Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[CH2:2]([O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=O)[CH3:3].[N:13]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N+:14]=[N-:15]>C(O)C>[N:13]([C:16](=[CH:7][C:6]1[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=1[O:4][CH2:2][CH3:3])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N+:14]=[N-:15]
Reactant: CCOc1ccccc1C=O
Reactant: CCOC(=O)CN=[N+]=[N-]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(=Cc1ccccc1OCC)N=[N+]=[N-]
Temperature: -18 °C
Reaction time: 3 h

Procedure:
Pieces of sodium (3.678 g, 160 mmol) were added to ethanol (200 ml) over a period of 30 minutes. The resulting solution was cooled to −18° C. and a mixture of 2-ethoxybenzaldehyde (6.007 g, 40 mmol) and ethyl azidoacetate (160 mmol) was then added, over one hour, at a rate which allowed the temperature to be maintained below −15° C. After three hours, the solution was stored at 5° C. for two days in order to give a crystalline product which was collected and washed with cold hexane in order to give an off-white solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.O1CCOCC1.[CH2:18]([N:24]=[C:25]=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>N1C=CC=CC=1>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:25](=[O:26])[NH:24][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCCCCCN=C=O
Reactant: Oc1ccc2ncccc2c1
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CCCCCCNC(=O)Oc1ccc2ncccc2c1
Temperature: 32 °C
Reaction time: 48 h

Procedure:
Mixture of quinolin-6-ol (0.58 g., 4 mmol), dry dioxane (20 ml), hexyl isocyanate (0.698 ml, 4.8 mmol) and dry pyridine (0.2 ml) was stirred at room temperature (32° C.) for 48 hours. Reaction mixture was concentrated under vaccum, titurated with water (1 ml) and crystallised with ether, to give 1a; yield: 0.80 g. (73.5%), m.p. 89° C., C16H20N2O2; 1H NMR δ ppm (CDCl3): 0.91 (bs, 3H), 1.33-1.34 (bs, 6H), 1.56-1.62 (m, 2H), 3.24-3.34 (m, 2H), 5.21 (bs, 1H), 7.35-7.42 (m, 1H), 7.48-7.52 (m, 1H), 7.60-7.61 (m, 1H), 8.07-8.12 (m, 2H), 8.86-8.89 (m, 1H); IR vmax (KBr) (cm−1): 478, 530, 674, 730, 788, 839, 909, 970, 1002, 1040, 1158, 1215, 1258, 1300, 1356, 1462, 1495, 1543, 1709, 1919, 2373, 2861, 2961, 3032, 3286, 3346, 3777, MS: m/z: 273 (M+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[C:3]=1[O:11][CH3:12].CN(C)CCN(C)C.C([Li])CCC.[CH:26](=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[N:29][CH:28]=1>CCOCC.CCCCCC.O>[N:29]1[CH:30]=[CH:31][CH:32]=[C:27]([CH:26]([OH:33])[C:5]2[C:4]([CH3:10])=[C:3]([O:11][CH3:12])[C:2]([CH3:1])=[CH:7][C:6]=2[O:8][CH3:9])[CH:28]=1
Reactant: COc1cc(C)c(OC)c(C)c1
Reactant: O=Cc1cccnc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: O
Product: COc1cc(C)c(OC)c(C)c1C(O)c1cccnc1
Temperature: -65 °C
Reaction time: 1 h

Procedure:
3.0 g of 1,3-dimethyl-2,5-dimethoxybenzene and 3.1 g of tetramethylethylenediamine were dissolved in 30 ml of dry ether and 17 ml of a 1.6M solution of n-butyllithium in hexane was added dropwise thereto in a nitrogen atmosphere at room temperature. After 1 hour, the mixture was cooled to -65° C. and a solution of 2.9 g of nicotinaldehyde in 10 ml of ether was added thereto. After 30 minutes, the reaction was ceased by adding water and the reaction mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate. After distilling off the solvent, 6.4 g of a crude product of the title compound was obtained.
Reaction SMILES: [C:1]1([NH:7][C:8]([NH2:10])=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH:12]([CH:18]([CH3:20])[CH3:19])[C:13](OCC)=[O:14]>>[NH:7]([C:8]1[S:9][CH:12]([CH:18]([CH3:20])[CH3:19])[C:13](=[O:14])[N:10]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(=S)Nc1ccccc1
Reactant: CCOC(=O)C(Br)C(C)C
Product: CC(C)C1SC(Nc2ccccc2)=NC1=O

Procedure:
Synthesis was performed from N-phenylthiourea and ethyl 2-bromo-3-methylbutanoate according to Method C.
Reaction SMILES: [Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([OH:9])=[O:8])[CH:3]=1.S(=O)(=O)(O)O.[CH3:15]O>>[CH3:15][O:8][C:7]([C:4]1[CH:3]=[C:2]([Br:1])[S:6][CH:5]=1)=[O:9]
Reactant: O=C(O)c1csc(Br)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1csc(Br)c1

Procedure:
5-Bromo-thiophene-3-carboxylic acid (13 g, 64 mmol) was dissolved in methanol (140 mL). Concentrated sulphuric acid (6.5 mL) was added and the mixture heated at reflux for 14 hours. The reaction was quenched by adding a solution of saturated aqueous sodium bicarbonate and most of the solvent was removed by evaporation under vacuum. The mixture was then diluted with a solution of saturated aqueous sodium bicarbonate and the product extracted with DCM. The organic solution was dried over sodium sulphate, filtered and the solvent removed by evaporation to give a white crystalline solid (13.2 g). 1H NMR (400 MHz, CDCl3): δ 8.0 (s, 1H), 7.5 (s, 1H), 3.85 (s, 3H).
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].[Cl:29][C:30]1[CH:35]=[CH:34][C:33](O)=[CH:32][CH:31]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CCOCC>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([O:28][C:33]2[CH:34]=[CH:35][C:30]([Cl:29])=[CH:31][CH:32]=2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Oc1ccc(Cl)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)cc2)CC1
Temperature: 0 °C
Yield: 125.7 %

Procedure:
A solution of DIAD (11.4 mL; 55.0 mmol) in THF (15 mL) was added dropwise over 35 min to an ice-cold solution of 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (10.06 g; 50.0 mmol), 4-chlorophenol (5.1 mL; 50.4 mmol) and triphenylphosphine (14.44 g; 55.1 mmol) in THF (40 mL). After 2.9 days at room temperature the solvent was removed on a rotary evaporator leaving a viscous liquid; hexanes was added then evaporated leaving a solid. Ether (25 mL), followed by hexanes (100 mL), was added and the solid was filtered and washed with hexanes. The filtrate was concentrated on a rotary evaporator leaving a golden, viscous liquid (19.6 g). The crude product was used as is. ESIMS 311.9/313.8 (25/10) [MH+], 296.9/298.8 (100/34) [MH+—C4H9+CH3CN], 255.9/257.8 (94/32) [MH+—C4H9], 212.0/214.0 (13/5) [MH+—C4H9—CO2].
Reaction SMILES: I.CO[C:4]1[C:9]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:18][C:19]([OH:21])=[O:20].S([O-])(O)=O.[Na+]>C(OC(=O)C)(=O)C>[Cl:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[S:10][C:9]1[C:4]2[O:21][C:19](=[O:20])[CH2:18][C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: COc1c(CC(=O)O)cccc1Sc1ccccc1Cl
Agent: I
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: O=C1Cc2cccc(Sc3ccccc3Cl)c2O1
Yield: 87.7 %

Procedure:
Hydriodic acid (58%, 10 ml) was added dropwise to a solution of 2-[2-methoxy-3-(2-chlorophenylthio)phenyl]acetic acid (1.4 g) in acetic anhydride (5 ml), and the mixture was refluxed under heating for 15 minutes. After cooling, the reaction mixture was poured into an aqueous solution of sodium hydrogen sulfite. The mixture was extracted with diethyl ether, and the extract was washed with aqueous sodium hydrogen sulfite and water in turn, dried and then evaporated under reduced pressure. To the residue was added acetic anhydride (10 ml), and the mixture was refluxed under heating for 10 minutes, and then evaporated under reduced pressure to give crystalline 7-(2-chlorophenylthio)-2,3-dihydrobenzofuran-2-one (1.1 g). This product was recrystallized from ethanol to give the pure product (0.8 g), mp. 145°-146° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([OH:13])=O)=[CH:7][C:6]=1[NH:14][C:15](=[O:33])[CH2:16][CH:17]([C:23]1[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=1[O:31][CH3:32])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:4])([CH3:3])[CH3:2].[NH2:34][C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])[NH:34][C:35]2[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=2)=[CH:7][C:6]=1[NH:14][C:15](=[O:33])[CH2:16][CH:17]([C:23]1[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=1[O:31][CH3:32])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:3])([CH3:4])[CH3:2]
Reactant: Nc1ccncc1
Reactant: CCCCCC(CC(=O)Nc1cc(C(=O)O)ccc1C(C)(C)C)c1c(OC)cccc1OC
Product: CCCCCC(CC(=O)Nc1cc(C(=O)Nc2ccncc2)ccc1C(C)(C)C)c1c(OC)cccc1OC

Procedure:
Following a similar procedure to that described in Example 8, but using N-(2-t-butyl-5-carboxyphenyl)-3-(2,6-dimethoxyphenyl)octanamide (prepared as described in Preparation 74E) and 4-aminopyridine, the title compound was obtained as colorless crystals, melting at 169-172° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.O[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31](=[O:33])[CH3:32])=[CH:25][CH:24]=1>>[O:33]=[C:31]([CH3:32])[CH2:30][CH2:29][C:26]1[CH:27]=[CH:28][C:23]([O:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:19])([F:20])[F:21])[C:5]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:15])([F:16])[F:14])[CH:6]=2)=[CH:24][CH:25]=1
Reactant: N#Cc1ccc(N(CCO)CC(F)(F)F)cc1C(F)(F)F
Reactant: CC(=O)CCc1ccc(O)cc1
Product: CC(=O)CCc1ccc(OCCN(CC(F)(F)F)c2ccc(C#N)c(C(F)(F)F)c2)cc1

Procedure:
Synthesized as described in Example 1C using 4-[(2-hydroxyethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile and 4-(4-hydroxyphenyl)-2-butanone: MS (APCI) m/z 459 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13])=[O:5].[Cl:19][CH2:20][C:21](Cl)=O>C(O)(=O)C>[Cl:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:2]2[C:3]=1[C:4](=[O:5])[N:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13])[C:21]([CH2:20][Cl:19])=[N:1]2
Reactant: Nc1cccc(Cl)c1C(=O)Nc1ccccc1Cl
Reactant: O=C(Cl)CCl
Solvent: CC(=O)O
Product: O=c1c2c(Cl)cccc2nc(CCl)n1-c1ccccc1Cl
Yield: 65.4 %

Procedure:
Prepared according to Procedure B with 1f (1.00 g, 3.56 mmol) and chloroacetyl chloride (0.85 mL, 10.7 mmol) in acetic acid (15 mL). Purified by recrystallization from isopropanol to afford 791 mg of an off-white crystalline solid (65%). 1H NMR (CDCl3) δ: 7.70 (s, 1H); 7.68 (d, J=3.8 Hz, 1H); 7.61-7.65 (m, 1H); 7.55 (dd, J=2.7, 6.4 Hz, 1H); 7.51 (d, J=3.1 Hz, 1H); 7.50 (s, 2H); 4.35 (d, J=12 Hz, 1H), 4.05 (d, J=12 Hz, 1H). MS (ES): m/z 339.0 (M+).
Reaction SMILES: [C:1]1([CH2:7]C(OCCl)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]([NH:16][C:17]1[C:18]([I:33])=[C:19]([N:28]([C:30](=[O:32])[CH3:31])[CH3:29])[C:20]([I:27])=[C:21]([C:24]([O-:26])=[O:25])[C:22]=1[I:23])(=[O:15])[CH3:14].[Cs+].[I-].[Na+]>CN(C=O)C>[C:13]([NH:16][C:17]1[C:18]([I:33])=[C:19]([N:28]([C:30](=[O:32])[CH3:31])[CH3:29])[C:20]([I:27])=[C:21]([C:24]([O:26][CH:7]([O:26][C:24](=[O:25])[CH3:21])[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:25])[C:22]=1[I:23])(=[O:15])[CH3:14]
Reactant: CC(=O)Nc1c(I)c(C(=O)[O-])c(I)c(N(C)C(C)=O)c1I
Reactant: O=C(Cc1ccccc1)OCCl
Agent: [Cs+]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1c(I)c(C(=O)OC(OC(C)=O)c2ccccc2)c(I)c(N(C)C(C)=O)c1I
Reaction time: 20 h

Procedure:
Chloromethyl phenylacetate (Neuenschwander, Markus et. al., Helv. Chin. Acta, 61 (1978) 2047) (1.59 g. 8.6 mmol) in dry DMF (20 ml) is added dropwise at 50° C. to a solution of cesium 5-(N-acetylamino)-3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzenecarboxylate (7.28 g, 9.6 mmol) and sodium iodide (64 mg, 0.42 mmol) in dry DMF (100 ml). The precipitate is removed by filtration after stirring for 20 hours and the solvent is removed at reduced pressure. The residue is dissolved in chloroform (200 ml) and washed twice with a saturated sodium hydrogen carbonate solution and twice with water. After drying with magnesium sulfate the solvent is removed at reduced pressure to give the title compound:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]([NH:15][C:16]3[N:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=3)[CH:12]=[CH:13][CH:14]=2)O1.[F-].[K+].Br[C:30]1[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[N:34][CH:35]=1.O>C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:37][O:36][C:33]1[N:34]=[CH:35][C:30]([C:9]2[CH:10]=[C:11]([NH:15][C:16]3[N:21]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:19]=[CH:18][N:17]=3)[CH:12]=[CH:13][CH:14]=2)=[CH:31][CH:32]=1
Reactant: CC1(C)OB(c2cccc(Nc3nccc(C(F)(F)F)n3)c2)OC1(C)C
Reactant: COc1ccc(Br)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2cccc(Nc3nccc(C(F)(F)F)n3)c2)cn1
Temperature: 75 °C

Procedure:
N-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (150 mg, 0.411 mmol) and potassium fluoride (71.6 mg, 1.23 mmol) were added to 3.00 mL of a stock solution of palladium(II) acetate (4.61 mg, 0.021 mmol) and butyl[di-(3S,5S,7S)-tricyclo[3.3.1.13,7]dec-1-yl]phosphane (14.7 mg, 0.041 mmol) in THF (3.00 mL) under nitrogen. 5-Bromo-2-methoxypyridine (0.069 mL, 0.534 mmol) and water (1.00 mL) were then added to the reaction mixture and was heated to 75° C. for 17 hours. Upon cooling to room temperature, the reaction mixture was quenched by the addition of 25% aqueous NH4OAc. The aqueous layer was extracted with ethyl acetate (2×) and the combined organic layers were washed sequentially with water and brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/dichloromethane) to afford N-[3-(6-methoxypyridin-3-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine as a beige solid. MS APC calc'd for C17H14F3N4O [M+H]+ 347. found 347.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:9]([CH3:10])=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])[NH:7][CH2:6]1)=[O:4]>C1(C)C=CC=CC=1.[Pd]>[CH3:1][O:2][C:3]([C:5]1[C:9]([CH3:10])=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])[NH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)C1CNC(c2ccccc2C(F)(F)F)=C1C
Agent: [Pd]
Solvent: Cc1ccccc1
Product: COC(=O)c1c[nH]c(-c2ccccc2C(F)(F)F)c1C
Yield: 29.3 %

Procedure:
To a solution of 4-methyl-5-(2-trifluoromethyl-phenyl)-2,3-dihydro-1H-pyrrole-3-carboxylic acid methyl ester (10 g, 35 mmol) in toluene was added 10% Pd/C (3.3 g). The resulting suspension was heated to reflux for 3 days. After cooling, the solids were removed by filtration. The filtrate was washed with toluene and concentrated under reduced pressure to yield an oil, which was purified by column chromatography (silica), eluting with EtOAc-hexane (1:1) to give the title compound (2.9 g, 29%). MS (ES): 284 (MH+).
Reaction SMILES: [NH2:1][N:2]1[C:10]2[C:6]([N:7]3[N:13]([CH2:14][CH:15]4[CH2:17][CH2:16]4)[C:12](=[O:18])[N:11]([CH2:19][CH2:20][N:21]4[CH:25]=[C:24]([C:26](O)=[O:27])[CH:23]=[N:22]4)[CH:8]3[N:9]=2)=[C:5]([C:29]2[O:30][CH:31]=[CH:32][CH:33]=2)[N:4]=[CH:3]1.S(Cl)(Cl)=O.[CH:38]1([NH2:41])[CH2:40][CH2:39]1>>[NH2:1][N:2]1[C:10]2[C:6]([N:7]3[N:13]([CH2:14][CH:15]4[CH2:17][CH2:16]4)[C:12](=[O:18])[N:11]([CH2:19][CH2:20][N:21]4[CH:25]=[C:24]([C:26]([NH:41][CH:38]5[CH2:40][CH2:39]5)=[O:27])[CH:23]=[N:22]4)[CH:8]3[N:9]=2)=[C:5]([C:29]2[O:30][CH:31]=[CH:32][CH:33]=2)[N:4]=[CH:3]1
Reactant: NC1CC1
Reactant: NN1C=NC(c2ccco2)=C2C1=NC1N(CCn3cc(C(=O)O)cn3)C(=O)N(CC3CC3)N21
Solvent: O=S(Cl)Cl
Product: NN1C=NC(c2ccco2)=C2C1=NC1N(CCn3cc(C(=O)NC4CC4)cn3)C(=O)N(CC3CC3)N21
Temperature: 75 °C
Reaction time: 2 h
Yield: 9.2 %

Procedure:
A mixture of 1-[2-[5-amino-1-(cyclopropylmethyl)-8-(2-furyl)-2-oxo-[1,2,4]triazolo[5,1-f]purin-3-yl]ethyl]pyrazole-4-carboxylic acid (0.050 g, 0.111 mmol) was taken in thionyl chloride (0.04 ml, 0.557 mmol) and stirred at 75° C. for 2 hours. The reaction mixture was concentrated and residue was dissolved in DCM (2 ml). To the above solution cyclopropyl amine (0.015 ml, 0.222 mmol) was added at 0° C. and stirred at same temperature for 2 hours and filtered to obtain 1-[2-[5-amino-1-(cyclopropylmethyl)-8-(2-furyl)-2-oxo-[1,2,4]triazolo[5,1-f]purin-3-yl]ethyl]-N-cyclopropyl-pyrazole-4-carboxamide (5.0 mg, 9%) as an off white solid.
Reaction SMILES: CN.CO[C:5]1[C:9]([NH:10][CH3:11])=[N:8][S:7](=[O:12])[N:6]=1.[CH3:13][N:14]([CH2:16][C:17]1[O:21][C:20]([CH2:22][S:23][CH2:24][CH2:25][NH2:26])=[CH:19][CH:18]=1)[CH3:15]>>[CH3:15][N:14]([CH2:16][C:17]1[O:21][C:20]([CH2:22][S:23][CH2:24][CH2:25][NH:26][C:5]2[C:9]([NH:10][CH3:11])=[N:8][S:7](=[O:12])[N:6]=2)=[CH:19][CH:18]=1)[CH3:13]
Reactant: CNC1=NS(=O)N=C1OC
Reactant: CN(C)Cc1ccc(CSCCN)o1
Agent: CN
Product: CNC1=NS(=O)N=C1NCCSCc1ccc(CN(C)C)o1

Procedure:
Reaction of a methanolic solution of 3,4-dimethoxy-1,2,5-thiadizole 1-oxide [prepared in Example 4, Step A] with one equivalent of methylamine and treatment of the resultant 3-methoxy-4-methylamino-1,2,5-thiadiazole 1-oxide with one equivalent of 2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamine yields the title compound, which is identical to the product prepared in Example 18.
Reaction SMILES: [S:1]1[C:5]2=[C:6]3[C:10](=[CH:11][CH:12]=[C:4]2[N:3]=[CH:2]1)[NH:9][C:8](=[O:13])[C:7]3=[O:14].O1CCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30]>CN(C)C=O>[CH3:30][CH:29]([CH3:31])[CH2:28][CH2:27][N:9]1[C:10]2[C:6](=[C:5]3[S:1][CH:2]=[N:3][C:4]3=[CH:12][CH:11]=2)[C:7](=[O:14])[C:8]1=[O:13]
Reactant: O=C1Nc2ccc3ncsc3c2C1=O
Reactant: CC(C)CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)CCN1C(=O)C(=O)c2c1ccc1ncsc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 57.7 %

Procedure:
To a stirred solution of 6H-thiazolo[5,4-e]indole-7,8-dione (2.83 g, 13.9 mmol) in a mixture of anhydrous tetrahydrofuran (120 mL) and N,N-dimethylformamide (80 mL) was added cesium carbonate (23.0 g, 70 mmol) at ambient temperature. The deep purple mixture was stirred for 0.5 h followed by the addition of 1-bromo-3-methylbutane (4.15 mL, 35.0 mmol) in one portion. The mixture was stirred at ambient temperature for 16 h and poured into 800 mL of ice-water and extracted with ethyl acetate. The orange solution was filtered through Celite, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to dryness and the residue was triturated with diethyl ether to afford 6-(3-methylbutyl)-6H-[1,3]thiazolo[5,4-e]indole-7,8-dione (2.2 g, 57%): 1H NMR (300 MHz, CDCl3) δ9.36 (s, 1H), 8.38 (d, J=8.6 Hz, 1H), 7.37 (d, J=8.6 Hz, 1H), 3.77-3.69 (m, 2H), 1.74-1.58 (m, 1H), 1.57-1.47 (m, 2H), 0.94 (d, J=6.5 Hz, 6H).
Reaction SMILES: [P:1]([CH:5]([C:10]([OH:12])=[O:11])[CH2:6][C:7]([OH:9])=[O:8])([OH:4])([OH:3])=[O:2].P([O-])(OCC)O[CH2:15]C>>[P:1]([C:5]([C:10]([OH:12])=[O:11])([CH2:6][C:7]([OH:9])=[O:8])[CH3:15])([OH:4])([OH:3])=[O:2]
Reactant: O=C(O)CC(C(=O)O)P(=O)(O)O
Reactant: CCOP([O-])OCC
Product: CC(CC(=O)O)(C(=O)O)P(=O)(O)O

Procedure:
1-Phosphono-1,2-ethane-dicarboxylic acid can be prepared by reaction of maleic ester (diethyl maleate) with diethyl phosphite in the presence of sodium alcoholate followed by acid saponification of the ester. 2-Phosphono-2,3-propane dicarboxylic acid can be obtained in the same manner with addition of the step of reacting the mixture with methyl chloride before the saponification step.
Reaction SMILES: C[O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[N:21]=[N:22][N:23]([CH3:34])[C:24]=4[NH:25][C:26]([O:28][C@H:29]([CH3:33])[CH:30]([CH3:32])[CH3:31])=[O:27])=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)[CH2:7][CH2:6]1)=[O:4].[OH-].[Na+]>C1COCC1.C(O)C>[CH3:33][C@@H:29]([O:28][C:26]([NH:25][C:24]1[N:23]([CH3:34])[N:22]=[N:21][C:20]=1[C:17]1[CH:18]=[CH:19][C:14]([C:11]2[CH:10]=[CH:9][C:8]([C:5]3([C:3]([OH:4])=[O:2])[CH2:7][CH2:6]3)=[CH:13][CH:12]=2)=[CH:15][CH:16]=1)=[O:27])[CH:30]([CH3:31])[CH3:32]
Reactant: COC(=O)C1(c2ccc(-c3ccc(-c4nnn(C)c4NC(=O)O[C@H](C)C(C)C)cc3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)[C@@H](C)OC(=O)Nc1c(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)nnn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.3 %

Procedure:
1-{4′-[5-((R)-1,2-Dimethyl-propoxycarbonylamino)-1-methyl-1H-[1,2,3]triazol-4-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid methyl ester (97 mg) was dissolved in 2 mL of THF and 2 mL of ethanol. To this clear solution was added 1N NaOH solution 2 mL. The clear solution was stirred at room temperature overnight. Solvents were evaporated and the residue was dissolved in water (12 mL). The solution was filtered. The filtrate was treated with hydrochloric acid (1N, 2.5 mL). The white precipitate was filtered and dried in air to provide 1-{4′-[5-((R)-1,2-dimethyl-propoxycarbonylamino)-1-methyl-1H-[1,2,3]triazol-4-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid as a pale yellow solid (84 mg, 89.3% yield). LC/MS calcd for C25H28N4O4 (m/e) 448.0, obsd 449.2 (M+H); 1H-NMR (300 MHz, DMSO-d6) δ ppm 0.52 (br, 1H), 0.88 (br, 5H), 1.04-1.25 (m, 5H), 1.35-1.43 (m, 2H), 1.62-1.85 (br, 1H), 3.80 (s, 3H), 4.55 (br, 1H), 7.35 (d, J=8.3 Hz, 2H), 7.57 (d, J=8.3 Hz, 2H), 7.68 (d, J=8.3 Hz, 2H), 7.78 (d, J=8.3 Hz, 2H), 9.34 and 9.67 (br s, 1H), 12.30 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:23]1[N:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][N:24]=1.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:23]3[N:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][N:24]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1-c1nccc(C(F)(F)F)n1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
2-Chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine (150 mg, 0.69 mmol) was dissolved in 5 mL dimethyl formamide. Potassium carbonate (190 mg, 1.37 mmol) and 2-chloro-4-trifluoromethyl-pyrimidine (189 mg, 0.66 mmol) were added and the reaction mixture was stirred at 80° C. overnight. The reaction mixture was poured into 70 mL water and extracted three times with ethyl acetate (100 mL each). The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product was recrystallized from diethyl ether and the desired compound was obtained as a white solid (190 mg, 76%), MS: m/e=364.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[NH:7][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:11]([OH:13])=[CH:12][C:4]=2[O:3]1.C(=O)([O-])[O-].[K+].[K+].[Br:21][CH2:22][CH2:23][CH2:24]Cl>CC(C)=O>[Br:21][CH2:22][CH2:23][CH2:24][O:13][C:11]1[CH:10]=[CH:9][C:5]2[C:6](=[O:8])[NH:7][C:2]([CH3:14])([CH3:1])[O:3][C:4]=2[CH:12]=1
Reactant: CC1(C)NC(=O)c2ccc(O)cc2O1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1(C)NC(=O)c2ccc(OCCCBr)cc2O1

Procedure:
A mixture of 38.6 g of 2,3-dihydro-2,2-dimethyl-7-hydroxy-4H-1,3-benzoxazin-4-one, 55.2 g of potassium carbonate, 47.2 g of 1-bromo-3-chloro-propane and 600 ml of acetone is refluxed for 24 hours. Filtering, concentrating the filtrate to 1/3 of the original volume and cooling yields 7-(3-bromopropoxy)-2,3-dihydro-2,2-dimethyl-4H-1,3-benzoxazin-4-one with a melting point of 111°-113°.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=2)=[CH:17][C:18]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[O:19])=[CH:12][N:11]=1.[H-].[Na+]>>[CH2:1]([O:8][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=2)=[CH:17][C:18]([N:20]2[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)=[O:19])=[CH:12][N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=CC(=O)N2CCOCC2)c2ccc(Cl)nc2)cc1OC
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(C(=CC(=O)N2CCOCC2)c2ccc(OCc3ccccc3)nc2)cc1OC
Yield: 76 %

Procedure:
In the same manner as in Example 2, using benzyl alcohol (554 mg), 4-[3-(2-chloro-5-pyridyl)-3-(3,4-dimethoxyphenyl)acryloyl]morpholine (1 g) and 60% sodium hydride (205 mg), 4-[3-(2-benzyloxy-5-pyridyl)-3-(3,4-dimethoxyphenyl)acryloyl]morpholine (Compound No.63) (0.9 g) was obtained as a resinous solid.