Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:33][CH2:34][CH2:35][N:36]4[CH2:41][CH2:40][N:39](C(OC(C)(C)C)=O)[CH2:38][CH2:37]4)=[C:24]([O:27][CH:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:12]=[CH:13][C:14]=1[F:15]>C(Cl)Cl>[Cl:8][C:9]1[CH:10]=[C:11]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:33][CH2:34][CH2:35][N:36]4[CH2:37][CH2:38][NH:39][CH2:40][CH2:41]4)=[C:24]([O:27][CH:28]4[CH2:29][CH2:30][CH2:31][CH2:32]4)[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:12]=[CH:13][C:14]=1[F:15]
Reactant: CC(C)(C)OC(=O)N1CCN(CCOc2cc3ncnc(Nc4ccc(F)c(Cl)c4)c3cc2OC2CCCC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1ccc(Nc2ncnc3cc(OCCN4CCNCC4)c(OC4CCCC4)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.00 ml trifluoroacetic acid are added dropwise to 740 mg of 4-[(3-chloro-4-fluorophenyl)amino]-6-cyclopentyloxy-7-{2-[4-(tert.butyloxycarbonyl)-piperazin-1-yl]-ethoxy}-quinazoline in 10 ml of methylene chloride. The reaction solution is stirred overnight at ambient temperature. For working up the reaction mixture is concentrated by evaporation, combined with 20 ml of water and made alkaline with concentrated aqueous ammonia solution. The aqueous phase is extracted with ethyl acetate. The combined extracts are washed with saturated sodium carbonate solution and saturated sodium chloride solution, dried over magnesium sulphate and concentrated by evaporation. A light yellow solid remains.
Reaction SMILES: [Na].[CH2:2]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([NH2:9])=[NH:8])[CH3:3].C([O:16][CH:17]=[C:18]([C:24](OCC)=O)[C:19]([O:21][CH2:22][CH3:23])=[O:20])C.Cl>C(O)C>[O:16]=[C:17]1[NH:9][C:7]([C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][CH2:2][CH3:3])=[N:8][CH:24]=[C:18]1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CCOc1ccccc1C(=N)N
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)c1cnc(-c2ccccc2OCC)[nH]c1=O
Temperature: 0 °C

Procedure:
To a cooled solution of sodium (1.04 g., 0.045 g -atom) in 35 ml. of ethanol was added all at once 2-ethoxybenzamidine (7.4 g., 45 mmole). There was then added to this suspension over a 5 minute period a solution of diethyl ethoxymethylenemalonate (9.7 g., 45 mmole) in 20 ml. of ethanol whereupon a pale yellow precipitate soon formed. An additional 25 ml. of ethanol was added to the reaction mixture which was then heated under reflux for 2 1/4 hours. The cooled solution was poured into about 500 ml. of ice-water and acidified with 6N HCl to produce a pale yellow solid. The solid was dried to give 10.2 g., 144°-149°, of title product. recrystallization from acetonitrile gave 9.8 g., m.p. 147°-150°, of purified product.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([N:8]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)(=[O:7])=[O:6].[Cl:27][C:28]1[CH:56]=[CH:55][C:31]([O:32][C:33]2[CH:38]=[CH:37][C:36]([N:39]3[C@@H:43]([C:44]4[CH:49]=[CH:48][CH:47]=[C:46]([C:50]([F:53])([F:52])[F:51])[CH:45]=4)[CH2:42][NH:41][C:40]3=[O:54])=[CH:35][CH:34]=2)=[CH:30][CH:29]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[Cl:27][C:28]1[CH:29]=[CH:30][C:31]([O:32][C:33]2[CH:34]=[CH:35][C:36]([N:39]3[C@@H:43]([C:44]4[CH:49]=[CH:48][CH:47]=[C:46]([C:50]([F:52])([F:51])[F:53])[CH:45]=4)[CH2:42][N:41]([CH2:2][CH2:3][CH2:4][S:5]([N:8]([CH2:9][C:10]4[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=4)[CH2:18][C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)(=[O:7])=[O:6])[C:40]3=[O:54])=[CH:37][CH:38]=2)=[CH:55][CH:56]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)S(=O)(=O)CCCCl)cc1
Reactant: O=C1NC[C@H](c2cccc(C(F)(F)F)c2)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)S(=O)(=O)CCCN2C[C@H](c3cccc(C(F)(F)F)c3)N(c3ccc(Oc4ccc(Cl)cc4)cc3)C2=O)cc1
Temperature: 80 °C
Reaction time: 14 h
Yield: 82.1 %

Procedure:
To a solution of 3-chloro-N,N-bis(4-methoxybenzyl)propane-1-sulfonamide (30.0 mg, 0.075 mmol) and (S)-1-(4-(4-chloro-phenoxy)-phenyl)-5-(3-(trifluoromethyl)-phenyl)-imidazolidin-2-one (20.0 mg, 0.046 mmol) in DMF (0.8 mL) is added Cs2CO3 (22 mg, 0.069 mmol) and KI (1 mg). The resulted mixture is stirred at 80° C. for 14 h and is cooled down to room temperature. The mixture is poured into water (5 mL) and extracted with EtOAc (3×3 mL). The combined organic layers are concentrated and purified by flash column chromatography to provide (S)-3-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)-N,N-bis(4-methoxybenzyl)propane-1-sulfonamide (30 mg, 82%). HPLC-MS calculated for C41H39ClF3N3O6S (M+H+) 794.2, found 794.2.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])[C:6]=1[Cl:7].[C:14]([C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15]>N1C=CC=CC=1>[Cl:7][C:6]1[C:5]([S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[CH:4][S:3][C:2]=1[NH:1][C:25]([NH:24][C:21]1[CH:22]=[CH:23][C:18]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:19][CH:20]=1)=[O:26]
Reactant: CC(C)S(=O)(=O)c1csc(N)c1Cl
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Solvent: c1ccncc1
Product: CC(C)S(=O)(=O)c1csc(NC(=O)Nc2ccc(C(C)(C)C)cc2)c1Cl
Yield: 35.5 %

Procedure:
2-Amino-3-chloro-4-isopropylsulfonylthiophene (260 mg) was stirred for 4 hours with 4-t-butylphenylisocyanate (119 mg) in 1 mL of pyridine at 60 ∞C. The pyridine was evaporated to dryness and the residue taken up in a mixture of ethyl acetate and 1N hydrochloric acid. The ethyl acetate layer was washed with water, saturated sodium bicarbonate and brine, and dried over anhydrous magnesium sulfate. Concentration and crystallization of the residue from ethanol and water gave 100 mg of N-[3-chloro-4-(isopropylsulfonyl)thien-2-yl]-N'-(4-t-butyl-phenyl)urea, an off-white solid.
Reaction SMILES: [C:1]([CH2:3][N:4]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[N:5]1)#[N:2].C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:21][OH:22]>C(O)C>[NH2:2]/[C:1](=[N:21]\[OH:22])/[CH2:3][N:4]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[N:5]1
Reactant: NO
Reactant: CCOC(=O)c1cnn(CC#N)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1cnn(C/C(N)=N/O)c1

Procedure:
The compound (1.6 g) obtained in Example 1a was suspended in ethanol (20 mL), and potassium carbonate (10.4 g) and hydroxylamine hydrochloride (5.2 g) were added. The reaction mixture was heated under reflux for 12 hr, and the insoluble material was removed by filtration. The solvent was evaporated under reduced pressure from the obtained filtrate to give the title compound as a bister solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:12])[CH2:10][CH3:11])=[CH:5][CH:4]=1.C([N-]C(C)C)(C)C.[Li+].Br[CH2:22][C:23]([O:25][CH3:26])=[O:24].Cl>C1COCC1.O>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:12])[CH:10]([CH3:11])[CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:5][CH:4]=1
Reactant: COC(=O)CBr
Reactant: CCC(=O)c1ccc(SC)cc1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CC(C)C(=O)c1ccc(SC)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The ketone from Step A (180 mg) in THF (2 ml) was added to a solution of lithium diisopropylamide (1.1 mmole) in THF (3 ml) at -78° under N2 atmosphere. After 15 minutes methyl bromoacetate (100 μl) was added and the mixture was warmed to ambient temperature and stirred 12 hours. The mixture was poured into water (15 ml) and conc. HCl (2 ml), extracted with CH2Cl2 and the extracts were dried (Na2SO4) evaporated to dryness and the residue purified by chromatography on silica gel to provide the title compound as an oil. NMR (CDCl3): 1.2 (3H, d), 2.55 (3H, s), 2.3-3.1 (2H, m), 3.65 (3H, s), 3.95 (1H, m), 7.3 (2H, d), 7.95 (2H, d).
Reaction SMILES: [CH:1]([C@H:3]1[C@@H:8]([CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:7][O:6][C@@H:5]([CH3:19])[O:4]1)=O.[NH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>CO.C(O)(=O)C>[CH3:18][O:17][C:15]([CH2:14][CH2:13][CH2:12]/[CH:11]=[CH:10]\[CH2:9][C@H:8]1[CH2:7][O:6][C@@H:5]([CH3:19])[O:4][C@H:3]1[CH2:1][NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)=[O:16]
Reactant: NCc1ccccn1
Reactant: COC(=O)CCC/C=C\C[C@H]1CO[C@@H](C)O[C@H]1C=O
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)CCC/C=C\C[C@H]1CO[C@@H](C)O[C@H]1CNCc1ccccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (2R,4R,5S)-4-formyl-5-[(Z)-6-methoxycarbonyl-2-hexenyl]-2-methyl-1,3-dioxane (200 mg) and 2-aminomethylpyridine (0.15 ml) in a mixture of methanol (4 ml) and acetic acid (1 ml) was added sodium cyanoborohydride (100 ml) and the solution was stirred at room temperature overnight. The mixture was neutralized with saturated aqueous sodium hydrogen carbonate and extracted with chloroform. The organic extract was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was chromatographed on a silica gel column (10 g) with a mixture of chloroform and methanol (30:1) as an eluent to give (2R,4R,5S)-5-[(Z)-6-methoxycarbonyl-2-hexenyl]-2-methyl-4-(2-pyridylmethylaminomethyl)-1,3-dioxane (165 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][OH:29])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][O:29][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCO)cc3)cc2)CC1
Reactant: BrCc1ccccn1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCOCc4ccccn4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 34, Step 4, using 1-{4′-[4-(2-hydroxy-ethyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 2-bromomethyl-pyridine.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:12])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5](Cl)=[O:6].[CH3:13][NH:14][CH2:15][CH2:16][OH:17]>C(Cl)Cl.[OH-].[Na+]>[Cl:1][C:2]1[C:3]([F:12])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([N:14]([CH2:15][CH2:16][OH:17])[CH3:13])=[O:6]
Reactant: CNCCO
Reactant: O=C(Cl)c1ccc(F)c(Cl)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CN(CCO)C(=O)c1ccc(F)c(Cl)c1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 61 %

Procedure:
3-Chloro-2,4-difluorobenzoylchloride (CAS no. 157373-00-7) (211 mg, 1 mmol) in DCM (1 mL) was added to a stirred solution of 2-(methylamino)ethanol (83 mg, 1.1 mmol) in a mixture of DCM (1 mL) and 10% sodium hydroxide solution (1 mL) at 0° C. The mixture was warmed to room temperature and stirred for approximately 4 hours. The two layers were separated and the aqueous layer was extracted with DCM (3×30 mL). The organic layers were combined, dried (MgSO4), filtered and evaporated to afford the product (180 mg, 61%). 1H NMR δ (400 MHz, CDCl3): 3.01 (s, 3H), 3.37 (t, 1H), 3.74 (t, 2H), 3.92 (t, 2H), 7.06 (td, 1H), 7.28-7.37 (m, 1H).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:20]([CH2:21][CH2:22][C@:6]12[CH3:7])[C@@H:19]1[C:14](=[CH:15][C:16](=[O:23])[CH2:17][CH2:18]1)[CH2:13][C@H:12]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][OH:29])(=[O:3])[CH3:2].[C:30](OC(=O)C)(=[O:32])[CH3:31]>N1C=CC=CC=1.C(OCC)(=O)C>[C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:20]([CH2:21][CH2:22][C@:6]12[CH3:7])[C@@H:19]1[C:14](=[CH:15][C:16](=[O:23])[CH2:17][CH2:18]1)[CH2:13][C@H:12]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30](=[O:32])[CH3:31])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@H]2[C@@H]3[C@H](CCCCCO)CC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]12C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)OCCCCC[C@@H]1CC2=CC(=O)CC[C@@H]2[C@H]2CC[C@]3(C)[C@@H](OC(C)=O)CC[C@H]3[C@H]12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 37.7 g of 17β-acetoxy-7α-(5-hydroxypentyl)-estr-4-en-3-one in 160 ml of pyridine is slowly mixed with 80 ml of acetic anhydride and stirred for 16 hours at 25° C. Then, it is diluted with ethyl acetate, and the organic phase, after washing with sodium bicarbonate solution, is dried and concentrated by evaporation. The residue is chromatographed on silica gel, and 26.6 g of 17β-acetoxy-7α-(5-acetoxypentyl)-estr-4-en-3-one is obtained as oil. [α]D22 =+20.0°(c=0.51% in chloroform)
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[N:12]([S:13]([C:16]3[S:17][C:18]([C:21]4[O:25][N:24]=[CH:23][CH:22]=4)=[CH:19][CH:20]=3)(=[O:15])=[O:14])[CH:11]=[C:10]([CH2:26][N:27](C)[C:28](=O)OC(C)(C)C)[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.C(OCC)(=O)C.[ClH:42]>C(O)C>[ClH:42].[F:1][C:2]1[C:7]([C:8]2[N:12]([S:13]([C:16]3[S:17][C:18]([C:21]4[O:25][N:24]=[CH:23][CH:22]=4)=[CH:19][CH:20]=3)(=[O:15])=[O:14])[CH:11]=[C:10]([CH2:26][NH:27][CH3:28])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CN(Cc1cc(-c2cccnc2F)n(S(=O)(=O)c2ccc(-c3ccno3)s2)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNCc1cc(-c2cccnc2F)n(S(=O)(=O)c2ccc(-c3ccno3)s2)c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 33 %

Procedure:
tert-Butyl ({5-(2-fluoropyridin-3-yl)-1-[(5-isoxazol-5-yl-2-thienyl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (80 mg) was dissolved in ethanol (5 mL), 4 mol/L hydrogen chloride-ethyl acetate solution (5 mL) was added, and the mixture was stirred at 50° C. for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from a mixed solvent of ethyl acetate-diethyl ether (1:1) to give the title compound as colorless crystals (yield 23 mg, 33%).
Reaction SMILES: [Na].[NH2:2][C:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][N:9]=2)[N:4]=1.C(#N)C=C[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[NH2:2][C:3]1[CH2:7][CH:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][N:9]=2)[N:4]=1
Reactant: NC1=NN(c2ccc(Cl)cn2)CC1
Reactant: N#CC=Cc1ccccc1
Agent: [Na]
Solvent: CCO
Product: NC1=NN(c2ccc(Cl)cn2)C(c2ccccc2)C1

Procedure:
A 0.5 g. amount of sodium metal is dissolved in 150 ml. of absolute ethanol, then 14.36 g. of 5-chloro-2-hydrazinopyridine (prepared as described in Example 3) is added followed by 12.92 g. of cinnamonitrile. The reaction mixture is refluxed for 16 hours. The solvent is removed in vacuo and water is added to the residue to separate a solid. The solid is collected by filtration and dissolved in dichloromethane. The solution is dried over anhydrous sodium sulfate and filtered through a hydrous magnesium silicate. The filtrate is concentrated while adding hexane to separate crystals. The material is recrystallized from ethyl acetate to give 11.68 g. of a light yellow crystalline material. The material is dried in vacuo to give the product of the Example as yellow crystals, m.p. 142°-147° C.
Reaction SMILES: [C:1]([NH:4][C@@H:5]([CH3:25])[CH2:6][O:7][C:8]1[CH:24]=[CH:23][C:11]([C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:16]=2[OH:22])=O)=[CH:10][CH:9]=1)(=[O:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[OH:21][C:18]1[CH:19]=[CH:20][C:15]2[N:14]=[C:12]([C:11]3[CH:23]=[CH:24][C:8]([O:7][CH2:6][C@@H:5]([NH:4][C:1](=[O:3])[CH3:2])[CH3:25])=[CH:9][CH:10]=3)[O:22][C:16]=2[CH:17]=1
Reactant: CC(=O)N[C@@H](C)COc1ccc(C(=O)Nc2ccc(O)cc2O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(=O)N[C@@H](C)COc1ccc(-c2nc3ccc(O)cc3o2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.8 %

Procedure:
To a solution of 4-{[(2S)-2-(acetylamino)propyl]oxy}-N-(2,4-dihydroxyphenyl)benzamide (628 mg) and triphenylphosphine (716 mg) in THF (6.0 mL) was added dropwise a toluene solution (2.2 M, 1.24 mL) of diethyl azodicarboxylate, and the mixture was stirred under a nitrogen atmosphere at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate/methanol) to give the title compound (326 mg).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=1)=O.O.[NH2:14][NH2:15]>O>[N+:10]([C:6]1[CH:5]=[C:4]([C:2](=[N:14][NH2:15])[CH3:1])[CH:9]=[CH:8][CH:7]=1)([O-:12])=[O:11]
Reactant: CC(=O)c1cccc([N+](=O)[O-])c1
Reactant: NN
Solvent: O
Product: CC(=NN)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 89.7 %

Procedure:
To a solution of 3-nitroacetophenone (200 g, 1.12 mol) in Industrial Methylated Spirits (1.2 l) was added hydrazine monohydrate (140 ml, 2.25 mol) and the reaction mixture was heated under reflux for 2 h. Water (1.2 l) was added and the reaction mixture was cooled to room temperature. The resulting precipitate was collected by filtration to afford the title compound as a yellow crystalline solid (180 g, 82%).
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:10][C:11]([F:16])([F:15])[C:12]([NH2:14])=[S:13]>C(O)C>[F:10][C:11]([F:16])([F:15])[C:12]1[S:13][CH:2]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:14]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: NC(=S)C(F)(F)F
Solvent: CCO
Product: CCOC(=O)c1csc(C(F)(F)F)n1
Yield: 27.9 %

Procedure:
A mixture of ethyl bromopyruvate (6.82 g), 2,2,2-trifluorothioacetamide (4.52 g) and ethanol (30 ml) was refluxed for 3 hours. The reaction mixture was cooled, then ethanol was distilled off under reduced pressure. To the residue was added water (40 ml), which was subjected to extraction with ethyl acetate (60 ml×2). The extract solution was washed with water (40 ml) and dried over magnesium sulfate, then the solvent was distilled off under reduced pressure. The residue was subjected to a silica gel chromatography (2.5×45 cm), eluting with ethyl acetate-hexane (1:5). The desired fraction was concentrated to give ethyl 2-trifluoromethyl-4-thiazolecarboxylate (2.2 g) as pale yellow needles.
Reaction SMILES: [C:1]1([C:7](=[N:14][CH:15]([CH2:23][CH2:24][CH:25]=[CH2:26])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].I[CH2:43][CH2:44][CH2:45][CH2:46][B:47]1[O:51][C:50]([CH3:53])([CH3:52])[C:49]([CH3:55])([CH3:54])[O:48]1>C(OCC)C>[C:1]1([C:7](=[N:14][C:15]([CH2:43][CH2:44][CH2:45][CH2:46][B:47]2[O:51][C:50]([CH3:53])([CH3:52])[C:49]([CH3:54])([CH3:55])[O:48]2)([CH2:23][CH2:24][CH:25]=[CH2:26])[C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC1(C)OB(CCCCI)OC1(C)C
Reactant: C=CCCC(N=C(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CCCC(CCCCB1OC(C)(C)C(C)(C)O1)(N=C(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 16 h
Yield: 79.7 %

Procedure:
While under an atmosphere of argon, a solution of tert-butyl 2-(diphenylmethyleneamino)hex-5-enoate (7.00 g, 20.06 mmol) in freshly distilled (THF 50 mL) was cooled to −78° C. and treated with sodium bis(trimethylsilyl)amide (60 mL, 1.0 M in THF). After stirring for 10 min 2-(4-iodobutyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (12.4 g, 40.0 mmol) was added and the reaction was warmed to room temperature and stirred for 16 h. Next, the reaction mixture was cooled to 0° C., diluted with ethyl ether and washed successively with saturated aqueous NaHCO3 and saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. Purification by MPLC (1-20% ethyl acetate in heptane with 0.5% triethylamine over 6 CV) gave tert-butyl 2-(diphenylmethyleneamino)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butyl)hex-5-enoate as a colorless oil (8.50 g, 80%). Rf 0.55 (30% ethyl acetate in heptane). ESI MS found for C33H46BNO4 m/z [532.5 (M+1)].
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH2:9])[CH:5]=[N:4][CH:3]=[N:2]1.O1CCCC1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]=[C:23]=[O:24])=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:9][CH2:8][CH2:7][CH2:6][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)=[O:24])=[CH:18][CH:17]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: NCCCn1cncn1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C(NCCCn1cncn1)Nc1ccc(Cl)cc1
Reaction time: 8 h

Procedure:
A 1.26 g. portion of 1H-1,2,4-triazole-1-propanamine was suspended in 15 ml. of toluene and 5 ml. of tetrahydrofuran was added to produce solution. A solution of 1.55 g. of freshly distilled p-chlorophenyl isocyanate in 15 ml. of toluene was added and the mixture was stirred overnight. The resulting crystals were recrystallized from toluene, giving 2.06 g. of the desired product, mp. 137°-139° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[O:12][C:11]3[C:13](B(O)O)=[CH:14][S:15][C:10]=3[C:9](=[O:19])[CH:8]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:27]1[C:28]([OH:36])=[C:29]([C:32]([O:34][CH3:35])=[O:33])[S:30][CH:31]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(COC)OC>[OH:36][C:28]1[C:27]([C:13]2[C:11]3[O:12][C:7]([N:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)=[CH:8][C:9](=[O:19])[C:10]=3[S:15][CH:14]=2)=[CH:31][S:30][C:29]=1[C:32]([O:34][CH3:35])=[O:33]
Reactant: O=c1cc(N2CCOCC2)oc2c(B(O)O)csc12
Reactant: COC(=O)c1scc(Br)c1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: COC(=O)c1scc(-c2csc3c(=O)cc(N4CCOCC4)oc23)c1O
Temperature: 140 °C

Procedure:
A 2 mL conical microwave vial was charged with a magnetic stirring bar, 5-morpholino-7-oxo-7H-thieno[3,2-b]pyran-3-ylboronic acid (69) (57 mg, 0.16 mmol), cesium carbonate (102 mg, 0.31 mmol), methyl 4-bromo-3-hydroxythiophene-2-carboxylate (56 mg, 0.24 mmol), tetrakis(triphenylphosphine)palladium(0) (9 mg, 0.08 mmol), and dimethoxyethane (0.5 mL). The reaction mixture was magnetically stirred and heated via microwave irradiation for 15 minutes at 140° C. Upon cooling to room temperature, the reaction was concentrated in vacuo and purified using high-pressure liquid chromatography to give methyl 3-hydroxy-4-(5-morpholino-7-oxo-7H-thieno[3,2-b]pyran-3-yl)thiophene-2-carboxylate (21).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([C:9](O)(O)[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].Cl.[NH2:15][NH:16][C:17]([NH2:19])=[O:18]>>[N:15](=[C:9]1[C:10](=[O:11])[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[C:7]1=[O:8])[NH:16][C:17]([NH2:19])=[O:18]
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Reactant: NNC(N)=O
Agent: Cl
Product: NC(=O)NN=c1c(=O)c2ccccc2c1=O

Procedure:
ninhydrin, semicarbazide hydrochloride.