Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].Br[CH:6]([C:12](=O)[CH:13]([CH3:15])[CH3:14])[C:7]([O:9][CH2:10][CH3:11])=[O:8].[NH4+].[OH-]>C(O)C>[NH2:1][C:2]1[S:3][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:12]([CH:13]([CH3:15])[CH3:14])[N:4]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)C(Br)C(=O)C(C)C
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)c1sc(N)nc1C(C)C
Temperature: 25 °C
Yield: 66.4 %

Procedure:
To a refluxing solution of thiourea (1.9 g, 25.6 mmol) in absolute ethanol (20 mL) was added ethyl 2-bromo-4-methyl-3-oxopentanoate (6.0 g, 25.3 mmol). The solution was stirred at reflux for another 1.5 hours. After cooling to room temperature, the solution was poured in ice/water (100 mL). The mixture was neutralized with concentrated NH4OH. The solid material was recovered by filtration, washed with water (2×20 mL) and hexanes (2×20 mL), and dried in vacuo, affording ethyl 2-amino-4-(propan-2-yl)-1,3-thiazole-5-carboxylate (3.6 g, 66% yield). The product was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][N:3]=1.[H-].[Na+].[Cl:10][C:11]1[S:12][C:13]([CH2:16]Cl)=[CH:14][N:15]=1>CN(C=O)C>[Cl:10][C:11]1[S:12][C:13]([CH2:16][N:3]2[C:2]([CH3:1])=[CH:6][C:5]([CH3:7])=[N:4]2)=[CH:14][N:15]=1
Reactant: Cc1cc(C)[nH]n1
Reactant: ClCc1cnc(Cl)s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C)n(Cc2cnc(Cl)s2)n1
Temperature: 50 °C
Reaction time: 0.08 h

Procedure:
A solution of 3,5-dimethyl-1H-pyrazole (Aldrich, 114 mg, 1.190 mmol) in DMF (5 ml) was added over NaH (Aldrich, 34.3 mg, 1.42 mmol) at 0° C. under N2 atmosphere. The mixture was stirred during 5 min and 2-chloro-5-(chloromethyl)-1,3-thiazole (AK scientific, 200 mg, 1.19 mmol) in DMF (2 ml) was added. The mixture was allowed to stir overnight. Finally, it was heated to 50° C. for 1 h. DMF was eliminated by washing with 14 ml of a mixture EtOAc/NH4Cl 1N (1:1). The organic layer was dried over Na2SO4 and the solution concentrated to dryness under vacuum, to afford a crude product which was chromatographed (silica gel cartridge, Hex/EtOAc) yielding the title compound. 1H NMR (300 MHz, CDCl3) δ ppm: 7.37 (s, 1H); 5.82 (s, 1H), 5.26 (s, 2H); 2.24 (s, 3H); 2.22 (s, 3H). [ES+MS] m/z: 228.1 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH3:16])([C:13]([OH:15])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC[N:19]([CH:23]([CH3:25])C)[CH:20]([CH3:22])C.N1CCCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH3:16])([C:13]([N:19]2[CH2:20][CH2:22][CH2:25][CH2:23]2)=[O:15])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCNC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C)(C(=O)N2CCCC2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.8 %

Procedure:
To a solution of 3-methylpyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester (348 mg, 1.52 mmol) in DMF (10 mL) were added DIPEA (0.53 mL, 3.04 mmol), pyrrolidine (0.25 mL, 3.04 mmol) and HATU (693 mg, 1.82 mmol). The reaction mixture was stirred at room temperature for 18 hours and then partitioned between water and EtOAc. The organic layer was separated and washed with a 0.1N aqueous HCl solution and brine, dried over Na2SO4, filtered and concentrated to give the desired product as a white solid (334 mg, 78%). 1H NMR (400 MHz, CHCl3-d): δ 3.61-3.38 (m, 8H); 2.00-1.79 (m, 6H); 1.47-1.44 (m, 9H); 1.33 (s, 3H).
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:9]2[C@@:5]([C:12]([O:14][CH3:15])=[O:13])([O:6][C:7]([CH3:11])([CH3:10])[O:8]2)[O:4][C@@H:3]1[CH2:16][OH:17].[S:18](Cl)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>N1C=CC=CC=1>[OH:1][C@@H:2]1[C@@H:9]2[C@@:5]([C:12]([O:14][CH3:15])=[O:13])([O:6][C:7]([CH3:11])([CH3:10])[O:8]2)[O:4][C@@H:3]1[CH2:16][O:17][S:18]([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)[C@]12O[C@H](CO)[C@H](O)[C@H]1OC(C)(C)O2
Solvent: c1ccncc1
Product: COC(=O)[C@]12O[C@H](COS(=O)(=O)c3ccc(C)cc3)[C@H](O)[C@H]1OC(C)(C)O2
Temperature: 25 °C
Reaction time: 16 h
Yield: 63 %

Procedure:
To a solution of 11 (1.0 g, 4.0 mmol) in pyridine (13 mL, Aldrich) at 0° C. (ice water bath) was added TsCl (0.76 g, 4.0 mmol, Aldrich) in portions. The resulting mixture was stirred at room temperature for 16 h. The solvent was removed in vacuo and the residue was partitioned between EtOAc/H2O. The EtOAc layer was washed with H2O (2×40 mL), brine (1×40 mL) and dried over MgSO4. EtOAc was evaporated and the crude material was purified by silica gel chromatography using EtOAc/Hexane. Product 17 was obtained as a white solid (1.0 g; yield 63%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2/[CH:14]=[CH:15]/[C:16]([OH:18])=[O:17])=[CH:4][CH:3]=1.O1CCCC1.[H][H]>[C].[Pd].C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: Cn1ncc(/C=C/C(=O)O)c1-c1ccc(F)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Cn1ncc(CCC(=O)O)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 96.7 %

Procedure:
A mixture of (2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]acrylic acid (0.80 g), 5% palladium-carbon (0.30 g), tetrahydrofuran (10 ml) and ethanol (10 ml) was stirred at room temperature for 6 hrs. in a hydrogen atmosphere at atmospheric pressure. Palladium-carbon was filtered off and the filtrate was concentrated to give 3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]propionic acid (0.78 g, yield 97%) as a colorless solid.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[C:46]3[N:50](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:49]=[N:48][N:47]=3)=[CH:36][CH:35]=2)[C:7]([C:11]([O:13][CH2:14][O:15][P:16]([O:31][CH3:32])([O:18][C@H:19]2[CH2:23][O:22][C@@H:21]3[C@H:24]([O:27][N+:28]([O-:30])=[O:29])[CH2:25][O:26][C@H:20]23)=[O:17])=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]>CO>[CH2:1]([C:5]1[N:6]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[C:46]3[NH:50][N:49]=[N:48][N:47]=3)=[CH:36][CH:35]=2)[C:7]([C:11]([O:13][CH2:14][O:15][P:16]([O:31][CH3:32])([O:18][C@H:19]2[CH2:23][O:22][C@@H:21]3[C@H:24]([O:27][N+:28]([O-:30])=[O:29])[CH2:25][O:26][C@H:20]23)=[O:17])=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(C(=O)OCOP(=O)(OC)O[C@H]2CO[C@H]3[C@@H]2OC[C@H]3O[N+](=O)[O-])n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Product: CCCCc1nc(Cl)c(C(=O)OCOP(=O)(OC)O[C@H]2CO[C@H]3[C@@H]2OC[C@H]3O[N+](=O)[O-])n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 70 °C

Procedure:
Each diastereomer of [(methoxy{[(3S,3aS,6R,6aS)-6-(nitrooxy)hexahydrofuro[3,2-b]furan-3-yl]oxy}phosphoryl)oxy]methyl 2-butyl-4-chloro-1-{[2′-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-imidazole-5-carboxylate was dissolved in methanol and heated to 70° C. for 2 hours. The residue was purified by HPLC reverse phase (C-18), eluting with acetonitrile/water+0.1% trifluoroacetic acid to give the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=1[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:16]([O-])=O.[Na+].[Sn](Cl)(Cl)(Cl)Cl>Cl.O>[CH2:1]([O:8][C:9]1[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=1[NH:11][NH2:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccccc1OCc1ccccc1
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccccc1OCc1ccccc1
Reaction time: 0.5 h

Procedure:
The 2-benzyloxyaniline (4.99 g, 25.0 mmol) partially dissolved in conc hydrochloric acid (15 mL) was cooled to less than 0° C. and a solution of the sodium nitrite (2.07 g, 30.0 mmol) in water (10 mL) was added dropwise. The reaction was stirred at the same temp for 30 min, when tin chloride (16.9 g, 75.0 mmol) in hydrochloric acid (10 mL) was added dropwise again keeping temp ca 0° C. The reaction was stored overnight in the fridge. The aqueous was decanted off the resulting black oily gum and triturated with sat NaCl (cf. 50 mL) and then ether:hexane 1:2 (50 mL) before neutralising with 10M NaOH (aq) with external cooling and extracted into ether (2×100 mL). The combined ether layers were washed with water (100 mL) dried (MgSO4) and evaporated to give a brown oil which crystallised on standing (4.52 g, 84%). Material was used crude without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](Cl)[N:9]=[C:10]=[O:11])=[CH:4][CH:3]=1.[O:13]=[C:14]1[CH2:19][CH:18]([C:20]([OH:22])=[O:21])[CH2:17][C:16]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)=[CH:15]1.O.[OH-].[Na+]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:14](=[O:13])[CH2:19][CH:18]([C:20]([OH:22])=[O:21])[CH2:17][C:16]=3[N:23]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[CH:25]=3)[C:10](=[O:11])[NH:9]2)=[CH:4][CH:3]=1
Reactant: O=C=NC(Cl)c1ccc(Br)cc1
Reactant: O=C1C=C(Nc2cccc(C(F)(F)F)c2)CC(C(=O)O)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: O=C1CC(C(=O)O)CC2=C1C(c1ccc(Br)cc1)NC(=O)N2c1cccc(C(F)(F)F)c1

Procedure:
A solution of 1-bromo-4-(chloro(isocyanato)methyl)benzene (1.07 g, 4.34 mmol) in dichloromethane (5 mL) is added to a solution of 5-oxo-3-(3-(trifluoromethyl)phenyl-amino)cyclohex-3-enecarboxylic acid (intermediate 22, 1.30 g, 4.34 mmol) in dichloromethane (15 mL) and the mixture is heated at reflux for 3 h. Water and aqueous sodium hydroxide solution are added and the mixture is washed with diethyl ether. The organic layer is discarded and the aqueous layer is acidified with aqueous hydrogen chloride and extracted twice with diethyl ether. The organic layers are combined, dried over Na2SO4 and concentrated under reduced pressure. Yield: 770 mg; ESI mass spectrum: [(79Br)-M+H]+=509, [(81Br)-M+H]+=511; Retention time HPLC: 1.25 min, 1.35 min (1:1 mixture of diastereomers) (V001—006).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:5]=[C:6]([NH:10][NH2:11])[CH:7]=[CH:8][CH:9]=1.[N:14]1[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][CH:15]=1>>[N:14]1[CH:19]=[CH:18][C:17](/[CH:20]=[N:11]/[NH:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:12])([F:13])[F:1])[CH:5]=2)=[CH:16][CH:15]=1
Reactant: NNc1cccc(OC(F)(F)F)c1
Reactant: O=Cc1ccncc1
Product: FC(F)(F)Oc1cccc(N/N=C/c2ccncc2)c1
Yield: 40 %

Procedure:
In analogy to the procedure described in Example 167A], 3-(trifluoromethoxy)phenylhydrazine and pyridine-4-carbaldehyde gave the title compound as a light yellow solid (40%). MS: 282.0 (MH+).
Reaction SMILES: CC(C)[CH2:3][O:4]CC1OC1.N1CCCC1.C[CH:16]([CH3:28])[CH2:17][O:18][CH2:19][CH:20]([OH:27])[CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>C(O)C>[CH3:3][O:4][CH:16]([CH3:28])[CH2:17][O:18][CH2:19][CH:20]([OH:27])[CH2:21][N:22]1[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: CC(C)COCC(O)CN1CCCC1
Reactant: CC(C)COCC1CO1
Solvent: C1CCNC1
Solvent: CCO
Product: COC(C)COCC(O)CN1CCCC1
Reaction time: 1 h

Procedure:
20 g. 1-(2-Methylpropoxy)-2,3-epoxypropane are dissolved in 40 ml. ethanol and the solution is warmed to 55° C. Subsequently, in the course of an hour and while stirring, there is added dropwise a solution of 13 g. pyrrolidine in 25 ml. ethanol. The temperature should thereby not increase above 70° C. After completion of the addition, stirring is continued for 1 hour at 70° C., the reaction mixture is then evaporated and the residue is distilled in a vacuum. There are obtained 35 g. 3-(2-methylpropoxy)-1-pyrrolidinopropan-2-ol; b.p. 134° C./14 mm.Hg.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:9]=[C:10]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][C:24]([O:27]C)=[CH:23][CH:22]=3)(=[O:20])=[O:19])[C:11]([NH:14][CH2:15][CH3:16])=[N:12][CH:13]=2)=[C:6]([NH:29][C@H:30]([C:32]2[N:37]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:36](=[O:44])[C:35]3=[C:45]([CH3:48])[CH:46]=[CH:47][N:34]3[N:33]=2)[CH3:31])[N:5]=[CH:4][N:3]=1.B(Br)(Br)Br>ClCCl>[NH2:1][C:2]1[C:7]([C:8]2[CH:9]=[C:10]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[C:11]([NH:14][CH2:15][CH3:16])=[N:12][CH:13]=2)=[C:6]([NH:29][C@H:30]([C:32]2[N:37]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:36](=[O:44])[C:35]3=[C:45]([CH3:48])[CH:46]=[CH:47][N:34]3[N:33]=2)[CH3:31])[N:5]=[CH:4][N:3]=1
Reactant: CCNc1ncc(-c2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)cc1NS(=O)(=O)c1ccc(OC)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCNc1ncc(-c2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)cc1NS(=O)(=O)c1ccc(O)cc1
Yield: 32 %

Procedure:
(S)—N-(5-(4-Amino-6-((1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)pyrimidin-5-yl)-2-(ethylamino)pyridin-3-yl)-4-methoxybenzenesulfonamide (18 mg, 0.03 mmol) was treated with boron tribromide (1M in dichloromethane, 0.1 ml, 0.10 mmol) with dichloromethane (1 ml) as a solvent according to the method described in Example 23. The residue was purified by reverse phase using SP1® Purification System to give 6 mg (32% yield) as a solid. Purity 93%.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:31]5[CH:36]=[C:35]([Cl:37])[C:34]([OH:38])=[C:33]([Cl:39])[CH:32]=5)[N:29]=4)[N:24]=[CH:23][C:22]=3[C:40]([CH:42]3[CH2:44][CH2:43]3)=[O:41])=[CH:16][N:15]=2)[CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O.FC(F)(F)C([O-])=O>>[NH2:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[N:15]=[CH:16][C:17]([NH:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:31]5[CH:32]=[C:33]([Cl:39])[C:34]([OH:38])=[C:35]([Cl:37])[CH:36]=5)[N:29]=4)[N:24]=[CH:23][C:22]=3[C:40]([CH:42]3[CH2:44][CH2:43]3)=[O:41])=[CH:18][CH:19]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(Cl)c(O)c(Cl)c5)nc34)cn2)C1
Agent: O=C([O-])C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H]1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(Cl)c(O)c(Cl)c5)nc34)cn2)C1
Yield: 67.7 %

Procedure:
Following general procedure IV-2, (R)-tert-butyl[1-(5-{[3-(cyclopropanecarbonyl)-6-(3,5-dichloro-4-hydroxyphenyl)-1,5-naphthyridin-4-yl}amino)pyridin-2-yl)piperidin-3-yl)carbamate (0.12 g, 0.18 mmol,) was reacted with TFA (2 mL). The resulting trifluoroacetate salt of the product was converted to the free base to afford the desired product (67 mg, 67%) as an orange solid: 1H NMR (500 MHz, CD3OD) δ 9.17 (s, 1H), 8.09 (d, J=9.0 Hz, 1H), 8.03 (d, J=9.0 Hz, 1H), 7.92 (d, J=2.5 Hz, 1H), 7.44 (s, 2H), 7.37 (dd, J=9.0, 2.5 Hz, 1H), 6.70 (d, J=9.0 Hz, 1H), 4.16-4.13 (m, 1H), 3.87-3.84 (m, 1H), 3.27-3.21 (m, 1H), 3.09-3.05 (m, 2H), 2.89-2.86 (m, 1H), 2.18-2.08 (m, 1H), 1.90-1.81 (m, 1H), 1.73-1.58 (m, 2H), 1.21-1.08 (m, 4H); ESI MS m/z 549 [M+H]+; HPLC>99% (AUC), tR=10.15 min.
Reaction SMILES: B1([O-])OO1.[OH2:5].O.O.O.[Na+].[Cl:10][C:11]1[C:12]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH:28]=[O:29])[CH:22]=2)=[N:13][CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1.O>C(O)(=O)C>[Cl:10][C:11]1[C:12]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([C:28]([OH:5])=[O:29])[CH:22]=2)=[N:13][CH:14]=[C:15]([C:17]([F:20])([F:18])[F:19])[CH:16]=1
Reactant: O=Cc1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Reactant: O
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: CC(=O)O
Product: O=C(O)c1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 81.5 %

Procedure:
38.5 g of sodium perborate tetrahydrate were added in portions over the course of 30 minutes to a solution of 16.0 g of 3-chloro-2-(4-chloro-3-formylphenyl)-5-trifluoromethylpyridine in 100 ml of glacial acetic acid at 100° C., followed by stirring at 100° C. for 1.5 hours. The mixture was cooled and then poured into 400 ml of water. The product was extracted from the aqueous phase with 3×100 ml of tert-butyl methyl ether. The combined organic phases were dried over sodium sulfate and then concentrated. The residue was triturated with n-hexane. The material insoluble in hexane was removed and extracted by boiling twice with ether, the pyridine N-oxide byproduct remaining undissolved. The combined ether phases were dried over sodium sulfate and concentrated to result in 13.7 g (81%) of colorless crystals; melting point: 149°-151° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]([NH:9][CH2:10][CH:11]([CH3:13])[CH3:12])=[NH:8])=[N:4][O:5][N:6]=1.Br[CH2:15][C:16](=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18].C(=O)(O)[O-].[Na+]>CC(O)C>[NH2:1][C:2]1[C:3]([C:7]2[N:9]([CH2:10][CH:11]([CH3:13])[CH3:12])[CH:15]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:8]=2)=[N:4][O:5][N:6]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: CC(C)CNC(=N)c1nonc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CCOC(=O)c1cn(CC(C)C)c(-c2nonc2N)n1

Procedure:
A mixture of 4-amino-N-isobutyl-1,2,5-oxadiazole-3-carboxamidine (18 mg, 0.1 mmol), ethyl bromopyruvate (28 μL, 0.2 mmol) and sodium bicarbonate (17 mg, 0.2 mmol) in iPrOH (1 mL) was microwaved for 20 minutes at 150° C. Crude reaction mixture was purified via preparative HPLC to afford the title compound as a white solid. MS 280.2 as M+1 peak. HPLC Method B Rt 3.5 min. 1HNMR (CDCl3) 7.65 (s, 1H); 5.65 (s, 2H); 5.32 (q, 2H); 4.2 (d, 2H); 2.1 (m, 1H); 1.35 (t, 3H); 0.91 (d, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[C:25]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:24]=[CH:23][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([CH:14]=[C:15]3[S:19][C:18](SC)=[N:17][C:16]3=[O:22])=[CH:11][CH:12]=2)[CH:7]=[N:6]1.[NH:31]1[CH2:36][CH2:35][NH:34][CH2:33][C:32]1=[O:37]>>[Cl:1][C:2]1[CH:26]=[C:25]([S:27]([CH3:30])(=[O:28])=[O:29])[CH:24]=[CH:23][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([CH:14]=[C:15]3[S:19][C:18]([N:34]4[CH2:35][CH2:36][NH:31][C:32](=[O:37])[CH2:33]4)=[N:17][C:16]3=[O:22])=[CH:11][CH:12]=2)[CH:7]=[N:6]1
Reactant: O=C1CNCCN1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(S(C)(=O)=O)cc3Cl)c2)S1
Product: CS(=O)(=O)c1ccc(Cn2ncc3cc(C=C4SC(N5CCNC(=O)C5)=NC4=O)ccc32)c(Cl)c1

Procedure:
4-{5-[1-(2-Chloro-4-methanesulfonyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperazin-2-one was prepared from 5-[1-(2-chloro-4-methanesulfonyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and piperazin-2-one following General Procedure C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]3[CH:14]=[CH:15][C:16]([N:18](S(C)(=O)=O)[S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][C:12]=3[O:11][C:10]([CH3:28])([CH3:27])[C:9]2=[O:29])=[CH:4][CH:3]=1.[OH-].[Na+].CC1(C)C(=O)NC2C=CC(N(S(C)(=O)=O)S(C)(=O)=O)=CC=2O1.Cl.CS(C)=O.O>CS(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13]3[CH:14]=[CH:15][C:16]([NH:18][S:19]([CH3:22])(=[O:20])=[O:21])=[CH:17][C:12]=3[O:11][C:10]([CH3:27])([CH3:28])[C:9]2=[O:29])=[CH:6][CH:7]=1
Reactant: CC1(C)Oc2cc(N(S(C)(=O)=O)S(C)(=O)=O)ccc2N(c2ccc(F)cc2)C1=O
Agent: CC1(C)Oc2cc(N(S(C)(=O)=O)S(C)(=O)=O)ccc2NC1=O
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC1(C)Oc2cc(NS(C)(=O)=O)ccc2N(c2ccc(F)cc2)C1=O
Reaction time: 8 h
Yield: 98.4 %

Procedure:
To a suspension of N-[4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]-N-(methylsulfonyl)methanesulfonamide (1 g) in dimethylsulfoxide (3 mL) was added dropwise an aqueous sodium hydroxide solution (0.18 g/3 mL) at 25° C., then dimethylsulfoxide/water (1:1.2 mL) was added thereto, and the mixture was stirred overnight at the same temperature. To the reaction mixture was added dropwise concentrated hydrochloric acid/dimethylsulfoxide/water (0.24 g/0.5 mL/0.35 mL) at 25° C., and the mixture was stirred for 5 hours. The precipitated crystals were collected by filtration, successively washed with a solution of dimethylsulfoxide/water (1:1.6 mL) and water (10 mL), and then dried under reduced pressure at 50° C. to obtain the title compound (0.81 g) as Form A crystals (yield: 98%, purity: 100%).
Reaction SMILES: [CH3:1][O:2][P:3]([O:13]C)([N:5]=[C:6]([S:10][CH2:11][CH3:12])[N:7]([CH3:9])[CH3:8])=[S:4].[CH3:15]I>CO>[CH3:1][O:2][P:3]([S:13][CH3:15])([N:5]=[C:6]([S:10][CH2:11][CH3:12])[N:7]([CH3:9])[CH3:8])=[O:4]
Reactant: CCSC(=NP(=S)(OC)OC)N(C)C
Reactant: CI
Solvent: CO
Product: CCSC(=NP(=O)(OC)SC)N(C)C
Reaction time: 6 h
Yield: 263.6 %

Procedure:
A mixture of 36.8 g of N'-(dimethoxyphosphinothioyl)-N,N-dimethylcarbamimidothioic acid, ethyl ester, 120 ml of methanol and 5.0 g of methyl iodide was heated under reflux for 18 hours, then another 5.0 g of methyl iodide was added and heating under reflux was continued for 6 hours. The mixture was concentrated under vacuum, the residue dissolved in methylene chloride, the methylene chloride solution washed once with water and dried over anhydrous magnesium sulfate. The solvent was removed in a rotary evaporator and the residual oil distilled in a Kugelrohr (bath temperature 140° C., pressure 0.3 mm) yielding 23.8 g (65% of theoretical) of N'-(methoxy(methylthio)phosphinyl)-N,N-dimethylcarbamimidothioic acid, ethyl ester. The IR and NMR spectra are in agreement with the assigned structure and identical to those obtained from the compound prepared by the method A.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][N:26]=1>>[F:18][C:17]1[C:12]2[N:13]([C:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([C:28]4[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[N:26][CH:27]=4)[CH:3]=3)=[CH:10][N:11]=2)[CH:14]=[CH:15][C:16]=1[C:19]([OH:22])([CH3:21])[CH3:20]
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Reactant: COc1ccc(B(O)O)cn1
Product: COc1ccc(-c2cc(-c3cnc4c(F)c(C(C)(C)O)ccn34)ccc2F)cn1
Yield: 7 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and 2-methoxypyridine-5-boronic acid were coupled in the same way as in Example 30 to give 2-{8-fluoro-3-[4-fluoro-3-(2-methoxypyridin-5-yl)phenyl]imidazo[1,2-α]pyridin-7-yl}propan-2-ol as an off-white solid (8 mg, 7%): m/z (ES+) 396 [MH+].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][C:22]2[N:23]([CH3:27])[CH:24]=[CH:25][N:26]=2)=[C:17]([Cl:28])[CH:16]=1.[CH2:29]1C[O:32][CH2:31][CH2:30]1.C(N(CC)CC)C.C(Cl)(=O)C=C>CN(C=O)C>[Cl:28][C:17]1[CH:16]=[C:15]([NH:14][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([NH:1][C:31](=[O:32])[CH:30]=[CH2:29])[CH:3]=3)[N:8]=[CH:7][C:6]=2[C:12]#[N:13])[CH:20]=[CH:19][C:18]=1[S:21][C:22]1[N:23]([CH3:27])[CH:24]=[CH:25][N:26]=1
Reactant: Cn1ccnc1Sc1ccc(Nc2c(C#N)cnc3ccc(N)cc23)cc1Cl
Reactant: C1CCOC1
Agent: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=CC(=O)Nc1ccc2ncc(C#N)c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c2c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Dissolved most of 1.00 g (2.46 mmol) 6-amino-4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)-phenylamino]-quinoline-3-carbonitrile in 3.5 ml hot DMF, added 12 ml THF and chilled to 0° C. Added 377 μl triethyl amine and 225 μl (2.70 mmol) acryloyl chloride. Removed ice bath at 15 minutes and stripped solvent at 2 hours. Slurried residue in water, collected solids and air dried overnight. Boiled in ethyl acetate, collected solids and dried in vacuo, giving 670 mg of yellow-brown solid: mass spectrum (electrospray m/e): M+H=461.1, 462.2.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:17])[CH2:13][N:14]([CH3:16])[CH3:15])=[C:7]([N+:18]([O-])=O)[CH:6]=1)[CH2:2][CH2:3][CH3:4].[H][H]>[Pt]=O.C(O)C>[NH2:18][C:7]1[CH:6]=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH:10]=[CH:9][C:8]=1[NH:11][C:12](=[O:17])[CH2:13][N:14]([CH3:16])[CH3:15]
Reactant: [H][H]
Reactant: CCCCc1ccc(NC(=O)CN(C)C)c([N+](=O)[O-])c1
Agent: O=[Pt]
Solvent: CCO
Product: CCCCc1ccc(NC(=O)CN(C)C)c(N)c1
Yield: 74.7 %

Procedure:
N-(4-n-butyl-2-nitrophenyl)-2-dimethylaminoacetamide (36 g), prepared as described above, platinum oxide (0.2 g) and ethanol (100 ml) were shaken together in an atmosphere of hydrogen at laboratory temperature and atmospheric pressure until the uptake of hydrogen was complete; 8.2 litres were absorbed. The mixture was filtered and the ethanol evaporated off. The resultant solid was recrystallised from petroleum spirit (b.p. 60°-80° C.) to give N-(2-amino-4-n-butylphenyl)-2-dimethylaminoacetamide (24.0 g), m.p. 63°-66° C.