Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[CH:8][N:9]([CH2:19][CH2:20][S:21]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])=[C:6]2[C:5](=[O:41])[N:4]([CH3:42])[C:3]1=[O:43].CSC1NC(=S)NC(=S)N=1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[SH:21][CH2:20][CH2:19][N:9]1[C:10]([C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[C:14]#[N:15])=[C:6]2[C:7]([N:2]([CH3:1])[C:3](=[O:43])[N:4]([CH3:42])[C:5]2=[O:41])=[CH:8]1
Reactant: Cn1c(=O)c2c(-c3cccc(C#N)c3)n(CCSC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2n(C)c1=O
Agent: CC[SiH](CC)CC
Agent: CSc1nc(=S)[nH]c(=S)[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1c(=O)c2c(-c3cccc(C#N)c3)n(CCS)cc2n(C)c1=O

Procedure:
3-(1,3-Dimethyl-2,4-dioxo-6-(2-(tritylthio)ethyl)-2,3,4,6-tetrahydro-1H-pyrrolo[3,4-d]pyrimidin-5-yl)benzonitrile (step 1)(573 mg, 0.983 mmol) was dissolved in DCM (20 ml) to form a clear brown solution and passed through 2×500 mg Isolute® Si-TMT (silica bound equivalent of 2,4,6-trimercatotriazine) cartridges to afford a colourless solution. The solution was placed under a nitrogen atmosphere and whilst stirring rapidly, treated dropwise with triethylsilane (1.571 ml, 9.83 mmol) followed TFA (3.79 ml, 49.2 mmol). After stirring at RT for 1 h, the reaction mixture was concentrated under reduced pressure to yield a white solid. The isolated crude product was triturated with diethyl ether and dried in a vacuum oven at 50° C. to afford the title compound;
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([CH2:18][N:19]4[CH:23]=[C:22]([C@:24]([OH:31])([C:27]([F:30])([F:29])[F:28])[CH2:25][CH3:26])[N:21]=[N:20]4)=[CH:15][CH:16]=3)[N:11]=[C:10]([C:32](=[O:34])[CH3:33])[CH:9]=2)=[CH:4][CH:3]=1.[CH3:35][Mg]Br.CCOCC>C1COCC1>[F:28][C:27]([F:29])([F:30])[C@:24]([C:22]1[N:21]=[N:20][N:19]([CH2:18][C:14]2[CH:13]=[C:12]3[C:17]([C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[CH:9][C:10]([C:32]([OH:34])([CH3:35])[CH3:33])=[N:11]3)=[CH:16][CH:15]=2)[CH:23]=1)([OH:31])[CH2:25][CH3:26]
Reactant: CC[C@](O)(c1cn(Cc2ccc3c(-c4ccc(F)cc4)cc(C(C)=O)nc3c2)nn1)C(F)(F)F
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC[C@](O)(c1cn(Cc2ccc3c(-c4ccc(F)cc4)cc(C(C)(C)O)nc3c2)nn1)C(F)(F)F
Temperature: 25 °C

Procedure:
To a solution of (S)-1-[4-(4-fluorophenyl)-7-({4-[1-hydroxy-1-(trifluoromethyl)propyl]-1H-1,2,3-triazol-1-yl}methyl)quinolin-2-yl]ethanone (100 mg, 0.21 mmol) in THF (5 mL) at −78° C. was added methylmagnesium bromide 3M in ether (210 μL, 0.63 mmole). The reaction was warmed up to rt over 2 h and quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduce pressure. Purification on silica gel (eluting with acetone/dichloromethane, 2:8) gave the title compound. MS (+ESI): 490 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:25])=[C:7]([C:9]2[NH:13][C:12](=[O:14])[N:11]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[N:10]=2)[CH:8]=1.[C:26](Cl)(=[O:30])[CH:27]([CH3:29])[CH3:28]>C1COCC1>[Cl:25][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])=[CH:8][C:7]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=2)[N:10]=1
Reactant: NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Reactant: CC(C)C(=O)Cl
Solvent: C1CCOC1
Product: CC(C)C(=O)NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Yield: 117.6 %

Procedure:
The title compound was prepared according to the procedure described in Example-108 by using 3-(5-(aminomethyl)-2-chlorophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5(4H)-one (Intermediate-63, 0.250 g, 0.678 mmol), isobutyryl chloride (0.108 g, 1.01 mmol), TEA (2.0 mL), and dry THF (5 mL) to afford 0.350 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 1.14 (d, J=6.6 Hz, 6H), 2.41-2.43 (m, 1H), 4.30 (d, J=6.3 Hz, 2H), 7.43 (d, J=8.1 Hz, 1H), 7.61-7.64 (m, 2H), 7.86 (d, J=9.3 Hz, 2H), 8.20 (d, J=8.4 Hz, 2H), 8.38 (m, 1H), 12.69 (s, 1H); MS (m/z): 43924 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.Br[CH:44]1CC[S:46](=[O:50])(=[O:49])[CH2:45]1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH:14]3[CH2:44][CH2:45][S:46](=[O:50])(=[O:49])[CH2:15]3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: O=S1(=O)CCC(Br)C1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(C3CCS(=O)(=O)C3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-bromo-tetrahydro-thiophene 1,1-dioxide and isolated as white solid. MS(m/e): 401.3 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[C:11]([C:16](=O)[CH3:17])[C:12]([O:14][CH3:15])=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[SH:26]>CN(C)C=O.CCOCC>[CH3:17][C:16]1[NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[S:26][CH:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[C:11]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)C(=Cc1ccc([N+](=O)[O-])cc1)C(C)=O
Reactant: Nc1ccccc1S
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)C1=C(C)Nc2ccccc2SC1c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
A solution of 2-[(4-nitrophenyl)methylene]-3-oxobutanoic acid, methyl ester (1.295 g., 5 mmoles) in dimethylformamide (5 ml.) is treated with 2-aminothiophenol (695 mg. of 90%, 5 mmoles). After stirring the reaction at room temperature for one hour, it is heated at 60°-65° for 24 hours. The reaction is allowed to cool down to ambient temperature and diluted with ether. The resulting yellow solution is washed thoroughly with water, 1N sodium hydroxide, and brine. After drying over anhydrous magnesium sulfate, the solvent is stripped off to give a yellow foam (1.3 g.). This product is purified by flash chromatography (20% ethyl acetate in hexane) and the residue is recrystallized from isopropyl ether-dichloromethane to provide 2,5-dihydro-4-methyl-2-(4-nitrophenyl)-1,5-benzothiazepine-3-carboxylic acid, methyl ester as yellow needles; m.p. 149.5°-151.5° (sinters at 140°). TLC (silica gel; acetone:hexane, 30:70) Rf =0.30.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=C1)([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[S:2].[CH3:13][O:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1CCN>C(#N)C>[CH3:13][O:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[CH2:11][CH2:12][NH:8][C:1]([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[S:2]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: COc1ccccc1CCN
Solvent: CC#N
Product: COc1ccccc1CCNC(=S)n1ccnc1
Yield: 53.6 %

Procedure:
A solution of 1,1'-thiocarbonyldiimidazole (1.78 g, 10 mmol) and 2-methoxyphenethylamine (1.51 g, 10 mmol) in acetonitrile 25 mL) was stirred at room temperature for 20 h. The resulting precipitate was collected by filtration to provide 1.40 g (53%) of the titled product: IR (KBr, cm-1) 2944, 1563, 1493, 1409, 1282, 1246, 1031, 755; 1H NMR (300 MHz, DMSO-d6) δ 12.0 (br s, 1H), 7.65 (s, 1H), 7.25 (m, 2H), 7.05-6.9 (m, 4H), 3.8 (m, 2H), 3.8 (s, 3H), 2.95 (t, J=7 Hz, 2H); MS (FD) m/e 261 (M+); UV (EtOH) 278 nm (ε=7083), 216 nm (ε=12683), 203 nm (ε=22221).
Reaction SMILES: CCN=C=NCCCN(C)C.CC1C=C(C)C=C(C)N=1.[OH:21][C:22]1[CH:27]=[CH:26][N:25]2[C:28]([C:31]([OH:33])=O)=[CH:29][N:30]=[C:24]2[CH:23]=1.[CH2:34]([N:41]1[C:49]2[CH:48]=[CH:47][CH:46]=[C:45]([NH2:50])[C:44]=2[CH:43]=[N:42]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C=O)C.CCOC(C)=O>[CH2:34]([N:41]1[C:49]2[C:44](=[C:45]([NH:50][C:31]([C:28]3[N:25]4[CH:26]=[CH:27][C:22]([OH:21])=[CH:23][C:24]4=[N:30][CH:29]=3)=[O:33])[CH:46]=[CH:47][CH:48]=2)[CH:43]=[N:42]1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: Nc1cccc2c1cnn2Cc1ccccc1
Reactant: O=C(O)c1cnc2cc(O)ccn12
Agent: CCN=C=NCCCN(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: Cc1cc(C)nc(C)c1
Product: O=C(Nc1cccc2c1cnn2Cc1ccccc1)c1cnc2cc(O)ccn12
Temperature: 25 °C
Reaction time: 2 h
Yield: 0.6 %

Procedure:
A suspension of EDCI (192 mg, 0.679 mmol), 2,4,6-trimethylpyridine (224 mg, 1.85 mmol), and 7-hydroxyimidazo[1,2-a]pyridine-3-carboxylic acid (110 mg, 0.617 mmol) in DMF (2 mL) was stirred at ambient temperature for two hours. A solution of 1-benzyl-1H-indazol-4-amine (138 mg, 0.617 mmol) in DMF (2 mL) was added, and the resulting mixture was sonicated for 5 minutes. The heterogeneous mixture was stirred at ambient temperature overnight, then diluted with EtOAc, and washed twice with 1M aqueous hydrochloric acid, followed by brine. The organic layer was concentrated and subjected to chromatography on silica with 10% MeOH/DCM as eluent to provide 1.5 mg of desired product. MS (ES+APCI) m/z=384 (M+H) detected.
Reaction SMILES: C[Al](C)C.[CH3:5][C:6]1[N:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.[OH:13][C@H:14]([CH2:19][O:20][C@@H:21]([CH3:34])[CH2:22][O:23][Si:24]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26])[C:15](OC)=[O:16]>C1(C)C=CC=CC=1>[OH:13][C@@H:14]([CH2:19][O:20][C@H:21]([CH3:34])[CH2:22][O:23][Si:24]([CH:28]([CH3:30])[CH3:29])([CH:31]([CH3:33])[CH3:32])[CH:25]([CH3:26])[CH3:27])[C:15]([NH:12][C:9]1[CH:8]=[N:7][C:6]([CH3:5])=[CH:11][N:10]=1)=[O:16]
Reactant: COC(=O)[C@H](O)CO[C@@H](C)CO[Si](C(C)C)(C(C)C)C(C)C
Reactant: Cc1cnc(N)cn1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cc1cnc(NC(=O)[C@@H](O)CO[C@H](C)CO[Si](C(C)C)(C(C)C)C(C)C)cn1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 56.5 %

Procedure:
Trimethylaluminium (2M solution in toluene) (5.98 mL, 11.96 mmol) was added to 5-methylpyrazin-2-amine (1.305 g, 11.96 mmol) in toluene (20 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 20 minutes. (R)-methyl 2-hydroxy-3-((S)-1-(triisopropylsilyloxy)propan-2-yloxy)propanoate (Intermediate AU5) (2 g, 5.98 mmol) in toluene (6 mL) was added and the reaction was allowed to warm to room temperature and then refluxed for 6 hours. The reaction mixture was allowed to cool and concentrated in vacuo. The residue was neutralised with citric acid (1M, aq.) and then diluted with water (25 mL) and extracted with EtOAc (2×50 mL). The combined organics were washed with brine (20 mL), then dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 30 to 50% EtOAc in isohexane to afford the product (1.390 g, 56.5%). 1H NMR (400 MHz, CDCl3) δ 1.04-1.17 (24H, m), 2.54 (3H, s), 3.62-3.67 (3H, m), 3.81-3.85 (1H, m), 4.05-4.09 (1H, m), 4.22 (1H, d), 4.34 (1H, q), 8.13 (1H, d), 9.12 (1H, s), 9.44 (1H, d); m/z (ES+) (M+H)+412.34; HPLC tR=3.82 min.
Reaction SMILES: S(Cl)(C)(=O)=O.[CH3:6][C:7]1[O:11][N:10]=[C:9]([C:12]2[N:16]3[N:17]=[C:18]([O:25][CH2:26][C:27]4[N:28]=[N:29][N:30]([CH2:32][CH2:33]O)[CH:31]=4)[C:19]4[C:24]([C:15]3=[N:14][N:13]=2)=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:8]=1.C[CH2:36][N:37](CC)[CH2:38]C.N(C)C>C(Cl)Cl.C1COCC1.O>[CH3:36][N:37]([CH3:38])[CH2:33][CH2:32][N:30]1[CH:31]=[C:27]([CH2:26][O:25][C:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:15]3=[N:14][N:13]=[C:12]([C:9]4[CH:8]=[C:7]([CH3:6])[O:11][N:10]=4)[N:16]3[N:17]=2)[N:28]=[N:29]1
Reactant: Cc1cc(-c2nnc3c4ccccc4c(OCc4cn(CCO)nn4)nn23)no1
Reactant: CCN(CC)CC
Agent: CNC
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cc(-c2nnc3c4ccccc4c(OCc4cn(CCN(C)C)nn4)nn23)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.9 %

Procedure:
Mesyl chloride (349 μl, 4.5 mmol) was added to a stirred suspension of 2-{4-[3-(5-methylisoxazol-3-yl)-[1,2,4]triazolo[3,4-α]phthalazin-6-yloxymethyl]-[1,2,3]triazol-1-yl}ethanol (354 mg, 0.9 mmol) in Et3N (629 μl, 4.5 mmol) and CH2Cl2 (50 ml) at 0° C. under N2. The reaction was stirred overnight slowly warming to room temperature. H2O (20 ml) was added and the organics separated, dried and concentrated under reduced pressure. The crude residue was taken up in DMF (5 ml) in a sealed tube and a solution of Me2NH (8 mmol) in THF (2.0 M, 4 ml) was added. The reaction was heated at 80° C. for 4 h. The reaction mixture was concentrated under reduced pressure and then taken up in MeOH/CH2Cl2 and dry loaded onto silica. The mixture was purified by column chromatography on silica using 1.5% MeOH/CH2Cl2 containing 1% NH3 as eluent to yield the desired phthalazine (30 mg, 8%). 1H NMR (360 MHz, CDCl3) δ 8:85 (1H, s), 8.64 (1H, d, J=7.4 Hz), 8.24 (1H, d, J=7.4 Hz), 7.93 (1H, t, J=7.4 Hz), 7.80 (1H, t, J=7.4 Hz), 6.90 (1H, s), 5.77 (2H, s), 4.46 (2H, t, J=6.5 Hz), 2.92 (2H, t, J=6.5 Hz), 2.60 (3H, s), 2.24 (6H, s). m/z (ES+) 420 (M+H+).
Reaction SMILES: [CH:1]1([N:4]2[C:8]([C:9]3[CH:10]=[C:11]4[N:20]([CH3:21])[CH:19]=[CH:18][C:12]4=[N:13][C:14]=3[C@@H:15]([NH2:17])[CH3:16])=[CH:7][CH:6]=[N:5]2)[CH2:3][CH2:2]1.Cl[C:23]1[N:31]=[C:30]([NH2:32])[N:29]=[C:28]2[C:24]=1[N:25]=[CH:26][NH:27]2.C(N(C(C)C)C(C)C)C>C(#N)C>[CH:1]1([N:4]2[C:8]([C:9]3[CH:10]=[C:11]4[N:20]([CH3:21])[CH:19]=[CH:18][C:12]4=[N:13][C:14]=3[C@@H:15]([NH:17][C:23]3[N:31]=[C:30]([NH2:32])[N:29]=[C:28]4[C:24]=3[N:25]=[CH:26][NH:27]4)[CH3:16])=[CH:7][CH:6]=[N:5]2)[CH2:2][CH2:3]1
Reactant: Nc1nc(Cl)c2nc[nH]c2n1
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1-c1ccnn1C1CC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1nc(N)nc2[nH]cnc12)c1nc2ccn(C)c2cc1-c1ccnn1C1CC1
Temperature: 120 °C
Yield: 9.4 %

Procedure:
(S)-1-(6-(1-Cyclopropyl-1H-pyrazol-5-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine (166 mg, 0.590 mmol), 6-chloro-9H-purin-2-amine (100 mg, 0.590 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.31 mL, 1.8 mmol) were combined in acetonitrile (6 mL). The reaction mixture was heated in a microwave reactor at 120° C. for 2 hours and then concentrated. The residue was taken up in DMF and was purified by preparative HPLC (acid mode) eluting with 10-15% ACN in water. The fractions containing the desired compound were combined and concentrated in vacuo. The residue was further purified by preparative HPLC (basic mode) eluting with 25-35% ACN in water. The fractions containing the desired product were combined and concentrated in vacuo to give the title compound as a white solid (23 mg, 9.2%). 1H NMR (500 MHz, CD3OD) δ ppm 0.59-0.75 (m, 2 H), 0.87-1.03 (m, 2H), 1.50 (d, J=6.35 Hz, 3 H), 3.38-3.47 (m, 1 H), 3.87 (d, J=0.98 Hz, 3 H), 5.56 (br s, 1 H), 6.44 (s, 1 H), 6.70 (d, J=2.93 Hz, 1 H), 7.54-7.71 (m, 3 H), 7.83 (s, 1 H); ESI-MS m/z [M+H]+ calc'd for C21H22N10, 415; found 415.
Reaction SMILES: [Br-].[CH2:2]([Al+2])[C:3]#[CH:4].[Br-].C(Br)C#C.[Al].CO[CH:14]([O:20][CH3:21])[C:15]1[O:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1.O1CCCC1>[O:19]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH:14]([O:20][CH3:21])[CH2:4][C:3]#[CH:2]
Reactant: C#CC[Al+2]
Reactant: COC(OC)c1ccco1
Agent: C#CCBr
Agent: [Al]
Agent: [Br-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C#CCC(OC)c1ccco1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of propargyl aluminum bromide, prepared from 52.9 g of 80% propargyl bromide in toluene, 6.41 g of aluminum splutters activated with 70 mg of mercuric choride and 80 ml of tetrahydrofuran, was added dropwise a solution of 42.2 g of furfural dimethyl acetal [J. Org. Chem., 40, 1478 (1975)] in 30 ml of tetrahydrofuran during a 15 minute period while maintaining a temperature of. 25° to 30° C. The mixture was stirred for 20 minutes at 25° C., then partitioned with ether and ice-water. The organic layer was separated, washed with water, then aqueous sodium bicarbonate, finally with brine and dried. After evaporation the residue was distilled, giving 39.8 g of the desired compound, bp 68°-69° C. (11 mm).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[Br:7][CH2:8][CH2:9][CH2:10][F:11].C(OCC)(=O)C>CN(C)C=O>[BrH:7].[NH:1]=[C:2]1[N:6]([CH2:8][CH2:9][CH2:10][F:11])[CH:5]=[CH:4][S:3]1
Reactant: FCCCBr
Reactant: Nc1nccs1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Br
Product: N=c1sccn1CCCF
Temperature: 80 °C
Reaction time: 7.5 h
Yield: 45.6 %

Procedure:
5 g (50 mmol) of 2-aminothiazole was dissolved in 15 ml of dimethylformamide, and 8.8 g (62.4 mmol) of 1-bromo-3-fluoropropane was added at room temperature. The reaction mixture was heated with stirring at 80° C. for 7.5 hours and then allowed to cool to room temperature. After addition of 300 ml of ethyl acetate, the reaction mixture was stirred at room temperature for 10 minutes. The resulting oily substance was separated from the ethyl acetate solution by decantation, and the same operation was repeated twice. The oily substance was crystallized by adding ethyl acetate and a small amount of methanol and filtered off to obtain 5.5 g of 2-imino-3-(3-fluoropropyl)thiazoline hydrobromide (4: Z=Br). Melting point 153°-155° C.
Reaction SMILES: [C:1]([C@H:5]1[C:33](=[O:34])[N:32]2[CH2:35][C@@H:29]([CH2:30][C@H:31]2[C:36]([O:38][CH3:39])=[O:37])[O:28][C:17]2=[N:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[C:25]([CH:26]=O)=[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[CH2:40][C@H:9]2[O:8][C:7](=[O:41])[NH:6]1)([CH3:4])([CH3:3])[CH3:2].[NH:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:1]([C@H:5]1[C:33](=[O:34])[N:32]2[CH2:35][C@@H:29]([CH2:30][C@H:31]2[C:36]([O:38][CH3:39])=[O:37])[O:28][C:17]2=[N:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[C:25]([CH2:26][N:42]3[CH2:47][CH2:46][O:45][CH2:44][CH2:43]3)=[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[CH2:40][C@H:9]2[O:8][C:7](=[O:41])[NH:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C1COCCN1
Reactant: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3ccccc3c1C=O)O2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3ccccc3c1CN1CCOCC1)O2
Reaction time: 0.5 h

Procedure:
To a solution of the product from Step 2 (34 mg, 0.060 mmol) in CH2Cl2 (3 ml) was added morpholine (0.016 ml, 0.180 mmol) and acetic acid (10.32 μl, 0.180 mmol) followed by sodium triacetoxyborohydride (38.2 mg, 0.180 mmol). The reaction was complete in 30 minutes at which stage it was quenched with water and extracted with dichloromethane. Purification by PTLC (40% EtOAc/hexane) provided the desired compound.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.[CH3:9][C@@H:10]1[CH2:15][NH:14][CH2:13][CH2:12][NH:11]1>CC(O)C.CCN(C(C)C)C(C)C>[F:8][C:5]1[CH:4]=[N:3][C:2]([N:14]2[CH2:13][CH2:12][NH:11][C@H:10]([CH3:9])[CH2:15]2)=[N:7][CH:6]=1
Reactant: C[C@@H]1CNCCN1
Reactant: Fc1cnc(Cl)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: C[C@@H]1CN(c2ncc(F)cn2)CCN1
Yield: 117.8 %

Procedure:
A solution of 2-chloro-5-fluoropyrimidine (239 mg, 1.80 mmol) and (R)-2-methylpiperazine (271 mg, 2.71 mmol) in iPrOH (1 mL) and DIEA (617 μL) was heated in MW at 130° C. for 30 min. Solvent was removed under reduced pressure and the crude (600 mg) was purified by chromatography on silica using DCM/methanol (9/1) as eluent to afford The title compound as a white solid (416 mg, quantitative). TLC—DCM/MeOH (8/2); Rf: 0.3. 1H NMR (DMSO-d6) δ 8.14 (s, 2H), 4.48 (d, J=13.2 Hz, 2H), 4.33 (brs, 1H), 2.98-3.13 (m, 2H), 2.83 (m, 2H), 2.67 (t, J=12.7 Hz, 1H), 1.20 (m, 3H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:21])([F:20])[C:5]1[CH:6]=[C:7]([CH:17]=[CH:18][CH:19]=1)[O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1.[I-].[CH3:23][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[F:3][C:4]([F:21])([F:20])[C:5]1[CH:19]=[CH:18][CH:17]=[C:7]([O:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[CH2:23])=[CH:11][CH:10]=2)[CH:6]=1
Reactant: O=Cc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=Cc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
NaH (23.66 g, 592 mmol) was added to the solution of 4-(3-(trifluoromethyl)phenoxy)-benzaldehyde (25 g, 94 mmol) and methyltriphenylphosphonium iodide (36.2 g, 101 mmol) in THF (180 mL) at 0° C. The reaction mixture was stirred at room temperature overnight. Purification via a flash column chromatography then afforded the title compound as a colorless oil (24.4 g, 98% yield).
Reaction SMILES: [OH:1][CH:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=2)[N:13]=1.C(N(CC)CC)C.[C:30](Cl)(=[O:34])[C:31]([CH3:33])=[CH2:32]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:30]([O:11][CH:4]1[C:5]2[C:10](=[N:9][CH:8]=[CH:7][N:6]=2)[C:2](=[O:1])[N:3]1[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=2)[N:13]=1)(=[O:34])[C:31]([CH3:33])=[CH2:32]
Reactant: O=C1c2nccnc2C(O)N1c1ccc2ccc(Cl)nc2n1
Reactant: C=C(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C(=O)OC1c2nccnc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Yield: 18.3 %

Procedure:
The procedure is as in Example 7, but starting with 5-hydroxy-6-(7-chloro-1,8-naphthyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine (6.3 g) in methylene chloride (80 cc), triethylamine (5.05 g), methacryloyl chloride (3.14 g) and 4-dimethylaminopyridine (50 mg). The residue obtained is purified by recrystallization in acetonitrile followed by chromatography on neutral alumina (50 g) contained in a column 1.5 cm in diameter, eluting with methylene chloride and collecting 15-cc fractions. Fractions 12 to 34 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. 6-(7-Chloro-1,8-naphthyridin-2yl)-7-oxo-6,7-dihydro-5H-pyrrolo [3,4-b]-pyrazin-5yl methacrylate (1.4 g), m.p. 255° C., is thereby obtained.
Reaction SMILES: C([N:3]([CH2:6][CH3:7])[CH2:4]C)C.C(Cl)(Cl)=S.[NH2:12][C:13]1[C:22]2[C:17](=[C:18]([O:25][CH3:26])[CH:19]=[C:20]([O:23][CH3:24])[CH:21]=2)[C:16]([CH2:27][N:28]2C(=O)C3C(=CC=CC=3)C2=O)=[N:15][CH:14]=1.[C:39]1(N)[CH:44]=[CH:43]C=C[C:40]=1[NH2:45]>ClCCl.[Hg]=O>[NH2:28][CH2:27][C:16]1[C:17]2[C:22](=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=2[O:25][CH3:26])[C:13]([NH:12][C:4]2[NH:3][C:6]3[CH:7]=[CH:43][CH:44]=[CH:39][C:40]=3[N:45]=2)=[CH:14][N:15]=1
Reactant: COc1cc(OC)c2c(CN3C(=O)c4ccccc4C3=O)ncc(N)c2c1
Reactant: CCN(CC)CC
Reactant: Nc1ccccc1N
Agent: O=[Hg]
Agent: S=C(Cl)Cl
Solvent: ClCCl
Product: COc1cc(OC)c2c(CN)ncc(Nc3nc4ccccc4[nH]3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.6 %

Procedure:
Triethylamine (210 μL, 1.52 mmol) and then thiophosgene (55 μL, 0.72 mmol) were added to a solution of Example 45C (200 mg, 0.55 mol) in dichloromethane (5 mL), and the reaction stirred 1 h at r.t. Organics were washed with 0.5 N HCl and brine, dried (MgSO4), and concentrated. The residue was dissolved in DMF (5 mL). Phenylenediamine (89 mg, 0.82 mmol) was added, and the reaction stirred at 90° C. for 2 h. Mercury(II) oxide was added, and the reaction stirred for 3 h longer before it was concentrated in vacuo. Deprotection was carried out in ethanol (5 mL) with hydrazine (0.2 mL) at r.t. for 1 h. Purification by Prep-HPLC gave 145 mg (46%) of the title compound (TFA salt) as a yellow solid. H1-NMR (MeOD-d4): δ 8.61 (s, 1H), 7.38-7.42 (m, 2H), 7.30-7.34 (m, 2H), 7.23 (s, 1H); 7.02 (d, 1H, J=2.0 Hz), 6.89 (d, 1H, J=2.0 Hz), 4.92 (s, 2H), 4.01 (s, 3H), 3.91 (s, 3H). MS (ES) (M+H) calc'd for C19H19N5O2, 350; found 350.