Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)=[O:13].[CH3:30][C:31]1[N:32]=[CH:33][NH:34][CH:35]=1>>[CH3:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([N:34]2[CH:35]=[C:31]([CH3:30])[N:32]=[CH:33]2)=[C:3]([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[CH:4]=1)(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc(I)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1
Reactant: Cc1c[nH]cn1
Product: Cc1cn(-c2ccc(S(C)(=O)=O)cc2C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)cn1
Yield: 32 %

Procedure:
The title compound was prepared according to the procedure described for example 199 from (2-Iodo-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone (compound CK) and 4-Methyl-1H-imidazole (32% yield, white solid, MS (m/e): 493.4 (M+H, 100%)
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:11])[CH2:9][O:10][C:6]=2[C:5]([N:12]=[C:13]=[O:14])=[CH:4][CH:3]=1.[H-].[Na+].[NH2:17]/[C:18](/[C:25]([F:28])([F:27])[F:26])=[CH:19]\[C:20](OCC)=[O:21]>>[Cl:1][C:2]1[C:7]2[C:8](=[O:11])[CH2:9][O:10][C:6]=2[C:5]([N:12]2[C:20](=[O:21])[CH:19]=[C:18]([C:25]([F:28])([F:27])[F:26])[NH:17][C:13]2=[O:14])=[CH:4][CH:3]=1
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Reactant: O=C=Nc1ccc(Cl)c2c1OCC2=O
Agent: [H-]
Agent: [Na+]
Product: O=C1COc2c(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)ccc(Cl)c21

Procedure:
By the method of Example 1, Step G, 2.10 g (0.010 mole) of 4-chloro-2,3-dihydrobenzofuran-3-on-7-yl isocyanate is reacted with 0.40 g (0.010 mole) of sodium hydride and 1.83 g (0.010 mole) of ethyl 3-amino-4,4,4-trifluorocrotonate, yielding 3-(4-chloro-2,3-dihydrobenzofuran-3-on-7-yl)-6-trifluoromethyluracil. This product is further reacted with 1.38 g (0.010 mole) of potassium carbonate and 2.80 g (0.020 mole) of methyl iodide, yielding 3-(4-chloro-2,3-dihydrobenzofuran-3-on-7-yl)-1-methyl-6-trifluoromethyluracil (Compound 30).
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=2)[C:8]([C:19](=[O:31])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH:27]([CH2:29][CH3:30])[CH3:28])[CH:21]=2)=[N:7][CH:6]=1.[OH-].[Na+]>CO>[CH:27]([O:26][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[C:19]([C:8]1[C:9]2[C:14](=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=2)[C:5]([CH2:4][C:3]([OH:32])=[O:2])=[CH:6][N:7]=1)=[O:31])([CH2:29][CH3:30])[CH3:28]
Reactant: CCC(C)Oc1cccc(C(=O)c2ncc(CC(=O)OC)c3cc(OC)c(OC)cc23)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC(C)Oc1cccc(C(=O)c2ncc(CC(=O)O)c3cc(OC)c(OC)cc23)c1
Temperature: 90 °C

Procedure:
To a stirred solution of [1-(3-sec-butoxy-benzoyl)-6,7-dimethoxy-isoquinolin-4-yl]-acetic acid methyl ester (170 mg, 0.39 mmol) in methanol (3.5 mL) was added 1.0 N sodium hydroxide solution (2.0 mL, 1.56 mmol). The reaction mixture was heated at 90° C. for 1 h, concentrated in vacuo and diluted with water (3 mL). The aqueous phase was extracted with diethyl ether (1×10) and then acidified to pH=4 by addition of 1N hydrogen chloride solution. The aqueous phase was then extracted with dichloromethane (3×15 mL). The combined extracts were washed with saturated aqueous sodium chloride solution (20 mL), dried with anhydrous magnesium sulfate, filtered and concentrated in vacuo. HPLC purification afforded [1-(3-sec-butoxy-benzoyl)-6,7-dimethoxy-isoquinolin-4-yl]-acetic acid trfluoroacetic acid salt (59 mg, 36% yield) as a light yellow solid. HR-MS m/e calcd for C24H15N1O6 (M−H+) 424.1755, found 424.1758; 1H NMR (300 MHz) compatible.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[N:10]=[CH:11][N:12]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:38]=[C:24]4[CH:25]([C:31]5[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=5)[CH2:26][C:27](=[O:30])[CH2:28][CH2:29][N:23]4[N:22]=3)=[CH:16][C:15]=2[O:39][CH3:40])[CH:13]=1.[CH2:41](O)[CH2:42][OH:43].O.CC1C=CC(S(O)(=O)=O)=CC=1.C(O)(C(F)(F)F)=O>C1C=CC=CC=1>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[N:10]=[CH:11][N:12]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:38]=[C:24]4[CH:25]([C:31]5[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=5)[CH2:26][C:27]5([CH2:28][CH2:29][N:23]4[N:22]=3)[O:43][CH2:42][CH2:41][O:30]5)=[CH:16][C:15]=2[O:39][CH3:40])[CH:13]=1
Reactant: COc1cc(Nc2nc3n(n2)CCC(=O)CC3c2ccc(F)cc2)ccc1-n1cnc(Cl)c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccccc1
Solvent: O
Product: COc1cc(Nc2nc3n(n2)CCC2(CC3c3ccc(F)cc3)OCCO2)ccc1-n1cnc(Cl)c1
Temperature: 25 °C
Yield: 35 %

Procedure:
A solution of 2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-9-(4-fluorophenyl)-8,9-dihydro-5H-[1,2,4]triazolo[1,5-a]azepin-7(6H)-one (84 mg, 0.180 mmol, from example 137) in benzene (1 mL) was treated with ethylene glycol (0.011 mL, 0.198 mmol), and 4-methylbenzenesulfonic acid, hydrate (34.2 mg, 0.180 mmol). The mixture was heated to reflux using a Dean-Stark trap for 6 h, the mixture was cooled to room temperature and quenched with saturated sodium bicarbonate and extracted with ethyl acetate. The aqueous phase was extracted twice more with ethyl acetate and the combined organic layers were combined and washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude product was purified using reverse phase preparatory HPLC (MeOH/water/trifluoroacetic acid) to afford the titled compound (39.4 mg, 34% yield) as a TFA salt. LC-MS (M+H)+ 511.3. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.75 (1 H, br. s.), 7.30-7.33 (1 H, m), 7.25-7.29 (2 H, m), 7.09-7.17 (3 H, m), 7.06 (1 H, br. s.), 7.02 (1 H, dd, J=8.5, 2.4 Hz), 4.45-4.54 (1 H, m), 4.32-4.42 (2 H, m), 4.02-4.11 (4 H, m), 3.83 (3 H, s), 2.32-2.40 (1 H, m), 2.23 (1 H, d, J=13.7 Hz), 2.08-2.19 (2 H, m).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([NH:23][C:24]2[CH:25]=[C:26]([C:36]([F:39])([F:38])[F:37])[CH:27]=[C:28]([N:30]3[CH:34]=[N:33][C:32]([CH3:35])=[CH:31]3)[CH:29]=2)=[O:22])=[CH:6][C:7]=1[NH:8][C:9]1[N:10]=[CH:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[N:19][CH:20]=2)[N:14]=1.[C:40]([OH:57])(=[O:56])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([NH:23][C:24]2[CH:25]=[C:26]([C:36]([F:38])([F:39])[F:37])[CH:27]=[C:28]([N:30]3[CH:34]=[N:33][C:32]([CH3:35])=[CH:31]3)[CH:29]=2)=[O:22])=[CH:6][C:7]=1[NH:8][C:9]1[N:10]=[CH:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[N:19][CH:20]=2)[N:14]=1.[C:40]([O-:57])(=[O:56])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55]
Reactant: CCCCCCCCCCCCCCCC(=O)O
Agent: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(Nc4nccc(-c5cccnc5)n4)c3)cc(C(F)(F)F)c2)cn1
Product: CCCCCCCCCCCCCCCC(=O)[O-]
Temperature: 40 °C
Reaction time: 4 h

Procedure:
Nilotinib base (0.300 g, 0.57 mmol) was dissolved in TFE (2 mL) at 40° C. The stirred mixture was added to a solution of palmitic acid (0.145 g, 0.57 mmol) in TFE (1 mL) at 40° C. The resulting clear solution was stirred for about 4 h at 40° C. and it was subsequently cooled to 5° C. and kept at this temperature overnight to obtain a precipitate The precipitate was filtered and the filter cake was dried at 40° C. in a vacuum oven overnight to give Nilotinib palmitate form I.
Reaction SMILES: [N+:1]([C:4]1[C:14]([N+:15]([O-])=O)=[CH:13][C:12]2[CH:11]3[CH2:18][CH:7]([CH2:8][N:9]([C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH2:10]3)[C:6]=2[CH:5]=1)([O-])=O.C([O-])=O.[NH4+]>CO.[OH-].[Pd+2].[OH-]>[NH2:1][C:4]1[C:14]([NH2:15])=[CH:13][C:12]2[CH:11]3[CH2:18][CH:7]([CH2:8][N:9]([C:19](=[O:24])[C:20]([F:23])([F:21])[F:22])[CH2:10]3)[C:6]=2[CH:5]=1
Reactant: O=C(N1CC2CC(C1)c1cc([N+](=O)[O-])c([N+](=O)[O-])cc12)C(F)(F)F
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Nc1cc2c(cc1N)C1CC2CN(C(=O)C(F)(F)F)C1
Temperature: 25 °C
Yield: 39.3 %

Procedure:
1-(4,5-Dinitro-10-aza-tricyclo[6.3.1.02.7]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone (40 g), ammonium formate (114.28 g) and 20% palladium hydroxide (4 g) were combined in methanol (400 ml) and refluxed for 30 minutes under a nitrogen atmosphere. The reaction mixture was cooled to 25° C. and filtered through a celite pad which was rinsed with methanol. The filtrate was concentrated and the product was extracted with methylene chloride (200 ml) and water (200 ml). The resulting two layers were extracted with methylene chloride (200 ml). The organic layer was washed with saturated aqueous sodium chloride solution (200 ml), dried over sodium sulfate and then concentrated. The residue was crystallized with diisopropyl ether (400 ml) followed by filtration to yield 13 g of 1-(4,5-diamino-10-aza-tricyclo[6.3.1.02.7]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone as pink crystals (Purity by HPLC: 99%).
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH2:16][C:17]1([CH3:22])[O:21][CH2:20][CH2:19][O:18]1)[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][C:6]=1[NH2:15].[C:24](OC)(OC)(OC)[CH3:25]>>[CH3:1][C:2]([CH3:23])([CH2:16][C:17]1([CH3:22])[O:21][CH2:20][CH2:19][O:18]1)[CH2:3][N:4]1[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:15]=[C:24]1[CH3:25]
Reactant: COC(C)(OC)OC
Reactant: CC(C)(CNc1c(N)cnc2ccccc12)CC1(C)OCCO1
Product: Cc1nc2cnc3ccccc3c2n1CC(C)(C)CC1(C)OCCO1
Yield: 67.3 %

Procedure:
The general method described in Step 3 of Example 6 was used to cyclize N4-[2,2-dimethyl-3-(2-methyl-[1,3]dioxolan-2-yl)propyl]quinoline-3,4-diamine (8.0 g, 25.4 mmol) by reaction with trimethyl orthoacetate (3.6 g, 30 mmol) to provide 1-[2,2-dimethyl-3-(2-methyl-[1,3]dioxolan-2-yl)propyl]-2-methyl-1H-imidazo[4,5-c]quinoline (5.80 g) as a solid after chromatography on silica gel (elution with a solution of 7% methanol in dichloromethane that contained about 5 mL of ammonium hydroxide solution per liter of eluent).
Reaction SMILES: C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[N:30]1[CH:35]=[C:34]([C:36]([NH:38][C:39]2([C:42]([OH:44])=O)[CH2:41][CH2:40]2)=[O:37])[CH:33]=[N:32][CH:31]=1.FC(F)(F)C(O)=O.[NH2:52][CH2:53][C:54]1[CH:68]=[CH:67][C:57]([O:58][C:59]2[CH:64]=[CH:63][C:62]([OH:65])=[CH:61][C:60]=2[Cl:66])=[CH:56][C:55]=1[Cl:69]>CN(C=O)C.C1COCC1>[Cl:69][C:55]1[CH:56]=[C:57]([O:58][C:59]2[CH:64]=[CH:63][C:62]([OH:65])=[CH:61][C:60]=2[Cl:66])[CH:67]=[CH:68][C:54]=1[CH2:53][NH:52][C:42]([C:39]1([NH:38][C:36]([C:34]2[CH:33]=[N:32][CH:31]=[N:30][CH:35]=2)=[O:37])[CH2:40][CH2:41]1)=[O:44]
Reactant: O=C(NC1(C(=O)O)CC1)c1cncnc1
Reactant: NCc1ccc(Oc2ccc(O)cc2Cl)cc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(NC1(C(=O)NCc2ccc(Oc3ccc(O)cc3Cl)cc2Cl)CC1)c1cncnc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
269 μl (1.93 mmol) of triethylamine and 166 mg (0.52 mmol) of TBTU were added to a solution of 100 mg (0.48 mmol) of 1-[(pyrimidin-5-carbonyl)-amino]-cyclopropanecarboxylic acid (from 1b) in 5 mL DMF and the mixture was stirred for 10 min at RT. Then 147 mg (0.37 mmol) of 4-(4-aminomethyl-3-chloro-phenoxy)-3-chloro-phenol-trifluoroacetic acid salt dissolved in 30 mL THF was added. The reaction mixture was stirred for 2 h at RT and evaporated to dryness. The residue was purified by chromatography (reversed phase).
Reaction SMILES: [BH4-].[Na+].[C:3]([C:11]1[CH:12]=[C:13]2[O:19][C:18](=[O:20])[N:17]([CH3:21])[C:14]2=[N:15][CH:16]=1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO>[C:4]1([CH:3]([C:11]2[CH:12]=[C:13]3[O:19][C:18](=[O:20])[N:17]([CH3:21])[C:14]3=[N:15][CH:16]=2)[OH:10])[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Cn1c(=O)oc2cc(C(=O)c3ccccc3)cnc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cn1c(=O)oc2cc(C(O)c3ccccc3)cnc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 84 %

Procedure:
Add 42 mg (1.1 mmol) of sodium borohydride to a previously prepared solution of 254 mg (1 mmol) of 6-benzoyl-3-methyloxazolo[4,5-b]pyridin-2(3H)-one in 20 ml of anhydrous methanol. Concentrate the reaction mixture to dryness under reduced pressure after stirring for 5 hours at room temperature, then take up the residue in water and isolate by filtration the resulting product; the title product is obtained in a yield of 84%.
Reaction SMILES: [OH-:1].[K+].[CH3:3][C:4]1[NH:8][C:7](=[O:9])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([S:16][C:17]3[CH:18]=[C:19]([C:23]4([C:29](N)=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[CH:20]=[CH:21][CH:22]=3)=[CH:12][CH:11]=2)[N:5]=1>CO.O1CCCC1>[CH3:3][C:4]1[NH:8][C:7](=[O:9])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([S:16][C:17]3[CH:18]=[C:19]([C:23]4([C:29]([OH:1])=[O:30])[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)[CH:20]=[CH:21][CH:22]=3)=[CH:12][CH:11]=2)[N:5]=1
Reactant: Cc1nn(-c2ccc(Sc3cccc(C4(C(N)=O)CCOCC4)c3)cc2)c(=O)[nH]1
Reactant: [OH-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nn(-c2ccc(Sc3cccc(C4(C(=O)O)CCOCC4)c3)cc2)c(=O)[nH]1

Procedure:
Potassium hydroxide (3.0 mmol) is added to a solution of 4-(3-{[4-(3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)phenyl]thio}phenyl)tetrahydro-2H-pyran-4-carboxamide (1.0 mmol) (example 10) in methanol and tetrahydrofuran (1:2) and the reaction mixture is refluxed for about 18 hours. The solvent is evaporated under vacuum. A small amount of water and concentrated hydrochloric acid are added to the residue to separate out the title compound.
Reaction SMILES: [CH2:1]([O:4][N:5]1[C:11](=[O:12])[N:10]2[CH2:13][C@H:6]1[C:7]([CH3:18])=[CH:8][C@H:9]2[C:14]([O:16]C)=[O:15])[CH:2]=[CH2:3].[OH-].[Li+].Cl>C1COCC1.O>[CH2:1]([O:4][N:5]1[C:11](=[O:12])[N:10]2[CH2:13][C@H:6]1[C:7]([CH3:18])=[CH:8][C@@H:9]2[C:14]([OH:16])=[O:15])[CH:2]=[CH2:3]
Reactant: C=CCON1C(=O)N2C[C@H]1C(C)=C[C@H]2C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C=CCON1C(=O)N2C[C@H]1C(C)=C[C@@H]2C(=O)O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of (2S,5R)-methyl 6-(allyloxy)-4-methyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-ene-2-carboxylate (Intermediate 30, 0.479 g, 1.90 mmol) in THF (10 mL) and water (5 mL) at 0° C. was added lithium hydroxide (0.045 g, 1.90 mmol). The reaction was stirred at 0° C. for 2 hours. Another 0.5 eq lithium hydroxide was added. After 2 hours the reaction mixture was neutralized carefully with 1N HCl at 0° C. and the THF was evaporated. The aqueous was frozen and lyophilized to afford a light orange solid (0.464 g, 103% crude).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[C:20]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[CH:14]=[C:13]2[C:21]([O:23]CC)=[O:22])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[I-].[Li+]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[C:20]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[CH:14]=[C:13]2[C:21]([OH:23])=[O:22])(=[O:10])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)c1cc2c(n1S(=O)(=O)c1ccc(Cl)c(Cl)c1)CCCC2
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: O=C(O)c1cc2c(n1S(=O)(=O)c1ccc(Cl)c(Cl)c1)CCCC2

Procedure:
Ethyl 1-(3,4-dichlorobenzenesulfonyl)-4,5,6,7-tetrahydroindole -2-carboxylate (66 mg) from Example 2d above and lithium iodide (228 mg) were dissolved in pyridine (5 ml) and heated at reflux for 5 hours, cooled, then concentrated in vacuo. The residue was partitioned between 2N HCl and ether. Combined organic extracts were dried (MgSO4), concentrated, and the residue triturated with ether to give the product as a white crystalline solid which was filtered and dried (18 mg, 28%), NMR d(DMSO) 1.65 (4H, m), 2.38 (2H, m), 2.80 (2H, m), 6.70 (1H, s), 7.90 (2H, m), 8.30 (1H, s); M/z (+) 373 (M-H+).
Reaction SMILES: CN(C)C=[N:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]3[CH:21]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)[CH:19]=[C:18]([CH3:32])[N:17]=3)[CH:11]=2)[N:9]=1.Cl.[OH-].[Na+]>C1COCC1>[CH3:32][C:18]1[N:17]=[C:16]([C:12]2[CH:11]=[C:10]([C:8]3[N:9]=[C:5]([NH2:4])[S:6][CH:7]=3)[CH:15]=[CH:14][CH:13]=2)[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:24][CH:23]=2)[CH:19]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3csc(N=CN(C)C)n3)c2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3csc(N)n3)c2)n1
Yield: 96.7 %

Procedure:
The above described N,N-dimethyl-N′-(4-{3-[6-methyl-4-(4-trifluoromethyl-phenyl)pyridin-2-yl]-phenyl}-thiazol-2-yl)-formamidine (880 mg, 1.886 mmol) was treated with 3 M HCl (20 mL) in THF (20 mL) at 50° C. for 16 h. Added 2 N NaOH until pH 10 was reached, extracted twice with EtOAc, dried combined organic layer over Na2SO4, filtered off and evaporated totally to give a crude product, which was triturated with ether to give the title compound (750 mg, 53%) as a white solid. MS (ISP) 412.2 [(M+H)+]; mp>250° C.
Reaction SMILES: [NH:1]([CH2:3][C:4]([O-:6])=[O:5])[CH3:2].[Na+].Cl.[N:9]#[C:10][NH2:11]>O>[OH2:5].[O:5]=[C:4]([CH2:3][N:1]([C:10](=[NH:9])[NH2:11])[CH3:2])[OH:6]
Reactant: N#CN
Reactant: CNCC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CN(CC(=O)O)C(=N)N
Temperature: 75 °C
Yield: 76.2 %

Procedure:
4625 g (16.7 mol) of a 40% by weight sodium sarcosinate solution prepared according to example 1 was added first. A pH of 9.6 (at 20° C.) was adjusted using concentrated hydrochloric acid while cooling externally with cold water and stirring vigorously. Subsequently it was heated to 75° C. 1403 g (16.7 mol) of a 50% by weight aqueous cyanamide solution (Degussa-Cyanamide L 500) was added uniformly over a period of 90 minutes while stirring vigorously at an internal temperature of 75 to 80° C. After the cyanamide addition was completed, the reaction mixture was stirred for a further 2 hours at an internal temperature of 75° C. After cooling to 5° C., the crystalline reaction product that can be readily filtered was suction filtered, washed three times chloride-free with 1250 ml water in each case and dried in a vacuum-drying cabinet at 40° C. and 20 mbar. The yield was 1897 g creatine monohydrate (corresponds to a yield of 76.2% of theory).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([O:9][CH2:10][CH:11]([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])=[CH:4][N:3]=1.CC(C)([O-])C.[K+].[CH3:24][O:25][C:26]1[N:31]=[C:30]2[S:32][C:33]([NH:35][C:36]3[C:45]4[C:40](=[CH:41][CH:42]=[C:43]([OH:46])[CH:44]=4)[N:39]=[CH:38][N:37]=3)=[N:34][C:29]2=[CH:28][CH:27]=1.[Cl-].[NH4+]>CN(C)C(=O)C>[Cl:8][C:7]1[C:2]([O:46][C:43]2[CH:44]=[C:45]3[C:40](=[CH:41][CH:42]=2)[N:39]=[CH:38][N:37]=[C:36]3[NH:35][C:33]2[S:32][C:30]3[C:29]([N:34]=2)=[CH:28][CH:27]=[C:26]([O:25][CH3:24])[N:31]=3)=[N:3][CH:4]=[C:5]([O:9][CH2:10][CH:11]([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])[CH:6]=1
Reactant: COc1ccc2nc(Nc3ncnc4ccc(O)cc34)sc2n1
Reactant: CCOC(COc1cnc(Cl)c(Cl)c1)OCC
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCOC(COc1cnc(Oc2ccc3ncnc(Nc4nc5ccc(OC)nc5s4)c3c2)c(Cl)c1)OCC
Temperature: 200 °C
Reaction time: 24 h
Yield: 2.4 %

Procedure:
2,3-Dichloro-5-(2,2-diethoxyethoxy)pyridine (240 mg, 0.85 mmol) and potassium tert-butoxide (100 mg, 0.92 mmol) were added to an N,N-dimethylacetamide suspension (1 ml) of 4-[(5-methoxy[1,3]thiazolo[5,4-b]pyridin-2-yl)amino]quinazolin-6-ol (120 mg, 0.37 mmol), and stirred for 24 hours at 200° C. in a sealed tube. The reaction solution was cooled to room temperature, then aqueous saturated ammonium chloride solution was added, filtered, and washed with a mixed solution of chloroform/methanol (9:1). The obtained filtrate was extracted with chloroform, the organic layer was washed with water and saturated saline water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by reversed-phase liquid chromatography (YMC CombiPrep Pro C18 AS-360-cc) to obtain 6-{[3-chloro-5-(2,2-diethoxyethoxy)pyridin-2-yl]oxy}-N-(5-methoxy[1,3]thiazolo[5,4-b]pyridin-2-yl)quinazoline-4-amine (5 mg, yield: 2%) as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]([NH:14][C:15]1[C:16](=[O:41])[N:17]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)[C@@H:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:30])([F:29])[F:28])[CH:21]=2)[CH:19]=1)([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[N:5]=1)[CH3:3].C([BH3-])#N.[Na+]>C(O)(=O)C.C1COCC1>[CH3:3][C:2]([NH:14][C@@H:15]1[CH2:19][C@H:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:28])([F:29])[F:30])[CH:21]=2)[N:17]([C:31]2[CH:32]=[CH:33][C:34]([C:37]([F:38])([F:40])[F:39])=[CH:35][CH:36]=2)[C:16]1=[O:41])([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]([F:11])([F:13])[F:12])[N:5]=1)[CH3:1]
Reactant: CC(C)(NC1=C[C@H](c2cccc(OC(F)(F)F)c2)N(c2ccc(C(F)(F)F)cc2)C1=O)c1ccnc(C(F)(F)F)n1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(N[C@@H]1C[C@H](c2cccc(OC(F)(F)F)c2)N(c2ccc(C(F)(F)F)cc2)C1=O)c1ccnc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.1 %

Procedure:
Cool a solution of (R)-3-[1-methyl-1-(2-trifluoromethyl-pyrimidin-4-yl)-ethylamino]-1-(4-trifluoromethyl-phenyl)-5-(3-trifluoromethoxy-phenyl)-1,5-dihydro-pyrrol-2-one (7.5 g, 12.7 mmol) in acetic acid (60 mL) and THF (15 mL) to 0° C. and add sodium cyanoborohydride (1.60 g, 25.4 mmol). Remove the cooling bath after 5 minutes and stir 60 minutes at ambient temperature. Dilute the reaction mixture with ethyl acetate and slowly pour into saturated aqueous sodium bicarbonate solution. Separate the organic layer and concentrate under reduced pressure. Purify the residue by silica gel chromatography (15-40% ethyl acetate-hexane) to obtain (3R,5R)-3-[1-methyl-1-(2-trifluoromethyl-pyrimidin-4-yl)-ethylamino]-5-(3-trifluoromethoxy-phenyl)-1-(4-trifluoromethyl-phenyl)-pyrrolidin-2-one (5.20 g, 69%) as a purple foam. To remove purple color, dissolve (3R,5R)-3-[1-methyl-1-(2-trifluoromethyl-pyrimidin-4-yl)-ethylamino]-5-(3-trifluoromethoxy-phenyl)-1-(4-trifluoromethyl-phenyl)-pyrrolidin-2-one in methanol (150 mL) and add activated carbon. Stir at ambient temperature for 20 min, filter, and concentrate under reduced pressure to give a white foam (4.6 g, 88%). 1H NMR (400 MHz, CDCl3): δ 8.79 (d, J=5.3 Hz, 1H), 7.90 (d, J=5.3 Hz, 1H), 7.46 (d, J=8.4 Hz, 2H), 7.36 (d, J=8.8 Hz, 2H), 7.27 (t, J=7.9 Hz, 1H), 7.08 (d, J=7.9 Hz, 1H), 7.04 (d, J=8.4 Hz, 1H), 6.98 (s, 1H), 5.04 (dd, J=6.2, 9.7 Hz, 1H), 3.51-3.45 (m, 1H), 2.90-2.81 (m, 1H), 1.89-1.81 (m, 1H), 1.56 (s, 3H), 1.50 (s, 3H). LC-MS ESI m/z: 593 (M+H)+, Tr=3.07 min., method 2.
Reaction SMILES: C(O[C@@H:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([O:11][CH2:12][C:13]2[N:14]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[O:16][C:17]=2[CH3:18])[CH2:6]1)C=C.I([O-])(=O)(=O)=O.[Na+].[C:32]([O:36]C)(C)(C)[CH3:33]>C(OCC)C.O.[Os](=O)(=O)(=O)=O>[F:25][C:22]1[CH:21]=[CH:20][C:19]([C:15]2[O:16][C:17]([CH3:18])=[C:13]([CH2:12][O:11][C@@H:7]3[CH2:8][CH2:9][CH2:10][C@H:5]([CH2:33][CH:32]=[O:36])[CH2:6]3)[N:14]=2)=[CH:24][CH:23]=1
Reactant: COC(C)(C)C
Reactant: C=CCO[C@@H]1CCC[C@H](OCc2nc(-c3ccc(F)cc3)oc2C)C1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CCOCC
Product: Cc1oc(-c2ccc(F)cc2)nc1CO[C@@H]1CCC[C@H](CC=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.0 g of 4-(cis-3-allyloxycyclohexyloxymethyl)-2-(4-fluorophenyl)-5-methyl-oxazole are dissolved in 50 ml of diethyl ether, and 3.8 g of sodium periodate, dissolved in 50 ml of water, are added. At 0° C., 1 ml of an osmium tetroxide solution (2.5% by weight in tert-butanol) is added, and the mixture is stirred vigorously at room temperature. After 8 hours, 100 ml of methyl tert-butyl ether are added, and the mixture is washed with a saturated sodium thiosulfate solution. The organic phase is dried over magnesium sulfate and the solvent is removed under reduced pressure. The residue is purified on silica gel (n-heptane:ethyl acetate=1:1→1:5). This gives 1.4 g of [cis-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl]acetaldehyde as a colorless oil. C20H25NO4 (343.42), MS (ESI): 344 (M+H+), Rf(n-heptane:ethylacetate=1:1)=0.25.