7.16 (m, 2 H) 7.23 (m, 4 H) 7.37 (d, J=8.9 Hz, 1 H) 8.45 (m, 2 H), 15.67 (s, 1 H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:29][CH2:30][CH2:31]O.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[F:29][CH2:30][CH2:31][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: OCCF
Reactant: O=Cc1ccc(O)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=Cc1ccc(OCCF)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 40.3 %

Procedure:
To a mixture of 4-hydroxybenzaldehyde (1.45 g, 11.9 mmol), triphenylphosphine (6.87 g, 26.2 mmol) and 2-fluoroethanol (1.68 g, 26.2 mmol) in dry THF (70 ml) at 0° C., was added DIAD (5.29 g, 26.2 mmol) dropwise. The reaction mixture was stirred at 0° C. for 1 h then allowed to rise to room temperature and stirred for 48 h. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (5:1 DCM/Hexane) to give the title compound (0.807 g, 40%) as a colourless solid.
Reaction SMILES: [ClH:1].[CH2:2]1[O:32][C:31]2[CH:30]=[CH:29][C:6]([O:7][CH2:8][C@H:9]3[C@H:14]([C:15]4[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=4)[CH2:13][CH2:12][N:11]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:10]3)=[CH:5][C:4]=2[O:3]1>C(O)C>[ClH:1].[NH2:21][C:18]1[CH:17]=[CH:16][C:15]([C@@H:14]2[CH2:13][CH2:12][N:11]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:10][C@H:9]2[CH2:8][O:7][C:6]2[CH:29]=[CH:30][C:31]3[O:32][CH2:2][O:3][C:4]=3[CH:5]=2)=[CH:20][CH:19]=1
Reactant: CCCCCN1CC[C@@H](c2ccc([N+](=O)[O-])cc2)[C@H](COc2ccc3c(c2)OCO3)C1
Agent: Cl
Solvent: CCO
Product: CCCCCN1CC[C@@H](c2ccc(N)cc2)[C@H](COc2ccc3c(c2)OCO3)C1

Procedure:
Compound (7) (0.39 g) in abs. ethanol (50 ml) was hydrogenated at atm. pressure using 5% PdC (50 mg) as catalyst. The reaction mixture was filtered, evaporated to dryness. Extraction with NaOH(4N)-ether, separation of the etheral layer, drying (MgSO4), followed by evaporation to dryness gave an yellow oil which was purified on a silica gel column and precipitated as a very hygroscopic hydrochloride from acetone-ether. Identified by 1H NMR.
Reaction SMILES: [CH2:1]([O:15][C:16]1[S:20][C:19]([C:21]([OH:23])=[O:22])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[C:24](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O.CO>CC(C)=O>[CH3:24][O:22][C:21]([C:19]1[S:20][C:16]([O:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:17][CH:18]=1)=[O:23]
Reactant: O=C([O-])[O-]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)O)s1
Agent: [K+]
Solvent: CO
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)OC)s1

Procedure:
A mixture of 10.6 g of (0.031 mole) of 5-tetradecyloxy-2-thiophene carboxylic acid, 200 ml of acetone, and 4.3 g (0.031 mole) of potassium carbonate is stirred at room temparature after which 3.9 g (0.031 mole) of dimethyl sulfate is added. The mixture is stirred with heating for about 21/2 hours during which time 10 ml of methanol is added. The mixture is then diluted with 100 ml of acetone and filtered. The filtrate is evaporated to dryness to give 5-tetradecyloxy-2-thiophene carboxylic acid methyl ester.