Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:11]([O:14][CH2:15][CH3:16])(=[O:13])[CH3:12].C[O:18][C:19]([CH:21]1[CH2:25][CH2:24][O:23][CH2:22]1)=O>C1COCC1>[CH2:15]([O:14][C:11](=[O:13])[CH2:12][C:19](=[O:18])[CH:21]1[CH2:25][CH2:24][O:23][CH2:22]1)[CH3:16]
Reactant: COC(=O)C1CCOC1
Reactant: CCOC(C)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)C1CCOC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.4 %

Procedure:
To a solution of lithium bis(trimethylsilyl)amide (1 M in hexanes; 100 mL) in THF (200 mL) at −78° C. was added dry ethyl acetate (10.8 g, 12 mL, 122.5 mmol) dropwise. After 30 min at −78° C., the mixture was treated with a solution of tetrahydro-furan-3-carboxylic acid methyl ester (6.0 g, 46.1 mmol) in THF (50 mL). After 4 h at −78° C., the reaction was quenched with satd. aq. NH4Cl, warmed to rt, and extracted with EtOAc (5×75 mL). The combined organic layers were washed with satd. aq. NaCl, dried, and concentrated to give a colorless oil. Chromatography on SiO2 (EtOAc/CH2Cl2) afforded the title compound (3.3 g).
Reaction SMILES: [C:1]([N:3]=[C:4](OCC)[CH3:5])#[N:2].[C:9]([C:11]1[CH:24]=[CH:23][C:14]2[O:15][C:16]([CH3:22])([CH3:21])[C@@H:17]([OH:20])[C@H:18]([NH2:19])[C:13]=2[CH:12]=1)#[N:10]>C(OCC)(=O)C>[C:9]([C:11]1[CH:24]=[CH:23][C:14]2[O:15][C:16]([CH3:22])([CH3:21])[C@@H:17]([OH:20])[C@H:18]([NH:19][C:4](=[N:3][C:1]#[N:2])[CH3:5])[C:13]=2[CH:12]=1)#[N:10]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Reactant: CCOC(C)=NC#N
Solvent: CCOC(C)=O
Product: CC(=NC#N)N[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O
Reaction time: 2 h

Procedure:
To 1.23 g of ethyl N-cyanoacetimidate, 2.18 g of 6-cyano-3,4-dihydro-2,2-dimethyl-trans-4-amino-2H-benzo[b]pyran-3-ol was added, and the mixture was stirred at a temperature of from 100° to 120° C. for 2 hours. The reaction mixture was cooled, then dissolved in 100 ml of ethyl acetate, washed twice with a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. Then, ethyl acetate was distilled off under reduced pressure. The residual oily substance was recrystallized from ethyl acetate/n-hexane to obtain 1.75 g of the above identified compound in the form of crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:28])[CH2:15][S:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)=[CH:4][CH:3]=1.[CH2:29]([O:31][C:32]([C:34]1([C:37]2[CH:42]=[CH:41][C:40](B3OC(C)(C)C(C)(C)O3)=[CH:39][CH:38]=2)[CH2:36][CH2:35]1)=[O:33])[CH3:30]>>[CH2:29]([O:31][C:32]([C:34]1([C:37]2[CH:42]=[CH:41][C:40]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([OH:28])[CH2:15][S:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:27])[F:25])[CH:19]=4)=[CH:6][CH:7]=3)=[CH:39][CH:38]=2)[CH2:35][CH2:36]1)=[O:33])[CH3:30]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)CSCc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)CSCc4cccc(C(F)(F)F)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-2-(3-trifluoromethyl-benzylsulfanyl)-ethanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH2:1]([N:3]1[CH2:9][CH:8]([OH:10])[C:7]2[CH:11]=[CH:12][S:13][C:6]=2[CH2:5][CH2:4]1)[CH3:2].[Br:14][C:15]1[C:16]([Cl:22])=[C:17](F)[CH:18]=[CH:19][CH:20]=1>>[Br:14][C:15]1[C:16]([Cl:22])=[C:17]([O:10][CH:8]2[CH2:9][N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][C:6]3[S:13][CH:12]=[CH:11][C:7]2=3)[CH:18]=[CH:19][CH:20]=1
Reactant: CCN1CCc2sccc2C(O)C1
Reactant: Fc1cccc(Br)c1Cl
Product: CCN1CCc2sccc2C(Oc2cccc(Br)c2Cl)C1

Procedure:
The same method as in Example 1 was conducted using 6-ethyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepin-4-ol (Reference Example 45) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3-bromo-2-chloro-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [OH:1][C:2]1[C:10]2[C:9]3[C:11]([OH:16])=[CH:12][C:13]([OH:15])=[CH:14][C:8]=3[O:7][C:6]=2[CH:5]=[C:4]([OH:17])[CH:3]=1.[Cl-].[Cl-].[Cl-].[Al+3].C(Cl)(Cl)Cl.[C:26](Cl)(=[O:31])[CH2:27][CH:28]([CH3:30])[CH3:29]>C(=S)=S>[OH:1][C:2]1[C:10]2[C:9]3[C:11]([OH:16])=[CH:12][C:13]([OH:15])=[C:14]([C:26](=[O:31])[CH2:27][CH:28]([CH3:30])[CH3:29])[C:8]=3[O:7][C:6]=2[CH:5]=[C:4]([OH:17])[C:3]=1[C:2](=[O:1])[CH2:10][CH:9]([CH3:11])[CH3:8]
Reactant: CC(C)CC(=O)Cl
Reactant: Oc1cc(O)c2c(c1)oc1cc(O)cc(O)c12
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: S=C=S
Product: CC(C)CC(=O)c1c(O)cc2oc3c(C(=O)CC(C)C)c(O)cc(O)c3c2c1O
Temperature: 50 °C
Reaction time: 2 h
Yield: 34.8 %

Procedure:
Compound 8 (100 mg, 0.431 mmol) and aluminum trichloride (287 mg, 2.15 mmol) were suspended in 5 mL of carbon disulfide at rt. Chloroform (6 mL) was added to the suspension and the reaction mixture was warmed to 50° C. in a water-bath. Isovaleryl chloride (259 mg, 2.15 mmol) was added dropwise and the reaction was stirred for 2 h at 50° C. After removing solvent in vacuo, and the crude reaction mixture was purified by column chromatography (1-5% ethyl acetate/hexane) to yield 3 (30 mg, 17%) as a white solid.
Reaction SMILES: O.O.[Sn](Cl)Cl.[NH2:6][C:7]1[C:8]([N+:21]([O-])=O)=[CH:9][C:10]([Cl:20])=[C:11]([N:13]2[CH2:17][CH2:16][CH:15]([C:18]#[N:19])[CH2:14]2)[CH:12]=1>CCOC(C)=O.O.N>[NH2:21][C:8]1[C:7]([NH2:6])=[CH:12][C:11]([N:13]2[CH2:17][CH2:16][CH:15]([C:18]#[N:19])[CH2:14]2)=[C:10]([Cl:20])[CH:9]=1
Reactant: N#CC1CCN(c2cc(N)c([N+](=O)[O-])cc2Cl)C1
Agent: Cl[Sn]Cl
Agent: N
Solvent: O
Solvent: CCOC(C)=O
Product: N#CC1CCN(c2cc(N)c(N)cc2Cl)C1

Procedure:
Tin dichloride dihydrate (410 mg, 1.8 mmol) was added to 1-(5-amino-2-chloro-4-nitro-phenyl)-pyrrolidine-3-carbonitrile (100 mg, 0.4 mmol) in EtOAc (5 mL). The reaction mixture was stirred at reflux for 1.5 h, cooled, diluted with EtOAc and water and basified with conc. ammonia. The mixture was filtered through a pad of celite. The organic layer was dried over Na2SO4 and concentrated to give the sub-title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[C:8]#[N:9])=[CH:4][CH:3]=1.C1C(=O)N([Br:26])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:26][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[C:8]#[N:9])=[CH:17][CH:18]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(OC(C#N)c2ccccc2Cl)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#CC(Oc1ccc(CBr)cc1)c1ccccc1Cl
Temperature: 25 °C
Yield: 71.3 %

Procedure:
To a CCl4 solution (5 mL) of the product (0.200 g) of Step B was added NBS (0.132 g, 0.95 eq) and a catalytic amount of AIBN. The reaction mixture was refluxed overnight. TLC indicated clean conversion to product, and the reaction mixture was cooled to room temperature and concentrated in vacuo. The crude product was purified on a silica gel flash chromatography column (120×30 mm) eluted with 5% ethyl acetate in hexane to afford 0.178 g (72%) of the title compound.
Reaction SMILES: CC1N=C(N[C:14]([N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)=[O:15])SC=1C1C=CN=CC=1.[CH3:21][C:22]1[N:23]=[C:24]([NH2:39])[S:25][C:26]=1[C:27]1[CH:32]=[CH:31][N:30]=[C:29]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[N:28]=1>>[CH3:21][C:22]1[N:23]=[C:24]([NH:39][C:14]([N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)=[O:15])[S:25][C:26]=1[C:27]1[CH:32]=[CH:31][N:30]=[C:29]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[N:28]=1
Reactant: Cc1nc(N)sc1-c1ccnc(N2CCOCC2)n1
Reactant: Cc1nc(NC(=O)n2ccnc2)sc1-c1ccncc1
Product: Cc1nc(NC(=O)n2ccnc2)sc1-c1ccnc(N2CCOCC2)n1

Procedure:
The titled compound is prepared by an analogous procedure to imidazole-1-carboxylic acid (4-methyl-5-pyridin-4-yl-thiazol-2-yl)-amide (example 18a) by replacing 4-methyl-5-pyridin-4-yl-thiazol-2-ylamine (see example 16 for reference) with 4-methyl-5-(2-morpholin-4-yl-pyrimidin-4-yl)-thiazol-2-ylamine (25d).
Reaction SMILES: [P:1]([O:38]C(C)(C)C)([O:33]C(C)(C)C)([O:3][CH2:4][CH:5]1[O:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:26][C@H:25]([CH2:27][NH:28][C:29](=[O:31])[CH3:30])[O:24][C:23]4=[O:32])=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[CH2:6]1)=[O:2].FC(F)(F)C(O)=O>ClCCl>[P:1]([OH:33])([OH:38])([O:3][CH2:4][CH:5]1[O:9][N:8]=[C:7]([C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:17]=[CH:18][C:19]([N:22]4[CH2:26][C@H:25]([CH2:27][NH:28][C:29](=[O:31])[CH3:30])[O:24][C:23]4=[O:32])=[CH:20][CH:21]=3)=[CH:14][CH:15]=2)[CH2:6]1)=[O:2]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(-c3ccc(C4=NOC(COP(=O)(OC(C)(C)C)OC(C)(C)C)C4)cc3)cc2)C(=O)O1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)NC[C@H]1CN(c2ccc(-c3ccc(C4=NOC(COP(=O)(O)O)C4)cc3)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
[3-(4′-{(5S)-5-[(Acetylamino)methyl]-2-oxo-1,3-oxazolidin-3-yl}-1,1′-biphenyl-4-yl)-4,5-dihydroisoxazol-5-yl]methyl di-tert-butyl phosphate (95 mg, 0.16 mmol) was dissolved in dichloromethane (1 ml) and trifluoroacetic acid (0.1 ml) was added. The solution was stirred for 1 h at ambient temperature, then concentrated in vacuo. Dichloromethane was added and the volatiles were removed in vacuo. This was repeated twice with dichloromethane and five times with diethyl ether. A pale yellow solid was obtained (78 mg) corresponding to the desired product.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[CH:13]=[CH:12][CH:11]=[C:5]2[C:6]([O:8][C:9](=[O:10])[C:4]=12)=O.Cl.[NH2:16][CH:17]1[CH2:22][CH2:21][C:20](=[O:23])[NH:19][C:18]1=[O:24].C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:14][N:2]([CH3:1])[C:3]1[CH:13]=[CH:12][CH:11]=[C:5]2[C:4]=1[C:9](=[O:10])[N:16]([CH:17]1[CH2:22][CH2:21][C:20](=[O:23])[NH:19][C:18]1=[O:24])[C:6]2=[O:8]
Reactant: CN(C)c1cccc2c1C(=O)OC2=O
Reactant: NC1CCC(=O)NC1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: CN(C)c1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O

Procedure:
4-Dimethylamino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione was prepared by the procedure of Example 1 from 3-dimethylaminophthalic anhydride (1.34 g, 7.0 mmol), 3-aminopiperidine-2,6-dione hydrogen chloride (1.15 g, 7.0 mmol) and sodium acetate (0.60 g, 7.3 mmol) in acetic acid (20 mL). The product was a yellow solid (1.59 g, 75% yield); mp, 214.5-216.5° C.; 1H NMR (DMSO-d6) δ1.98-2.09 (m, 1H, CHH), 2.49-2.62 (m, 2H, CH2), 2.81-2.95 (m, 1H, CHH), 3.04 (s, 6H, CH3), 5.08 (dd, J=5.5, 12.7 Hz, 1H, NCH), 7.23 (d, J=6.6 Hz, 1H, Ar), 7.26 (d, J=8.1 Hz, 1H, Ar), 7.63 (dd, J=6.9, 8.6 Hz, 1H, Ar), 11.09 (br s, 1H, NH); 13C NMR (DMSO-d6) δ22.10, 30.96, 42.95, 48.77, 112.99, 113.41, 122.59, 133.90, 135.22, 149.88, 166.29, 167.13, 170.06, 172.83; Anal Calcd for C15H15N3O4: C, 59.80; H, 5.02; N, 13.95. Found: C, 59.60; H, 4.94; N, 13.80.
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][C:5]([N:7]([CH3:15])[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)=[O:6].[NH2:17][C:18]([NH2:20])=[S:19]>C(O)C>[NH2:20][C:18]1[S:19][CH:2]=[C:3]([CH2:4][C:5](=[O:6])[N:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[CH3:15])[N:17]=1
Reactant: CN(C(=O)CC(=O)CBr)c1ccc(Cl)cc1
Reactant: NC(N)=S
Solvent: CCO
Product: CN(C(=O)Cc1csc(N)n1)c1ccc(Cl)cc1
Yield: 66.7 %

Procedure:
A 500 ml reaction flask equipped with a condenser, magnetic stirrer, thermometer and heating mantle was charged with 20.2 g (0.066 mole) of 4-bromo-4'-chloro-N-methylacetoacetanilide, 200 ml of ethanol and 5.4 g (0.071 mole) of thiourea. The reaction solution was refluxed for three hours. After cooling, about one-half of the solvent was removed on the rotary evaporator and the solution was poured into 300 ml of water. After adding sufficient ammonium hydroxide to pH 8, additional water was added. The precipitated crystalline product was dried in a vacuum oven. There was obtained 12.4 g (66.7%) of white material, M.P. 148°-50°. N.M.R. (dimethyl-d6 sulfoxide, CDCl3) ∂3.2 (NCH3), 3.3 (CH2), 6.0 (heteroaromatic), 7.3-7.5 (aromatic).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[H-].[Na+].[C:14](=O)([O:18]CC)[O:15][CH2:16][CH3:17].Cl>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9](=[O:11])[CH2:10][C:14]([O:15][CH2:16][CH3:17])=[O:18]
Reactant: CC(=O)c1cc(Cl)ccc1Cl
Reactant: CCOC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CC(=O)c1cc(Cl)ccc1Cl
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
A mixture of 2′,5′-dichloroacetophenone (10.0 g), sodium hydride (60%, oil, 2.12 g) and diethyl carbonate (80 ml) was stirred at 80° C. for 20 min. Water was added to the reaction mixture, and the mixture was neutralized with dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-(2,5-dichlorophenyl)-3-oxopropionate was obtained as an oil from a fraction eluted with ethyl acetate-hexane (1:9, volume ratio). A mixture of this oil and N,N-dimethylformamide dimethylacetal (9.46 g) was refluxed for 1 hr. The reaction mixture was concentrated, and the residue was dissolved in ethanol (80 ml). To the obtained solution was added hydroxylamine hydrochloride (7.35 g), and the mixture was refluxed for 2 hr. The reaction mixture was concentrated, water was added to the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 5-(2,5-dichlorophenyl)isoxazole-4-carboxylate (6.40 g, yield 42%) was obtained as an oil from a fraction eluted with ethyl acetate-hexane (1:5, volume ratio). NMR (CDCl3) δ: 1.23 (3H, t, J=7 Hz), 4.25 (2H, q, J=7 Hz), 7.4–7.6 (3H, m), 8.68 (1H, s).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][C:12]3[N:16]4[N:17]=[C:18]([C:21](=O)[CH3:22])[CH:19]=[CH:20][C:15]4=[N:14][CH:13]=3)=[CH:8][CH:9]=2)[CH:4]=[N:3]1.[NH:24]([C:26]([NH2:28])=[O:27])[NH2:25]>C1COCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][C:12]3[N:16]4[N:17]=[C:18](/[C:21](=[N:25]/[NH:24][C:26]([NH2:28])=[O:27])/[CH3:22])[CH:19]=[CH:20][C:15]4=[N:14][CH:13]=3)=[CH:8][CH:9]=2)[CH:4]=[N:3]1
Reactant: NNC(N)=O
Reactant: CC(=O)c1ccc2ncc(Cc3ccc4c(cnn4C)c3)n2n1
Solvent: C1CCOC1
Product: C/C(=N\NC(N)=O)c1ccc2ncc(Cc3ccc4c(cnn4C)c3)n2n1
Yield: 88.9 %

Procedure:
A solution of 1-(3-((1-methyl-1H-indazol-5-yl)methyl)imidazo[1,2-b]pyridazin-6-yl)ethanone (40.0 mg, 0.09 mmol) and hydrazinecarboxamide (19.47 mg, 0.26 mmol) in 10 mL THF was stirred at 40° C. for overnight. Solvent was removed in vacuo. The crude product was purified on flash chromatography (DCM:MeOH=20:1) to give the title compound as a white solid (29.0 mg, 88%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.71 (s, 1H), 8.18 (d, 1H), 7.95 (m, 2H), 7.69 (s, 1H), 7.60 (s, 1H), 7.75 (d, 1H), 7.40 (dd, 1H), 6.76 (bs, 2H), 4.41 (s, 2H), 3.99 (s, 3H), 2.29 (s, 3H). LCMS (method A): [MH]+=363, tR=4.42 min.
Reaction SMILES: N[C:2]1[S:3][C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.P(=O)(O)(O)O.[N+]([O-])(O)=O.N([O-])=O.[Na+].[I-:29].[K+]>O>[I:29][C:2]1[S:3][C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1
Reactant: CCOC(=O)c1sc(N)nc1C(F)(F)F
Reactant: [I-]
Agent: O=N[O-]
Agent: O=P(O)(O)O
Agent: [K+]
Solvent: O=[N+]([O-])O
Solvent: O
Product: CCOC(=O)c1sc(I)nc1C(F)(F)F
Reaction time: 0.17 h
Yield: 25.7 %

Procedure:
To a cold (-5° C.) solution of 4.0 g (0.0166 mole) of ethyl 2-amino-4-trifluoromethyl-5-thiazolecarboxylate, prepared according to U.S. Pat. No. 2,726,237, in 30 ml. of 85% phosphoric acid and 30 ml. of 70% nitric acid was added a solution of 1.26 g (0.0166 mole) of sodium nitrite in 10 ml. of water in 10 minutes. The reaction mixture was stirred for 10 minutes and poured into a solution of 10 g of potassium iodide in 100 ml. of water. The reaction mixture was stirred overnight and extracted with ether. The ether solution was dried and concentrated and the residue was chromatographed on silica gel to give 1.5 g of the desired product, m.p. 75°-76° C.
Reaction SMILES: Br[C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[CH:19])=[CH:14][CH:13]=1>C(N(CC)CC)C.[Cu]I>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:2]2[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:14][CH:13]=1
Reactant: C#Cc1ccc(OC)cc1
Reactant: O=Cc1cccnc1Br
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COc1ccc(C#Cc2ncccc2C=O)cc1
Temperature: 50 °C
Yield: 99.1 %

Procedure:
To a solution of 2-bromo-3-pyridinecarboxaldehyde (1.86 g, 10 mmol) and 4′-methoxy phenylacetylene (1.58 g, 12 mmol) in triethylamine (40 mL) were added dichlorobis(triphenylphosphine) palladium(II) (140 mg, 2 mol %) and copper (I) iodide (20 mg, 1 mol %). The reaction mixture was heated at 50° C. under nitrogen for 3 h, then cooled to room temperature. The ammonium salt was removed by filtration. The filtrate was concentrated under reduced pressure leaving 2-(4-methoxy phenylethynyl)pyridine-3-carboxaldehyde (2.35g, 99%) as yellow solid. 2-(4-Methoxyphenylethynyl)pyridine-3-carboxaldehyde (2.28 g, 9.60 mmol) and tert-butylamine (3.83 g, 60 mmol) were stirred under nitrogen for 24 h at rt. The resulting mixture was extracted with ether and dried over anhydrous Na2SO4. Removal of solvent gave the imine (2.72 g, 97%) which was used in next step without further purification. To a solution of this imine (2.7 g, 9.23 mmol) in 50 mL anhydrous DMF was added (0.190 g, 0.1 mmol) copper (I) iodide. The reaction mixture was heated at 100° C. for 4 h, then cooled to room temperature and diluted with ether (200 mL). The organic layer was washed with sat. aqueous ammonium chloride solution (3×100 mL). The organic layer was dried over anhydrous Na2SO4. Removal of solvent gave the crude compound as a dark colored solid. Purification by column chromatography (Silica Gel 230-400 mesh; 30% ethyl acetate in hexanes as eluent) afforded 7-(4-methoxy phenyl)[1,6]naphthridine (0.730 g, 33%) as a brown solid. To a solution of 7-(4-methoxyphenyl) [1,6]naphthridine (0.485 g, 2.05 mmol) in anhydrous N-methyl -2-pyrrolidinone (5 mL) was added thiophenol (0.25 g, 2.26 mmol) and potassium carbonate (0.028 g, 0.205 mmol). The reaction mixture was stirred at 190° C. for 1 h under nitrogen. The reaction mixture was cooled to room temperature. The crude compound was adsorbed onto silica gel and purified by column chromatography (Silica Gel 230-400 mesh; 20-70% ethyl acetate in hexanes as fluent) to give 4-(1,6-naphthyridin-7-yl)phenol (0.33 g, 71%) as a pale yellow solid. MS (ES) m/z: 223.95 (M+1), 222.95 (M); Mp. 219-221° C.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[C:8]([NH2:17])[NH:7][N:6]=1)[CH3:2].[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=O)[CH2:26][C:27](OCC)=[O:28])=[CH:21][CH:20]=1>N1C=CC=CC=1>[CH2:1]([O:3][CH2:4][C:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)=[C:8]2[NH:17][C:27](=[O:28])[CH:26]=[C:25]([C:22]3[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=3)[N:7]2[N:6]=1)[CH3:2]
Reactant: CCOCc1n[nH]c(N)c1-c1ccc(C)cc1
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1
Solvent: c1ccncc1
Product: CCOCc1nn2c(-c3ccc(F)cc3)cc(=O)[nH]c2c1-c1ccc(C)cc1
Temperature: 25 °C

Procedure:
3-(Ethoxymethyl)-4-(4-methylphenyl)-1H-pyrazol-5-amine (133 mg) and ethyl 3-(4-fluorophenyl)-3-oxopropanoate (0.2 mL) are stirred at 84° C. for 14 hours in a pyridine (10 mL) solvent. After cooling to room temperature, the reaction solvent is removed by distillation under reduced pressure. The remainder is extracted with ethyl acetate and water. The extracted organic layer is washed with brine and dehydrated with anhydrous MgSO4. The dehydrated organic layer is distilled under reduced pressure and purified by column chromatography to yield 132 mg of the target compound. 1H NMR (CDCl3, 300 MHz): δ 10.08 (s, 1H), 7.98 (m, 2H), 7.28 (m, 4H), 7.13 (m, 2H), 4.43 (s, 2H), 4.04 (br, 1H), 3.50 (m, 2H), 2.35 (s, 3H), 1.06 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8]C)[C:3]=1[CH2:10][S:11][C:12]1[N:17]=[C:16]([OH:18])[CH:15]=[C:14]([CH3:19])[N:13]=1.B(Br)(Br)Br.O.[O-]S([O-])(=O)=O.[Na+].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[CH2:10][S:11][C:12]1[N:17]=[C:16]([OH:18])[CH:15]=[C:14]([CH3:19])[N:13]=1
Reactant: COc1cccc(Cl)c1CSc1nc(C)cc(O)n1
Agent: BrB(Br)Br
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1cc(O)nc(SCc2c(O)cccc2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
In a 250 mL round bottom flask, 2-{[(2-chloro-6-methoxyphenyl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (200 mg, 0.67 mmol) was dissolved in DCM (10 mL). BBr3 (1.42 mL, 1.42 mmol) was added dropwise. The resulting mixture was stirred at room temperature overnight. Water (5 mL) was added, followed by Na2SO4 (20 g) and DCM (100 mL) after 5 minutes. The solution was filtered and evaporated. The crude product was purified by column chromatography to provide the title compound as a white solid (180 mg, 95% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.06 (s, 3H), 4.48 (s, 2H), 6.02 (br, 1H), 6.83 (d, 1H), 6.93 (d, 1H), 7.15 (t, 1H), 10.44 (br, 1H); M+ 283.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26]O[CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C([C:32]1[N:33]=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.CN1CCNCC1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][N:33]([CH3:32])[CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CN1CCNCC1
Product: CN1CCN(c2nc(C(C)(C)C)nc3c2nnn3Cc2ccccc2Cl)CC1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-methylpiperazine and isolated as light-yellow solid (13.4 mg, 71%). MS(m/e): 400.4 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:12])[O:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.N([O-])=O.[Na+].[N-:17]=[N+:18]=[N-].[Na+]>Cl>[N:1]([C:2]1[C:3](=[O:12])[O:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1cc2ccccc2oc1=O
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Product: [N-]=[N+]=Nc1cc2ccccc2oc1=O
Temperature: 2.5 °C
Reaction time: 2 h

Procedure:
3-Aminocoumarin (250 mg, 1.6 mmol) was dissolved in 30 mL of 3% HCl at room temperature. After cooling to 0-5° C., the solution was added drop-wise to a solution of NaNO2 (160 mg, 2.3 mmol) and stirred for two hours. Upon addition of NaN3 (150 mg, 2.3 mmol), the mixture was stirred at 0-5° C. for two hours followed by stirring at room temperature for three and a half hours. The precipitate was filtered, washed to neutral pH with water and dried under vacuum to afford a white solid; yield (226 mg, 78%); mp: 108-112° C.; 1H-NMR (300 MHz, CDCl3): δ 7.2-7.6 (m, 5H).
Reaction SMILES: O=S(Cl)Cl.[N+:5]([C:8]1[CH:19]=[CH:18][C:11]([CH2:12][C@@H:13]([C:15]([OH:17])=[O:16])[NH2:14])=[CH:10][CH:9]=1)([O-:7])=[O:6].[CH3:20]O>>[CH3:20][O:16][C:15](=[O:17])[C@H:13]([CH2:12][C:11]1[CH:10]=[CH:9][C:8]([N+:5]([O-:7])=[O:6])=[CH:19][CH:18]=1)[NH2:14]
Reactant: N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@H](N)Cc1ccc([N+](=O)[O-])cc1
Yield: 97 %

Procedure:
10 mL of SOCl2 and 40 mL of methanol were thoroughly mixed in an ice bath for 30 minutes, followed by mixing with 0.51 g of p-nitrophenylalanine to obtain a reaction solution. The reaction solution was subjected to reflux reaction at 70° C. for 24 hours, followed by evaporating, re-crystallizing in ether, and filtering to obtain a product of 0.53 g (97.0%) of a white solid of NBPDA.