Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](=[NH:7])[NH2:6].[CH:11]1([C:14](=O)[CH2:15][C:16](OCC)=[O:17])[CH2:13][CH2:12]1.C[O-].[Na+].CO>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[NH:6][C:16](=[O:17])[CH:15]=[C:14]([CH:11]3[CH2:13][CH2:12]3)[N:7]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)CC(=O)C1CC1
Reactant: N=C(N)c1cccc(Cl)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: O=c1cc(C2CC2)nc(-c2cccc(Cl)c2)[nH]1
Temperature: 0 °C
Yield: 33.1 %

Procedure:
A 500-mL round bottomed flask was charged with 3-chlorobenzimidamide (5.75 g, 30.1 mmol), ethyl 3-cyclopropyl-3-oxopropanoate (5.00 g, 32.0 mmol), and ethanol (100 mL) and the mixture cooled to 0° C. To the stirred mixture was added 25% sodium methoxide in methanol (15.0 mL, 64.0 mmol). The resulting mixture was stirred at reflux for 20 h. After cooling to room temperature, the mixture was evaporated under reduced pressure to 25 mL. The residual slurry was cautiously treated with 2N HCl (50 mL) forming a solid. The solid was collected by filtration and washed with water followed by ether to afford the title compound (2.46 g, 31%) as a white solid, which was carried forward into the next step without further purification. MW=246.69. 1H NMR (DMSO-d6, 500 MHz) δ 12.55 (s, 1H), 8.13 (s, 1H), 8.06 (d, J=7.5 Hz, 1H), 7.64-7.60 (m, 1H), 7.54 (t, J=8.0 Hz, 1H), 6.34 (s, 1H), 2.00-1.93 (m, 1H), 1.08-1.02 (m, 2H), 0.99-0.91 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][N+:5]([O-])=[CH:4][C:3]=1[CH3:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1c[n+]([O-])cc(C)c1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1cncc(C)c1Br
Temperature: 180 °C
Yield: 38 %

Procedure:
To a microwave tube was added 4-bromo-3,5-dimethylpyridine 1-oxide (2.00 g, 9.90 mmol), triphenylphosphine (3.12 g, 11.9 mmol) and toluene (10 mL). The tube was sealed and heated at 180° C. overnight. The reaction solution was diluted with ethyl acetate, and filtered. The filtrate was concentrated and purified by flash chromatography (10% to 40% ethyl acetate in hexanes) to afford the desired product as a yellow oil (700 mg, 38%). 1H NMR (400 MHz, CDCl3): δ 8.22 (s, 2H), 2.38 (s, 6H); LCMS calculated for C2H9BrN(M+H)+: m/z=186.0.
Reaction SMILES: [C:1]([N:4]1[CH2:10][C:9]2[CH:11]=[C:12]([O:16][CH3:17])[C:13]([NH2:15])=[CH:14][C:8]=2[NH:7][C:6](=[O:18])[CH2:5]1)(=[O:3])[CH3:2].Cl[C:20]1[N:25]=[C:24]([NH:26][C@@H:27]2[CH2:32][CH2:31][CH2:30][CH2:29][C@H:28]2[NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[C:23]([Cl:38])=[CH:22][N:21]=1>CO.C(Cl)Cl>[C:1]([N:4]1[CH2:10][C:9]2[CH:11]=[C:12]([O:16][CH3:17])[C:13]([NH:15][C:20]3[N:25]=[C:24]([NH:26][C@@H:27]4[CH2:32][CH2:31][CH2:30][CH2:29][C@H:28]4[NH:33][S:34]([CH3:37])(=[O:35])=[O:36])[C:23]([Cl:38])=[CH:22][N:21]=3)=[CH:14][C:8]=2[NH:7][C:6](=[O:18])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: COc1cc2c(cc1N)NC(=O)CN(C(C)=O)C2
Solvent: ClCCl
Solvent: CO
Product: COc1cc2c(cc1Nc1ncc(Cl)c(N[C@@H]3CCCC[C@H]3NS(C)(=O)=O)n1)NC(=O)CN(C(C)=O)C2
Yield: 10.6 %

Procedure:
In an analogous manner to procedure 1656g, 4-acetyl-8-amino-7-methoxy-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (60 mg, 0.24 mmol) and N-[(1R,2R)-2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (82 mg, 0.24 mmol) were coupled to provide N-{(1R,2R)-2-[2-(4-Acetyl-7-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]di-azepin-8-ylamino)-5-chloro-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide (14 mg, 10%) as a pale yellow solid following preparative tlc (10% MeOH-DCM); 1H NMR (400 MHz, DMSO-d6) δ 8.23 (s, 1H), 8.15 (s, 1H), 8.00 (s, 1H), 7.47 (s, 1H), 6.73 (s, 1H), 5.63 (d, J=7 Hz, 1H), 5.46 (d, J=7 Hz, 1H), 4.00 (s, 2H), 3.92 (s, 3H), 3.53 (s, 2H), 3.29 (m, 1H), 2.89 (s, 3H), 2.21 (m, 2H), 2.17 (s, 3H), 1.83 (m, 2H), 1.65 (m, 1H), 1.38 (m, 2H), 1.25 (m, 2H); MS (m/e) 553 (M+1); mp 167° C. (dec.).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[C:8]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)(=[O:20])=[O:19])[N:7]([CH3:27])[N:6]=1.[H-].[Na+].[Cl:30][C:31]1[CH:32]=[N:33][C:34](S(C)(=O)=O)=[N:35][CH:36]=1.O>O1CCCC1>[Cl:30][C:31]1[CH:32]=[N:33][C:34]([O:1][CH2:2][CH2:3][O:4][C:5]2[C:9]([C:10]3[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=3)=[C:8]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)(=[O:19])=[O:20])[N:7]([CH3:27])[N:6]=2)=[N:35][CH:36]=1
Reactant: CS(=O)(=O)c1ncc(Cl)cn1
Reactant: Cc1ccc(-c2c(OCCO)nn(C)c2NS(=O)(=O)c2ccccn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(OCCOc3ncc(Cl)cn3)nn(C)c2NS(=O)(=O)c2ccccn2)cc1
Reaction time: 0.17 h
Yield: 46.5 %

Procedure:
To N-[3-(2-hydroxyethoxy)-1-methyl-4-(4-methylphenyl)-1H-pyrazol-5-yl]-2-pyridine sulphonamide (Example 52) (200 mg) in dry tetrahydrofuran (2 ml) at room temperature was added sodium hydride (80% dispersion in oil, 35 mg) the mixture was stirred for 10 minutes. A solution of 5-chloro-2-methylsulphonylpyrimidine (134 mg) in dry tetrahydrofuran (2.5 ml) was then added and the mixture was stirred for a further 4 hours. The mixture was stirred for 4 hours. The reaction was treated with water (50 ml) and extracted with ethyl acetate (50 ml). The aqueous phase was neutralised to pH 7 with 2N hydrochloric acid (aq.). The organic fraction was washed with brine (50 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (10 g) eluted with a solvent gradient of pentane:ethyl acetate (1:1 to 0:1) to yield the tile compound as a colourless foam (120 mg).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8](F)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:21]([OH:23])[CH3:22].Cl>CN(C=O)C.O>[CH2:21]([O:23][C:8]1[C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:2]([F:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5])[CH3:22]
Reactant: O=C(O)c1cc(F)c([N+](=O)[O-])cc1F
Reactant: CCO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(C(=O)O)c(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 110 %

Procedure:
2,5-difluoro-4-nitrobenzoic acid (Fluorochem; 1 g, 4.92 mmol) was stirred and dissolved in DMF (10 mL) and caesium carbonate (4.8 g, 14.7 mmol) was added followed by ethanol (2.3 g, 49.9 mmol). The resulting white mixture was stirred at ambient temperature for 3 hours, diluted with water, acidified to pH1 with 2N HCl (aq), extracted with EtOAc (×3). Combined extracts were washed with water, dried (MgSO4), filtered and evaporated to yield the title compound as a yellow solid (1.24 g, 100%).
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:10]([CH2:11][CH3:12])=[N:9][C:8]2[N:13]([CH2:16][CH3:17])[N:14]=[CH:15][C:7]=2[C:6]=1[NH:18][CH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[N+]=[N-]>[Pd].C(O)C>[NH2:1][CH2:4][C:5]1[C:10]([CH2:11][CH3:12])=[N:9][C:8]2[N:13]([CH2:16][CH3:17])[N:14]=[CH:15][C:7]=2[C:6]=1[NH:18][CH:19]1[CH2:20][CH2:21][O:22][CH2:23][CH2:24]1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN=[N+]=[N-]
Agent: [Pd]
Solvent: CCO
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Reaction time: 16 h
Yield: 89 %

Procedure:
Palladium on charcoal (10%, 50% w/w water, 8 g) was treated with ethanol (200 mL) followed by a solution of 5-(azidomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (39.94 g, 121 mmol) in ethanol (1,200 mL). The mixture was stirred under an atmosphere of hydrogen for 16 h. The catalyst was then removed by filtration and the filtrate removed of solvent in vacuo to reveal 41.24 g of a black oil. The product was purified by flash chomatography on 1 kg of silica using a step gradient from 5-20% methanol in dichloromethane to afford 32.66 g of the title compound. LC-MS m/z 304 (M+H)+, 1.71 min (ret time).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[O:8]=[C:9]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:16]2[C:11]([C:12]([NH2:24])=[CH:13][CH:14]=[CH:15]2)=[N:10]1.N1C=CC=CC=1>O>[O:8]=[C:9]1[CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:16]2[C:11](=[C:12]([NH:24][C:5](=[O:7])[CH3:6])[CH:13]=[CH:14][CH:15]=2)[NH:10]1
Reactant: Nc1cccc2c1=NC(=O)C=2c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Nc1cccc2c1NC(=O)C2c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Ten milliliters of acetic anhydride were added to a solution of 2-oxo-3-phenyl-7-aminoindole (0.7 g.) in 40 ml. of pyridine. The reaction mixture was stirred at ambient temperature for 18 hours. Ten milliliters of water were then added and the solvent removed in vacuo. The residue was treated with 100 ml. of 1 N aqueous hydrochloric acid. The resulting solids were separated by filtration and the filter cake washed with water. Recrystallization of the filtered material from methanol yielded N-(2-oxo-3-phenyl-7-indolinyl)acetamide formed in the above reaction melting at 258°-62° C.; yield = 490 mg.
Reaction SMILES: [CH:1]([N:14]1[C:17](=[O:18])[CH2:16][CH:15]1[C:19](OCC)=[O:20])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.O>C(OCC)(=O)C>[CH:1]([N:14]1[CH:15]([CH2:19][OH:20])[CH2:16][C:17]1=[O:18])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CC(=O)N1C(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C1CC(CO)N1C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Yield: 73 %

Procedure:
To a solution of 1.3 g. (4.2 mmoles) of ethyl 1-benzhydryl-4-oxo-2-azetidine-carboxylate in 5 ml. of methanol 0.32 g. (8.4 mmoles) of sodium tetrahydrido-borate(III) are added with outer cooling with ice water and stirring. The mixture is stirred for 10 minutes, whereupon it is poured onto 20 ml. of water and shaken with three 10-ml. portions of ethyl acetate. The ethyl acetate solution is dried with magnesium sulfate, filtered and the filtrate is evaporated. The oily residue is crystallized by trituration with 10 ml. of ether. 0.82 g. (73%) of the named compound are obtained, melting at 101° to 102° C. (ethyl acetate/petroleum ether).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]([C:11]([OH:13])=[O:12])[NH2:10])[CH:5]=[CH:6][C:7]=1[OH:8].O.C1(C)C(S(O)(=O)=O)=CC=CC=1.[C:26]1([C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[N+]=[N-])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CCOCC>CN(C)C=O>[OH:1][C:2]1[CH:3]=[C:4]([CH:9]([C:11]([O:13][CH:32]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:12])[NH2:10])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: NC(C(=O)O)c1ccc(O)c(O)c1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: NC(C(=O)OC(c1ccccc1)c1ccccc1)c1ccc(O)c(O)c1
Reaction time: 0.17 h

Procedure:
Into a stirred suspension of 1.83 g (10.0 mmol) of α-(3,4-dihydroxyphenyl)glycine and 1.96 g (10.0 mmol) of toluenesulfonic acid monohydrate (97%) in 5 ml of dry dimethylformamide, a solution of freshly prepared diphenyldiazomethane (2.91 g, 15.0 mmoles) in 10 ml of dimethylformamide was dropped at 50° C. and stirring was continued for 10 minutes. The solvent was evaporated in vacuo, the residue was taken up in ice water/ethyl acetate and the pH was brought to 7.5 by addition of dilute sodium hydroxide. The organic layer was separated, washed with sodium bicarbonate solution and brine, dried (sodium sulfate) and evaporated in vacuo to leave a solid which was stirred with ether. Yield (after filtration and drying in vacuo): 1.89 g, melting point 155°-158° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([O:8][CH3:9])[CH:7]=1.[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13].C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[Cl:10][C:5]1[CH:4]=[CH:3][C:2]([C:16]#[C:15][Si:12]([CH3:14])([CH3:13])[CH3:11])=[CH:7][C:6]=1[O:8][CH3:9]
Reactant: COc1cc(Br)ccc1Cl
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc(C#C[Si](C)(C)C)ccc1Cl
Temperature: 95 °C

Procedure:
Commercially available 5-bromo-2-chloroanisole (1.0 g, 4.52 mmol), trimethylsilylacetylene (1.07 mL, 7.5 mmol) and triethylamine (15 mL) were added to anhydrous toluene (15 mL) and degassed by purging with nitrogen. Bis(acetato)bis(triphenylphosphine)palladium II (340 mg, 0.45 mmol) was added and the reaction mixture was heated to ˜95° C. for 30 min. The reaction mixture was cooled to room temperature, filtered to remove the catalyst, and diluted with ethyl acetate (150 mL). The organic layer was washed with saturated sodium bicarbonate (50 mL) and brine (50 mL) separated, dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash column chromatography over silica gel eluted with hexane/ethyl acetate 20:1 to yield A60.1 (807 mg, 75%). 1H NMR (400 MHz): δ 7.40-7.25 (m, 2H), 7.10-7.00 (m, 1H), 3.90, (s, 3H), 0.24 (s, 9H).
Reaction SMILES: [CH2:1]1[NH:6][CH2:5][CH2:4][N:3]2[C:7]3[CH:13]=[CH:12][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][C:8]=3[N:9]=[C:2]12.[C:19](O)(=O)C.C=O.C([BH3-])#N.[Na+]>CO>[CH3:19][N:6]1[CH2:5][CH2:4][N:3]2[C:7]3[CH:13]=[CH:12][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][C:8]=3[N:9]=[C:2]2[CH2:1]1
Reactant: CC(=O)O
Reactant: CCOC(=O)c1ccc2c(c1)nc1n2CCNC1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)c1ccc2c(c1)nc1n2CCN(C)C1
Reaction time: 0.5 h
Yield: 92 %

Procedure:
Ethyl 1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate (0.98 g, 4.00 mmol) prepared in the Step 38-1-5 was dissolved in methanol (100 ml), and acetic acid (1.00 ml) and a 37% formaldehyde aqueous solution (1.2 ml) were added thereto. Thereafter, sodium cyanoborohydride (0.57 g, 9.07 mmol) was added to the mixture, and the resulting mixture was stirred. After 30 minutes, the mixture was concentrated under a reduced pressure. Chloroform was added to the concentrate, and the resulting mixture was washed with a saturated sodium bicarbonate solution. The washed product was dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by silica gel column chromatography (chloroform:methanol=10:1) to give the title compound (958 mg, 92%) as a light-brown powder.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([NH2:20])=O)[CH:16]=3)[NH:11][N:10]=2)=[CH:5][CH:4]=1.COC(OC)[N:25]([CH3:27])C.[NH2:30]N>C(O)(=O)C>[NH:30]1[C:18]([C:15]2[CH:16]=[C:17]3[C:12](=[CH:13][CH:14]=2)[NH:11][N:10]=[C:9]3[C:6]2[CH:7]=[CH:8][C:3]([N:2]([CH3:21])[CH3:1])=[CH:4][CH:5]=2)=[N:20][CH:27]=[N:25]1
Reactant: CN(C)c1ccc(-c2n[nH]c3ccc(C(N)=O)cc23)cc1
Reactant: NN
Reactant: COC(OC)N(C)C
Solvent: CC(=O)O
Product: CN(C)c1ccc(-c2n[nH]c3ccc(-c4ncn[nH]4)cc23)cc1
Temperature: 93 °C
Yield: 293.3 %

Procedure:
A mixture of 3-[4-(dimethylamino)phenyl]-1H-indazole-5-carboxamide (60 mg, 0.214 mmol) and N,N-dimethylformamide dimethyl acetal (10.0 mL, 75.3 mmol, 352 equiv.) was heated at 93° C. for 4.5 h and then concentrated. To the concentrate was added 4.0 mL of glacial acetic acid (AcOH), and anhydrous hydrazine (180 mg, 5.62 mmol, 26.3 equiv.). The mixture was heated at 93° C. for 3 h and concentrated. The residue was partitioned between EtOAc and 6.0 N aq. NaOH and the layers separated. The aqueous layer was extracted with 2×EtOAc and then the pH adjusted between 10–11 with 6.0 N aq. HCl. The resulting precipitate was collected by filtration, washed with H2O, and dried in a vacuum oven to afford the title compound (191 mg, 29.3% yield): 1H NMR (DMSO-d6 D2O containing one drop of aqueous HCl) δ 9.30 (s, 1H), 8.89 (s, 1H), 8.27 (d, 2H), 8.12 (d, 1H), 7.96–7.88 (m, 3H), 3.29 (s, 6H); ES-MS (m/z) 305 [M+1]+.
Reaction SMILES: Br.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[O:19][C:18]([NH2:20])=[N:17][N:16]=3)=[CH:11][CH:10]=2)[CH:3]=1.[F:21][C:22]([F:34])([F:33])[O:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>N1C=CC=CC=1.CO>[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[O:19][C:18]([NH:20][C:26](=[O:27])[C:25]4[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=4[O:23][C:22]([F:21])([F:33])[F:34])=[N:17][N:16]=3)=[CH:13][CH:14]=2)[CH:3]=1
Reactant: Nc1nnc(-c2ccc(Oc3cccnc3)cc2)o1
Reactant: O=C(Cl)c1ccccc1OC(F)(F)F
Agent: Br
Solvent: CO
Solvent: c1ccncc1
Product: O=C(Nc1nnc(-c2ccc(Oc3cccnc3)cc2)o1)c1ccccc1OC(F)(F)F
Reaction time: 18 h
Yield: 9.1 %

Procedure:
5-[4-(Pyridin-3-yloxy)phenyl]-1,3,4-oxadiazol-2-amine hydrobromide salt (167.5 mg, 0.5 mmol) was suspended in 2 mL of anhydrous pyridine. Neat 2-trifluoromethoxybenzoyl chloride (100 uL) was added directly into the solution. It was left to stir for 18 hours. The reaction mixture formed an orange solution with a yellow precipitate. Then it was diluted with ca. 1 mL of MeOH, filtered through 0.22 u syringe filter and purified by reverse phase preparative HPLC using acetonitrile/water mixture containing 0.01% of TFA. Fractions, containing the product, were combined and partitioned between ca. 40 mL of EtOAc and ca. 40 mL of saturated aqueous NaHCO3. The EtOAc layer was washed with brine, dried over anhydrous sodium sulfate and filtered. Solvent was removed in vacuo to give the title product as a bright-yellow solid (20.2 mg). Yield 9.1%.
Reaction SMILES: CN1CCCC1=O.[CH3:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([NH2:18])[CH:10]=1.[Cl:19][C:20]1[CH:25]=[C:24](Cl)[N:23]=[CH:22][N:21]=1.C([O-])([O-])=O.[Na+].[Na+]>O>[Cl:19][C:20]1[N:21]=[CH:22][N:23]=[C:24]([NH:18][N:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:9]([CH3:8])=[CH:10]2)[CH:25]=1
Reactant: Cc1cn(N)c2ccccc12
Reactant: Clc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cn(Nc2cc(Cl)ncn2)c2ccccc12
Temperature: 120 °C
Reaction time: 4 h

Procedure:
To 125 ml of 1-methyl-2-pyrrolidinone was added 3-methyl-1H-indol-1-amine (10.0 g), and this mixture was heated to 120° C. Then 4,6-dichloropyrimidine (10.43 g), was added to the hot solution and this mixture was stirred for four hours. The reaction was cooled, poured into water, basified with Na2CO3 (aq) extracted with ethyl acetate and the organic layer washed with water and dried (sat. NaCl, anhy. MgSO4).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:39][C:40]1[CH:41]=[C:42]([CH:45]=[CH:46][CH:47]=1)[CH2:43][NH2:44]>>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](=[O:22])[NH:44][CH2:43][C:42]3[CH:45]=[CH:46][CH:47]=[C:40]([CH3:39])[CH:41]=3)=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1cccc(CN)c1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)O)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Product: Cc1cccc(CNC(=O)c2ccc(Sc3ccc(NC(=O)OC(C)(C)C)cc3)c(Nc3ncnc4nc(C(C)C)ccc34)c2)c1

Procedure:
According to the procedure in Example 385F, the title compound was prepared using 4-(4-tert-butoxycarbonylamino-phenylsulfanyl)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzoic acid (prepared in Example 385E) and m-methylbenzylamine.
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([NH:12][C:13]3[CH:18]=[CH:17][C:16](OCCN4CCCC4)=[CH:15][CH:14]=3)=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:27][N:28]([CH2:30]C1C=C(NC(N)=S)C=CC=1)[CH3:29]>C(Cl)Cl.CO>[CH3:27][N:28]([CH2:30][C:17]1[CH:18]=[C:13]([NH:12][C:10]2[S:11][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][N:9]=2)[CH:14]=[CH:15][CH:16]=1)[CH3:29]
Reactant: c1ccc(-c2cnc(Nc3ccc(OCCN4CCCC4)cc3)s2)cc1
Reactant: CN(C)Cc1cccc(NC(N)=S)c1
Solvent: ClCCl
Solvent: CO
Product: CN(C)Cc1cccc(Nc2ncc(-c3ccccc3)s2)c1

Procedure:
The title compound is prepared as described in Example 1 for (5-phenyl-thiazol-2-yl)-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-amine but using (3-dimethylaminomethyl-phenyl)-thiourea. Title compound: ES-MS: 310.1 [M+H]+; single peak at tR=6.65 min (System 1); Rf=0.63 (CH2Cl2/MeOH, 80/20).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7](Cl)=[CH:8][N:9]=1)(=[O:3])[CH3:2].[SH:11][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([NH:4][C:5]1[S:6][C:7]([S:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[CH:8][N:9]=1)(=[O:3])[CH3:2]
Reactant: Sc1ccncc1
Reactant: CC(=O)Nc1ncc(Cl)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ncc(Sc2ccncc2)s1
Temperature: 120 °C
Yield: 83.5 %

Procedure:
A mixture of 2-acetylamino-5-chlorothiazole (5.3 g), 4-mercaptopyridine (3.4 g) and potassium carbonate in N,N-dimethylformamide (50 ml) was heated at 120° C. for 2.5 hours with stirring. The reaction mixture was concentrated under reduced pressure and the residue was triturated with water. The precipitates were collected by filtration, washed with water and dried in vacuo to give 2-acetylamino-5-(4-pyridylthio)thiazole (6.3 g, yield: 83.7%). IR (Nujol): 3150, 1680, 1580, 1300 cm-1NMR (DMSO-d6, 90 MHZ, ppm): 2.23 (3H, s), 7.10 (2H, d, J=6 Hz), 7.80 (1H, s), 8.40 (2H, d, J=6 Hz), 11.90 (1H, br s)
Reaction SMILES: [CH3:1][C:2]1([C:5]([OH:7])=O)[CH2:4][CH2:3]1.C(Cl)(=O)C(Cl)=O.Br.[NH2:15][C:16]1[C:24](O)=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=[O:19].C(N(CC)CC)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl.O>[CH3:1][C:2]1([C:5]2[O:7][C:24]3[C:16](=[C:17]([C:18]([OH:20])=[O:19])[CH:21]=[CH:22][CH:23]=3)[N:15]=2)[CH2:4][CH2:3]1
Reactant: Nc1c(O)cccc1C(=O)O
Reactant: CC1(C(=O)O)CC1
Agent: Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC1(c2nc3c(C(=O)O)cccc3o2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.8 %

Procedure:
To an ice-cold solution of 1-methylcyclopropanecarboxylic acid (214 mg, 2.14 mmol) in dichloromethane (10 mL) was added oxalyl chloride (0.19 mL, 2.14 mmol) dropwise. The ice bath was removed and stirring was continued for 1 h. 2-Amino-3-hydroxybenzoic acid hydrobromide (500 mg, 2.14 mmol) was added followed by triethylamine (0.90 mL, 6.42 mmol). The resulting reaction mixture was stirred at room temperature overnight. The reaction was quenched with aqueous 1 N HCl (25 mL) until the solution reached pH 1. The reaction mixture was extracted with dichloromethane. The combined organic layers were dried over Na2SO4, filtered and concentrated to a brown solid. The crude was dissolved in toluene (10 mL) and the solution was treated with p-toluenesulfonic acid monohydrate (477 mg, 2.50 mmol). The reaction mixture was then heated to reflux for 1 h. The reaction was cooled to room temperature, poured into water and extracted with ethyl acetate. The organic layer was separated, then washed with water (5×50 mL), brine, dried (Na2SO4), filtered and concentrated to afford 2-(1-methylcyclopropyl)benzoxazole-4-carboxylic acid (306 mg, 65%) as a light yellow solid: 1H NMR (500 MHz, DMSO-d6) δ 12.89 (br s, 1H), 7.85 (dd, J=8.0, 0.9 Hz, 1H), 7.81 (dd, J=7.7, 0.9 Hz, 1H), 7.39 (t, J=7.9 Hz, 1H), 2.91 (s, 3H), 1.42-1.37 (m, 2H), 1.10-1.05 (m, 2H); MS (ESI+) m/z 218 (M+H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[C:11]([F:14])([F:13])[F:12].[NH:15]1[C:23]2[C:18](=[CH:19][C:20]([CH:24]=[O:25])=[CH:21][CH:22]=2)[CH:17]=[N:16]1>>[CH:24]([C:20]1[CH:19]=[C:18]2[C:23](=[CH:22][CH:21]=1)[N:15]([CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[C:11]([F:14])([F:13])[F:12])[N:16]=[CH:17]2)=[O:25]
Reactant: O=Cc1ccc2[nH]ncc2c1
Reactant: N#Cc1ccc(CBr)c(C(F)(F)F)c1
Product: N#Cc1ccc(Cn2ncc3cc(C=O)ccc32)c(C(F)(F)F)c1

Procedure:
4-(5-Formyl-indazol-1-ylmethyl)-3-trifluoromethyl-benzonitrile was prepared from 4-bromomethyl-3-trifluoromethyl-benzonitrile and 1H-indazole-5-carbaldehyde following General Procedure A.