Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:20]=[CH:19][C:10]3[NH:11][C:12]([NH:14][C:15](=[O:18])[O:16][CH3:17])=[N:13][C:9]=3[CH:8]=2)=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[O:32])[CH:27]=[CH:28][CH:29]=1.C(OCC)C>C1COCC1>[Cl:23][C:24]1[CH:25]=[C:26]([NH:30][C:31]([NH:1][C:2]2[CH:22]=[CH:21][C:5]([O:6][C:7]3[CH:20]=[CH:19][C:10]4[NH:11][C:12]([NH:14][C:15](=[O:18])[O:16][CH3:17])=[N:13][C:9]=4[CH:8]=3)=[CH:4][CH:3]=2)=[O:32])[CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)Nc1nc2cc(Oc3ccc(N)cc3)ccc2[nH]1
Reactant: O=C=Nc1cccc(Cl)c1
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)Nc1nc2cc(Oc3ccc(NC(=O)Nc4cccc(Cl)c4)cc3)ccc2[nH]1
Temperature: 45 °C
Yield: 68 %

Procedure:
A mixture of methyl (5-(4aminophenoxy)-1H-benzimidazol-2-yl)carbamate (Intermediate 3) (80 mg, 0.27 mmol) and 3-chlorophenylisocyanate (49 mg, 0.32 mmol) in dry THF (2 ml) was heated to 45° C. overnight. After cooling, diethyl ether was added to form a precipitate. The solid was collected by filtration to provide the title compound (83 mg, 69%): 1H NMR (DMSO-d6) δ 11.60 (brs, 2H), 9.00 (s, 1H), 8.83 (s, 1H), 7.70 (m, 1H), 7.42 (d, 2H), 7.38 (d, 1H), 7.32–7.24 (m, 2H), 7.01 (m, 2H), 6.93 (d, 2H), 6.80 (dd, 1H) 3.75 (s, 3H); MS m/e 452 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=[O:15])[CH:5]([CH2:10][C:11](=O)[CH2:12][CH3:13])C(OC)=O.C([O-])([O-])=O.[Na+].[Na+]>>[CH2:12]([C:11]1[CH2:10][CH2:5][C:4](=[O:15])[C:3]=1[O:2][CH3:1])[CH3:13]
Reactant: CCC(=O)CC(C(=O)COC)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCC1=C(OC)C(=O)CC1
Yield: 29.1 %

Procedure:
21.60 g(100 mmol) of methyl 4-methoxy-2-(2-oxobutyl)-acetoacetate are held at reflux temperature for 8 hours with 212.0 g (50 mmol) of 2.5% Na2CO3 solution. After cooling the reaction mixture is extracted 3 times with 200 ml of CH2Cl2 each time. The combined organic phases are dried over magnesium sulphate and concentrated on a rotary evaporator. The crude product is column chromatographed over SiO2 and gives 4.08 g (29.1%) of 3-ethyl-2-methoxy-2-cyclopenten-1-one.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[C:20](=[O:22])=[O:21]>O.O1CCCC1.CCCCCC>[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[C:20]([OH:22])=[O:21]
Reactant: O=C=O
Reactant: Brc1cccnc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(O)c1ccncc1Br

Procedure:
A mixture of 3.54 g of diisopropylamine and 50 ml of tetrahydrofuran was stirred while cooling in a dry ice-acetone bath. To the reaction mixture, 20 ml of 1.6 M hexane solution of n-butyllithium was added so that the temperature of the reaction mixture did not exceed −40° C. The reaction mixture was stirred for 30 minutes. Then, a mixture of 4.74 g of 3-bromopyridine and 5 ml of tetrahydrofuran was added so that the temperature of the reaction mixture did not exceed −60° C. The reaction mixture was stirred for further 30 minutes. Crushed dry ice was added to the reaction mixture and then cooling was stopped. The reaction mixture was stirred until the temperature retuned to room temperature. Water was added thereto, most of hexane and tetrahydrofuran was removed under reduced pressure. The residue was washed with tert-butyl methyl ether, and the aqueous layers were collected. To the collected aqueous layers, concentrated hydrochloric acid was added while ice-cooling so that pH of the mixture was made to be 3 and stirred for one hour, followed by extraction with ethyl acetate three times. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 0.69 g of 3-bromo isonicotinic acid.
Reaction SMILES: [O:1]=[C:2]1[N:6]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[CH2:13][CH:5]2[CH:4]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:3]1.CS(O)(=O)=O.[C:24](OC(=O)C)(=[O:26])[CH3:25].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:24]([C:10]1[CH:9]=[CH:8][C:7]2[N:6]3[C:2](=[O:1])[O:3][CH:4]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[CH:5]3[CH2:13][C:12]=2[CH:11]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)NCC1OC(=O)N2c3ccccc3CC12
Reactant: CC(=O)OC(C)=O
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)NCC1OC(=O)N2c3ccc(C(C)=O)cc3CC12
Reaction time: 1 h

Procedure:
A mixture of (±) (1S,9aS/1R,9aR) N-[(9,9a-dihydro-3-oxo-1H,3H-oxazolo[3,4-a]indol-1-yl)methyl]acetamide (X diastereomer B, EXAMPLE 11, 8 mg), methane sulfonic acid (0.5 ml), and acetic anhydride (10 μl) is stirred in methylene chloride (0.2 ml) from 0° to 20° for 19.5 hours. After this time the mixture is cooled in an ice bath and additional acetic anhydride (10 μl) is added. The mixture is stirred for one hour then added to a small amount of ice and saturated aqueous sodium bicarbonate (7 ml) is added, then solid sodium bicarbonate is added until alkaline. The mixture is then extracted with methylene chloride (5×, 20 ml total). The combined extract layers provide 8 mg of material. The 8 mg is then purified by chromatography (5 cm×0.5 cm disposable pipet, 40-63 μ silica) eluting with 1% and 2.5% methanol/methylene chloride gradient while collecting 0.4 ml fractions. The appropriate fractions are pooled and concentrated to provide the title compound.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[N:11][N:12]=2)=[CH:4][CH:3]=1.[CH3:25][C:26]1[NH:27][CH:28]=[CH:29][N:30]=1>>[CH3:25][C:26]1[N:27]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:9][C:10]([C:13]4[C:14]([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)=[N:15][O:16][C:17]=4[CH3:18])=[N:11][N:12]=3)=[CH:4][CH:3]=2)[CH:28]=[CH:29][N:30]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(F)cc2)o1
Reactant: Cc1ncc[nH]1
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(-n3ccnc3C)cc2)o1
Yield: 46 %

Procedure:
As described for example 47, 2-(4-fluoro-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole (200 mg, 0.62 mmol) was converted using 2-methyl-imidazole instead of piperidine to the title compound (110 mg, 46%) which was obtained a light-brown waxy solid. MS: m/e=384.0 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].Br[CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:17][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: COCCOCCBr
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOCCOc1cccc(C=O)c1
Temperature: 57 °C
Yield: 101.1 %

Procedure:
To a solution of 3-hydroxybenzaldehyde (5.0 g, 41 mmol) in N,N-dimethylformamide (100 mL) was added bromo-2-(2-methoxyethoxy)ethane (6.0 mL, 45 mmol) followed by addition of solid potassium carbonate (17 g, 122 mmol). The resulting slurry was heated under nitrogen at 57° C. for 19 h. The reaction mixture was cooled to room temperature and filtered. The filter cake was washed with methanol and the filtrate was reduced in vacuo to ˜50 mL and poured into water (200 mL). The solution was acidified to pH˜4 with hydrochloric acid (1 M) and extracted with ethyl acetate (3×150 mL). The combined organic layer was washed with aqueous copper sulphate (75 mL), water (100 mL) and brine (100 mL), dried over sodium sulphate, filtered and concentrated in vacuo to a viscous oil. The oil was dried in vacuo to give 9,3 g (99% yield) of the title compound as a tan oil. 1HNMR (300 MHz, DMSO-d6, TFA-d) δ 9.98 (s, 1H), 7.51 (m, 2H), 7.44 (s, 1H), 7.30 (m, 1H), 4.18 (t J=5 Hz, 2H), 3.76 (t, J=5 Hz, 2H), 3.60 (t, J=5 Hz, 2H), 3.46 (t, J=5 Hz, 2H), 3.25 (s, 3H).
Reaction SMILES: [CH3:1][C:2](=[CH2:14])[CH2:3][C:4]1[C:9]([CH3:10])=[CH:8][C:7]([CH3:11])=[C:6]([CH3:12])[C:5]=1[OH:13].C(=O)([O-])[OH:16].[Na+]>C(Cl)Cl>[OH:16][CH2:14][C:2]1([CH3:1])[CH2:3][CH:4]2[CH:9]([CH3:10])[CH:8]=[C:7]([CH3:11])[C:6]([CH3:12])=[C:5]2[O:13]1
Reactant: O=C([O-])O
Reactant: C=C(C)Cc1c(C)cc(C)c(C)c1O
Agent: [Na+]
Solvent: ClCCl
Product: CC1=CC(C)C2CC(C)(CO)OC2=C1C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
31.86 g of 2-(2-methyl-2-propenyl)-3,5,6-trimethylphenol was dissolved in 600 ml of methylene chloride and 47.5 g of methchloroperbenzoic acid was gradually charged while maintaining at 0° C. After stirring at 0° C. for 2 hours, the solution was poured into an aqueous sodium hydrogen carbonate. The organic layer was extracted with chloroform, washed with an aqueous saturated sodium hydrogen carbonate solution and dried over anhydrous magnesium sulfate and, after the solvent was distilled off, the residue was purified by silica gel column chromatography (chloroform) to obtain 17 g of the objective product.
Reaction SMILES: [CH2:1](N=C=O)C.[NH2:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:10]=[CH:9][C:8]=1[C:19](=[O:32])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([NH:29][CH2:30][CH3:31])=[O:28])[CH:21]=1>>[NH2:6][C:7]1[N:11]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[N:10]=[CH:9][C:8]=1[C:19](=[O:32])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([NH:29][CH:30]([CH3:1])[CH3:31])=[O:28])[CH:21]=1
Reactant: CCNC(=O)Oc1cccc(C(=O)c2cnn(-c3ccc(F)cc3)c2N)c1
Reactant: CCN=C=O
Product: CC(C)NC(=O)Oc1cccc(C(=O)c2cnn(-c3ccc(F)cc3)c2N)c1

Procedure:
Replacing isopropyl isocyanate with ethyl isocyanate was made 5-amino-1-(4-fluorophenyl)-4-[3-ethylaminocarbonyloxybenzoyl]pyrazole (84). Mpt. 201.2-202.8° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([NH:11][C:12]3[O:13][CH2:14][C:15]4[CH:21]=[C:20]([NH2:22])[CH:19]=[CH:18][C:16]=4[N:17]=3)[C:4]=2[O:3]1.[NH:24]1[CH:28]=[CH:27][N:26]=[C:25]1[CH:29]=O>>[CH3:1][C:2]1([CH3:23])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([NH:11][C:12]3[O:13][CH2:14][C:15]4[CH:21]=[C:20]([NH:22][CH2:29][C:25]5[NH:24][CH:28]=[CH:27][N:26]=5)[CH:19]=[CH:18][C:16]=4[N:17]=3)[C:4]=2[O:3]1
Reactant: CC1(C)Cc2cccc(NC3=Nc4ccc(N)cc4CO3)c2O1
Reactant: O=Cc1ncc[nH]1
Product: CC1(C)Cc2cccc(NC3=Nc4ccc(NCc5ncc[nH]5)cc4CO3)c2O1

Procedure:
Prepared from N2-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yl)-4H-benzo[d][1,3]oxazine-2,6-diamine (example 139, step B) and 2-imidazolecarboxaldehyde according to the procedure described for example 88. The title compound was obtained as a brown solid, MS (ISP) m/e=390.3 [(M+H)+].
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:6]2[N:7]=[CH:8][N:9]([C:40]=2[N:41]=[C:42]([NH2:44])[N:43]=1)[C@@H:10]1[O:39][C@H:29]([CH2:30][O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[C@@H:20]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[C@H:11]1O[Si](C(C)(C)C)(C)C)[CH:2]=[CH2:3].C([O-])([O-])=O.[Cs+].[Cs+]>C(O)C=C>[CH2:1]([O:4][C:5]1[C:6]2[N:7]=[CH:8][N:9]([C:40]=2[N:41]=[C:42]([NH2:44])[N:43]=1)[C@@H:10]1[O:39][C@H:29]([CH2:30][O:31][Si:32]([C:35]([CH3:36])([CH3:37])[CH3:38])([CH3:34])[CH3:33])[C@@H:20]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:23])[CH3:24])[CH2:11]1)[CH:2]=[CH2:3]
Reactant: C=CCOc1nc(N)nc2c1ncn2[C@@H]1O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1O[Si](C)(C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C=CCO
Product: C=CCOc1nc(N)nc2c1ncn2[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)O1
Yield: 87 %

Procedure:
As described for the synthesis of 1a, this compound was prepared by a reaction of O6-(benzotriazol-1H-yl)-3′,5′-di-O-(tert-butyldimethylsilyl)-2′-deoxyguanosine25 (5.0 g, 8.16 mmol), allyl alcohol (50 mL) and Cs2CO3 (5.64 g, 17.1 mmol). Chromatographic purification of the crude material on a silica gel column using 30% EtOAc in hexanes) afforded 3.71 g (87% yield) of 1b as a white foam. Rf (SiO2/40% EtOAc in hexanes)=0.60. 1H NMR (CDCl3): δ 7.93 (s, 1H, Ar—H), 6.34 (t, 1H, H-1′, J=6.5 Hz), 6.17-6.09 (m, 1H, ═CH), 5.43 (dd, 1H, ═CHtrans, J=1.4, 17.2 Hz), 5.27 (dd, 1H, ═CHcis, J=1.4, 10.4 Hz), 5.01 (d, 2H, OCH2, J=5.7 Hz), 4.94 (s, 1H, NH2), 4.66-4.58 (m, 1H, H-3′), 3.99 (app q, 1H, H-4′, Japp˜3.5 Hz), 3.83 (dd, 1H, H-5′, J=4.4, 11.2 Hz), 3.77 (dd, 1H, H-5′, J=3.4, 11.2 Hz), 2.57 (app quint, 1H, H-2′, Japp˜6.5 Hz), 2.37 (ddd, 1H, H-2′, J=4.0, 6.0, 13.0 Hz), 0.92 (s, 18H, t-Bu), 0.11 and 0.09 (2s, 12H, SiCH3). 13C NMR (CDCl3): δ 160.0, 159.2, 153.5, 137.8, 132.8, 118.4, 116.0, 87.8, 88.8, 72.1, 67.5, 63.0, 41.1, 26.1, 25.9, 18.6, 18.1, −4.4, −4.6, −5.2, −5.3. HRMS calculated for C25H46N5O4Si2 [M+H]+: 536.3083. found: 536.3093.
Reaction SMILES: [C:1]1([CH:7]2[CH2:13][C:12](=[O:14])[O:11][C:9](=[O:10])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]([NH:32][NH2:33])([O:17][CH2:18][CH:19]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16]>C1COCC1>[CH:21]1[C:20]2[CH:19]([CH2:18][O:17][C:15]([NH:32][NH:33][C:12](=[O:14])[CH2:13][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:8][C:9]([OH:11])=[O:10])=[O:16])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]=2[CH:24]=[CH:23][CH:22]=1
Reactant: NNC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: O=C1CC(c2ccccc2)CC(=O)O1
Solvent: C1CCOC1
Product: O=C(O)CC(CC(=O)NNC(=O)OCC1c2ccccc2-c2ccccc21)c1ccccc1

Procedure:
2.0 mmol of 3-phenylglutaric anhydride and 2.0 mmol of Fmoc-hydrazine are dissolved in 30 ml of THF and heated under reflux for 16 hours. The product is then extracted with 50 ml of DCM and 50 ml of 1N HCl solution and the organic phase is dried with MgSO4 and filtered off. Removal of the solvent gives 5-[N′-(9H-fluoren-9-ylmethoxycarbonyl)hydrazino]-5-oxo-3-phenylpentanoic acid.
Reaction SMILES: [Br:1]Br.II.[C:5]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:10])[CH2:6][C:7]([CH3:9])=[O:8].O>C(O)(=O)C>[Br:1][CH2:9][C:7](=[O:8])[CH2:6][C:5]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10]
Reactant: CC(=O)CC(=O)Nc1ccccc1
Reactant: BrBr
Agent: II
Solvent: CC(=O)O
Solvent: O
Product: O=C(CBr)CC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.1 %

Procedure:
Under a nitrogen atmosphere, a solution of bromine (1.16 ml, 22.59 mmol) in 17 ml of acetic acid containing a small crystal of iodine was added over 2.5 hours to a solution of acetoacetanilide (4.0 g, 22.57 mmol) in 12 ml of acetic acid, at room temperature (cooling with cold water). The reaction mixture was stirred at room temperature for 3 hours, then poured into 100 ml of ice-cold water and the crude solid product was filtered off. Following crystallization from ethanol, 3.30 g of 4-bromoacetoacetanilide were obtained, m.p 130°-132° C.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([CH2:7][Cl:8])[N:3]=1.C([Sn](CCCC)(CCCC)[C:14]1[N:18]2[CH:19]=[CH:20][C:21]([C:23]([F:26])([F:25])[F:24])=[N:22][C:17]2=[N:16][CH:15]=1)CCC>>[Cl:8][CH2:7][C:4]1[N:3]=[C:2]([C:14]2[N:18]3[CH:19]=[CH:20][C:21]([C:23]([F:24])([F:25])[F:26])=[N:22][C:17]3=[N:16][CH:15]=2)[S:6][N:5]=1
Reactant: ClCc1nsc(Cl)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Product: FC(F)(F)c1ccn2c(-c3nc(CCl)ns3)cnc2n1
Yield: 25.7 %

Procedure:
5-Chloro-3-chloromethyl-[1,2,4]thiadiazole (360 mg, 2.13 mmol) was coupled to 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (1.4 mmol) by the method of Example 1 to afford 3-(3-chloromethyl-[1,2,4]thiadiazol-5-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine (115 mg) as a yellow solid: δH (400 MHz, DMSO) 5.08 (2H, s), 7.94 (1H, d, J 7), 9.12 (1H, s), 10.03 (1H, d, J 7); m/z (ES+) 320 (M++H).
Reaction SMILES: N[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH:31]([CH3:33])[CH3:32])=[CH:8][C:9]=2[C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)=[O:19])=[CH:13][CH:12]=2)[N:4]([CH3:34])[N:3]=1.S(=O)(=O)(O)O.N([O-])=O.[Na+]>>[CH:31]([C:7]1[N:6]=[C:5]2[N:4]([CH3:34])[N:3]=[CH:2][C:10]2=[C:9]([C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=3)=[O:19])=[CH:15][CH:16]=2)[CH:8]=1)([CH3:33])[CH3:32]
Reactant: CC(C)c1cc(-c2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2)c2c(N)nn(C)c2n1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(C)c1cc(-c2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2)c2cnn(C)c2n1
Yield: 11.8 %

Procedure:
In analogy to GP 6, reaction of 200 mg of 1-[4-(3-Amino-6-isopropyl-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-phenyl]-3-(3-trifluoromethyl-phenyl)-urea (0.43 mmol, 1 eq.) with 67 μL concentrated sulphuric acid and 146 mg sodium nitrite (5 eq.) yielded 23 mg of the desired product (12% yield).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[F:28][C:29]([F:37])([F:36])[C@H:30]([OH:35])[CH2:31][C:32](O)=[O:33]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:32](=[O:33])[CH2:31][C@@H:30]([OH:35])[C:29]([F:37])([F:36])[F:28])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: O=C(O)C[C@@H](O)C(F)(F)F
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: O=C(C[C@@H](O)C(F)(F)F)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, white solid (133 mg, 94%), MS (ISP) m/z=471.5 [(M+H)+], mp 214.5° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and (R)-4,4,4-trifluoro-3-hydroxybutanoic acid.
Reaction SMILES: C(OC(N=NC(OC(C)C)=O)=O)(C)C.[CH2:15]([O:17][C:18]([C:20]1[S:21][C:22]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:23]([OH:26])[C:24]=1[OH:25])=[O:19])[CH3:16].[F:32][C:33]([F:38])([CH2:36]O)[CH2:34]O.C(P(CCCC)CCCC)CCC>O1CCCC1>[CH2:30]([O:29][C:27]([C:22]1[S:21][C:20]([C:18]([O:17][CH2:15][CH3:16])=[O:19])=[C:24]2[C:23]=1[O:26][CH2:36][C:33]([F:38])([F:32])[CH2:34][O:25]2)=[O:28])[CH3:31]
Reactant: OCC(F)(F)CO
Reactant: CCOC(=O)c1sc(C(=O)OCC)c(O)c1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1sc(C(=O)OCC)c2c1OCC(F)(F)CO2
Temperature: 100 °C
Reaction time: 96 h

Procedure:
3,3-Difluoro-3,4-dihydro-2H-thieno[3,4-b][1,4]-dioxepine-6,8-dicarboxylic acid diethyl ester was synthesized by adding dropwise 3.4 mL (17.2 mmol) of azodicarboxylic acid diisopropyl ester (ADC) to a mixture of 1.77 g (6.67 mmol) of 3,4-dihydroxythiophen-2,5-dicarboxylic acid diethyl ester, 748 mg of 2,2-difluoro-1,3-propanediol and 4.3 mL of tributylphosphine in 12 mL of absolute tetrahydrofuran under argon at 20° C. with ice-cooling. After completion of the addition of ADC the resulting mixture was allowed to stand at room temperature for 4 days. The tetrahydrofuran was then distilled off and the residue heated for 12.5 hours at 100° C. after which it was dissolved in ethyl acetate. The ethyl acetate solution was washed three times with saturated sodium bicarbonate solution, then with deionized water, dried with anhydrous magnesium sulphate, concentrated and the residue chromatographically purified on a kieselgel 60 column with heptane/ethyl acetate as eluant. 335 mg (corresponding to a yield of 15%) of the desired product was obtained with a melting point of 121–122° C., as characterized by:
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH:15]=O)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[N:18]1([C:24]2[C:29]3[CH:30]=[CH:31][S:32][C:28]=3[CH:27]=[CH:26][N:25]=2)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.CC(O)=O.C([O-])(O)=O.[Na+]>ClCCCl>[C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][N:21]2[CH2:22][CH2:23][N:18]([C:24]3[C:29]4[CH:30]=[CH:31][S:32][C:28]=4[CH:27]=[CH:26][N:25]=3)[CH2:19][CH2:20]2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: c1cc2sccc2c(N2CCNCC2)n1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC=O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4sccc34)CC2)CC1

Procedure:
trans-[4-(2-oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester [CAS-Nr. 215790-29-7] (1.0 g, 4 mmol) was added to a solution under N2 of commercially available 4-piperazine-1-yl-thieno[3,2-c]pyridine [CAS-Nr. 106261-27-2] (0.85 g, 4 mmol) in 1,2-dichloroethane (45 ml) and AcOH (0.22 ml, 4 mmol). The resulting reaction mixture was stirred 8 h at room temperature before addition of Na(AcO)3BH (1.2 g, 6 mmol). Stirring was continued over night at room temperature. Sat. aq. NaHCO3 sol. was added and the product was extracted with EtOAc (2×). The combined organic layers were washed with H2O and brine. After drying (MgSO4) the solvent was evaporated and the product was purified by flash chromatography on silica gel (CH2Cl2/MeOH, 100:0 to 90:10) to yield trans-{4-[2-(4-thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-carbamic acid tert-butyl ester as a light yellow solid (1.2 g, 72%), MS (ISP) m/z=445.3 [(M+H)+].
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C@H:6]([NH:13]C(=O)C)[CH2:5][CH2:4]1.[OH-].[K+].C(O)CO>O>[CH3:1][O:2][C@H:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C@H:6]([NH2:13])[CH2:5][CH2:4]1
Reactant: CO[C@@H]1CC[C@@H](NC(C)=O)c2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: CO[C@@H]1CC[C@@H](N)c2ccccc21

Procedure:
A mixture of 6.9 g. of cis and trans-N-(1,2,3,4-tetrahydro-4-methoxy-1-naphthyl)acetamide, 56.11 g. of potassium hydroxide, 50 ml. of ethylene glycol and 20 ml. of water is stirred and heated at reflux for an overnight period. The mixture is cooled, 100 ml. of water is added and the mixture extracted with methylene chloride (3 × 50 ml.). The combined extract was washed with 125 ml. of 10% sodium hydroxide solution, dried and evaporated in vacuo to afford 5.7 g. of title product - an oil. This oily amine is used without further purification for the preparation of the urea derivative.
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([C:22]4[C:23]([Br:39])=[CH:24][C:25]([F:38])=[C:26]([NH:28][C:29]([NH:31][C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)=[O:30])[CH:27]=4)[C:15](=[O:21])[N:16]3[CH2:19][CH3:20])=[CH:11][N:10]=2)=CC=1.C(O)(C(F)(F)F)=O>>[NH2:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[C:14]([C:22]3[C:23]([Br:39])=[CH:24][C:25]([F:38])=[C:26]([NH:28][C:29]([NH:31][C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)=[O:30])[CH:27]=3)[C:15](=[O:21])[N:16]2[CH2:19][CH3:20])=[CH:11][N:10]=1
Reactant: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccccc3)c(F)cc2Br)cc2cnc(NCc3ccc(OC)cc3)cc21
Solvent: O=C(O)C(F)(F)F
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccccc3)c(F)cc2Br)cc2cnc(N)cc21
Temperature: 25 °C
Yield: 43.7 %

Procedure:
1-(5-(7-(4-methoxybenzylamino)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-bromo-2-fluorophenyl)-3-phenylurea (0.256 g, 0.415 mmol) was dissolved in TFA (4 mL, 51.9 mmol) and stirred at RT. After 4 h the reaction mixture was concentrated to dryness, the residue was diluted with MeOH, and the precipitated solids were removed by filtration. The filtrate was treated with satd. NaHCO3 and the resulting solid collected by filtration, rinsed with H2O, dried under vacuum, and purified by reverse phase chromatography (MeCN/H2O with 0.1% TFA). The organics were removed under reduced pressure, the aqueous residue treated with satd. NaHCO3 and the resulting solids were collected by filtration, washed with H2O and dried to afford 1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-bromo-2-fluorophenyl)-3-phenylurea (90 mg, 44% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.08 (s, 1H), 8.68 (d, 1H, J=2.4 Hz), 8.36 (s, 1H), 8.17 (d, 1H, J=8.8 Hz), 7.70 (s, 1H), 7.65 (d, 1H, J=10.8 Hz), 7.42-7.40 (m, 2H), 7.28-7.24 (m, 2H), 6.98-6.95 (m, 1H), 6.54 (br s, 2H), 6.34 (s, 1H), 4.08 (q, 2H, J=7.2 Hz), 1.20 (t, 3H, J=7.2 Hz); MS (ESI) m/z: 496.1 (M+H+), 498.1 (M+2+H+).