Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C1(CC([NH:11][CH:12]2[C:33](=[O:34])[N:14]3[CH:15]([C:20]4[N:24]([CH2:25][O:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[N:23]=[N:22][N:21]=4)[C:16]([CH3:19])([CH3:18])[S:17][C@H:13]23)=O)C=CC=CC=1.[K+].[Br-]>>[NH2:11][CH:12]1[C:33](=[O:34])[N:14]2[CH:15]([C:20]3[N:24]([CH2:25][O:26][C:27](=[O:32])[C:28]([CH3:30])([CH3:29])[CH3:31])[N:23]=[N:22][N:21]=3)[C:16]([CH3:18])([CH3:19])[S:17][C@H:13]12
Reactant: CC(C)(C)C(=O)OCn1nnnc1C1N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2SC1(C)C
Agent: Cl
Agent: [Br-]
Agent: [K+]
Product: CC(C)(C)C(=O)OCn1nnnc1C1N2C(=O)C(N)[C@H]2SC1(C)C
Yield: 90 %

Procedure:
The title compound is prepared as its hydrochloride in 90% yield, from 6-(2-phenylacetamido)-2,2-dimethyl-3-(1-[pivaloyloxymethyl]-tetrazol-5-yl)penam, using the method of Preparation V. The infrared spectrum (KBr disc) shows absorptions at 1780 cm-1 (β-lactam) and 1740 cm-1 (ester). The NMR spectrum (DMSO-d6) shows absorptions at 6.71 ppm (singlet, 2H, pivaloyloxy methylene hydrogens), 5.88 ppm (singlet, 1H, C-3 hydrogen), 5.83 ppm (doublet, 1H, C-5 hydrogen), 5.20 ppm (doublet, 1H, C-6 hydrogen), 1.80 ppm (singlet, 3H, C-2 methyl hydrogens), 1.20 ppm (singlet, 9H, t-butyl hydrogens) and 1.16 ppm (singlet, 3H, C-2 methyl hydrogens).
Reaction SMILES: [N:1]1([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:31][CH2:30][CH2:29][C@H:2]1[C:3]([NH:5][C@H:6]([C:14]([NH:16][C@H:17]([C:25]([NH:27]N)=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].N[C@@H:40]([C:42]([NH:44][C@H:45]([C:50]([NH:52][C@H:53]([C:58]([NH2:60])=[O:59])[CH2:54][CH2:55][S:56][CH3:57])=[O:51])[CH2:46][CH:47]([CH3:49])[CH3:48])=[O:43])[CH3:41]>>[N:1]1([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:31][CH2:30][CH2:29][C@H:2]1[C:3]([NH:5][C@H:6]([C:14]([NH:16][C@H:17]([C:25]([NH:27][C@@H:40]([C:42]([NH:44][C@H:45]([C:50]([NH:52][C@H:53]([C:58]([NH2:60])=[O:59])[CH2:54][CH2:55][S:56][CH3:57])=[O:51])[CH2:46][CH:47]([CH3:49])[CH3:48])=[O:43])[CH3:41])=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)NN
Reactant: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](C)N)C(N)=O
Product: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](C)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(N)=O
Yield: 66 %

Procedure:
Condensation of BocPro-Phe-PheNHNH2 (1.31 g.) and HDAla-Leu-MetNH2 (0.85 g.) by the acyl azide method (Yajima et al., Chem. Pharm. Bull., vol. 19, p. 1900, 1971) gave BocPro-Phe-Phe-DAla-Leu-MetNH2 in 66% yield. De-t-butoxycarbonylation of BocPro-Phe-Phe-DAla-Leu-MetNH2 (1.10 g.) using hydrogen chloride in acetic acid gave HPro-Phe-Phe-DAla-Leu-MetNH2, which was isolated as the amorphous white solid phosphate (1:1) salt sesquihydrate in 66% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:21])=[C:16](F)[C:17]=2[F:19])[C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10]1.[CH:26]([NH:28][CH2:29][CH2:30][CH:31]1[O:36][CH2:35][CH2:34][NH:33][CH2:32]1)=[O:27]>>[F:19][C:17]1[CH:16]=[C:15]([F:21])[CH:14]=[CH:13][C:18]=1[N:9]1[C:3]2[C:4](=[CH:5][C:6]([F:8])=[C:7]([N:33]3[CH2:34][CH2:35][O:36][CH:31]([CH2:30][CH2:29][NH:28][CH:26]=[O:27])[CH2:32]3)[C:2]=2[F:1])[C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10]1
Reactant: O=CNCCC1CNCCO1
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2c(F)c(F)c(F)cc2c1=O
Product: O=CNCCC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4ccc(F)cc4F)c3c2F)CCO1

Procedure:
By the use of 1-(2,4-difluorophenyl)-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 2-(2formylaminoethyl)morpholine, the reaction is similarly carried out as Example 26 to give 1-(2,4-difluorophenyl)-6,8-difluoro-7-[2-(2-formylaminoethyl)morpholino]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([O:24][C:25]([F:28])([F:27])[F:26])=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([OH:23])=O)=[CH:17][CH:16]=2)[CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:29]([S:32]([N:35]1[CH2:40][CH2:39][N:38]([CH2:41][C:42]2[CH:47]=[CH:46][C:45]([NH2:48])=[CH:44][CH:43]=2)[CH2:37][CH2:36]1)(=[O:34])=[O:33])[CH2:30][CH3:31].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:23])[NH:48][C:45]3[CH:46]=[CH:47][C:42]([CH2:41][N:38]4[CH2:37][CH2:36][N:35]([S:32]([CH2:29][CH2:30][CH3:31])(=[O:34])=[O:33])[CH2:40][CH2:39]4)=[CH:43][CH:44]=3)=[CH:17][CH:16]=2)[C:12]([O:24][C:25]([F:26])([F:27])[F:28])=[CH:11][CH:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)c(-c2ccc(C(=O)O)cc2)c1
Reactant: CCCS(=O)(=O)N1CCN(Cc2ccc(N)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)N1CCN(Cc2ccc(NC(=O)c3ccc(-c4cc(NC(=O)OC(C)(C)C)ccc4OC(F)(F)F)cc3)cc2)CC1
Reaction time: 16 h

Procedure:
A mixture of 5′-tert-butoxycarbonylamino-2′-trifluoromethoxy-biphenyl-4-carboxylic acid (300 mg), 4-[4-(propane-1-sulfonyl)-piperazin-1-ylmethyl]-phenylamine (224 mg), EDAC (144 mg), HOBT (102 mg) and N-Methylmorpholine (166 ul) in dry DMF (3 ml) was stirred for 16 hrs.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH2:28]([O:30][CH:31]([C:45]([O:47]CC)=O)[NH:32][C:33](=[O:44])[C:34]1[C:35](=[C:39]([F:43])[CH:40]=[CH:41][CH:42]=1)[C:36]([OH:38])=O)[CH3:29].C(OC(C(OCC)=O)NC(=O)C1C(=CC=CC=1F)C(O)=O)C.[CH2:72]([O:79][C:80](=[O:92])/[N:81]=[C:82](\[NH2:91])/[C:83]1[CH:88]=[CH:87][C:86]([CH2:89][NH2:90])=[CH:85][CH:84]=1)[C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1>>[CH2:72]([O:79][C:80](=[O:92])/[N:81]=[C:82](\[NH2:91])/[C:83]1[CH:84]=[CH:85][C:86]([CH2:89][NH:90][C:45](=[O:47])[CH:31]([O:30][CH2:28][CH3:29])[N:32]2[C:36](=[O:38])[C:35]3[C:34](=[CH:42][CH:41]=[CH:40][C:39]=3[F:43])[C:33]2=[O:44])=[CH:87][CH:88]=1)[C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1
Reactant: CCOC(=O)C(NC(=O)c1cccc(F)c1C(=O)O)OCC
Reactant: NCc1ccc(/C(N)=N/C(=O)OCc2ccccc2)cc1
Agent: CCOC(=O)C(NC(=O)c1c(F)cccc1C(=O)O)OCC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CCOC(C(=O)NCc1ccc(/C(N)=N/C(=O)OCc2ccccc2)cc1)N1C(=O)c2cccc(F)c2C1=O

Procedure:
According to general procedure C, but using 2.2 eq. of BOP coupling reagent and adding the amine component after a delay time of 1 h, (RS)-N-(ethoxy-ethoxycarbonyl-methyl)-6-fluoro-phthalamic acid and its regioisomer (RS)-N-(ethoxy-ethoxycarbonyl-methyl)-3-fluoro-phthalamic acid was reacted with [1-amino-1-(4-aminomethyl-phenyl)-meth-(Z)-ylidene]-carbamic acid benzyl ester to give (RS)-[1-amino-1-(4-{[2-ethoxy-2-(4-fluoro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-acetylamino]-methyl}-phenyl)-meth-(Z)-ylidene]-carbamic acid benzyl ester, MS 533.4 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH:12]=[C:11]([C:13]([O:15]C)=O)[S:10][C:4]=2[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[NH3:17]>CO>[Br:1][C:2]1[C:3]2[CH:12]=[C:11]([C:13]([NH2:17])=[O:15])[S:10][C:4]=2[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: COC(=O)c1cc2c(Br)cn(C)c(=O)c2s1
Reactant: N
Solvent: CO
Product: Cn1cc(Br)c2cc(C(N)=O)sc2c1=O
Temperature: 45 °C
Yield: 95 %

Procedure:
Using a sealed tube, a solution of methyl 4-bromo-6-methyl-7-oxothieno[2,3-c]pyridine-2-carboxylate (250 mg, 65 mmol) in MeOH (6 mL) stirred at rt was treated with 2N NH3 in methanol (8 ml). The sealed tube was heated to 45° C. for 60 h. After cooling to 0° C., the resulting suspension was filtered; the filter cake was washed with cooled (0° C.) MeOH (3 mL) and isopropyl ether (3 mL) to afford the title compound (215 mg, 95%) as a white solid. LCMS (M+H)+=288.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([OH:23])[CH2:11][CH2:12][O:13][CH2:14][P:15](=[O:22])([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O[N:25]1[CH:33]=[N:32][C:31]2[C:26]1=[N:27][CH:28]=[N:29][C:30]=2[N:34]1[C:38](=[O:39])[C:37]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:36]2[C:35]1=[O:44].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Si:1]([O:8][CH2:9][CH:10]([O:23][N:25]1[CH:33]=[N:32][C:31]2[C:26]1=[N:27][CH:28]=[N:29][C:30]=2[N:34]1[C:35](=[O:44])[C:36]2=[CH:43][CH:42]=[CH:41][CH:40]=[C:37]2[C:38]1=[O:39])[CH2:11][CH2:12][O:13][CH2:14][P:15]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])=[O:22])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOP(=O)(COCCC(O)CO[Si](C)(C)C(C)(C)C)OCC
Reactant: O=C1c2ccccc2C(=O)N1c1ncnc2c1ncn2O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOP(=O)(COCCC(CO[Si](C)(C)C(C)(C)C)On1cnc2c(N3C(=O)c4ccccc4C3=O)ncnc21)OCC
Temperature: 20 °C
Reaction time: 4 h
Yield: 69.3 %

Procedure:
A solution of diethyl 4-t-butyldimethylsilyloxy-3-hydroxybutoxymethylphosphonate (0.49 g, 1.31 mmol), 9-hydroxy-6-phthalimidopurine (0.5 g, 1.31 mmol) and triphenylphosphine (0.52 g, l.97 mmol) in dry tetrahydrofuran (50 ml) was stirred under nitrogen at O° C. during the addition of diethyl azodicarboxylate (0.31 ml, 1.97 mmol). The solution was then stirred at 20° C. for 4 h and evaporated in vacuo. The residue was chromatographed on silica, eluting with hexane-acetone 4:1, affording 9-[1-(t-butyldimethylsilyloxy)-4-(diethoxyphosphorylmethoxy)but-2-oxy]-6-phthalimidopurine (575mg, 69%) as a clear oil. νmax (film) 3500, 1790, 1740, 1600 and 1580 cm-1 ; δH [(CD3)2SO] 0.04 (6H, s, CH3SiCH3), 0.74 (9H, s, (CH3)3CSi), 1.22 (6H, t, J6.9 Hz, 2×CH3CH 2), 2.04 (2H, m, SiOCH2CHCH2), 3.79 (2H, m, CH2OSi), 3.88 (2H, d, J8.2 Hz, CH2P), 3.96 (2H, m, CH2OCH2P), 4.03 (4H, m, 2×CH3CH2), 4.69 (1H, m, CHON), 8.05 (4H, m, ArH), 8.91 (1H, s, H-2/H-8), 9.07 (1H, s, H-2/H-8); m/z (FAB+ve Ion), 656 (MNa+) and 634 (MH+). Found: C, 53.10 H, 6.30; N, 10.83%; C28H40N5O8PSi requires C, 53.07; H, 6.36,; N, 11.05%.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].[H-].[Na+].Cl[C:13]1[CH:18]=[C:17](Cl)[CH:16]=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21]>CN(C=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][C:13]2[CH:18]=[C:17]([O:9][C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[CH:16]=[CH:15][C:14]=2[N+:20]([O-:22])=[O:21])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2ccc([N+](=O)[O-])c(Oc3ccc(C#N)cc3)c2)cc1
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 66.6 %

Procedure:
4-cyanophenol 4.5 g (23.0 mmol), dissolved in 5 ml of DMF, was added to a stirred suspension of sodium hydride 0.92 g (23.0 mmol) in 5 ml of DMF cooled to 5° C. The reaction flask was stirred for 10 min at the same temperature and this was followed by dropwise addition (over 15 min) of 2,4-dichloronitrobenzene 2.0 g (10.5 mmol) dissolved in 5 ml of DMF. The reaction mixture was stirred for 6 h at 70° C. The reaction mass was poured into ice-cold water and extracted with 200 ml of ethylacetate. The organic phase was washed with 1 M Na2CO3 and saturated brine solution. The solution was dried over sodium sulphate and concentrated to afford an oily residue, which was purified by column chromatography using chlorofrom-ethyl acetate (10:2) to afford 2.5 g of the required product. 1H NMR (DMSO-d6): δ 6.79 (1H, d), 6.93 (1H, d), 7.06 (2H, d), 7.18 (2H, d), 7.75 (4H, d), 8.16 (1H, d).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:29]=[CH:28][C:7]([CH2:8][O:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([OH:26])[C:22]([F:25])([F:24])[F:23])[C:13]3=[O:27])=[CH:6][CH:5]=1.I[CH3:31].O>O1CCCC1>[F:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([O:26][CH3:31])[C:22]([F:24])([F:25])[F:23])[C:13]3=[O:27])=[CH:28][CH:29]=1
Reactant: O=C1c2ccc(OCc3ccc(F)cc3)cc2C(=O)N1CC(O)C(F)(F)F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(CN1C(=O)c2ccc(OCc3ccc(F)cc3)cc2C1=O)C(F)(F)F
Reaction time: 14 h
Yield: 33.6 %

Procedure:
To a suspension of sodium hydride (45 mg, 1.0 mmol) in tetrahydrofuran (8 mL) was added 5-(4-fluoro-benzyloxy)-2-(3,3,3-trifluoro-2-hydroxy-propyl)-isoindole-1,3-dione (360 mg, 0.9 mmol) at room temperature and then iodomethane (159 mg, 1.1 mmol) was added and then after 14 h, water was added. The mixture was then extracted with ethylacetate and the combined organic extracts washed with water, brine and then dried over sodium sulfate. Filtration and evaporation gave a residue which was purified by chromatography (SiO2, hexane-EtOAc 3:1) to afford the title compound (120 mg, 32%) as a white solid. MS: m/e=398.4 (M+H+).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[N:13]1[CH:18]=[CH:17][CH:16]=[N:15][C:14]=1[NH2:19].CC1C=CC=CC=1>C(O)(=O)C.O>[N:13]1[CH:18]=[CH:17][CH:16]=[N:15][C:14]=1[N:19]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1
Reactant: Nc1ncccn1
Reactant: CCOC(=O)N1CCC(=O)CC1
Solvent: CC(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCC(=Nc2ncccn2)CC1

Procedure:
A mixture of 34 parts of ethyl 4-oxo-1-piperidinecarboxylate, 20 parts of 2-pyrimidinamine, 8 drops of acetic acid and 90 parts of methylbenzene is stirred and refluxed for 28 hours with water-separator. The reaction mixture is evaporated, yielding 50 parts of ethyl 4-(2-pyrimidinylimino)-1-piperidinecarboxylate as a residue.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.[CH3:14][O:15][C:16](=[O:19])[CH2:17][NH2:18].C(N(CC)CC)C.[CH2:27]([P:34](Cl)([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:35])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.P([O-])(OCC1C=CC=CC=1)OCC1C=CC=CC=1.S(Cl)(Cl)(=O)=O>C(Cl)(Cl)Cl>[CH2:36]([P:34]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:35])[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1.[CH3:14][O:15][C:16](=[O:19])[CH2:17][NH2:18]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=P(Cl)(Cc1ccccc1)Cc1ccccc1
Agent: COC(=O)CN
Agent: Cl
Agent: [O-]P(OCc1ccccc1)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O=S(=O)(Cl)Cl
Product: O=C(O)[C@H](Cc1ccccc1)NP(=O)(Cc1ccccc1)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2g of L-phenylalanine-glycine methyl ester hydrochloride (7.4 mmoles) are put in suspension in 20 ml of anhydrous chloroform. 1.50 g of triethylamine (15 mmoles) are added. The solid enters into solution. The solution is cooled to 0° C. and 2.17 g (7.4 mmoles) of dibenzyl phosphoryl chloride freshly prepared from dibenzyl phosphite and sulfuryl chloride are added while stirring for 30 minutes. The mixture is allowed to stand for 20 hours at room temperature. The precipitate formed is filtered and the filtrate is washed in succession with 30 ml of 1N HCl, 20 ml of water, 20 ml of 10% bicarbonate, then 2×30 ml of water. The organic solution is dried on anhydrous Na2SO4 and evaporated under a vacuum. A pale yellow solid is obtained which is recrystallized in ethyl acetate.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([S:12][C:13]1[N:17]3[N:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]3=[N:15][N:14]=1)=[CH:7][CH:6]=2.CC1(C)C(C)(C)OB([C:31]2[CH:32]=[N:33][N:34](COCC[Si](C)(C)C)[CH:35]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].C(O)(C(F)(F)F)=O>O1CCOCC1>[CH3:22][C:19]1[CH:20]=[CH:21][C:16]2[N:17]([C:13]([S:12][C:8]3[CH:9]=[C:10]4[C:5](=[CH:6][CH:7]=3)[N:4]=[CH:3][C:2]([C:31]3[CH:32]=[N:33][NH:34][CH:35]=3)=[CH:11]4)=[N:14][N:15]=2)[N:18]=1
Reactant: CC1(C)OB(c2cnn(COCC[Si](C)(C)C)c2)OC1(C)C
Reactant: Cc1ccc2nnc(Sc3ccc4ncc(Br)cc4c3)n2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: Cc1ccc2nnc(Sc3ccc4ncc(-c5cn[nH]c5)cc4c3)n2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.5 %

Procedure:
A microwave vessel was charged with 3-bromo-6-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl)-quinoline (970 mg, 2.606 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazole (930 mg, 2.866 mmol), and dichlorobis(triphenylphosphine) palladium(0) (92 mg, 0.13 mmol). 1,4-Dioxane (10 mL) and a 2 M aqueous solution of sodium carbonate (5 mL) were added. The vessel was capped and microwaved at 130° C. for 30 min. The reaction mixture was partitioned between water and 10% methanol/dichloromethane. The aqueous layer was extracted with 10% methanol/dichloromethane, and the combined organics were adsorbed on silica gel. Purification by flash chromatography on silica gel using a gradient of 0-8% methanol/dichloromethane afforded 1.073 g of the crude coupling product as a light brown oil. The oil was treated with TFA (10 mL). The reaction mixture was stirred at room temperature for 2 h, before concentrating in vacuo. The residue was treated with 1 N aqueous NaOH, and the precipitate was filtered, washed sequentially with water and ethyl acetate. The resulting yellow solid was dissolved in 10% methanol/dichloromethane and adsorbed on silica gel. Purification by flash chromatography on silica gel using a gradient of 0-10% methanol/dichloromethane afforded 417 mg of impure 6-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl)-3-(1H-pyrazol-4-yl)-quinoline. Purification of 30 mg of material by mass-triggered HPLC (5-95% CH3CN/H2O, 0.1% HCOOH modifier) provided 12 mg of pure 6-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl)-3-(1H-pyrazol-4-yl)-quinoline.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]([F:23])([F:22])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][N:12]1[CH:16]([C:17]([O:19]C)=[O:18])[CH2:15][CH2:14][C:13]1=[O:21]>O>[F:23][C:4]([F:3])([F:22])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][N:12]1[C:13](=[O:21])[CH2:14][CH2:15][CH:16]1[C:17]([OH:19])=[O:18]
Reactant: COC(=O)C1CCC(=O)N1Cc1ccccc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C1CCC(=O)N1Cc1ccccc1C(F)(F)F
Temperature: 25 °C
Yield: 39.9 %

Procedure:
A solution of 17.40 g of sodium hydroxide pellets in 275 ml of water was treated with 131 g of (±)-1-[(2-trifluoromethylphenyl)methyl]-5-methoxycarbonyl-2-pyrrolidinone and was heated for four hours with a steam bath. The solution was cooled down to room temperature and extracted with diethyl ether (total volume=1000 ml). The aqueous phase was acidified with 50 ml of concentrated hydrochloric acid and extracted with dichloromethane (total volume=900 ml). The organic phase was dried over anhydrous sodium sulfate and concentrated to a solid. The solid was recrystallized from toluene (800 ml) which afforded 49.8 g of crystals, m.p. 139°-141°.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Br:11]Br.N1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:11][C:9]1[CH:8]=[N:7][CH:6]=[C:5]2[C:10]=1[N:1]=[CH:2][CH:3]=[CH:4]2
Reactant: c1cnc2ccncc2c1
Reactant: BrBr
Solvent: c1ccncc1
Solvent: ClC(Cl)(Cl)Cl
Product: Brc1cncc2cccnc12
Reaction time: 1 h
Yield: 26.7 %

Procedure:
To a stirred solution of [1,6]-naphthyridine (4.73 g, 36.4 mmol) in CCl4 (200 25 mL) was added Br2 (2.25 mL, 43.7 mmol) in CCl4 (35 mL) dropwise via an addition funnel. The resulting solution was heated at reflux for 1 hour. Pyridine (2.94 mL, 36.4 mmol) in CCl4 (30 mL) was added dropwise to the refluxing solution, and the mixture was refluxed overnight. The cooled reaction mixture was filtered, and the solids were digested with 1 M NaOH (200 mL) for 1 hour. The basic solution was extracted into CH2Cl2 (2×200 mL), and the organic fractions were combined, dried over Na2SO4 and concentrated. The resulting oil was purified by column chromatography (10% EtOAc/CH2Cl2) affording 2.03 g (27%) of the title compound as yellow crystals: mp 79-81° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:8]2[CH:9]=[C:10]3[N:14]([C:7]=2[CH:6]=[CH:5][N:4]=1)[CH2:13][CH2:12][C:11]3=[O:15].Br[CH2:17][C:18]([O:20][CH3:21])=[O:19]>C1COCC1>[OH:15][C:11]1([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:10]2[N:14]([C:7]3[CH:6]=[CH:5][N:4]=[C:3]([S:2][CH3:1])[C:8]=3[CH:9]=2)[CH2:13][CH2:12]1
Reactant: CSc1nccc2c1cc1n2CCC1=O
Reactant: COC(=O)CBr
Solvent: C1CCOC1
Product: COC(=O)CC1(O)CCn2c1cc1c(SC)nccc12
Temperature: 60 °C

Procedure:
A mixture of 1-(methylthio)-6,7-dihydro-8H-pyrido[3,4-b]pyrrolizin-8-one (0.15 g, 0.68 mmol), methyl bromoacetate (0.34 mL), Zn—Cu (0.226 g) in THF (3.0 mL) was sonicated for 2 h. The mixture was then heated at 60° C. for 5 min. until completion of the reaction. The reaction mixture was partitioned between EtOAc and NH4Cl. The organic phase was separated, dried over Na2SO4, filtered and evaporated under reduced pressure to provide the title compound. The compound was purified by flash chromatography.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[N:17]=[C:18]([NH:34][C:35]3[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=3)[C:19]3[N:24]=[C:23]([CH2:25][C:26]4[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=4[Cl:33])[S:22][C:20]=3[N:21]=2)[CH2:10]1)=O)(C)(C)C>>[ClH:32].[Cl:33][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([Cl:32])[C:26]=1[CH2:25][C:23]1[S:22][C:20]2[N:21]=[C:16]([NH:15][CH2:14][C@@H:11]3[CH2:12][CH2:13][NH:9][CH2:10]3)[N:17]=[C:18]([NH:34][C:35]3[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=3)[C:19]=2[N:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2nc(Nc3ccc(C(F)(F)F)cc3)c3nc(Cc4c(Cl)cccc4Cl)sc3n2)C1
Agent: Cl
Product: FC(F)(F)c1ccc(Nc2nc(NC[C@@H]3CCNC3)nc3sc(Cc4c(Cl)cccc4Cl)nc23)cc1
Yield: 80.5 %

Procedure:
A solution of HCl (4 N in dioxane; 2 mL) and 3-{[2-(2,6-dichloro-benzyl)-7-(4-trifluoromethyl-phenylamino)-thiazolo[5,4-d]pyrimidin-5-ylamino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (50 mg, 0.08 mmol) was stirred at rt for 6 h. The mixture was filtered and the resulting solid was washed with Et2O (10 mL) to provided the title compound as yellow solid (19 mg, 43%). MS (ESI): mass calcd. for C24H21Cl2F3N6S, 552.1; m/z found, 553.1 [M+H]+. 1H NMR ((CD3)2SO): 9.98 (s, 1H), 8.89 (s, 1H), 8.21 (d, J=8.6 Hz, 2H), 7.77-7.32 (m, 5H), 5.87-5.78 (m, 1H), 4.67 (s, 2H), 4.17-3.93 (m, 4H), 3.77-3.63 (m, 2H), 2.96-2.84 (m, 1H), 2.05-1.95 (m, 1H), 1.73-1.59 (m, 1H).
Reaction SMILES: C([O:3][C:4](=[O:19])[CH2:5][CH:6]1[C:10]2[NH:11][C:12]3[CH:13]=[CH:14][C:15]([F:18])=[CH:16][C:17]=3[C:9]=2[CH2:8][CH2:7]1)C.CO.[OH-].[Na+].C(OCC)(=O)C>O1CCCC1>[F:18][C:15]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:6]([CH2:5][C:4]([OH:19])=[O:3])[CH2:7][CH2:8][C:9]=3[C:17]=2[CH:16]=1
Reactant: CCOC(=O)CC1CCc2c1[nH]c1ccc(F)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CC1CCc2c1[nH]c1ccc(F)cc21
Reaction time: 2.5 h

Procedure:
To a solution of 1.24 g of the ester from Step 1 in 14 mL of tetrahydrofuran (THF) at room temperature, 7 mL of MeOH followed by 7 mL of 2N NaOH were added. After 2.5 h, the reaction mixture was poured into a separatory funnel containing ethyl acetate (EtOAc)/1N HCl. The phases were separated and the acidic phase was extracted twice with EtOAc. The organic layers were combined, washed with brine, dried over anhydrous Na2SO4 and evaporated to dryness to yield 1.08 g of a crude and unstable waxy brown oil that was used as such in the next step (>90% purity).