Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=2)[N:5]2[CH:15]=[CH:16][N:17]=[C:4]2[N:3]=1.[SH:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([CH:28]2[CH2:30][CH2:29]2)=[O:27])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:14][C:12]1[NH:11][N:10]=[C:9]([NH:8][C:6]2[N:5]3[CH:15]=[CH:16][N:17]=[C:4]3[N:3]=[C:2]([S:18][C:19]3[CH:20]=[CH:21][C:22]([NH:25][C:26]([CH:28]4[CH2:29][CH2:30]4)=[O:27])=[CH:23][CH:24]=3)[CH:7]=2)[CH:13]=1
Reactant: O=C(Nc1ccc(S)cc1)C1CC1
Reactant: Cc1cc(Nc2cc(Cl)nc3nccn23)n[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Nc2cc(Sc3ccc(NC(=O)C4CC4)cc3)nc3nccn23)n[nH]1
Temperature: 190 °C

Procedure:
A mixture of (7-Chloro-imidazo[1,2-a]pyrimidin-5-yl)-(5-methyl-1H-pyrazol-3-yl)-amine (73 mg, 0.29 mmol), N-(4-mercaptophenyl)cyclopropane carboxamide (170 mg, 0.88 mmol), potassium carbonate (81 mg, 0.58 mmol) in DMF (1 ml) was heated with microwave at 190° C. for 30 minutes. The reaction mixture was then purified by HPLC to give the title compound Example 10 as an off-white solid (110 mg). 1H NMR (400 MHz, DMSO) δ 10.54 (s, 1H) 8.26 (d, J=2.8 Hz, 1H) 7.97 (d, J=2.4 Hz, 1H) 7.79 (d, J=8.8 Hz, 2H) 7.57 (d, J=8.8 Hz, 2H) 6.89 (s, 1H) 5.82 (s, 1H) 2.20 (s, 3H) 1.81-1.85 (m, 1H) 0.84-0.86 (m, 4H). [M+H] calc'd for C20H19N7OS, 406; found, 406.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:25][CH3:26])=[C:21]([OH:24])[CH:22]=2)[N:17]=[CH:16][N:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:46]([O:50][C:51]([N:53]1[CH2:58][CH2:57][CH2:56][CH:55](O)[CH2:54]1)=[O:52])([CH3:49])([CH3:48])[CH3:47]>ClCCl>[Cl:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:25][CH3:26])=[C:21]([O:24][CH:57]3[CH2:56][CH2:55][CH2:54][N:53]([C:51]([O:50][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:52])[CH2:58]3)[CH:22]=2)[N:17]=[CH:16][N:15]=1
Reactant: COc1cc2ncnc(Cl)c2cc1O
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2ncnc(Cl)c2cc1OC1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 40 °C
Reaction time: 8 h
Yield: 45.5 %

Procedure:
Diethyl azodicarboxylate (9.41 ml, 40% solution in toluene) was added to a mixture of 4-chloro-6-hydroxy-7-methoxyquinazoline (2.90 g; prepared as described in Example 16-preparation of starting materials), triphenylphosphine (5.43 g) and tert-butoxycarbonyl-3-hydroxypiperidine (4.15 g) in dichloromethane (75 ml). The resulting solution was heated to 40° C. for 6 hours, and then allowed to stand overnight at room temperature. This was purified by flash column chromatography eluting with isohexane (79%), acetone (20%), and triethylamine (1%) to give 4-chloro-7-methoxy-6-[1-(tert-butoxycarbonyl)piperidin-3-yloxy]quinazoline as a white solid (2.47 g, 53%); 1H NMR Spectrum: (CDCl3) 1.5 (m, 9H); 1.6 (m, 1H); 1.9 (m, 2H); 2.1 (m, 1H); 3.5 (m, 1H); 3.6 (m, 1H); 4.0 (s, 3H); 4.2-3.9 (m, 2H); 4.5 (m, 1H); 7.3 (s, 1H); 7.4 (s, 1H); 8.9 (s, 1H); Mass Spectrum: (M+H): 394.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[C:9]1[S:10][CH:11]=[C:12]([C:14](=[N+]=[N-])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:31]([OH:34])([CH3:33])[CH3:32]>C(Cl)Cl.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[C:1]([O:5][C:6]([N:8]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[C:9]1[S:10][CH:11]=[C:12]([CH:14]([O:34][CH:31]([CH3:33])[CH3:32])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:13]=1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)O
Reactant: CCOC(=O)C(=[N+]=[N-])c1csc(N(Cc2ccc(OC)cc2)C(=O)OC(C)(C)C)n1
Agent: [Rh]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)C(OC(C)C)c1csc(N(Cc2ccc(OC)cc2)C(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
Ethyl 2-[2-[tert-butoxycarbonyl-[(4-methoxyphenyl)methyl]amino]thiazol-4-yl]-2-diazo-acetate (0.6 g, 1.38 mmol) was dissolved in DCM (10 mL) under argon atmosphere. To this solution, iso-propanol (0.12 mL, 1.66 mmol) was added followed by rhodium (II) acetate dimer (12 mg, 0.028 mmol). Mixture was stirred at room temperature for 30 min. then diluted with DCM (10 mL). Organic layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product which was purified by silica gel column chromatography using 20% ethyl acetate in hexane to provide ethyl 2-[2-[tert-butoxycarbonyl-[(4-methoxyphenyl)methyl]amino]thiazol-4-yl]-2-isopropoxy-acetate (0.55 g).
Reaction SMILES: [CH2:1]([N:8]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:9][CH2:10][C:11]([CH3:14])(O)[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(S(F)(F)[F:28])CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([N:8]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:9][CH2:10][C:11]([F:28])([CH3:14])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(O)CCN(Cc1ccccc1)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(F)CCN(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.5 %

Procedure:
Treat a −78° C. solution of 4-(dibenzylamino)-2-methylbutan-2-ol (110.0 g, 0.39 mol) in DCM (1 L) drop-wise with diethylaminosulfur trifluoride (75 g, 0.47 mol) under N2, allow it to warm to RT and stir overnight. Re-cool the mixture to −78° C., treat drop-wise with saturated NaHCO3 (300 mL), warm to RT, extract with EtOAc (3×), wash the combined organics with brine, dry over Na2SO4, concentrate to dryness and purify via silica gel chromatography (0.1-0.2% EtOAc/pet ether) to afford the title compound (44.0 g, 40% yield). MS (m/z): 286.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[C:12]([NH:16][C:17]([CH:19]3[CH2:23][CH2:22][C:21](=[O:24])[O:20]3)=[O:18])[CH:13]=[CH:14][CH:15]=2)[CH:5]=[C:4]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[OH:31])[N:3]=1.[OH-:32].[Na+:33]>CO>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:18])[CH:19]([OH:32])[CH2:23][CH2:22][C:21]([O-:20])=[O:24])[CH:13]=[CH:14][CH:15]=2)[CH:5]=[C:4]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[OH:31])[N:3]=1.[Na+:33]
Reactant: [OH-]
Reactant: N#Cc1c(-c2cccc(NC(=O)C3CCC(=O)O3)c2)cc(-c2ccccc2O)nc1N
Agent: [Na+]
Solvent: CO
Product: N#Cc1c(-c2cccc(NC(=O)C(O)CCC(=O)[O-])c2)cc(-c2ccccc2O)nc1N
Reaction time: 0.17 h
Yield: 60 %

Procedure:
To a suspension of N-{3-[2-amino-3-cyano-6-(2-hydroxyphenyl)-4-pyridinyl]phenyl}-5-oxotetrahydro-2-furancarboxamide (0.250 g, 0.603 mmol) in methanol (10 mL) was added dropwise 2N NaOH solution (0.3 mL). After the mixture was stirred for 10 minutes, insoluble solid was filtered off. The filtrate was concentrated under reduced pressure and the residue was crystallized from methanol and ethyl ether. The resulting solid was collected by filtration under an argon atmosphere, washed with ethyl ether, and dried under reduced pressure to give Sodium 5-({3-[2-amino-3-cyano-6-(2-hydroxyphenyl)-4-pyridinyl]phenyl}amino)-4-hydroxy-5-oxopentanoate as a pale yellow solid (0.165 g, yield 60%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][N:12]([C:14]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[O:15])[CH2:11][CH:10]2[N:22]([CH3:37])[C:23](=[O:36])[C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([C:32]([F:35])([F:34])[F:33])[CH:25]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[CH2:39][C:40]([F:42])=[CH2:41]>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][N:12]([C:14]([CH:16]3[CH2:21][CH2:20][N:19]([CH2:41][C:40]([F:42])=[CH2:39])[CH2:18][CH2:17]3)=[O:15])[CH2:11][CH:10]2[N:22]([CH3:37])[C:23](=[O:36])[C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([C:32]([F:33])([F:34])[F:35])[CH:25]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1ccc(C(=O)N(C)C2CN(C(=O)C3CCNCC3)CC2c2ccc(Cl)c(Cl)c2)cc1C(F)(F)F
Reactant: C=C(F)CCl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=C(F)CN1CCC(C(=O)N2CC(c3ccc(Cl)c(Cl)c3)C(N(C)C(=O)c3ccc(OC)c(C(F)(F)F)c3)C2)CC1
Reaction time: 20 h
Yield: 46.9 %

Procedure:
To a solution of N-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide (50 mg, 0.090 mmol) in THF (1 mL) was added under an atmosphere of nitrogen potassium bis(trimethylsilyl)amide (0.885 M in THF, 132 μL, 0.116 mmol). After stirring for 15 min at ambient temperature 3-chloro-2-fluoroprop-1-ene (13 mg, 0.13 mmol) was added and the reaction mixture was stirred for 20 h at this temperature. It was diluted with ethyl acetate (10 mL) and washed with an aqueous solution of sodium carbonate (1 M, 10 mL) and brine (10 mL). The aqueous layers were extracted with ethyl acetate (10 mL) and the combined organic layers dried over sodium sulfate. Purification by chromatography (SiO2, ethyl acetate:(ethyl acetate:triethylamine=95:5):methanol=100:0:0 to 0:90:10) afforded the title compound (26 mg, 47%) as a light brown foam. MS m/e: 616.4 [M]+.
Reaction SMILES: [O:1]([C:8]1[C:13]2=[C:14]([CH3:18])[C:15]([OH:17])=[CH:16][N:12]2[N:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][S:20]([CH2:23][CH2:24][CH2:25]O)(=[O:22])=[O:21].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:19][S:20]([CH2:23][CH2:24][CH2:25][O:17][C:15]1[C:14]([CH3:18])=[C:13]2[N:12]([CH:16]=1)[N:11]=[CH:10][N:9]=[C:8]2[O:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)CCCO
Reactant: Cc1c(O)cn2ncnc(Oc3ccccc3)c12
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1c(OCCCS(C)(=O)=O)cn2ncnc(Oc3ccccc3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
To a solution of 4-phenoxy-5-methyl-6-hydroxypyrrolo-[2,1-f][1,2,4]triazine (1.0 g, 4.15 mmol, as prepared in WO 00/71129, which is hereby incorporated by reference), 3-methanesulfonylpropan-1-ol (1.15 g, 8.3 mmol) and PPh3 (2.17 g, 8.3 mmol) in THF (12 mL) at 0° C., was added DEAD (1.42 g, 8.3 mmol). The mixture was stirred at RT for 1 h. The solvent was removed in vacuo. The residue was dissolved in dichloromethane, washed with brine and dried (Na2SO4). The volatiles were removed and the solid obtained was triturated with dichloromethane to afford 6-(3-methanesulfonylpropoxy)-5-methyl-4-phenoxypyrrolo[2,1-f][1,2,4]triazine as a white solid (1.1 g, 73% yield). MS: (M+H)+=362.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:7]#[N:8])([O-])=O.[H][H]>CCO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:7]#[N:8]
Reactant: Cc1ccc(C#N)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(C#N)cc1N
Yield: 97.1 %

Procedure:
120 g of 3-Nitro-4-methylbenzonitrile were suspended in 1.2 l of EtOH and hydrogenated in the presence of 7 g of Pd/C (10%) with 50 l of hydrogen at room temperature. After removal of the catalyst, the solvent was stripped off. 95 g of pure product were obtained (97%). 1H-NMR (DMSO-d6 ; δ in ppm): 7.1 (dd, 1H); 6.90 (d, 1H); 6.85 (dd, 1H); 5.35 (s, 2H, NH2 [sic]); 2.15 (s, 3H)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[N:12]=2)=[CH:4][CH:3]=1.[Br:19]N1C(=O)CCC1=O>ClCCl>[Br:19][C:10]1[S:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[N:12][C:11]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Fc1ccc(-c2nc(-c3ccccn3)cs2)cc1
Solvent: ClCCl
Product: Fc1ccc(-c2nc(-c3ccccn3)c(Br)s2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-[2-(4-Fluoro-phenyl)-1,3-thiazol-4-yl]pyridine from step 1 (400 mg, 1.56 mmol) was dissolved in dichloromethane (10 mL), and N-bromosuccinimide (330 mg, 1.87 mmol) was added. The reaction was stirred at room temperature for 2 h. Then the solution was washed with water, and dried (Na2SO4). The drying agent was filtered off, and the filtrate was concentrated. The resulting residue was purified on a silica gel flash chromatography column eluted with 0-20% EtOAc-hexane to give the title compound. LC-MS m/z 337.0 [M+1]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[CH:19](OCC)[CH2:20][NH2:21])C.CCN=C=NCCCN(C)C.Cl>C(#N)C>[CH2:1]([O:8][C:9]([N:11]1[CH:19]=[CH:20][NH:21][C:13](=[O:15])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(CN)OCC
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC#N
Product: O=C1CN(C(=O)OCc2ccccc2)C=CN1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.2 %

Procedure:
To a solution of N-benzyloxycarbonylglycine (10.5 g) and 2,2-diethoxyethylamine (7.33 g) in acetonitrile (50 ml) was added WSC hydrochloride (10.5 g) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, and to the residue were added ethyl acetate and dilute hydrochloric acid. The organic layer was separated, washed with saturated and saturated brine, dried (MgSO4) and concentrated. To the residue were added p-toluenesulfonic acid (951 mg) and toluene (150 ml), and the mixture was refluxed for 30 minutes. The mixture was cooled, and to the reaction solution was added ethyl acetate. The mixture was washed with saturated sodium bicarbonate solution and saturated brine, dried (MgSO4) and concentrated. The resulting crystals were filtered, washed with ether and dried to give colorless crystals of the title compound (7.37 g).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9]2[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11](S(C)(=O)=O)[N:10]=2)[CH2:4][C:3]1([CH3:22])[CH3:21].[CH3:23][N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([CH2:33][CH2:34][NH2:35])=[CH:25]1.CCN(C(C)C)C(C)C>C1COCC1>[OH:1][C@H:2]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9]2[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11]([NH:35][CH2:34][CH2:33][C:26]3[C:27]4[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:24]([CH3:23])[CH:25]=3)[N:10]=2)[CH2:4][C:3]1([CH3:22])[CH3:21]
Reactant: Cn1cc(CCN)c2ccccc21
Reactant: CC1(C)C[C@H](Nc2nc(S(C)(=O)=O)ncc2C#N)CC[C@@H]1O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cn1cc(CCNc2ncc(C#N)c(N[C@@H]3CC[C@H](O)C(C)(C)C3)n2)c2ccccc21
Temperature: 100 °C
Reaction time: 1 h
Yield: 18.4 %

Procedure:
A mixture of 4-(((1R,4S)-4-hydroxy-3,3-dimethylcyclohexyl)amino)-2-(methylsulfonyl)pyrimidine-5-carbonitrile (90 mg, crude), 2-(1-methyl-1H-indol-3-yl)ethanamine (60 mg, 0.34 mmol), and DIEA (72 mg, 0.56 mmol) in THF (3 mL) was stirred at 100° C. in a microwave reactor for 1 h. After cooling to room temperature, the reaction mixture was concentrated and the residue was purified by standard methods to afford the title compound (21.5 mg, 0.051 mmol, 15% yield). 1H NMR (400 MHz, CD3OD) δ (ppm) 8.00 (s, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 7.14 (t, J=7.6 Hz, 1H), 7.00 (t, J=8.0 Hz, 1H), 6.94 (s, 1H), 4.28-4.23 (m, 1H), 3.75 (s, 3H), 3.75-3.62 (m, 2H), 3.02 (t, J=7.6 Hz, 1H), 1.82-1.26 (m, 6H), 1.02-0.87 (m, 6H). MS (ESI) m/z 419.2 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:35])[C@@H:4]([NH:14][C:15]([C:17]1[S:18][C:19]([C:23](=[O:34])[NH:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[C:28]([OH:33])[CH:27]=2)=[CH:20][C:21]=1[CH3:22])=[O:16])[CH2:5][NH:6][C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8].O.[OH-].[Li+].Cl>C1COCC1.O>[F:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][NH:24][C:23]([C:19]2[S:18][C:17]([C:15]([NH:14][C@@H:4]([CH2:5][NH:6][C:7]([C:9]3[S:10][CH:11]=[CH:12][CH:13]=3)=[O:8])[C:3]([OH:35])=[O:2])=[O:16])=[C:21]([CH3:22])[CH:20]=2)=[O:34])=[CH:27][C:28]=1[OH:33]
Reactant: COC(=O)[C@H](CNC(=O)c1cccs1)NC(=O)c1sc(C(=O)NCc2ccc(F)c(O)c2)cc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C(=O)NCc2ccc(F)c(O)c2)sc1C(=O)N[C@@H](CNC(=O)c1cccs1)C(=O)O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of (S)-2-{[5-(4-Fluoro-3-hydroxy-benzylcarbamoyl)-3-methyl-thiophene-2-carbonyl]-amino}-3-[(thiophene-2-carbonyl)-amino]-propionic acidmethyl ester (14 mg, 0.027 mmol) in THF (2 mL) was added a solution of lithium hydroxide monohydrate (11 mg, 0.269 mmol) in water (2.5 mL). The mixture was then stirred at room temperature 15 h. The mixture was then acidified with 1N HCl and extracted with EtOAc (×3). The extracts were combined, washed with water and brine, dried over sodium sulfate, filtered, and evaporated to pure product, 12.3 mg (68%). MS m/e 506.2 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][C:9]2[S:10][C:11]3[C:17]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:16][CH:15]=[C:14]([O:24][CH3:25])[C:12]=3[N:13]=2)=[O:7])=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:34][C@H:35]1[O:40][C@@H:39]([CH3:41])[CH2:38][NH:37][CH2:36]1>CN1C(=O)CCC1>[CH3:41][C@H:39]1[O:40][C@@H:35]([CH3:34])[CH2:36][N:37]([C:2]2[CH:27]=[CH:26][C:5]([C:6]([NH:8][C:9]3[S:10][C:11]4[C:17]([N:18]5[CH2:19][CH2:20][O:21][CH2:22][CH2:23]5)=[CH:16][CH:15]=[C:14]([O:24][CH3:25])[C:12]=4[N:13]=3)=[O:7])=[CH:4][N:3]=2)[CH2:38]1
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(Cl)nc3)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(N4C[C@@H](C)O[C@@H](C)C4)nc3)nc12

Procedure:
From 6-chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-nicotinamide with cesium carbonate and cis-2,6-dimethyl-morpholine in NMP. ES-MS m/e (%): 506 (M+Na+, 31), 484 (M+H+, 100).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][S:13]2(=[O:19])=[O:18])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].Cl.CO.N([O-])=[O:24].[Na+]>O>[O:18]=[S:13]1(=[O:19])[CH2:14][CH2:15][CH2:16][CH2:17][N:12]1[C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([OH:24])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(N)cc(N2CCCCS2(=O)=O)c1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(O)cc(N2CCCCS2(=O)=O)c1
Temperature: 95 °C
Reaction time: 1 h
Yield: 3.8 %

Procedure:
To a solution of methyl 3-amino-5-(1,1-dioxidotetrahydro-2H-1,2-thiazin-2-yl)benzoate (D267) (7.5 g, 26.4 mol, 1 equiv) in a 2N aqueous HCl solution (75 ml) and MeOH (75 ml) at 0° C. was added NaNO2 (4.0 g, 58.1 mmol, 2.2 equiv) portionwise over 20 min. MeOH (50 ml) and H2O (200 ml) were added and the resulting mixture was stirred at 95° C. for 1 h then cooled to room temperature. Most of the MeOH was removed in vacuo and the resulting aqueous phase was extracted with AcOEt. The insoluble material was filtered off to give methyl 3-(1,1-dioxidotetrahydro-2H-1,2-thiazin-2-yl)-5-hydroxybenzoate (D) (0.63 g, 8%). The organic phase was washed with brine, dried over MgSO4 and concentrated in vacuo to give a brown residue which was redissolved in AcOEt. The organic phase was extracted with a saturated aqueous Na2CO3 solution and the aqueous phase was extracted three times with Et2O then acidified to pH 1 and re-extracted three times with AcOEt. The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo to give methyl 3-(1,1-dioxidotetrahydro-2H-1,2-thiazin-2-yl)-5-hydroxybenzoate (D268) (2.2 g, 30%).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.Br[CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11]>>[SH:7][C:4]1[S:3][C:2]([S:1][CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:6][N:5]=1
Reactant: CCOC(=O)C(C)Br
Reactant: Sc1nnc(S)s1
Product: CCOC(=O)C(C)Sc1nnc(S)s1
Yield: 76 %

Procedure:
By following the same procedure as Reference Example 6 using 7.5 g of 2,5-dimercapto-1,3,4-thiadiazole and 5.8 g of ethyl 2-bromopropionate as the starting materials, 6.1 g of ethyl 2-[(5-mercapto-1,3,4-thiadiazol-2-yl)thio]propionate was obtained as an oily product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:16])O.[BrH:17].O>C(O)(=O)C>[Br:17][CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:16])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: Br
Reactant: OC(c1ccccc1Cl)c1ccccc1Cl
Solvent: O
Solvent: CC(=O)O
Product: Clc1ccccc1C(Br)c1ccccc1Cl
Temperature: 22.5 °C

Procedure:
Under N2, bis(2-chlorophenyl)methanol (70 g, 0.28 mol) was added in 4 portions at 20 to 25° C. to HBr (97 ml) in acetic acid (33% by weight). The mixture was stirred at 20 to 25° C. and the reaction was followed by HPLC. After complete reaction (60 to 90 min), the mixture was cooled to 0 to 10° C. and water (700 ml) was added over 30 min. The suspension was stirred at 0 to 10° C. for a further 30 min. The product was isolated by filtration and washed with water (4×140 ml). The product was dried under vacuum at 25° C. to constant weight. Yield: 82.6 g (95%). Assay (HPLC): 100% pure vs. standard
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([CH:12]2[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[SH:8].[Cl:15][C:16]1[N:21]=[C:20](S(C)(=O)=O)[N:19]=[C:18]([NH:26][C:27]2[NH:31][N:30]=[C:29]([CH3:32])[CH:28]=2)[CH:17]=1>C(O)(C)(C)C.CCOC(C)=O>[CH3:32][C:29]1[CH:28]=[C:27]([NH:26][C:18]2[CH:17]=[C:16]([Cl:15])[N:21]=[C:20]([S:8][C:7]3[CH:6]=[CH:5][C:4]([NH:9][C:10]([CH:12]4[CH2:13][CH2:14]4)=[O:11])=[CH:3][C:2]=3[F:1])[N:19]=2)[NH:31][N:30]=1
Reactant: Cc1cc(Nc2cc(Cl)nc(S(C)(=O)=O)n2)[nH]n1
Reactant: O=C(Nc1ccc(S)c(F)c1)C1CC1
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Product: Cc1cc(Nc2cc(Cl)nc(Sc3ccc(NC(=O)C4CC4)cc3F)n2)[nH]n1
Temperature: 25 °C
Yield: 39.8 %

Procedure:
A solution of N-(3-fluoro-4-mercaptophenyl)cyclopropane-carboxamide (1.0 g, 4.8 mmol) and 6-chloro-N-(3-methyl-1H-pyrazol-5-yl)-2-(methylsulfonyl)pyrimidin-4-amine (1.4 g, 4.8 mmol) in t-butanol (10 ml) was heated 70° C. for 18 h. Reaction mixture cooled to room temperature then diluted with EtOAc (60 ml), washed with sat. NaHCO3 solution (30 ml), brine (30 ml), dried (MgSO4), filtered and concentrated in vacuo. Crude product was purified by flash chromatography on silica (EtOAc/Petrol 20 to 60%) to give the title compound as white solid (800 mg, 40%). ES+ 419.
Reaction SMILES: Br[C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[O:4][C:5]1[CH:23]=[CH:22][C:8]([C:9]([NH:11][CH2:12][C:13]2[C:14]([OH:21])=[N:15][C:16]([CH3:20])=[CH:17][C:18]=2[CH3:19])=[O:10])=[CH:7][C:6]=1[Cl:24].[N:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:24][C:6]1[CH:7]=[C:8]([CH:22]=[CH:23][C:5]=1[O:4][C:3]1[CH:25]=[CH:26][CH:27]=[CH:28][C:2]=1[C:32]1[CH:33]=[CH:34][N:29]=[CH:30][CH:31]=1)[C:9]([NH:11][CH2:12][C:13]1[C:14]([OH:21])=[N:15][C:16]([CH3:20])=[CH:17][C:18]=1[CH3:19])=[O:10]
Reactant: Cc1cc(C)c(CNC(=O)c2ccc(Oc3ccccc3Br)c(Cl)c2)c(O)n1
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2ccc(Oc3ccccc3-c3ccncc3)c(Cl)c2)c(O)n1
Temperature: 90 °C
Reaction time: 12 h
Yield: 32.6 %

Procedure:
4-(2-Bromophenoxy)-3-chloro-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)benzamide (90 mg, 0.2 mmol), pyridin-4-ylboronic acid (48 mg, 0.4 mmol), tetrakis(triphenylphosphine)palladium (45 mg, 0.04 mmol), sodium carbonate (62 mg, 0.6 mmol), dioxane (8 mL) and water (2 mL) were added to a flask. The mixture was stirred at 90° C. for 12 hours under nitrogen atmosphere. The resultant mixture was concentrated to give a residue. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give 3-chloro-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(2-(pyridin-4-yl)phenoxy)benzamide as a light yellow solid (30 mg, 32%). LRMS (M+H+) m/z: calcd 459.13. found 459. HPLC purity (214 nm): 98%. 1H NMR (300 MHz, d6-DMSO): δ 11.46 (s, 1H), 8.57 (d, J=6.3 Hz, 2H), 8.40 (t, J=4.5 Hz, 1H), 8.02 (d, J=1.8 Hz, 1H), 7.73 (dd, J=8.7 Hz, J=2.1 Hz, 1H), 7.62-7.46 (m, 4H), 7.36 (t, J=6.3 Hz, 1H), 7.16 (d, J=2.1 Hz, 1H), 6.78 (d, J=6.3 Hz, 1H), 5.84 (s, 1H), 4.24 (d, J=4.5 Hz, 2H), 2.15 (s, 3H), 2.10 (s, 3H).