Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]4)[C:14]([F:24])=[CH:13][N:12]=3)=[CH:9][N:8]([S:25]([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:5]2=[N:6][CH:7]=1.[CH3:35][O:36][CH2:37][CH:38]1[CH2:40][O:39]1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][N:20]([CH2:40][CH:38]([OH:39])[CH2:37][O:36][CH3:35])[CH2:19]4)[C:14]([F:24])=[CH:13][N:12]=3)=[CH:9][N:8]([S:25]([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCCNC4)n3)c3cc(Cl)cnc32)cc1
Reactant: COCC1CO1
Solvent: CCO
Product: COCC(O)CN1CCC[C@H](Nc2nc(-c3cn(S(=O)(=O)c4ccc(C)cc4)c4ncc(Cl)cc34)ncc2F)C1
Temperature: 140 °C

Procedure:
To a solution of 2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[5,4-b]pyridin-3-yl]-5-fluoro-N-[(3S)-3-piperidyl]pyrimidin-4-amine, 1c, (0.20 g, 0.40 mmol) in ethanol was added 2-(methoxymethyl)oxirane (0.04 mL, 0.40 mmol). The reaction mixture was heated in a microwave reactor at 140° C. for 5 minutes. The reaction was evaporated to dryness and the resulting residue was purified via silica gel chromatography (0-10% MeOH: CH2Cl2) to afford the desired product (1d).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:28]=[CH:27][C:7]([CH2:8][N:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10]2)=[CH:6][CH:5]=1.Cl[CH2:30][C:31]1[N:32]=[C:33]([C:36]2[O:37][CH:38]=[CH:39][CH:40]=2)[S:34][CH:35]=1.O>CN(C)C=O>[O:37]1[CH:38]=[CH:39][CH:40]=[C:36]1[C:33]1[S:34][CH:35]=[C:31]([CH2:30][O:3][C:4]2[CH:28]=[CH:27][C:7]([CH2:8][N:9]3[CH:13]=[C:12]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:11]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10]3)=[CH:6][CH:5]=2)[N:32]=1
Reactant: ClCc1csc(-c2ccco2)n1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)cc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3csc(-c4ccco4)n3)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83.8 %

Procedure:
Sodium hydride (60%, oily, 60.0 mg) was added to a solution of ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (524 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 15 minutes. 4-Chloromethyl-2-(2-furyl)thiazole (299 mg) was added to the mixture, which was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[1-[4-[2-(2-furyl)-4-thiazolylmethoxy]benzyl]-4-phenyl-3-pyrrolyl]propionate (643 mg, yield: 84%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (1:3, volume ratio).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:13]([CH2:14][CH2:15][CH2:16][C:17](OCC)=[O:18])[C:12]3[C:22]([CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29])=[CH:23][CH:24]=[C:25]([Cl:26])[C:11]=3[N:10]=2)=[C:4]([CH3:32])[CH:3]=1.[BH4-].[Li+]>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:13]([CH2:14][CH2:15][CH2:16][CH2:17][OH:18])[C:12]3[C:22]([CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29])=[CH:23][CH:24]=[C:25]([Cl:26])[C:11]=3[N:10]=2)=[C:4]([CH3:32])[CH:3]=1
Reactant: CCOC(=O)CCCn1c(Nc2ccc(Br)cc2C)nc2c(Cl)ccc(C(CC)CC)c21
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(CC)c1ccc(Cl)c2nc(Nc3ccc(Br)cc3C)n(CCCCO)c12
Temperature: 25 °C
Reaction time: 19 h
Yield: 57.9 %

Procedure:
To a solution of ethyl 4-[2-[(4-bromo-2-methylphenyl)amino]-4-chloro-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]butanoate (2.07 g, 3.97 mmol) in tetrahydrofuran (40 mL) was added lithium tetrahydroborate (260 mg, 11.9 mmol) at 0° C. The mixture was stirred at room temperature for 19 hr, and the reaction was quenched by methanol. The mixture was concentrated in vacuo, neutralized with aqueous saturated ammonium chloride, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was recrystallized from ethyl acetate to give the title compound as a colorless crystal (1.10 g, 2.30 mmol, 58%).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:13]([C:14]([NH2:16])=[O:15])=[CH:12][N:11]=[C:10]3[N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:18]=[CH:19][C:9]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:28](OCC)(OCC)[O:29]CC>>[CH:1]1([NH:7][C:8]2[C:13]([C:14]([NH:16][CH:28]=[O:29])=[O:15])=[CH:12][N:11]=[C:10]3[N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:18]=[CH:19][C:9]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(NC3CCCCC3)c(C(N)=O)cnc21
Reactant: CCOC(OCC)OCC
Product: C[Si](C)(C)CCOCn1ccc2c(NC3CCCCC3)c(C(=O)NC=O)cnc21
Temperature: 25 °C
Yield: 27 %

Procedure:
4-(Cyclohexylamino)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (45 mg, 0.12 mmol) in triethyl orthoformate (2 mL) was stirred at 120° C. for one day. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1→0/1 (v/v)) to give the title compound as a pale yellow amorphous (12.4 mg, yield 27%).
Reaction SMILES: [OH-].[Na+:2].CO.[CH3:5][C:6]1[O:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH2:17][O:18][C:19]1[CH:36]=[CH:35][C:22]([CH2:23][O:24][C:25]2[C:30]([CH2:31][C:32]([OH:34])=[O:33])=[CH:29][CH:28]=[CH:27][N:26]=2)=[CH:21][CH:20]=1>CC(C)=O>[CH3:5][C:6]1[O:10][C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[N:8][C:7]=1[CH2:17][O:18][C:19]1[CH:36]=[CH:35][C:22]([CH2:23][O:24][C:25]2[C:30]([CH2:31][C:32]([O-:34])=[O:33])=[CH:29][CH:28]=[CH:27][N:26]=2)=[CH:21][CH:20]=1.[Na+:2]
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2ncccc2CC(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2ncccc2CC(=O)[O-])cc1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
1N Sodium hydroxide-methanol solution (2.4 ml) was added to 2-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]acetic acid (1.0 g) and the mixture was heated to 40° C. The obtained solution was allowed to cool and acetone (10 ml) was added. The mixture was stirred at room temperature for 30 min and acetone (5 ml) was further added. The mixture was stirred at room temperature for 1 hr, and under ice-cooling for 1 hr. The precipitated crystals were collected by filtration, washed with acetone (10 ml) ice-cooled in advance, and dried under reduced pressure to give sodium 2-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]acetate as white crystals.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH3:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[CH3:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=1[N:22]1[CH2:23][CH2:24][N:25]([C:9]([C:8]2[CH:7]=[CH:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:13][CH:12]=2)=[O:11])[CH2:26][CH2:27]1
Reactant: CC(=O)Nc1ccc(C(=O)O)cc1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Product: CC(=O)Nc1ccc(C(=O)N2CCN(c3ccc(C)cc3C)CC2)cc1
Yield: 99.7 %

Procedure:
Using 4-(acetylamino)benzoic acid (179 mg) and 1-(2,4-dimethylphenyl)piperazine (190 mg) and by the reaction and treatment in the same manner as in Example 93, the title compound (350 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[C:4]([C:21]([F:24])([F:23])[F:22])[CH:3]=1.Cl.[CH2:26]([O:28][C:29](=[O:33])[CH2:30][CH2:31][NH2:32])[CH3:27].O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>>[CH2:26]([O:28][C:29](=[O:33])[CH2:30][CH2:31][NH:32][C:16](=[O:17])[C:15]1[CH:14]=[CH:13][C:12]([S:9](=[O:11])(=[O:10])[NH:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=2[C:21]([F:22])([F:23])[F:24])=[CH:20][CH:19]=1)[CH3:27]
Reactant: O=C(O)c1ccc(S(=O)(=O)Nc2ccc(F)cc2C(F)(F)F)cc1
Reactant: CCOC(=O)CCN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)CCNC(=O)c1ccc(S(=O)(=O)Nc2ccc(F)cc2C(F)(F)F)cc1

Procedure:
Under the conditions of Example 2(a), 3.633 g (10 mmol) of 4-[N-(4-fluoro-2-trifluoromethylphenyl)sulfamoyl]benzoic acid, 1.536 g (10 mmol) of β-alanine ethyl ester hydrochloride, 1.531 g (10 mmol) of hydroxybenzotriazole, hydrate, as well as 1.012 g (10 mmol) of triethylamine and 2.063 g (10 mmol) of dicyclohexylcarbodiimide are reacted and worked up analogously. The crude product is chromatographed on silica gel and the title compound eluted with ethyl acetate.
Reaction SMILES: [CH3:1][CH2:2][O-:3].[Na+].[Na].C(O)C.[CH3:9][N:10]1[C:18]2[N:17]=[CH:16][N:15]([CH2:19][C:20](=[N:22]O)[NH2:21])[C:14]=2[C:13](=[O:24])[NH:12][C:11]1=[O:25]>C(OCC)(=O)C>[CH3:9][N:10]1[C:18]2[N:17]=[CH:16][N:15]([CH2:19][C:20]3[N:22]=[C:2]([CH3:1])[O:3][N:21]=3)[C:14]=2[C:13](=[O:24])[NH:12][C:11]1=[O:25]
Reactant: Cn1c(=O)[nH]c(=O)c2c1ncn2CC(N)=NO
Reactant: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1nc(Cn2cnc3c2c(=O)[nH]c(=O)n3C)no1
Reaction time: 4 h

Procedure:
A mixture of a sodium ethylate solution prepared from 6.76 g of metallic sodium and 290 ml of anhydrous ethanol, 35 g of 2-(3-methyl-xanthine-7-yl)-acetamidoxime and 43.0 g of ethyl acetate is heated to boiling under stirring for 4 hours. The hot reaction mixture is filtered, the filtrate is evaporated in vacuo and the residue is dissolved in 200 ml of water. The pH of the solution is adjusted to 7 by adding 10% hydrochloric acid, the precipitate is filtered by suction and crystallized twice from water. Thus, 18.0 g of 3,7-dihydro-3-methyl-7-([5-methyl-1,2,4-oxadiazole-3-yl]-methyl)-1H-purine-2,6-dione are obtained, m.p.: 262°-264° C.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:23][CH3:24])=[C:19]([OH:22])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[C:25]([N:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35]O)[CH2:30][CH2:29]1)(=[O:27])[CH3:26].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>ClCCl>[C:25]([N:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][O:22][C:19]2[CH:20]=[C:21]3[C:16](=[CH:17][C:18]=2[O:23][CH3:24])[N:15]=[CH:14][N:13]=[C:12]3[O:11][C:10]2[C:2]([F:1])=[C:3]3[C:7](=[CH:8][CH:9]=2)[NH:6][CH:5]=[CH:4]3)[CH2:30][CH2:29]1)(=[O:27])[CH3:26]
Reactant: CC(=O)N1CCN(CCO)CC1
Reactant: COc1cc2ncnc(Oc3ccc4[nH]ccc4c3F)c2cc1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2ncnc(Oc3ccc4[nH]ccc4c3F)c2cc1OCCN1CCN(C(C)=O)CC1
Yield: 67.8 %

Procedure:
A mixture of 4-[(4-fluoro-1H-indol-5-yl)oxy]-6-hydroxy-7-methoxyquinazoline (260 mg, 0.80 mmol), (prepared as described for the starting material in Example 10), 2-(4-acetylpiperazin-1-yl)ethanol (165 mg, 0.96 mmol), (prepared as described for the starting material in Example 28), and triphenylphosphine (252 mg, 0.96 mmol) in dichloromethane (15 ml) was stirred and cooled in an ice/water bath. Diisopropyl azodicarboxylate (189 μl, 0.96 mmol) was added. The mixture was stirred for 3 hours and then a further 0.5 mole equivalent of 2-(4-acetylpiperazin-1-yl)ethanol, triphenylphosphine and diisopropyl azodicarboxylate were added. The mixture was stirred for a further 1 hour and then concentrated under reduced pressure. The residue was purified by column chromatography eluting with methylene chloride/methanol (95/5) to give 6-[2-(4-acetylpiperazin-1-yl)ethoxy]-4-[(4-fluoro-1H-indol-5-yl)oxy]-7-methoxyquinazoline (260 mg, 68%) as a white solid.
Reaction SMILES: CS([C:5]1[C:6]([CH3:16])=[C:7]([CH3:15])[C:8]2[N:9]([C:11]([NH2:14])=[N:12][N:13]=2)[N:10]=1)(=O)=O.[C-:17]#[N:18].[K+]>CN(C=O)C>[NH2:14][C:11]1[N:9]2[N:10]=[C:5]([C:17]#[N:18])[C:6]([CH3:16])=[C:7]([CH3:15])[C:8]2=[N:13][N:12]=1
Reactant: [C-]#N
Reactant: Cc1c(S(C)(=O)=O)nn2c(N)nnc2c1C
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(C#N)nn2c(N)nnc2c1C
Temperature: 100 °C
Reaction time: 1 h
Yield: 71.8 %

Procedure:
6-Methane sulfonyl-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine (W1.130; 1.0 g) was dissolved in DMF (30 ml) and admixed with potassium cyanide (405 mg). After stirring at 100° C. for 1 h, the mixture was dried. The residue was stirred in EA and chromatographed using a short silica gel column with EA. Fractions concentrated by rotary evaporation. 560 mg of the title compound were obtained.
Reaction SMILES: [CH:1]([C:3]1[N:4]=[CH:5][N:6]2[CH:10]=[CH:9][S:8][C:7]=12)=O.[CH3:11][O:12][NH3+:13].[Cl-].[OH-].[Na+]>C(O)C>[CH3:11][O:12][N:13]=[CH:1][C:3]1[N:4]=[CH:5][N:6]2[CH:10]=[CH:9][S:8][C:7]=12
Reactant: CO[NH3+]
Reactant: O=Cc1ncn2ccsc12
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CON=Cc1ncn2ccsc12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a suspension of 249 mg of 7-formylimidazo[5,1-b]thiazole in 10 ml of ethanol were added 219 mg of o-methylhydroxylamine hydrochloride and 2.67 ml of a 1N sodium hydroxide solution. The reaction mixture was stirred at room temperature for 20 hours, concentrated, then diluted with 50 ml of water, and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by column chromatography on silica gel (dichloromethane:ethyl acetate=1:1) to give 7-methoxyiminomethylimidazo[5,1-b]thiazole (low polar geometrical isomer) in a yield of 164 mg from the low polarity fraction.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[CH3:15])=[O:4].[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(N(C(C)C)CC)(C)C>C1COCC1>[CH3:15][C:7]1[C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=[CH:11][C:6]=1[NH:5][C:3](=[O:4])[CH2:2][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: Cc1c(NC(=O)CBr)cccc1[N+](=O)[O-]
Reactant: C1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1c(NC(=O)CN2CCOCC2)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-Bromo-N-(2-methyl-3-nitrophenyl)acetamide (0.5 g, 1.8 mmol) was dissolved in 15 ml of THF and to this was added morpholine (0.17 g, 2.0 mmol) and diisopropylethylamine (0.71 g, 5.5 mmol). The reaction was stirred at room temperature for 16 hours. The reaction was then partitioned between EtOAc and H2O. The aqueous mixture was extracted with EtOAc, and the combined organic layers were washed with H2O, brine and then dried over MgSO4. Solvent evaporation afforded N-(2-methyl-3-nitrophenyl)-2-morpholinoacetamide as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:19])[N:8]([CH3:18])[C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[C:11]([CH3:17])[N:10]=2)=[O:5])[CH3:2].[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:19])[N:8]([CH3:18])[C:9]2[C:14]([C:15]=1[N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)=[CH:13][CH:12]=[C:11]([CH3:17])[N:10]=2)=[O:5])[CH3:2]
Reactant: C1CCNC1
Reactant: CCOC(=O)c1c(Cl)c2ccc(C)nc2n(C)c1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(N2CCCC2)c2ccc(C)nc2n(C)c1=O

Procedure:
A stirred mixture of 2.8 g. (0.01 mole) of 4-chloro-1,7-dimethyl-1,2-dihydro-2-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester, 0.7 g. (0.01 mole) of pyrrolidine and 1.06 g. (0.01 mole) of sodium carbonate in 30 ml. of ethanol was heated under reflux for 5 hours. The mixture was filtered and the filtrate was cooled in ice. The precipitate which formed was collected and was recrystallized from heptane to give 1.7 g. of product, m.p. 108°-111° C.
Reaction SMILES: Cl[S:2]([NH:5][CH2:6][CH2:7][P:8](=[O:15])([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11])(=[O:4])=[O:3].[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[C:25]([Cl:27])[CH:26]=1)[CH2:23][N:22]([CH3:28])[CH2:21][CH:20]2[C:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=1.C(N(C(C)C)C(C)C)C>C(#N)C>[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[C:25]([Cl:27])[CH:26]=1)[CH2:23][N:22]([CH3:28])[CH2:21][CH:20]2[C:29]1[CH:34]=[CH:33][C:32]([NH:35][S:2]([NH:5][CH2:6][CH2:7][P:8](=[O:15])([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11])(=[O:4])=[O:3])=[CH:31][CH:30]=1
Reactant: CCOP(=O)(CCNS(=O)(=O)Cl)OCC
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(N)cc2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOP(=O)(CCNS(=O)(=O)Nc1ccc(C2CN(C)Cc3c(Cl)cc(Cl)cc32)cc1)OCC
Temperature: 60 °C
Reaction time: 3 h
Yield: 16.7 %

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed diethyl 2-(chlorosulfonylamino)ethylphosphonate (intermediate 30.8) (670 mg, 2.40 mmol, 1.47 equiv), 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenamine (intermediate 30.7) (500 mg, 1.63 mmol, 1.00 equiv), N-ethyl-N-isopropylpropan-2-amine (400 mg, 3.10 mmol, 1.91 equiv) in acetonitrile (20 mL). The resulting solution was stirred for 3 h at 60° C. The resulting mixture was concentrated under vacuum and the residue was applied to a silica gel column and eluted with dichloromethane/methanol (20:1). This resulted in 150 mg (16%) of the title compound as a light yellow solid.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.N1[C:19]2[C:14](=[C:15]([C:20](C3C=CC=CC=3)=[CH:21][C:22]#[N:23])[CH:16]=[CH:17][CH:18]=2)C=C1>>[NH:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([C:20]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:14]=3)=[CH:21][C:22]#[N:23])[CH:10]=2)[CH:6]=[CH:7]1
Reactant: Brc1ccc2cc[nH]c2c1
Reactant: N#CC=C(c1ccccc1)c1cccc2[nH]ccc12
Product: N#CC=C(c1ccccc1)c1ccc2cc[nH]c2c1
Yield: 61 %

Procedure:
3-(1H-Indol-6-yl)-3-phenyl-acrylonitrile XII (1.46 g, 61% yield) was prepared from 6-bromo-indole using the procedure described for 3-(1H-indol-4-yl)-3-phenyl-acrylonitrile I.
Reaction SMILES: N[C:2]1[C:3]2[C:4]3[C:5](=[CH:13][N:14]([C@@H:16]4[O:22][C@H:21]([CH2:23][OH:24])[C@@H:19]([OH:20])[C@@:17]4([CH3:25])[OH:18])[N:15]=2)[CH:6]=[CH:7][C:8]=3[C:9](=[O:12])[NH:10][N:11]=1.N([O-])=[O:27].[Na+]>C(O)(=O)C.CC[N+](CC)(CC)CC.[Br-]>[CH3:25][C@@:17]1([OH:18])[C@H:19]([OH:20])[C@@H:21]([CH2:23][OH:24])[O:22][C@H:16]1[N:14]1[CH2:13][C:5]2=[CH:6][CH:7]=[C:8]3[C:9](=[O:12])[NH:10][NH:11][C:2](=[O:27])[C:3](=[C:4]23)[NH:15]1
Reactant: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1cc2ccc3c(=O)[nH]nc(N)c(n1)c23
Reactant: O=N[O-]
Agent: CC[N+](CC)(CC)CC
Agent: [Br-]
Agent: [Na+]
Solvent: CC(=O)O
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1N1Cc2ccc3c(=O)[nH][nH]c(=O)c(c2-3)N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.9 %

Procedure:
To a solution 4-amino-2-(2-C-methyl-β-D-ribofuranosyl)-2,6-dihydro-7H-2,3,5,6-tetraazabenzo[cd]azulene-7-one 15.6 (35 mg, 0.1 mmol) in 50% aqueous acetic acid (5 mL) was added sodium nitrite (42 mg, 0.6 mmol) and the mixture stirred at room temperature for 4 hr. The mixture was neutralized with 1M TEAB buffer and purified by reversed phase ion-pairing HPLC on a Phenomenex Luna C18(2) 250×21 mm 10 μm column. 100 mM triethylammonium acetate (TEAA), pH 7 was used as the ion-pairing agent. A gradient of 20% to 55% MeOH over 40 min was applied. The target compound eluted at 26 min followed by two smaller peaks at 29 and 31 min. TEAA was removed by repeated lyophilzation to yield the target compound as a fluffy yellow material (28 mg, 80%).
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]#[CH:19].[CH3:20]OS(OC)(=O)=O.O>O1CCCC1>[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]#[C:19][CH3:20]
Reactant: COS(=O)(=O)OC
Reactant: C#Cc1ccccc1Br
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC#Cc1ccccc1Br
Reaction time: 0.5 h

Procedure:
1M Lithium hexamethyldisilazide solution (6 mL) was added to 1-bromo-2-ethynylbenzene (1 g) in 20 mL tetrahydrofuran at room temperature, and the reaction was stirred 30 minutes. (CH3)2SO4 (0.58 mL) was added and the reaction was stirred 30 minutes. The reaction was poured into 20 mL water, extracted with 2×50 mL ether, and the combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[N:5]=[C:6]2[S:20][CH:19]=[CH:18][N:7]2[C:8](=[O:17])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)[CH3:3].[NH2:21][C:22]1[N:30]=[C:29]2[C:25]([NH:26][CH:27]=[N:28]2)=[C:24](Br)[N:23]=1.C(N(CC)C(C)C)(C)C>C(O)C>[NH2:21][C:22]1[N:30]=[C:29]2[C:25]([N:26]=[CH:27][NH:28]2)=[C:24]([NH:1][CH:2]([C:4]2[N:5]=[C:6]3[S:20][CH:19]=[CH:18][N:7]3[C:8](=[O:17])[C:9]=2[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[CH3:3])[N:23]=1
Reactant: CC(N)c1nc2sccn2c(=O)c1-c1cccc(F)c1
Reactant: Nc1nc(Br)c2[nH]cnc2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(Nc1nc(N)nc2[nH]cnc12)c1nc2sccn2c(=O)c1-c1cccc(F)c1
Temperature: 110 °C

Procedure:
A mixture of 7-(1-aminoethyl)-6-(3-fluorophenyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.025 g, 0.086 mmol), 2-amino-6-bromopurine (0.033 g, 0.16 mmol), and N,N-diisopropylethylamine (0.027 mL, 0.16 mmol) in ethanol (0.5 mL) was heated at 110° C. overnight. The mixture was filtered and the filtrate was purified on preparative-LCMS (XBridge C18 Column, eluting with a gradient of acetonitrile/water containing 0.15% NH4OH) to give the desired product. LCMS calculated for C19H16FN8OS (M+H)+: m/z=423.1. Found: 423.0. 1H NMR (DMSO-d6, 400 MHz) δ 7.98 (1H, d, J=4.8 Hz), 7.63 (1H, s), 7.52 (1H, d, J=4.8 Hz), 7.46 (1H, m), 7.20 (2H, m), 6.84 (1H, br s), 5.41 (1H, br s), 5.07 (1H, m), 1.26 (3H, d, J=6.8 Hz) ppm. 19F NMR (DMSO-d6, 376.3 MHz) δ −114 ppm.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)CCC.[N+:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1I)([O-:22])=[O:21].[Cl-].[Na+]>O1CCCC1>[N:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[N+:20]([O-:22])=[O:21]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: O=[N+]([O-])c1ccccc1I
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccccc1-c1ccccn1
Yield: 24 %

Procedure:
The reaction of 8.0 g (0.022 mole) of 2-tributylstannylpyridine with 4.92 g (0.020 mole) of ortho-nitroiodobenzene was carried out in the presence of 0.70 g (0.001 mole) of dichlorobis(triphenlylphosphine)palladium in 100 ml of tetrahydrofuran at 110° C. After 24 hours from the start of the reaction, a saturated aqueous sodium chloride solution was added to the reaction mixture and the reaction product was extracted with ether. The ether layer was then washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated. The resulting liquid was purified by column chromatography and concentrated to give 0.96 g (0.0048 mole, 24.9%) of ortho-(2-pyridyl)nitrobenzene as brown liquid.