Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([O:6][C:7]2[CH:8]=[CH:9][C:10]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]4[CH:30]=[C:29]([C:31]([CH3:34])([CH3:33])[CH3:32])[O:28][N:27]=4)=[O:24])=[CH:18][CH:17]=3)=[O:14])=[N:11][CH:12]=2)[CH2:3]1.Cl.[C:36](C1ON=C(NC(=O)NC2C=CC(NC(=O)C3C=C(OC4CCNCC4)C=CN=3)=CC=2)C=1)(C)(C)[CH3:37]>>[C:31]([C:29]1[O:28][N:27]=[C:26]([NH:25][C:23](=[O:24])[NH:22][C:19]2[CH:18]=[CH:17][C:16]([NH:15][C:13](=[O:14])[C:10]3[CH:9]=[CH:8][C:7]([O:6][CH:4]4[CH2:5][N:2]([CH2:36][CH3:37])[CH2:3]4)=[CH:12][N:11]=3)=[CH:21][CH:20]=2)[CH:30]=1)([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(NC(=O)c3cc(OC4CCNCC4)ccn3)cc2)no1
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(NC(=O)c3ccc(OC4CNC4)cn3)cc2)no1
Agent: Cl
Product: CCN1CC(Oc2ccc(C(=O)Nc3ccc(NC(=O)Nc4cc(C(C)(C)C)on4)cc3)nc2)C1
Yield: 34 %

Procedure:
N-(4-(3-(5-tert-Butylisoxazol-3-yl)ureido)phenyl)-5-(1-ethylazetidin-3-yloxy)picolinamide (13 mg, 34%) was prepared as an off-white powder using a procedure analogous to that described in Example 2, substituting 5-(azetidin-3-yloxy)-N-(4-(3-(5-tert-butylisoxazol-3-yl)ureido)phenyl)picolinamide hydrochloride from Step 2 of this example for N-(4-(3-(5-tert-butylisoxazol-3-yl)ureido)phenyl)-4-(piperidin-4-yloxy)picolinamide hydrochloride used in Example 2. LC-MS (ESI) m/z 479 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 10.41 (s, 1H), 9.51 (s, 1H), 8.81 (s, 1H), 8.32 (br. s., 1H), 8.08 (d, J=8.29 Hz, 1H), 7.81 (d, J=8.29 Hz, 2H), 7.49 (d, J=8.85 Hz, 1H), 7.42 (d, J=7.54 Hz, 2H), 6.50 (s, 1H), 4.99 (t, J=4.71 Hz, 1H), 3.61-3.82 (m, 2H), 2.99 (t, J=5.93 Hz, 2H), 2.46 (br. s., 2H), 1.30 (s, 9H), 0.90 (t, J=6.97 Hz, 3H).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[CH:12]=[C:11]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[NH:10][N:9]=1)=[O:7])C>CO>[O:14]([CH2:13][C:11]1[NH:10][N:9]=[C:8]([C:6]([OH:7])=[O:5])[CH:12]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1cc(COc2ccccc2)[nH]n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc(COc2ccccc2)[nH]n1
Yield: 88.3 %

Procedure:
Freshly prepared aq. NaOH (10 M in H2O, 10.49 mmol) was added to a stirring, room temperature solution of 41 (0.5164 g, 2.10 mmol) in MeOH (5.2 mL, 0.4 M) under N2. The reaction was then heated to reflux until the reaction was judged complete by HPLC (20 min): The reaction was concentrated and then dissolved in 4.2 mL H2O. 10% aq. HCl was added dropwise until the pH=2. The white solid that precipitated from the reaction was filtered off and washed with cold H2O. The solid was dried under vacuum overnight to obtain 0.4044 g (88.4%) of 42 as a white solid. Note. An undesired impurity that does not crash out of solution upon HCl addition has a retention time of 9.127 min by 1H (CDCl3, 400 MHz): δ 7.26 (2H, t, J=8.0 Hz), 6.99 (2H, d, J=8.3 Hz), 6.94 (1H, t, J=7.3 Hz), 6.85 (1H, s), 5.10 (2H, s) ppm. 13C (CDCl3, 100 MHz): δ 163.68, 159.73, 146.60, 141.13, 130.51, 122.27, 115.83, 108.88, 63.06 ppm. DEPT (CDCl3, 100 MHz): CH2 carbons: 63.06; CH carbons: 130.51, 122.27, 115.83, 108.88 ppm. HPLC: 8.272 min.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[CH:16]=O.N1CCCCC1>C1C=CC=CC=1>[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[CH:16]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]1=[O:10]
Reactant: O=C1Cc2ccccc2N1
Reactant: O=Cc1cccs1
Solvent: c1ccccc1
Solvent: C1CCNCC1
Product: O=C1Nc2ccccc2C1=Cc1cccs1
Yield: 55 %

Procedure:
A mixture of oxindole (16.5 g, 0.12 mole), thiophene-2-carboxaldehyde (19.1 g, 0.17 mole) and piperidine (1 ml) in 200 ml of benzene is heated at reflux temperature for 4 hours, during which time water is separated by means of a Dean-Stark trap. Solvent is removed in vacuo and the residue is crystallized twice from ethanol to give 15 g of the product: m.p. 208.5°-210°.
Reaction SMILES: [N+:1]([O-])([OH:3])=[O:2].[CH2:5]([O:12][C:13]1[CH:18]=[C:17](/[CH:19]=[CH:20]/[N+:21]([O-:23])=[O:22])[CH:16]=[CH:15][C:14]=1[O:24][CH2:25][CH2:26][O:27][CH2:28][CH3:29])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(O)(=O)C>[CH2:5]([O:12][C:13]1[CH:18]=[C:17](/[CH:19]=[CH:20]/[N+:21]([O-:23])=[O:22])[C:16]([N+:1]([O-:3])=[O:2])=[CH:15][C:14]=1[O:24][CH2:25][CH2:26][O:27][CH2:28][CH3:29])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=[N+]([O-])O
Reactant: CCOCCOc1ccc(/C=C/[N+](=O)[O-])cc1OCc1ccccc1
Solvent: CC(=O)O
Product: CCOCCOc1cc([N+](=O)[O-])c(/C=C/[N+](=O)[O-])cc1OCc1ccccc1
Reaction time: 6 h

Procedure:
69% Nitric acid (11 mL, 171 mmol) was added to a solution of (E)-2-(benzyloxy)-1-(2-ethoxyethoxy)-4-(2-nitrovinyl)benzene described in Production Example 24-3 (15.4 g, 44.9 mmol) and acetic acid (100 mL) at 25° C., and the mixture was stirred for 6 hours. The reaction liquid was poured onto ice. The suspension was subjected to suction filtration and the product was washed with water to quantitatively obtain the title compound.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)=[C:2]=[S:3].[F:14][C:15]1[CH:21]=[C:20]([I:22])[CH:19]=[CH:18][C:16]=1[NH2:17]>>[F:14][C:15]1[CH:21]=[C:20]([I:22])[CH:19]=[CH:18][C:16]=1[NH:17][C:2](=[S:3])[NH:1][C:4]1[CH:5]=[C:6]([S:10]([NH2:13])(=[O:11])=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: Nc1ccc(I)cc1F
Reactant: NS(=O)(=O)c1cccc(N=C=S)c1
Product: NS(=O)(=O)c1cccc(NC(=S)Nc2ccc(I)cc2F)c1

Procedure:
The subject compound was prepared utilizing the procedure described above from 3-isothiocyanatobenzenesulfonamide and 2-fluoro-4-iodoaniline. 1H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 9.67 (s, 1H), 7.96 (m, 1H), 7.70 (m, 2H), 7.58-7.49 (m, 3H), 7.38 (bs, 3H); (M+H)+ (452).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH2:13][C@H:12]1[C:42](O)=[O:43])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:45]1([CH:51]2[CH2:55][CH2:54][NH:53][CH2:52]2)[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH2:13][C@H:12]1[C:42]([N:53]1[CH2:54][CH2:55][CH:51]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:52]1)=[O:43])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)[C@H](C(=O)O)C[C@@H]3c3ccc(OC)cc3)cc21
Reactant: c1ccc(C2CCNC2)cc1
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)[C@H](C(=O)N4CCC(c5ccccc5)C4)C[C@@H]3c3ccc(OC)cc3)cc21

Procedure:
According to general procedure D, 0.10 g of (2S,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1,2-dicarboxylic acid 1-benzyl ester (from example 3b) and 3-phenylpyrrolidine are reacted to afford the title compound as a colourless solid. Rf=0.15 (EtOAc-heptane 1:1); Rt=5.47.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CN1CCOCC1.[BH4-].[Na+].C([O-])(O)=O.[Na+]>C1COCC1>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:12]=[CH:11][C:7]([CH2:8][OH:9])=[CH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc(C(=O)O)cc1-c1ccccc1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COC(=O)c1ccc(CO)cc1-c1ccccc1
Temperature: 0 °C

Procedure:
The resultant acid from Example 16A (1.0 equivalent) is treated with a slight excess of N-methylmorpholine (1.1 equivalent) and isobutylchworoformate (1.0 equivalent) in THF at 0° C. The mixture is then treated with NaBH4 (1.0 equivalent) and aqueous NaHCO3 and stirred at 0° C. until the reaction is judged complete by TLC analysis. The mixture is poured into dilute aqueous acid and extracted into ethyl acetate which is dried and evaporated. The product is purified by chromatography on silica gel.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.Cl.[CH3:11][O:12][C:13]1[NH:17][N:16]=[C:15]([NH2:18])[CH:14]=1>C(O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:18][C:15]2[CH:14]=[C:13]([O:12][CH3:11])[NH:17][N:16]=2)[CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: COc1cc(N)n[nH]1
Reactant: Clc1cc(Cl)nc(Cl)n1
Agent: Cl
Solvent: CCO
Product: COc1cc(Nc2cc(Cl)nc(Cl)n2)n[nH]1
Temperature: 25 °C
Yield: 51 %

Procedure:
To a solution of 2,4,6-trichloro-pyrimidine (1.7 g) in absolute ethanol (100 mL) was added DIEPA (4.1 mL) and 5-methoxy-1H-pyrazol-3-amine hydrogen chloride salt (1.46 g). The resulting solution was stirred at room temperature for over night. The solvent was evaporated under reduced pressure. The crude compound was purified by Gilson (10-60% MeCN/H2O, 15 minutes) to give the titled compound as solid (1.23 g). 1H NMR δ 12.19 (s, 1H) 10.68 (s, 1H) 6.76 (s, 1H) 5.40 (s, 1H) 3.82 (s, 3H); m/z 260.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[N:12]=[C:11]([N:13]([CH2:15][CH:16]2[CH2:18][CH2:17]2)[CH3:14])[CH:10]=[N:9][CH:8]=1.O.CN([CH:23]=[O:24])C>>[Cl:6][C:7]1[C:8]([CH:23]=[O:24])=[N:9][CH:10]=[C:11]([N:13]([CH2:15][CH:16]2[CH2:18][CH2:17]2)[CH3:14])[N:12]=1
Reactant: CN(CC1CC1)c1cncc(Cl)n1
Reactant: CN(C)C=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CN(CC1CC1)c1cnc(C=O)c(Cl)n1
Reaction time: 0.25 h
Yield: 71 %

Procedure:
Phosphoryl chloride (0.43 mL) was added dropwise to DMF (1 mL) at 0° C. The mixture was stirred for 15 min, and a solution of 6-chloro-N-(cyclopropylmethyl)-N-methylpyrazin-2-amine (0.46 g) in DMF (1 mL) was added dropwise thereto. The mixture was stirred at 50° C. for 16 hr, water (5 mL) was added at 0° C., and the mixture was stirred at room temperature for 1.5 hr. The mixture was extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient: 5→20% ethyl acetate/hexane) to give the title compound (0.37 g, 71%) as a pale-yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([NH2:14])=[N:12][CH:13]=2)=[CH:4][CH:3]=1.Cl[CH:16]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[CH:17]=O.C(O)CCCC>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[N:12][C:11]3[N:10]([C:16]([CH2:19][C:20]4[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=4)=[CH:17][N:14]=3)[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Nc1ncc(-c2ccc(F)cc2)cn1
Reactant: COc1ccc(CC(Cl)C=O)cc1
Solvent: CCCCCO
Product: COc1ccc(Cc2cnc3ncc(-c4ccc(F)cc4)cn23)cc1
Temperature: 130 °C

Procedure:
A mixture of 5-(4-fluorophenyl)pyrimidin-2-amine (50 mg, 0.3 mmol), 2-chloro-3-(4-methoxyphenyl)propanal (52 mg, 0.26 mmol) in tent-amyl alcohol (1.0 mL) in a sealed reaction vial was heated at 130° C. for 3 hours. After cooling, the mixture was purified by preparative HPLC to afford the desired product. LCMS: (M+H)=334.0.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]([CH2:23][OH:24])[C:19](=[O:22])[O:20][CH3:21])=[C:14]([CH3:25])[CH:13]=1.S(=O)(=O)(O)O.[C:31]1([CH:38]=CC(O)=[CH:34][CH:33]=1)O>C(O)CCC.S([O-])(O)(=O)=O.[Na+]>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]([CH2:23][O:24][CH2:38][CH2:31][CH2:33][CH3:34])[C:19](=[O:22])[O:20][CH3:21])=[C:14]([CH3:25])[CH:13]=1
Reactant: Oc1ccc(O)cc1
Reactant: COC(=O)N(CO)c1ccc(OCc2nc3ccccc3s2)cc1C
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CCCCO
Product: CCCCOCN(C(=O)OC)c1ccc(OCc2nc3ccccc3s2)cc1C
Temperature: 85 °C
Reaction time: 1 h
Yield: 9330.4 %

Procedure:
49.8 mg of methyl N-hydroxymethyl-N-[4-(benzothiazol-2-ylmethoxy)-2-methylphenyl]carbamate [prepared as described in Example 19] were dissolved in 2 ml of butanol at room temperature, and the pH of the resulting solution was adjusted with concentrated sulfuric acid to pH 3. A catalytic amount of hydroquinone (2 mg) was added to the resulting mixture at room temperature and the mixture was then stirred for 1 hour at 85° C. The reaction mixture was then cooled to room temperature, diluted with aqueous sodium hydrogen sulfate and then extracted with ethyl acetate. The resulting extract was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure to give a residue which was purified by column chromatography through silica gel using a 2:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 702.5 mg (yield 94.1%) of the title compound as an oil.
Reaction SMILES: Br[C:2]1[N:6]=[C:5]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[S:4][N:3]=1.[NH:15]1[C:23]2[C:18](=[CH:19][C:20](B(O)O)=[CH:21][CH:22]=2)[CH:17]=[CH:16]1.C([O-])([O-])=O.[K+].[K+]>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>[NH:15]1[C:23]2[C:18](=[CH:19][C:20]([C:2]3[N:6]=[C:5]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[S:4][N:3]=3)=[CH:21][CH:22]=2)[CH:17]=[CH:16]1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)Nc1nc(Br)ns1
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: [K+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1nc(-c2ccc3[nH]ccc3c2)ns1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 44 %

Procedure:
To a mixture of tert-butyl (3-bromo-1,2,4-thiadiazol-5-yl)carbamate (100 mg, 0.359 mmol) and indole-5-boronic acid (57.9 mg, 0.359 mmol) in 1,4-dioxane (5 mL) was added Pd(PPh3)4 (20.77 mg, 0.017 mmol) and 1M aq K2CO3 solution (0.539 mL, 0.539 mmol). N2 gas was purged for 15 min. After 15 min, the reaction was heated at reflux for 4 h. The reaction mixture was cooled to RT and treated with H2O (5 mL), extracted with EtOAc (25 mL). The aqueous layer was back extracted with EtOAc (25 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated. The crude was further purified by silica gel column chromatography (eluent: 10% EtOAc in petroleum ether) to afford tert-butyl (3-(1H-indol-5-yl)-1,2,4-thiadiazol-5-yl)carbamate (50 mg, 44.2%) as an off white solid. MS (ESI, pos. ion) m/z: 261 (M+1); 1H NMR (400 MHz, DMSO-d6): δ 12.40 (s, 1H), 11.31 (s, 1H), 8.35 (s, 1H), 7.91 (dd, J=1.2 Hz & 8.4 Hz, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.41-7.40 (m, 1H), 6.35 (s, 1H), 1.52 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[S:22][CH:23]=[CH:24][N:25]=2)[O:9][CH:10]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:11]([NH:13][CH2:14][C:15]#[N:16])=[O:12])=[CH:4][CH:3]=1.[N:26]1([C:32]2[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=2)[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[C:15]([CH2:14][NH:13][C:11](=[O:12])[CH:10]([O:9][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([C:35]2[CH:34]=[CH:33][C:32]([N:26]3[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]3)=[CH:37][CH:36]=2)=[CH:3][CH:4]=1)[C:21]1[S:22][CH:23]=[CH:24][N:25]=1)[CH2:17][CH:18]([CH3:20])[CH3:19])#[N:16]
Reactant: CC(C)CC(OC(c1ccc(Br)cc1)c1nccs1)C(=O)NCC#N
Reactant: OB(O)c1ccc(N2CCNCC2)cc1
Product: CC(C)CC(OC(c1ccc(-c2ccc(N3CCNCC3)cc2)cc1)c1nccs1)C(=O)NCC#N

Procedure:
Using the same protocol as described in example 21, 2-[(4-bromophenyl)(1,3-thiazol-2-yl)methoxy]-N-(cyanomethyl)-4-methylpentanamide from example 27, step 4 (225 mg, 0.53 mmol) was coupled with 4-piperazin-1-ylphenylboronic acid (141 mg, 0.58 mmol). The crude residue obtained was chromatographed on silica gel using 1% NH4OH and 9% MeOH in dichloromethane to afford the title compound.
Reaction SMILES: [H][H].[N+:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[O:16][C:15]([NH2:17])=[N:14][N:13]=1)([O-])=O>>[NH2:3][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[O:16][C:15]([NH2:17])=[N:14][N:13]=1
Reactant: [H][H]
Reactant: Nc1nnc(-c2ccccc2[N+](=O)[O-])o1
Product: Nc1nnc(-c2ccccc2N)o1

Procedure:
Hydrogen was introduced at atmospheric pressure into the solution of 350 mg of 5-(2-nitrophenyl)-[1,3,4]oxadiazol-2-ylamine until the theoretical amount had been taken up. After filtering off the catalyst with suction and concentrating the mixture under reduced pressure, the remaining oily residue was purified by column chromatography (solvent: 95:5 dichloromethane/methanol; silica gel).
Reaction SMILES: [C:1]1([S:7]([CH2:10][C@@H:11]2[CH2:16][C@H:15]([NH:17][CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13][C@@H:12]2[N:21]2[CH2:26][CH2:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=3)=[CH:23][C:22]2=[O:37])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.[C:40]([BH3-])#N.[Na+].O>CO>[C:1]1([S:7]([CH2:10][C@@H:11]2[CH2:16][C@H:15]([N:17]([CH:18]([CH3:20])[CH3:19])[CH3:40])[CH2:14][CH2:13][C@@H:12]2[N:21]2[CH2:26][CH2:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=3)=[CH:23][C:22]2=[O:37])(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)N[C@@H]1CC[C@H](N2CCC(c3cccc(C(F)(F)F)c3)=CC2=O)[C@H](CS(=O)(=O)c2ccccc2)C1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)N(C)[C@@H]1CC[C@H](N2CCC(c3cccc(C(F)(F)F)c3)=CC2=O)[C@H](CS(=O)(=O)c2ccccc2)C1
Reaction time: 0.75 h
Yield: 99.4 %

Procedure:
A solution of 1-([(1S,2R,4R)-2-benzenesulfonylmethyl-4-isopropylamino-cyclohexyl)-4-(3-trifluoromethylphenyl)-5,6-dihydro-1H-pyridin-2-one (41 mg, 0.077 mmol) in methanol (1 mL) was treated with aqueous formaldehyde (37%, 0.029 mL, 0.383 mmol) and the mixture was stirred for 45 min. Sodium cyanoborohydride (7 mg, 0.115 mmol) was added, and the mixture stirred at room temperature for 2 h. Water was added and the mixture was extracted with ethyl acetate. The extracts were washed with brine, dried over sodium sulfate and concentrated under vacuum to provide the title product (42 mg) as a white glassy solid. MS found: (M+H)+=548.67.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.F[C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[N:1]1([C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(-n2ccnc2)cc1
Temperature: 90 °C
Yield: 56.4 %

Procedure:
Imidazole (0.816 g, 0.01 mol), ethyl 4-fluorobenzoate (2 g, 0.01 mol) and anhydrous potassium carbonate (1.43 g, 0.011 mol) was dissolved in DMSO (30 ml) and heated to 90° C. for 18 h. The solution was poured into water (50 ml), extracted with ethyl acetate (50 ml), dried (sodium sulphate), filtered and evaporated to dryness under reduced pressure. The white solid was purified by flash column chromatography (silica, diethyl ether) to afford a white solid (1.22 g, 56%).
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=2)[CH2:5][CH2:4]1.[NH2:19][C:20]1[C:21]2[CH:34]=[C:33]([C:35]([NH:37][N:38]([CH3:45])[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:36])[S:32][C:22]=2[N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[N:24]=1.CN1CCN(CC2C=CC(C(Cl)=O)=CC=2)CC1.O>N1C=CC=CC=1>[CH3:45][N:38]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[NH:37][C:35]([C:33]1[S:32][C:22]2[N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:29])[CH3:30])=[O:26])[N:24]=[C:20]([NH:19][C:14](=[O:15])[C:13]3[CH:17]=[CH:18][C:10]([CH2:9][N:6]4[CH2:7][CH2:8][N:3]([CH3:2])[CH2:4][CH2:5]4)=[CH:11][CH:12]=3)[C:21]=2[CH:34]=1)=[O:36]
Reactant: CN1CCN(Cc2ccc(C(=O)Cl)cc2)CC1
Reactant: CN(NC(=O)c1cc2c(N)nn(C(=O)OC(C)(C)C)c2s1)c1ccccc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CN1CCN(Cc2ccc(C(=O)Nc3nn(C(=O)OC(C)(C)C)c4sc(C(=O)NN(C)c5ccccc5)cc34)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.1 %

Procedure:
391 mg (1.55 mmol) of 4-(4-methylpiperazin-1-ylmethyl)benzoyl chloride hydrochloride are added to a solution of 0.30 g (0.77 mmol) of tert-butyl 3-amino-5-(N′-methyl-N′-phenylhydrazinocarbonyl)thieno[2,3-c]pyrazole-1-carboxylate in 16 mL of pyridine under argon. The reaction mixture is stirred at a temperature in the region of 25° C. for 16 hours, a further 294 mg (1.16 mmol) of 4-(4-methylpiperazin-1-ylmethyl)benzoyl chloride are then added and stirring is continued for 5 hours. The reaction mixture is then cooled to a temperature in the region of 10° C. and then treated with 50 mL of water. The mixture is extracted twice with 100 mL of ethyl acetate. The organic phases are combined, washed with water to neutral pH, dried over magnesium sulfate, filtered and then concentrated to dryness under vacuum (3 kPa) at a temperature in the region of 30° C. The residue is purified by chromatography on a cartridge of 25 g of silica gel (0.015-0.040 mm), eluting successively with dichloromethane/methanol mixtures (98/2 by volume, and then 97/3, then 96/4 and finally 95/5) at a flow rate of 15 mL/min. The fractions containing the expected product are combined and then concentrated to dryness under reduced pressure (3 kPa) at a temperature in the region of 30° C. 0.14 g of tert-butyl 5-(N′-methyl-N′-phenylhydrazinocarbonyl)-3-[4-(4-methylpiperazin-1-ylmethyl)benzoylamino]thieno[2,3-c]pyrazole-1-carboxylate is thus obtained in the form of an off-white solid melting at 218° C. tert-Butyl 3-amino-5-(N′-methyl-N′-phenylhydrazinocarbonyl)thieno[2,3-c]pyrazole-1-carboxylate is described in example 8. 4-(4-Methylpiperazin-1-ylmethyl)benzoyl chloride may be prepared according to patent WO 03/066 613 A1.
Reaction SMILES: [NH2:1][N:2]1[CH2:6][C:5](=[O:7])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)[C:3]1=[S:17].[CH3:18][C:19]1[CH:20]=[C:21]([N:26]2[C:30]([OH:31])=[C:29]([CH:32]=O)[C:28]([CH3:34])=[N:27]2)[CH:22]=[CH:23][C:24]=1[CH3:25].C(O)C>CO>[C:14]([C:11]1[CH:10]=[CH:9][C:8]([N:4]2[C:5](=[O:7])[CH2:6][N:2]([N:1]=[CH:32][C:29]3[C:28]([CH3:34])=[N:27][N:26]([C:21]4[CH:22]=[CH:23][C:24]([CH3:25])=[C:19]([CH3:18])[CH:20]=4)[C:30]=3[OH:31])[C:3]2=[S:17])=[CH:13][CH:12]=1)([OH:16])=[O:15]
Reactant: Cc1ccc(-n2nc(C)c(C=O)c2O)cc1C
Reactant: NN1CC(=O)N(c2ccc(C(=O)O)cc2)C1=S
Solvent: CCO
Solvent: CO
Product: Cc1ccc(-n2nc(C)c(C=NN3CC(=O)N(c4ccc(C(=O)O)cc4)C3=S)c2O)cc1C
Yield: 93.8 %

Procedure:
50 mg (0.2 mmol) of the 1-amino-3-(4-carboxyphenyl)-2-thioxoimidazolidin-4-one synthesized above in 1) and 55 mg (0.22 mmol) of the 1-(3,4-dimethylphenyl)-5-hydroxy-3-methyl-1H-pyrazole-4-carbaldehyde synthesized in 1) of Reference Synthetic Example 1 were stirred in a liquid mixture of 10 ml of ethanol and 5 ml of methanol at room temperature for 96 hours. The resulting insoluble was collected by filtration to obtain 87 mg of the desired product as a yellow solid (yield 85%).