Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=2)[N:10]=[C:9]1[CH3:20].C(OC(=O)C)(=O)C.[CH3:28][C:29]1[S:30][CH:31]=[C:32]([CH:34]=O)[N:33]=1>O.[Cl-].[Zn+2].[Cl-]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=2)[N:10]=[C:9]1[CH:20]=[CH:34][C:32]1[N:33]=[C:29]([CH3:28])[S:30][CH:31]=1
Reactant: Cc1nc(C=O)cs1
Reactant: Cc1nc2ccc(F)cc2c(=O)n1-c1ccccc1Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: Cc1nc(C=Cc2nc3ccc(F)cc3c(=O)n2-c2ccccc2Cl)cs1
Temperature: 25 °C
Yield: 82.1 %

Procedure:
Anhydrous zinc chloride (0.133 g, 0.98 mmol) was fused with a nitrogen purge in a round bottom flask with an open flame. The reaction vessel was allowed to return to ambient temperature, at which time dioxane (7 mL) was then added. To this mixture was added 3-(2-chloro-phenyl)-6-fluoro-2-methyl-3H-quinazolin-4-one (0.14 g, 0.49 mmol), acetic anhydride (0.138 mL, 1.46 mmol), and 2-methylthiazole-4-carboxaldehyde (0.185 g, 1.46 mmol in 4 mL of dioxane). The reaction was refluxed for 4 hours, at which time it was allowed to cool to ambient temperature. Once the reaction had cooled to ambient temperature it was diluted with water. The mixture was repeatedly extracted with chloroform. The chloroform extracts were combined to form a chloroform layer which was washed with water and brine, dried over sodium sulfate and concentrated to yield a dark residue. This residue was triturated with ether, filtered and dried to afford 0.16 g (57%) of 3-(2-chloro-phenyl)-6-fluoro-2-[2-(2-methyl-thiazol-4-yl)-vinyl]-3H-quinazolin-4-one as tan solid.
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=4[Cl:37])[N:21]=3)[CH:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:37][C:31]1[CH:32]=[C:33]([Cl:36])[CH:34]=[CH:35][C:30]=1[C:22]1[CH:23]=[C:24]([C:26]([F:28])([F:27])[F:29])[N:25]=[C:20]([C:16]2[CH:15]=[C:14]([C:11]3[S:10][C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:13][CH:12]=3)[CH:19]=[CH:18][CH:17]=2)[N:21]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2cccc(-c3nc(-c4ccc(Cl)cc4Cl)cc(C(F)(F)F)n3)c2)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccc(-c2cccc(-c3nc(-c4ccc(Cl)cc4Cl)cc(C(F)(F)F)n3)c2)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 35.9 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-5-{3-[6-(2,4-dichloro-phenyl)-4-trifluoromethyl-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid amide (0.4 g) in dichloromethane (6 ml) was added TFA (6 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N Na2CO3 solution (25 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (ethyl acetate/heptane) yielded the title compound as an off-white solid (0.13 g, 25%). MS (ISP) 530.0 [(M+H)+]; mp 237.5° C.
Reaction SMILES: Cl[N:2]1[NH:6][CH:5]=[C:4]([C:7]2[N:8]([CH3:15])[C:9]([N+:12]([O-:14])=[O:13])=[CH:10][N:11]=2)[S:3]1.[CH:16]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>O1CCOCC1>[CH:16]1([NH:22][N:2]2[NH:6][CH:5]=[C:4]([C:7]3[N:8]([CH3:15])[C:9]([N+:12]([O-:14])=[O:13])=[CH:10][N:11]=3)[S:3]2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: NC1CCCCC1
Reactant: Cn1c([N+](=O)[O-])cnc1C1=CNN(Cl)S1
Solvent: C1COCCO1
Product: Cn1c([N+](=O)[O-])cnc1C1=CNN(NC2CCCCC2)S1

Procedure:
A mixture of 5.0 g. of 2-(2-chloro-5-thiadiazolyl)-1-methyl-5-nitroimidazole, 6.0 g. of cyclohexylamine and 125 ml. of dioxane is stirred at reflux until thin-layer chromatographic analysis indicates that the chloro intermediate is completely utilized. The dioxane is removed under reduced pressure and the residue triturated with aqueous sodium bicarbonate solution. Recrystallization from a mixture of ethylacetate and acetone yields the pure compound melting at 215°-217° C.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6](Cl)=[C:5]([CH2:12][CH2:13][CH2:14][CH3:15])[N:4]=1)#[N:2].[CH3:16][NH2:17]>C1C=CC=CC=1>[C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6]([NH:17][CH3:16])=[C:5]([CH2:12][CH2:13][CH2:14][CH3:15])[N:4]=1)#[N:2]
Reactant: CCCCc1nc(C#N)c(C#N)nc1Cl
Reactant: CN
Solvent: c1ccccc1
Product: CCCCc1nc(C#N)c(C#N)nc1NC
Temperature: 30 °C
Yield: 81 %

Procedure:
2,3-Dicyano-5-chloro-6-n-butylpyrazine (2.21 g; 0.01 mole) was dissolved in 30 ml of benzene, and with stirring at 30° C., 1.55 g (0.02 mole) of a 40% aqueous solution of methylamine was added. Then, the mixture was stirred at 30° to 40° C. for 2 hours. The reaction mixture was worked up in the same way as in Example 13 to afford 1.75 g (yield 81%) of 2,3-dicyano-5-methylamino-6-n-butylpyrazine.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]1.CC(C)([O-])C.Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[S:25][C:26]3[C:31]([N:32]=2)=[CH:30][CH:29]=[C:28]([C:33]2([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH2:35][CH2:34]2)[N:27]=3)=[C:20]([F:42])[CH:19]=1>C(O)C>[F:42][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][C:21]=1[C:24]1[S:25][C:26]2[C:31]([N:32]=1)=[CH:30][CH:29]=[C:28]([C:33]1([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH2:34][CH2:35]1)[N:27]=2)[CH2:17][N:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]1
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: Fc1cc(CBr)ccc1-c1nc2ccc(C3(c4ccccc4)CC3)nc2s1
Agent: CC(C)(C)[O-]
Solvent: CCO
Product: CCOC(=O)c1cnn(Cc2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)c1
Temperature: 70 °C

Procedure:
In a reactor tube was dissolved ethyl 4-pyrazolecarboxylate (0.0957 g, 0.683 mmol) methyl 4-imidazolecarboxylate (0.047 g, 0.37 mmol) in ethyl alcohol (2 mL). To this solution was added tert-butoxide (0.0656 g, 0.683 mmol) followed by 2-(4-(bromomethyl)-2-fluorophenyl)-5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine (0.150 g, 0.341 mmol) and the reaction mixture was heated to 70° C. for 90 min. The solid observed was collected by filtration, rinsed with Et2O to afford ethyl 1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzyl)-1H-pyrazole-4-carboxylate. MS (ESI) m/z: calculated: 498.2; Observed: 499.0 (M++1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][NH:12][C:13]2[N:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[F:22][C:23]([F:34])([F:33])[O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][N:12]([CH2:29][C:28]2[CH:31]=[CH:32][C:25]([O:24][C:23]([F:22])([F:33])[F:34])=[CH:26][CH:27]=2)[C:13]2[N:14]=[CH:15][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:17][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Reactant: COc1ccc(CCNc2ncc(C(C)C)cn2)cc1Br
Solvent: C1CCOC1
Product: COc1ccc(CCN(Cc2ccc(OC(F)(F)F)cc2)c2ncc(C(C)C)cn2)cc1Br
Reaction time: 0.25 h

Procedure:
A solution of N-[2-(3-bromo-4-methoxyphenyl)ethyl]-5-isopropylpyrimidin-2-amine (157 mg; 0.45 mmol) in dry THF was treated under nitrogen with KtBuO (75 mg; 0.67 mmol). After stirring for 15 minutes, 4-trifluoromethoxybenzyl bromide (171 mg; 0.67 mmol) was added and stirred for 30 minutes. The reaction was quenched by addition of an aqueous solution of NaHSO4 and extracted with dichloromethane. The organic phase was washed with brine, dried over MgSO4, filtered and concentrated to afford N-[2-(3-bromo-4-methoxyphenyl)ethyl]-5-isopropyl-N-[4-(trifluoromethoxy)benzyl]pyrimidin-2-amine as an oil in moderate yield, which was used in the next step without further purification
Reaction SMILES: [I-].CS[C:4]1[S:5][CH2:6][C@@H:7]2[CH2:16][C:15]3[CH:14]=[CH:13][C:12]([N+:17]([O-:19])=[O:18])=[CH:11][C:10]=3[CH2:9][N+:8]=12.[NH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1>N1C=CC=CC=1>[N+:17]([C:12]1[CH:13]=[CH:14][C:15]2[CH2:16][C@H:7]3[CH2:6][S:5][C:4](=[N:20][C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[N:8]3[CH2:9][C:10]=2[CH:11]=1)([O-:19])=[O:18]
Reactant: CSC1=[N+]2Cc3cc([N+](=O)[O-])ccc3C[C@H]2CS1
Reactant: Nc1cccnc1
Agent: [I-]
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc2c(c1)CN1C(=Nc3cccnc3)SC[C@@H]1C2
Reaction time: 6 h
Yield: 88.1 %

Procedure:
(S)-3-Methylthio-7-nitro-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinolinium iodide (23 g.) is added to a solution of 3-aminopyridine (11 g.) in pyridine (400 cc.). After 6 hours at a temperature of about 20° C., the mixture is concentrated to dryness under reduced pressure (25 mm.Hg). The residue is dissolved in a mixture consisting of methylene chloride (1,500 cc.) and water (500 cc.). The organic phase is decanted, washed with water (3 × 200 cc.), dried over magnesium sulphate, filtered and then concentrated to dryness. The residue obtained is recrystallised from a mixture of acetonitrile and ethanol (1:1 by volume). (S)-7-Nitro-3-(pyrid-3-ylimino)-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline (16.2 g.) is thus obtained in the form of yellow crystals melting at 234° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]3[N:22]=[CH:23][C:24]([C:25](O)=[O:26])=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[NH2:28][C:29]1[CH:34]=[C:33]([C:35]([NH:37]O)=[NH:36])[CH:32]=[CH:31][N:30]=1>>[CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:19])[F:20])[N:15]3[N:22]=[CH:23][C:24]([C:25]4[O:26][N:37]=[C:35]([C:33]5[CH:32]=[CH:31][N:30]=[C:29]([NH2:28])[CH:34]=5)[N:36]=4)=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:10])([F:11])[F:9]
Reactant: N=C(NO)c1ccnc(N)c1
Reactant: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)O)c3n2)ccc1C(F)(F)F
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(-c4nc(-c5ccnc(N)c5)no4)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 5-(3-methyl-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.8) (195 mg, 0.5 mmol) and 2-amino-N-hydroxy-pyridine-4-carboxamidine (example B.6) (114 mg, 0.75 mmol) according to general procedure II. Obtained after trituration with water and further purification by crystallization (dichloromethane/hexane) as a yellow solid (167 mg, 66%). MS (EI) 505.2 [(M)+]; mp 245° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Br)[C:5]([C:9]#[N:10])=[C:4]([S:11][CH3:12])[N:3]=1.C([Sn](CCCC)(CCCC)[C:18]1[O:19][CH:20]=[CH:21][N:22]=1)CCC.C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Cu]I>[NH2:1][C:2]1[N:3]=[C:4]([S:11][CH3:12])[C:5]([C:9]#[N:10])=[C:6]([C:18]2[O:19][CH:20]=[CH:21][N:22]=2)[N:7]=1
Reactant: CSc1nc(N)nc(Br)c1C#N
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncco1
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: CSc1nc(N)nc(-c2ncco2)c1C#N
Temperature: 95 °C
Yield: 8.1 %

Procedure:
To a stirred solution of 2.37 g (9.67 mmol) 2-amino-4-bromo-6-methylsulfanyl-pyrimidine-5-carbonitrile in 50 ml dry DMF under argon at room temperature were added 4.50 g (12.6 mmol) 2-tributylstannanyl-oxazole, 889 mg (0.97 mmol) tris(dibenzylidene-acetone)dipalladium(O), 1.48 g (4.84 mmol) triphenylarsine and 185 mg (0.97 mmol) copper(I) iodide. The reaction mixture was heated at 95° C. for 48 h, then cooled to room temperature and partitioned between ethyl acetate and water. The phases were separated and the organic phase dried over sodium sulfate and concentrated in vacuo. Flash chromatography (ethyl acetate/hexane 1/1 followed by ethyl acetate) afforded 182 mg (7%) 2-amino-4-methylsulfanyl-6-oxazol-2-yl-pyrimidine-5-carbonitrile as a yellow crystalline solid. ES-MS m/e (%): 234 (M+H+, 100).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([CH:10]2[CH:15]3[O:16][CH:12]([CH2:13][CH2:14]3)[CH:11]2[C:17]([OH:19])=O)=[O:9])[CH2:4][CH2:3]1.S(Cl)([Cl:22])=O>C(Cl)Cl.CN(C=O)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([CH:10]2[CH:15]3[O:16][CH:12]([CH2:13][CH2:14]3)[CH:11]2[C:17]([Cl:22])=[O:19])=[O:9])[CH2:4][CH2:3]1
Reactant: O=S(Cl)Cl
Reactant: CN1CCN(C(=O)C2C3CCC(O3)C2C(=O)O)CC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)C2C3CCC(O3)C2C(=O)Cl)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice-cold solution of 3-(4-methylpiperazine-1-carbonyl)-7-oxa-bicyclo[2,2,1]-heptane-2-carboxylic acid (938 mg, 3.5 mmole) in methylene chloride (30 mL) was added thionyl chloride (1 mL) followed by a few drops of DMF. After stirring at ice-cold temperature for 30 min, the ice-bath was removed and stirring continued at room temperature overnight. The excess thionyl chloride was removed using oil-free vacuum pump at −50° C. and to the residue was added methylene chloride (10 mL). The resulted thin slurry of 1 was used as such in the next reaction.
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][C:6]1([CH2:23][CH2:24][CH3:25])[C:11]2[NH:12][C:13]3[C:18]([C:10]=2[CH2:9][CH2:8][O:7]1)=[C:17]([C:19]#[N:20])[C:16]([F:21])=[CH:15][C:14]=3[CH3:22])C.[OH-].[Na+]>C1COCC1.CO>[C:19]([C:17]1[C:16]([F:21])=[CH:15][C:14]([CH3:22])=[C:13]2[C:18]=1[C:10]1[CH2:9][CH2:8][O:7][C:6]([CH2:23][CH2:24][CH3:25])([CH2:5][C:4]([OH:26])=[O:3])[C:11]=1[NH:12]2)#[N:20]
Reactant: CCCC1(CC(=O)OCC)OCCc2c1[nH]c1c(C)cc(F)c(C#N)c21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCC1(CC(=O)O)OCCc2c1[nH]c1c(C)cc(F)c(C#N)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
To a solution of 5-cyano-6-fluoro-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid ethyl ester (404 mg, 1.13 mmol) in THF/MeOH (2.5 mL/5 mL) was added 1 N NaOH (2.26 mL, 2.26 mmol). The reaction mixture was stirred at ambient temperature overnight. Most of the THF/MeOH was removed under reduced pressure and the resulting mixture was acidified with 1 N HCl. The mixture was extracted with EtOAc (3×10 mL). The combined organic phase was washed with brine (20 mL), dried over Na2SO4 and concentrated to provide 341 mg (91%) of title compound as a white solid. 1H NMR (DMSO): 300 MHz δ 12.02 (bs, 1H), 11.33 (bs, 1H), 7.00 (d, J=9.00 Hz, 1H), 3.96 (m, 2H), 2.95 (d, J=10.3 Hz, 1H), 2.83 (t, J=3.9 Hz, 1H), 2.72 (d, J=10.3 Hz, 1H), 2.54 (s, 3H), 1.99 (m, 2H), 1.28 (m, 1H), 0.85 (m, 1H), 0.79 (t, J=5.41 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:20]([Cl:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24](O)[C:25]([F:28])([F:27])[F:26])=[CH:4][CH:3]=1.S(Cl)([Cl:32])=O.CN(C)C=O>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:20]([Cl:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([Cl:32])[C:25]([F:28])([F:27])[F:26])=[CH:4][CH:3]=1
Reactant: OC(c1ccc(Cl)c2nc3n(c12)CCCN3c1c(Cl)cc(Cl)cc1Cl)C(F)(F)F
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: FC(F)(F)C(Cl)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.1 %

Procedure:
A mixture of 1-[9-chloro-1-(2,4,6-trichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]-2,2,2-trifluoroethanol (325 mg, 0.670 mmol), thionyl chloride (0.0978 mL, 1.34 mmol) and catalytic amount of N,N-dimethylformamide in tetrahydrofuran (6.7 mL) was stirred at room temperature for 2 h. The mixture was quenched with aqueous saturated sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-30% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (297 mg, 0.590 mmol, 88%).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:12])[C:5]2[S:10][C:9](=[O:11])[NH:8][C:6]=2[N:7]=1.[C:13]([O:21][CH:22]([C@@H:24]1[CH2:28][C@@H:27]([N:29]=[N+:30]=[N-:31])[CH:26](OC)[O:25]1)[CH3:23])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C>C(#N)C>[C:13]([O:21][CH:22]([C@@H:24]1[CH2:28][C@@H:27]([N:29]=[N+:30]=[N-:31])[C@H:26]([N:8]2[C:6]3[N:7]=[C:2]([NH2:1])[NH:3][C:4](=[O:12])[C:5]=3[S:10][C:9]2=[O:11])[O:25]1)[CH3:23])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC1O[C@H](C(C)OC(=O)c2ccccc2)C[C@H]1N=[N+]=[N-]
Reactant: Nc1nc2[nH]c(=O)sc2c(=O)[nH]1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Product: CC(OC(=O)c1ccccc1)[C@@H]1C[C@@H](N=[N+]=[N-])[C@H](n2c(=O)sc3c(=O)[nH]c(N)nc32)O1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 135.3 %

Procedure:
To a suspension of 5-amino-3,6-dihydrothiazolo[4,5-d]pyrimidine-2,7-dione (186 mg, 1 mmol) in ACN (10 mL) was added BSA (630 mg, 3 mmol). The resulting reaction mixture was then stirred at 70° C. under argon for 0.5 hour to form a clear solution. After the solution was cooled to room temperature, 1-[(2S,4R)-4-azido-5-methoxy-tetrahydrofuran-2-yl]ethyl benzoate (compound 25k, 300 mg, 1.0 mmol) and TMSOTf (1.15 g, 5 mmol) were added in sequence. After being heated at 70° C. for 14 hours, the solvent was removed in vacuo. The residue was partitioned between EtOAc and saturated NaHCO3 solution (30 mL). The organic layer was separated and the aqueous phase was extracted with EtOAc (30 mL) twice. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to afford 600 mg crude product of 1-[(2S,4R,5R)-5-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)-4-azido-tetrahydrofuran-2-yl]ethyl benzoate (compound 25l), which was used in next step without further purification. MS obsd. (ESI+) [(M+H)+]: 442.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[OH-].[Ba+2].[OH-].COCCOC.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O>O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1
Reactant: Cc1ccc(Br)nc1
Reactant: OB(O)c1ccccc1C(F)(F)F
Agent: [Pd]
Agent: [Ba+2]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(-c2ccccc2C(F)(F)F)nc1
Temperature: 80 °C

Procedure:
To a solution of 2 bromo-5-methyl pyridine (1.81 g, 10.53 mmol) and barium hydroxide (4.97 g, 15.78 mmol) in water (15 mL) was added DME (80 mL). This mixture was treated sequentially with 2-(trifluoromethyl)phenylboronic acid (2.00 g, 10.53 mmol) and palladium tetrakis(triphenylphosphine) (553 mg, 0.48 mmol) and the mixture warmed to 80° C. for 48 hours. Water (100 mL) was added and the pH of the solution was adjusted to 10 and extracted with EtOAc (3×200 mL).
Reaction SMILES: Cl.[C:2]([C:4]1[C:5]([O:37][CH:38]([CH3:40])[CH3:39])=[CH:6][C:7]([NH:10][C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([CH2:28][N:29]4[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][C:30]4=[O:36])=[C:20]([CH:23](OC)[O:24]C)[N:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[N:8][CH:9]=1)#[N:3].C([O-])(O)=O.[Na+].CCOC(C)=O>C1COCC1.O>[C:2]([C:4]1[C:5]([O:37][CH:38]([CH3:40])[CH3:39])=[CH:6][C:7]([NH:10][C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([CH2:28][N:29]4[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][C:30]4=[O:36])=[C:20]([CH:23]=[O:24])[N:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[N:8][CH:9]=1)#[N:3]
Reactant: COC(OC)c1nc2c(cc1CN1CCN(C)CC1=O)CCCN2C(=O)Nc1cc(OC(C)C)c(C#N)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)Oc1cc(NC(=O)N2CCCc3cc(CN4CCN(C)CC4=O)c(C=O)nc32)ncc1C#N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Concentrated hydrochloric acid (0.15 ml) was added to a solution of N-(5-cyano-4-isopropoxypyridin-2-yl)-7-(dimethoxymethyl)-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 95, 188 mg, 0.301 mmol) in THF (1.1 ml) and water (0.4 ml) at room temperature. After stirring for 4 h at room temperature the reaction was assessed to be complete by HPLC/MS and saturated aqueous NaHCO3 was added, the mixture extracted with DCM (3×), the organic layers dried over Na2SO4 and evaporated. The crude residue was sonicated with EtOAc (6 ml) and pentane (6 ml) and then filtered. The white solid obtained was then heated and sonicated with EtOAc added (3 ml). Filtration of the cooled suspension and drying gave the title compound as a white solid.
Reaction SMILES: [H-].[Na+].[N:3]1([C:8]2[CH:9]=[C:10]([C:18]3[S:22][C:21]([NH2:23])=[N:20][C:19]=3[CH3:24])[CH:11]=[CH:12][C:13]=2[S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:6][N:5]=[CH:4]1.[C:25](N1C=CN=C1)([N:27]1[CH:31]=[CH:30][N:29]=[CH:28]1)=[O:26]>CN(C)C=O>[N:3]1([C:8]2[CH:9]=[C:10]([C:18]3[S:22][C:21]([NH:23][C:25]([N:27]4[CH:31]=[CH:30][N:29]=[CH:28]4)=[O:26])=[N:20][C:19]=3[CH3:24])[CH:11]=[CH:12][C:13]=2[S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: Cc1nc(N)sc1-c1ccc(S(C)(=O)=O)c(-n2ccnc2)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(NC(=O)n2ccnc2)sc1-c1ccc(S(C)(=O)=O)c(-n2ccnc2)c1
Temperature: 40 °C

Procedure:
Sodium hydride (60% dispersion in oil, 0.137 g, 3.42 mmol) is added to a stirred suspension of 5-(3-Imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (148) (1.04 g, 3.1 mmol) in dry dimethylformamide (10 ml) at room temperature under argon. 1,1′-Carbonyl diimidazole (0.757 g, 4.67 mmol) is added and the stirred suspension is heated to 40° C. for 1 h. The reaction mixture is cooled and the resulting solid filtered and washed with DCM and ether to afford the title compound.
Reaction SMILES: C([O-])=O.[NH4+].[CH2:5]([N:8]1[C:16](=[O:17])[C:15]2[C:10](=[N:11][C:12]([S:18][CH3:19])=[N:13][CH:14]=2)[N:9]1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([OH:29])([CH3:28])[CH3:27])[N:21]=1)[CH:6]=[CH2:7].[H-].[Na+].C(Br)C#C.C(=O)([O-])O.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.CN(C)C=O.O1CCCC1>[OH:29][C:26]([C:22]1[N:21]=[C:20]([N:9]2[C:10]3=[N:11][C:12]([S:18][CH3:19])=[N:13][CH:14]=[C:15]3[C:16](=[O:17])[N:8]2[CH2:5][C:6]#[CH:7])[CH:25]=[CH:24][CH:23]=1)([CH3:28])[CH3:27]
Reactant: C=CCn1c(=O)c2cnc(SC)nc2n1-c1cccc(C(C)(C)O)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: C#CCBr
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C#CCn1c(=O)c2cnc(SC)nc2n1-c1cccc(C(C)(C)O)n1
Temperature: 90 °C
Reaction time: 3 h
Yield: 51.1 %

Procedure:
440 mg of ammonium formate and 230 mg of [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride were added to tetrahydrofuran (13.6 mL) solution of 500 mg of 2-allyl-1-[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one produced in Example 53, and stirred at 90° C. for 3 hours. The reaction liquid was cooled to room temperature, distilled water was added thereof, and extracted with a mixed solution of chloroform/isopropanol (80/20). This was dried with anhydrous sodium sulfate, and the solvent was evaporated away under reduced pressure to obtain 770 mg of a black amorphous substance. 61.0 mg of sodium hydride was added to N,N-dimethylformamide (14.0 mL) solution of the resulting compound, and stirred for 30 minutes. 0.316 mL of propargyl bromide was added to the reaction solution, and stirred for 3.5 hours. Aqueous saturated sodium hydrogencarbonate solution and saturated saline water were added to the reaction liquid, and extracted with a mixed solution of chloroform/isopropanol (80/20). This was dried with anhydrous sodium sulfate, and the solvent was evaporated away under reduced pressure to obtain a black amorphous substance. The resulting amorphous substance was purified through silica gel column chromatography (hexane/ethyl acetate) to obtain 254 mg of the entitled compound as a white compound.