Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:15]2[CH:2]1[C:3](=[O:25])[C@@H:4]([C@H:14]2/[CH:16]=[CH:17]/[C@@H:18]([OH:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:5]/[CH:6]=[CH:7]\[CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12].N1C=CC=CC=1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>O>[C:32]([O:24][C@@H:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])/[CH:17]=[CH:16]/[C@@H:14]1[C@@H:4]([CH2:5]/[CH:6]=[CH:7]\[CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])[C:3](=[O:25])[CH:2]2[O:1][CH:15]12)(=[O:34])[CH3:33]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCC[C@H](O)/C=C/[C@H]1C2OC2C(=O)[C@@H]1C/C=C\CCCC(=O)O
Solvent: O
Solvent: c1ccncc1
Product: CCCCC[C@@H](/C=C/[C@H]1C2OC2C(=O)[C@@H]1C/C=C\CCCC(=O)O)OC(C)=O
Reaction time: 18 h

Procedure:
to a solution of 1 part of (5Z,13E,15S)-10ξ,11ξ-epoxy-15-hydroxy-9-oxoprosta-5,13-dien-1-oic acid in 30 parts of pyridine at 5° is added 10 parts of acetic anhydride. The resultant mixture is allowed to stand at 5° for 18 hours, whereupon it is poured into 10 volumes of water. The mixture thus obtained is allowed to stand for 1 hour, then extracted with ethyl acetate. The extract is washed with water, dried over anhydrous sodium sulfate, and stripped of solvent by vacuum distillation. The residual red oil is taken up in benzene; and the benzene solution is chromatographed on silica gel, using benzene and mixtures thereof with increasing amounts of ethyl acetate as developing solvents. From an eluate comprising 20% ethyl acetate in benzene, on evaporation of solvent, (5Z,13E,15S)-15-acetoxy-10ξ,11ξ-epoxy-9-oxoprosta-5,13-dien-1-oic acid is obtained as a pale yellow oil.
Reaction SMILES: F[C:2](F)(F)[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH2:16]([N:18]1[C:24]2[N:25]=[CH:26][CH:27]=[CH:28][C:23]=2[C:22](=O)[NH:21][C:20]2[C:30]([CH3:35])=[CH:31][C:32]([CH3:34])=[N:33][C:19]1=2)[CH3:17].C(Cl)Cl.C(N(C(C)C)CC)(C)C>[C-]#N.C([N+](CC)(CC)CC)C.C(OCC)(=O)C>[CH2:16]([N:18]1[C:24]2[N:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH:22]([O:6][S:3]([CH3:2])(=[O:5])=[O:4])[NH:21][C:20]2[C:30]([CH3:35])=[CH:31][C:32]([CH3:34])=[N:33][C:19]1=2)[CH3:17]
Reactant: CCN1c2ncccc2C(=O)Nc2c(C)cc(C)nc21
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: CC[N+](CC)(CC)CC
Agent: [C-]#N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCN1c2ncccc2C(OS(C)(=O)=O)Nc2c(C)cc(C)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.9 %

Procedure:
Trifluoromethanesulfonic anhydride (0.24 ml, 14 mmol) was added to a solution of 0.314 g (1.2 mmol) 5,11-dihydro-11-ethyl-2,4-dimethyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one in 15 ml of methylene chloride containing 0.25 ml (14 mmol) of diisopropylethylamine, and the resulting mixture was refluxed under argon for three hours. Ethyl acetate (~200 mL) was then added and the solution was washed three times with water and four times with brine. After drying (magnesium sulfate), the solution was concentrated in vacuo and the residue dried under high vacuum for 2 hr. The residue was dissolved in 20 ml of methylene chloride, and 0.23 g (14 mol) of tetraethylammonium cyanide was added. After stirring the resulting solution overnight at room temperature, the reaction mixture was concentrated in vacuo. The residue was dissolved in 100 ml of ethyl acetate, and the solution was washed with water and brine. The dried (magnesium sulfate) solution was concentrated in vacuo and the residue was chromatographed over silica with 5% ethyl acetate/hexane. The resulting solid was crystallized from heptane to provide 0.033 g of the title compound as red crystals. m.p. 154°-155° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][C:11](=[O:16])[CH2:12][C:13]([CH3:15])=O)=[CH:4][CH:3]=1.[NH2:17]/[C:18](/[CH3:24])=[CH:19]\[C:20]([O:22][CH3:23])=[O:21].[N+:25]([C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH:31]=O)([O-:27])=[O:26]>CO>[CH3:24][C:18]1[NH:17][C:13]([CH3:15])=[C:12]([C:11]([O:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)=[O:16])[CH:31]([C:30]2[CH:33]=[CH:34][CH:35]=[C:28]([N+:25]([O-:27])=[O:26])[CH:29]=2)[C:19]=1[C:20]([O:22][CH3:23])=[O:21]
Reactant: CC(=O)CC(=O)OCCc1ccc(O)cc1
Reactant: COC(=O)/C=C(/C)N
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Solvent: CO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCc2ccc(O)cc2)C1c1cccc([N+](=O)[O-])c1
Yield: 68 %

Procedure:
A mixture of 4.3 g of 2-(4-hydroxyphenyl)ethylacetoacetate (10), 2.3 g of methyl β-amino-crotonate, 2.9 g of 3-nitrobenzaldehyde and 70 mL of methanol was heated at reflux for 12 hours. The solvent was removed under reduced pressure and the residue purified by silica gel chromatography using 50:50 ethyl acetate-hexane to yield 5.9 g of 2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-5-[2-(4-hydroxyphenyl)ethoxycarbonyl]-1,4-dihydropyridine (11), as an amorphous solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[CH:9]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:8]2)(=[O:3])[CH3:2].C[O-:20].[Na+].[CH:22]([C:24]([CH3:26])=O)=[CH2:23]>CO>[C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[C:9]([CH2:23][CH2:22][CH2:24][CH3:26])([CH2:15][CH2:16][C:17](=[O:20])[CH3:18])[CH2:8]2)(=[O:3])[CH3:2]
Reactant: C[O-]
Reactant: CCCCC1Cc2cc(NC(C)=O)ccc2C1=O
Reactant: C=CC(C)=O
Agent: [Na+]
Solvent: CO
Product: CCCCC1(CCC(C)=O)Cc2cc(NC(C)=O)ccc2C1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 87 %

Procedure:
A solution of 5-(acetylamino)-2-butyl-1-indanone (8.8 g, 35.9 mmol) in MeOH (95 mL) was treated with 0.5M NaOMe in MeOH (14.4 mL, 7.2 mmol). The resulting solution was placed under a N2 atmosphere, treated with methyl vinyl ketone (4.5 mL, 54 mmol), and then stirred at room temperature for three days. The mixture was partitioned between EtOAc and saturated aqueous NH4Cl, and the aqueous phase was back-extracted with EtOAc. The combined organics were washed with 5% NaHCO3, water, and brine, dried over MgSO4, filtered, and concentrated under vacuum to an oil (11.8 g). The crude product was purified by Biotage flash chromatography on a 75 L silica gel column (7.5×35 cm), eluting with 2:1 hexane-EtOAc, to provide 5-(acetylamino)-2-butyl-2-(3-oxobutyl)-1-indanone (9.8 g, 87%) as a clear oil.
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH2:5][CH:6]1[C:20](=[O:21])[C:10]2[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:12][O:13][C:9]=2[CH2:8][CH2:7]1)[CH3:4].[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[OH2:13].[ClH:1].[N:3]1([CH2:5][CH:6]2[C:20](=[O:21])[C:10]3[C:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)=[N:12][O:13][C:9]=3[CH2:8][CH2:7]2)[CH2:2][CH2:25][CH2:24][CH2:23][CH2:4]1.[N:22]1([CH2:5][CH:6]2[C:20](=[O:21])[C:10]3[C:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)=[N:12][O:13][C:9]=3[CH2:8][CH2:7]2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.[ClH:1]
Reactant: CN(C)CC1CCc2onc(-c3ccccc3)c2C1=O
Reactant: C1CCNCC1
Agent: Cl
Product: O
Product: O=C1c2c(-c3ccccc3)noc2CCC1CN1CCCCC1

Procedure:
6,7-Dihydro-5-dimethylaminomethyl-3-phenyl-1,2-benzisoxazol-4(5H)-one hydrochloride (0.80 g) was warmed with 5 ml of piperidine (4.31 g) at 90° C. for 20 minutes. The excess piperidine was removed in vacuo and the hydrochloride was formed in ethereal HCl to give 0.95 g of 6,7-dihydro-5-(1-piperidinylmethyl)-3-phenyl-1,2-benzisoxazol-4(5H)-one hydrochloride hemihydrate, m.p. 182°-183° C.
Reaction SMILES: N[C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=2[CH3:19])=[CH:4][N:3]=1.C(I)[I:22].CCOC(C)=O>C1COCC1.[Cu]I>[I:22][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=2[CH3:19])=[CH:4][N:3]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)Nc1cnc(N)nc1
Reactant: ICI
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc([N+](=O)[O-])cc1C(=O)Nc1cnc(I)nc1
Temperature: 70 °C

Procedure:
N-(2-Aminopyrimidin-5-yl)-2-methyl-5-nitrobenzamide [prepared according to Specific Method 1] (200 mg, 0.732 mmol), CuI (140 mg, 0.732 mmol) and CH2I2 (0.30 mL, 3.73 mmol) were taken up in THF (3.7 mL) in a 16×100 mm resealable pyrex tube. The tube was sealed and the mixture was heated at 70° C. for 2 h. After cooling to rt, the crude reaction mixture was taken up in 1:1 EtOAc:1N HCl and the layers were separated. The organics were washed with saturated NH4Cl then dried over Na2SO4. Purification by MPLC (Isco—100% EtOAc eluent) afforded N-(2-iodopyrimidin-5-yl)-2-methyl-5-nitrobenzamide as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4]([NH2:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH3:13])=[C:8]([CH2:14][CH3:15])[CH:7]=1.[NH:18]1[CH2:23][CH2:22][CH:21]([N:24]2[CH2:30][CH2:29][C:28]3[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=3[NH:26][C:25]2=[O:35])[CH2:20][CH2:19]1.C1C[O:39][CH2:38]C1>C(=O)(O)[O-].[Na+]>[CH3:1][O:2][C:3](=[O:17])[CH:4]([NH:16][C:38]([N:18]1[CH2:19][CH2:20][CH:21]([N:24]2[CH2:30][CH2:29][C:28]3[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=3[NH:26][C:25]2=[O:35])[CH2:22][CH2:23]1)=[O:39])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH3:13])=[C:8]([CH2:14][CH3:15])[CH:7]=1
Reactant: O=C1Nc2ccccc2CCN1C1CCNCC1
Reactant: C1CCOC1
Reactant: CCc1ccc(CC(N)C(=O)OC)cc1CC
Agent: O=C([O-])O
Agent: [Na+]
Product: CCc1ccc(CC(NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)OC)cc1CC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
7.4 g (45 mmol) of CDT was added to a solution of 10.5 g (44.6 mmol) methyl-2-amino-3-(3,4-diethyl-phenyl)-propionate (Intermediate product 48) in 250 mL THF cooled to 0° C. and the resulting mixture was stirred for a further 30 minutes at this temperature. Then 10.9 g (44.6 mmol) 3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one was added, while the reaction solution was kept at this temperature for a further 20 minutes, before being refluxed for 30 minutes. The solvent was eliminated in vacuo, the residue was taken up in sat. sodium bicarbonate solution, exhaustively extracted with ether/EtOAc (1:1) and dried over magnesium sulphate. After removal of the drying agent and solvent the crude product was reacted without any further purification.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:6][CH:7]=[CH2:8])[C:3]([OH:5])=[O:4].CC(C)([O-])C.[K+].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1>CN(C=O)C>[CH3:1][C:2]([CH3:9])([CH2:6][CH:7]=[CH2:8])[C:3]([O:5][CH2:22][C:21]1[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=1)=[O:4]
Reactant: C=CCC(C)(C)C(=O)O
Reactant: COc1ccc(CCl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCC(C)(C)C(=O)OCc1ccc(OC)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 95.8 %

Procedure:
To a solution of 2,2-dimethyl-4-pentenoic acid (11.5 g, 90 mmol) in DMF (250 mL) at room temperature, was added potassium tert-butoxide (11.1 g, 99 mmol). The reaction mixture was stirred at 60° C. for 1 h. 4-Methoxybenzyl chloride (16.9 g, 108 mmol) was added and the reaction mixture was stirred at 60° C. for 4 h. The DMF was evaporated under vacuum, the residue was dissolved in ether (500 mL) and washed with water (3×200 mL). The organic phase was dried with Na2SO4 and evaporated to give 21.4 g of 4-methoxybenzyl 2,2-dimethyl-4-pentenoate.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:16])/[CH:9]=[CH:10]/[C:11]1[CH:15]=[CH:14][NH:13][CH:12]=1)([CH3:6])([CH3:5])[CH3:4].[Br:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.O>C1COCC1>[C:3]([O:7][C:8](=[O:16])/[CH:9]=[CH:10]/[C:11]1[CH:15]=[CH:14][N:13]([S:25]([C:22]2[CH:21]=[CH:20][C:19]([CH2:18][Br:17])=[CH:24][CH:23]=2)(=[O:26])=[O:27])[CH:12]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: O=S(=O)(Cl)c1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)/C=C/c1cc[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)/C=C/c1ccn(S(=O)(=O)c2ccc(CBr)cc2)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
4.25 g of sodium hydride (60% strength) are suspended in 300 ml of THF under nitrogen at −30° C. 9.78 g of (E)-3-(1H-pyrrol-3-yl)-acrylic acid tert-butyl ester (compound D1) are added to the suspension and warmed slowly to room temperature during 55 min. Afterwards it is recooled to −30° C. and it is added 13.98 g of 4-(bromomethyl)-benzenesulphonylchloride and stirred for 45 min. Then it is warmed to room temperature and stirred for 2 hour. After cooling to 0-5° C. water is added. Then the mixture is extracted with ethyl acetate and the organic phase is dried over sodium sulfate. The organic phase is evaporated under vacuum. The crude product is purified by silica gel flash chromatography using a gradient of hexane and ethyl acetate from 9:1-7:1.
Reaction SMILES: [NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[O:7])=[C:4]([OH:19])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:39](O)[CH2:40][CH:41]([OH:43])[CH3:42].N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:12][CH3:13])[CH2:14][CH3:15])=[O:7])=[C:4]([O:19][CH2:39][CH2:40][CH:41]([OH:43])[CH3:42])[CH:3]=1
Reactant: CC(O)CCO
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OCCC(C)O
Reaction time: 8 h
Yield: 29.3 %

Procedure:
A stirred solution of 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-hydroxybenzamide (2.86 g, 10 mmoles; prepared according to Preparation B), triphenylphosphine (2.62 g, 10 mmoles), (±) 1,3 butandiol (0.90 g, 10 mmoles) in dry tetrahydrofuran (50 ml) was treated dropwise with diethyl azodicarboxylate (1.75 g of 95% purity material, 10 mmoles). The solution was left to stir overnight. After evaporation of the solvent the residue was taken up in methylene chloride. The solution was washed with 0.4N NaOH, water, dried and the solvent evaporated. The residue was chromatographed over deactivated silica using methylene chloride (100), methanol (3), ammonium hydroxide (0.5) solvent system. The appropriate fractions were combined and the solvent evaporated. The residue was crystallized from methylene chloride-pentane to yield 1.05 g (29%) of the title compound. m.p. 136.5°-137.5° C. An additional amount of 0.56 g of material was obtained from the mother liquor after crystallization from toluene, followed by recrystallization from methylene chloride-pentate, and from a dilute solution of ethyl acetate, m.p. 135°-137° C.
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[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:30]=[N:31][CH:32]=[C:33]([O:35][CH:36]([CH3:38])[CH3:37])[CH:34]=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[NH:27][C:29]4[CH:30]=[N:31][CH:32]=[C:33]([O:35][CH:36]([CH3:38])[CH3:37])[CH:34]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CC(C)Oc1cncc(Br)c1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cncc(OC(C)C)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 290, Step 1, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 3-bromo-5-isopropoxy-pyridine.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH3:13])[CH:8]=1.CN(C)[CH:16]=[O:17]>C1COCC1>[CH3:13][C:9]1[CH:8]=[C:7]([CH:16]=[O:17])[CH:12]=[CH:11][N:10]=1
Reactant: Cc1cc(Br)ccn1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(C=O)ccn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of n-butyllithium (1.6 M solution in hexanes, 6.32 mL, 12.6 mmol) in THF (50 mL) was cooled to −78° C. A solution of 4-bromo-2-methyl-pyridine (2.00 g, 11.6 mmol.) in anhydrous THF (5 mL) was added. The resulting mixture was stirred for 5 minutes, then anhydrous N,N dimethylformamide (3.39 g, 46.4 mmol,) was added. The solution was stirred for 90 min at −78° C. and quenched with saturated aqueous NH4Cl solution (30 mL). The reaction mixture was warmed to room temperature. The mixture was extracted with ethyl acetate (3×100 mL), and the combined organic phase was washed with brine (100 mL) and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to give 2-methyl-pyridine-4-carbaldehyde. Yield: 1.20 g, (85%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][NH2:14])=[O:12].C(N(CC)CC)C.C1C=CC(O[C:29](OC2C=CC=CC=2)=[N:30][C:31]#[N:32])=CC=1>C(O)(C)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[O:12][CH:29]([NH:30][C:31]#[N:32])[NH:14][N:13]=1
Reactant: NNC(=O)c1ccc2ccccc2c1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: N#CNC1NN=C(c2ccc3ccccc3c2)O1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 50.2 %

Procedure:
To a stirred solution of naphthalene-2-carboxylic acid hydrazide (0.7 g, 3.76 mmol) in isopropanol (40 ml) was added triethylamine (630 μl, 4.51 mmol) and diphenyl cyanocarbonimidate (0.99 g, 4.14 mmol) and the resulting reaction mixture was stirred at room temperature for 1.5 h. The volatiles were evaporated in vacuo and to the residue was added water (50 ml) and diethyl ether (50 ml). The organic phase was separated and the aqueous phase was acidified to pH=1 with concentrated hydrochloric acid. The precipitate was filtered off and washed with water (3×10 ml) and diethyl ether (2×10 ml) and dried in vacuo at 50° C. which afforded 0.45 g (51%) of the title compound as a solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:17])[CH:10]=2)=[CH:6][CH:5]=[C:4]([N+:23]([O-])=O)[N:3]=1.[NH4+].[Cl-]>CO.C1COCC1.CCOC(C)=O.[Zn]>[NH2:23][C:4]1[N:3]=[C:2]([CH3:1])[C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:17])[CH:10]=2)=[CH:6][CH:5]=1
Reactant: Cc1nc([N+](=O)[O-])ccc1Oc1ccnc(NC(=O)N2CCCC2)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nc(N)ccc1Oc1ccnc(NC(=O)N2CCCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
A mixture of N-(4-((2-methyl-6-nitropyridin-3-yl)oxy)pyridin-2-yl)pyrrolidine-1-carboxamide (0.720 g, 2.097 mmol) and NH4Cl (3.37 g, 62.9 mmol) in MeOH (10 mL) and THF (10 mL) was treated with zinc dust (1.371 g, 20.97 mmol) and stirred at RT overnight. The mixture was diluted with EtOAc, the solids removed via filtration and the filtrate concentrated to dryness to afford N-(4-((6-amino-2-methylpyridin-3-yl)oxy)pyridin-2-yl)pyrrolidine-1-carboxamide (658 mg, 100%). MS (ESI) m/z: 314.2 (M+H+).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@H:12]2[O:16][C@@H:15]([N:17]3[CH:25]=[C:23]([CH3:24])[C:21](=[O:22])[NH:20][C:18]3=[O:19])[CH2:14][C@@H:13]2[OH:26])(=O)=O)=CC=1.[CH3:28][NH2:29].[K+].[Br-]>O>[CH3:28][NH:29][CH2:11][C@H:12]1[O:16][C@@H:15]([N:17]2[CH:25]=[C:23]([CH3:24])[C:21](=[O:22])[NH:20][C:18]2=[O:19])[CH2:14][C@@H:13]1[OH:26]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@H]2O)cc1
Reactant: CN
Agent: [Br-]
Agent: [K+]
Solvent: O
Product: CNC[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1O
Reaction time: 72 h

Procedure:
5'-O-(p-toluenesulfonyl)thymidine (19.8 g, 50 mmol) was placed in a pressure vessel into which monomethylamine (250 g) was condensed. The vessel was sealed and allowed to stand at room temperature for 3 days. The vessel was cooled, opened, and the monomethylamine allowed to evaporate. The remaining contents of the vessel were removed by rinsing with water. The aqueous solution was passed through a column (6.5×20 cm) of AG50Wx8 ion-exchange resin (H+ form). The column was washed with water until the washings were neutral. The product was then eluted with 1N aqueous ammonium hydroxide. The eluent was stripped down and the resulting solid chromatographed on a column (6.5×20 cm) of silica gel with methylene chloride/methanol/concentrated aqueous ammonium hydroxide (85:13:2) as the eluting solvent. The product containing fractions were stripped down, then taken up in water and lyophilized. The product was a pale-yellow, amorphous solid (8.81 g, 69%). A satisfactory combustion analysis could not be obtained for this material.) [α]D25 (c=1.0 in water): +25.9 deg. ir (KBr): cm-1 1693, 1472, 1273, 1076. NMR (DMSO-d6): δ1.790 (s, 3H), 2.051 (ddd, 13.4, 6.3, 3.5 hz, 1H), 2.142 (dt, 13.4, 6.9 hz, 1H), 2.314 (s, 3H), 2.658 (d, 5.5 hz, 2H), 3.775 (td, 5.3, 3.2 hz, 1H), 4.171 (dt, 6.3, 3.2 hz, 1H), 6.134 (t, 6.9 hz, 1H) and 7.639 (s, 1H).
Reaction SMILES: [CH2:1]([O:5][P:6]([C:13]1[CH:17]=[CH:16][S:15][C:14]=1I)([O:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:7])[CH2:2][CH2:3][CH3:4].C([Sn](CCCC)(CCCC)[C:24]1[S:25][CH:26]=[CH:27][C:28]=1[P:29]([O:36][CH2:37][CH2:38][CH2:39][CH3:40])([O:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:30])CCC.Cl>CN(C=O)C.[Cu]Cl>[CH2:1]([O:5][P:6]([C:13]1[CH:17]=[CH:16][S:15][C:14]=1[C:24]1[S:25][CH:26]=[CH:27][C:28]=1[P:29]([O:36][CH2:37][CH2:38][CH2:39][CH3:40])([O:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:30])([O:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOP(=O)(OCCCC)c1ccsc1[Sn](CCCC)(CCCC)CCCC
Reactant: CCCCOP(=O)(OCCCC)c1ccsc1I
Agent: Cl[Cu]
Agent: Cl
Solvent: CN(C)C=O
Product: CCCCOP(=O)(OCCCC)c1ccsc1-c1sccc1P(=O)(OCCCC)OCCCC
Temperature: 80 °C
Reaction time: 10 h
Yield: 55 %

Procedure:
At room temperature, 0.8045 g (2.00 mmols) of 3-(dibutoxyphosphoryl)-2-iodothiophene and 1.1308 g (2.00 mmols) of 2-(tributylstannyl)-3-(dibutoxyphosphoryl)thiophene were dissolved in DMF, to which 0.2376 g (2.40 mmols) of commercially available copper(I) chloride was added at room temperature. Thereafter, the reaction mixture was heated to 80° C. and stirred for 10 hours. After the reaction, the reaction mixture was cooled down to room temperature, to which a 10% hydrochloric acid aqueous solution, followed by extraction of the resulting product with ethyl acetate. The organic phase was washed with a saturated saline solution and dried over anhydrous sodium sulfate. The solvent was removed by distilling off under reduced pressure, and the resulting crude product was purified with a silica gel column (gradiated from ethyl acetate:hexane=1:1 with acetone) to obtain the specified substance in the form of white crystals at a yield of 1.6012 g (yield: 55%).
Reaction SMILES: CS(O[CH2:6][C:7]([C:16]#[N:17])([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[CH3:8])(=O)=O.[NH:18]1[CH:22]=[CH:21][N:20]=[CH:19]1.CN(C)C=O>O>[ClH:15].[C:16]([C:7]([C:9]1[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=1)([CH3:8])[CH2:6][N:18]1[CH:22]=[CH:21][N:20]=[CH:19]1)#[N:17]
Reactant: c1c[nH]cn1
Reactant: CC(C#N)(COS(C)(=O)=O)c1ccc(Cl)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C#N)(Cn1ccnc1)c1ccc(Cl)cc1
Product: Cl
Temperature: 130 °C
Reaction time: 24 h
Yield: 58.6 %

Procedure:
A mixture of 2-cyano-2-(4-chlorophenyl)propyl methane sulfonate (63 g., 0.23 mole), imidazole (62.6 g., 0.9 mole) and N,N-dimethylformamide (3 ml.) is heated with stirring at 130° C. for 24 hours. The reaction mixture is poured into water and extracted with ether. The combined ether extracts are washed with water and dried over magnesium sulfate. Into the ethereal solution is bubbled dry hydrogen chloride gas. The white solid which precipitate is collected and dried to give 38 g. (58.6%) of the expected product, which is identified by nmr.