Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([N:11]([CH2:40][CH2:41][CH2:42][CH3:43])[CH2:12][CH2:13][S:14]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([C:26]2[N:34]3[C:29]([CH:30]=[CH:31][CH:32]=[CH:33]3)=[C:28]([O:35][CH3:36])[C:27]=2[CH3:37])=[O:25])=[CH:20][C:19]=1[O:38][CH3:39])(=[O:16])=[O:15])[CH2:8][CH2:9][CH3:10].Br[CH2:45][C:46]([O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:47].O>CN(C)C=O.C(OCC)(=O)C>[CH2:7]([N:11]([CH2:40][CH2:41][CH2:42][CH3:43])[CH2:12][CH2:13][S:14]([N:17]([CH2:45][C:46]([O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:47])[C:18]1[CH:23]=[CH:22][C:21]([C:24]([C:26]2[N:34]3[C:29]([CH:30]=[CH:31][CH:32]=[CH:33]3)=[C:28]([O:35][CH3:36])[C:27]=2[CH3:37])=[O:25])=[CH:20][C:19]=1[O:38][CH3:39])(=[O:16])=[O:15])[CH2:8][CH2:9][CH3:10]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CCCCN(CCCC)CCS(=O)(=O)Nc1ccc(C(=O)c2c(C)c(OC)c3ccccn23)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCN(CCCC)CCS(=O)(=O)N(CC(=O)OCc1ccccc1)c1ccc(C(=O)c2c(C)c(OC)c3ccccn23)cc1OC
Temperature: 60 °C

Procedure:
125 mg (0.906 mmol) of potassium carbonate are added to 400 mg (0.755 mmol) of 2-(dibutylamino)-N-{2-methoxy-4-[(1-methoxy-2-methylindolizin-3-yl)carbonyl]phenyl}-1-ethanesulphonamide, a compound of Example 207, in solution in 10 ml of dimethylformamide, followed by 142 μl (0.906 mmol) of benzyl bromoacetate, and the medium is heated at 60° C. for 1 hour. The reaction medium is poured over water and ethyl acetate.
Reaction SMILES: S(Cl)([Cl:3])=O.[N:5]([C:16]([CH3:24])([CH3:23])[C:17]([NH:19][CH2:20]CO)=[O:18])=[N:6][C:7]([CH3:15])([CH3:14])[C:8]([NH:10][CH2:11][CH2:12]O)=[O:9].C1CCCCC1.Cl[CH2:32][Cl:33]>>[N:5]([C:16]([CH3:24])([CH3:23])[C:17]([NH:19][CH2:20][CH2:32][Cl:33])=[O:18])=[N:6][C:7]([CH3:15])([CH3:14])[C:8]([NH:10][CH2:11][CH2:12][Cl:3])=[O:9]
Reactant: O=S(Cl)Cl
Reactant: ClCCl
Reactant: CC(C)(N=NC(C)(C)C(=O)NCCO)C(=O)NCCO
Solvent: C1CCCCC1
Product: CC(C)(N=NC(C)(C)C(=O)NCCCl)C(=O)NCCCl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Thionyl chloride (50 ml) was added at 0° C. under an atmosphere of inert gas (argon) to a suspension of 2,2′-azobis[2-methyl-N-(2-hydroxyethyl)propionamide] (38.3 g) in dichloromethane (180 ml) over a period of 30 minutes. The mixture was stirred at room temperature for 18 h, and the precipitate which formed was filtered off, suspended in 100 ml of water and stirred for 5 min. The solid was separated off and dried under reduced pressure at room temperature for 24 h (8.9 g). Further product was isolated from the organic phase of the reaction mixture by adding cyclohexane (250 ml) and cooling to 0° C. The precipitate which formed was filtered off, and worked up and isolated as described above (10.8 g). Finally, the remaining organic filtrate was concentrated to low volume. The precipitate which formed was subjected to the procedure described above (7.6 g).
Reaction SMILES: [CH2:1]([C:3]1[C:8]([CH2:9][CH:10]=O)=[CH:7][CH:6]=[CH:5][C:4]=1[C:12]1[S:16][C:15]([C:17]2[CH:18]=[CH:19][C:20]([O:25][CH:26]([CH3:28])[CH3:27])=[C:21]([CH:24]=2)[C:22]#[N:23])=[N:14][CH:13]=1)[CH3:2].C(O)(=O)C.C([O-])(=O)C.[Na+].[NH:38]1[CH2:43][CH2:42][CH:41]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH2:40][CH2:39]1>C(O)C>[C:22]([C:21]1[CH:24]=[C:17]([C:15]2[S:16][C:12]([C:4]3[C:3]([CH2:1][CH3:2])=[C:8]([CH2:9][CH2:10][N:38]4[CH2:43][CH2:42][CH:41]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH2:40][CH2:39]4)[CH:7]=[CH:6][CH:5]=3)=[CH:13][N:14]=2)[CH:18]=[CH:19][C:20]=1[O:25][CH:26]([CH3:28])[CH3:27])#[N:23]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CCc1c(CC=O)cccc1-c1cnc(-c2ccc(OC(C)C)c(C#N)c2)s1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C1CCN(CCc2cccc(-c3cnc(-c4ccc(OC(C)C)c(C#N)c4)s3)c2CC)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
To a solution of 5-{5-[2-ethyl-3-(2-oxoethyl)phenyl]-1,3-thiazol-2-yl}-2-[(1-methylethyl)oxy]benzonitrile (D76) (150 mg), acetic acid (0.044 mL) and sodium acetate (63.0 mg) in ethanol (20.00 mL) stirred under nitrogen at room temperature was added ethyl 4-piperidinecarboxylate (181 mg) in one charge. The reaction mixture was stirred at room temperature for 30 min, then the solvent was evaporated in vacuo. The residue was dissolved in dichloromethane (DCM) (20 mL), sodium triacetoxyborohydride (204 mg) was added to the mixture. The reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate (100 mL) and saturated brine (30 mL). The organic phase was dried over sodium sulphate and evaporated in vacuo to give the crude product ethyl 1-{2-[3-(2-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-2-ethylphenyl]ethyl}-4-piperidinecarboxylate (D86) (204 mg) as a brown oil. The crude product was used for next step without further purification. MS (ES): C31H37N3O3S requires 531. found 532.3 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].Cl.[CH3:12][NH:13][O:14][CH3:15].C(NC(C)C)(C)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([N:13]([O:14][CH3:15])[CH3:12])=[O:6]
Reactant: CNOC
Reactant: O=C(Cl)c1cccc(Br)c1
Agent: Cl
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: CON(C)C(=O)c1cccc(Br)c1
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
A solution of 3-bromobenzoyl chloride (20 g, 91.1 mmol) in CH2Cl2 was added dropwise to a cold (0° C.) solution of N,O-dimethylhydroxylamine hydrochloride (33.6 g, 319 mmol), diisopropylamine (98 mL, 551 mmol) in CH2Cl2 over 1 hour. The stirring continued at room temperature for 30 minutes then concentrated under vacuo. The resultant residue was dispersed in water and extracted with ethyl ether. The organic extracts were combined, dried over MgSO4 and concentrated in vacuo. This residue was purified on silica gel (ISCO) using hexanes/EtOAc (4/1) as the eluting solvent to give 3-bromo-N-methoxy-N-methylbenzamide as light yellow solid (20 g, 89% yield). m/e (M+H)+ 244. 1H NMR (400 MHz, DMSO-d6) δ ppm, 3.21 (s, 3H), 3.50 (s, 3H), 7.37-7.39, (m, 1H), 7.53-7.55 (m, 1H), 7.64-7.66 (m, 1H), 7.67-7.69 (m, 1H).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:34](=[O:35])[N:6]2[C:7]([C:28]([O:30][CH2:31][CH:32]=[CH2:33])=[O:29])=[C:8](OP(OC3C=CC=CC=3)(OC3C=CC=CC=3)=O)[C@H:9]([CH3:10])[C@@H:5]12)[CH3:3].[CH2:36]([O:39][C:40]([N:42]1[CH2:46][C@@H:45]([SH:47])[CH2:44][C@H:43]1[CH2:48][CH:49]1[CH2:53][N:52]([C:54]([O:56][CH2:57][CH:58]=[CH2:59])=[O:55])[C@H:51]([C:60](=[O:63])[NH:61][CH3:62])[CH2:50]1)=[O:41])[CH:37]=[CH2:38].C(N(CC)C(C)C)(C)C>>[CH2:36]([O:39][C:40]([N:42]1[CH2:46][C@@H:45]([S:47][C:8]2[C@H:9]([CH3:10])[C@@H:5]3[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:34](=[O:35])[N:6]3[C:7]=2[C:28]([O:30][CH2:31][CH:32]=[CH2:33])=[O:29])[CH2:44][C@H:43]1[CH2:48][CH:49]1[CH2:53][N:52]([C:54]([O:56][CH2:57][CH:58]=[CH2:59])=[O:55])[C@H:51]([C:60](=[O:63])[NH:61][CH3:62])[CH2:50]1)=[O:41])[CH:37]=[CH2:38]
Reactant: C=CCOC(=O)C1=C(OP(=O)(Oc2ccccc2)Oc2ccccc2)[C@H](C)[C@H]2[C@@H]([C@@H](C)O)C(=O)N12
Reactant: C=CCOC(=O)N1C[C@@H](S)C[C@H]1CC1C[C@@H](C(=O)NC)N(C(=O)OCC=C)C1
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](CC3C[C@@H](C(=O)NC)N(C(=O)OCC=C)C3)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 66.4 %

Procedure:
The same procedure as in Example 8-1 was carried out by using allyl (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-diphenoxyphosphoryloxy-1-carbapen-2-em-3-carboxylate (204 mg, 0.41 mmol), (2R,4S)-N-allyloxycarbonyl-2-[(2S)-N-allyloxycarbonyl-2-(methylcarbamoyl)pyrrolidin-4-ylmethyl]-4-mercaptopyrrolidine (168 mg, 0.41 mmol) and N,N-diisopropylethylamine (71 μl, 0.41 mmol) to obtain allyl (1R,5S,6S)-2-[(2R,4S)-N-allyloxycarbonyl-2-[(2S)-N-allyloxycarbonyl-2-(methylcarbamoyl)pyrrolidin-4-ylmethyl]pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (180 mg, yield: 67%).
Reaction SMILES: CS([C@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=O)=O.[C-:30]#[N:31].[K+].C(OCC)(=O)C>CN(C=O)C.O>[C:30]([CH:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)#[N:31]
Reactant: [C-]#N
Reactant: CS(=O)(=O)[C@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: N#CC1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.2 %

Procedure:
To a solution of 12.3 g of (3R, 4R)-4-methylsulfonyl-3-tritylamino-2-azetidinone in 150 ml of DMF is added a solution of 1.6 g of potassium cyanide in 24 ml of water under ice-cooling and the mixture is stirred at room temperature (approx. 25° C.) for 30 minutes. To the reaction mixture are added ice water and ethyl acetate, and the ethyl acetate layer is taken, washed with water and dried over anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure and the residue is chromatographed on a silica gel column [eluant: ethyl acetate-n-hexane (1:1)] to give 6.7 g of (3S, 4RS)-4-cyano-3-tritylamino-2-azetidinone (4R:4S=1:1).
Reaction SMILES: [CH3:1][CH:2]1[C:7](=O)[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.Cl.C[NH:18][OH:19].[C:20](=O)([O-])O.[Na+]>C1COCC1.O>[CH3:1][CH:2]1[CH2:3][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:6]/[C:7]/1=[N:18]\[O:19][CH3:20]
Reactant: CC1CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: O=C([O-])O
Reactant: CNO
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CO/N=C1\CCN(C(=O)OC(C)(C)C)CC1C
Reaction time: 8 h
Yield: 47.3 %

Procedure:
A solution of 1,1-dimethylethyl 3-methyl-4-oxo-1-piperidinecarboxylate (367 mg, 1.72 mmol) in THF (10 mL) was treated with methylhydroxylamine hydrochloride (503 mg, 6.02 mmol) followed by a solution of sodium hydrogencarbonate (506 mg, 6.02 mmol) in water (3 mL). The reaction was stirred vigorously overnight. The reaction was then filtered, diluted with water, and extracted with dichloromethane. The crude material was purified by column chromatography (0-10% ethyl acetate/hexanes) to provide 197 mg of the desired product as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.1 (d, J=6.8 Hz, 3 H) 1.5 (s, 9 H) 2.5 (m, 1 H) 2.6 (m, 2 H) 3.5 (m, 4 H) 3.8 (s, 3 H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([CH:9]2[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:11][CH2:10]2)[CH:5]=[CH:4][C:3]=1[CH:20]1[CH2:25][CH2:24][CH:23]([CH:26]2[CH2:35][CH2:34][C:29]3(OCC[O:30]3)[CH2:28][CH2:27]2)[CH2:22][CH2:21]1.C(O)=O.O>C1(C)C=CC=CC=1>[F:1][C:2]1[C:7]([F:8])=[C:6]([CH:9]2[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:11][CH2:10]2)[CH:5]=[CH:4][C:3]=1[CH:20]1[CH2:25][CH2:24][CH:23]([CH:26]2[CH2:27][CH2:28][C:29](=[O:30])[CH2:34][CH2:35]2)[CH2:22][CH2:21]1
Reactant: CCCCCC1CCC(c2ccc(C3CCC(C4CCC5(CC4)OCCO5)CC3)c(F)c2F)CC1
Solvent: Cc1ccccc1
Solvent: O=CO
Solvent: O
Product: CCCCCC1CCC(c2ccc(C3CCC(C4CCC(=O)CC4)CC3)c(F)c2F)CC1
Temperature: 25 °C
Yield: 45.8 %

Procedure:
The compound (46) (36.7 g), formic acid (120 g) and toluene (120 ml) were put in a reaction vessel under a nitrogen atmosphere, heated under reflux for 3 hours, and cooled slowly to room temperature. Water (300 ml) and toluene (300 ml) were added and mixed thereto. The mixture was allowed to stand until it had separated into two phases, the organic and aqueous phases, and an extractive operation to an organic phase was carried out. The organic phase was fractionated, and washed sequentially with a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the residue was purified with a fractional operation by means of column chromatography using a mixed solvent of toluene and ethyl acetate (toluene:ethyl acetate=9:1 by volume) as an eluent and silica gel as a stationary phase powder. The residue was further purified by means of recrystallization from a mixed solvent of toluene and heptane (toluene: heptane=1:1 by volume), and dried, giving 15.3 g of 4′-(2,3-difluoro-4-(4-pentylcyclohexyl)phenyl)bi(cyclohexane)-4-one (47). The yield based on the compound (46) was 45.9%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[C:11]1(=[O:16])[CH2:15][CH2:14][CH2:13][CH2:12]1>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1/[CH:5]=[C:12]1/[C:11](=[O:16])[CH2:15][CH2:14][CH2:13]/1
Reactant: COc1ccccc1C=O
Reactant: O=C1CCCC1
Product: COc1ccccc1/C=C1\CCCC1=O

Procedure:
The procedure was similar to that in Example 4 by reacting 2-methoxybenzaldehyde with the morpholine enamine of cyclopentanone to give 2-(E)-[(2-methoxy) benzylidene]cyclopentanone. The melting popint of this intermediate compound was determined to be 80°-82° C. A subsequent Mannich reaction yielded the 2-Dimethylaminomethyl-5-(E)-[(2-methoxy) benzylidene] cyclopentanone hydrochloride. The melting point of the product was determined to be 167°-169° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[Br:16][CH2:17][CH2:18][C:19](Cl)=[O:20]>C1(C)C=CC=CC=1>[Br:16][CH2:17][CH2:18][C:19]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)=[O:20]
Reactant: O=C(Cl)CCBr
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Solvent: Cc1ccccc1
Product: CC1CC(=O)NN=C1c1ccc(NC(=O)CCBr)cc1
Yield: 96.2 %

Procedure:
A suspension of 6-(4-aminophenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone (Curran et al., J. Med. Chem. 17, 273 (1974)) (75.0 g, 0.369 mol) and 3-bromoproionylchloride (100 g, 0.583 mol) in toluene (800 ml) was stirred under reflux for 16 hours. The reaction mixture was allowed to cool and the solid product collected, dried and stirred with water (500 ml) for 30 minutes. The crude product was collected, washed with water (500 ml) and dried to give 6-[4-(3-bromopropionamido)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone (120 g, 97%), m.p. 215°-217° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].C(N(C(C)C)CC)(C)C.[C:32](Cl)(=[O:42])[C:33]1[CH:41]=[CH:40][C:39]2[O:38][CH2:37][O:36][C:35]=2[CH:34]=1>C(Cl)Cl>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:32]([C:33]3[CH:41]=[CH:40][C:39]4[O:38][CH2:37][O:36][C:35]=4[CH:34]=3)=[O:42])[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4ccc5c(c4)OCO5)c3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.1 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.16 mmol) in CH2Cl2 (60 ml), was added diisopropylethylamine (0.94 mL, 5.4 mmol) and piperonyloyl chloride (0.5 g, 2.8 mmol). The mixture was stirred at room temperature overnight and a suspension was obtained. The reaction mixture was quenched by the addition of MeOH (1 mL). The suspension was filtered, and the solid was rinsed with CH2Cl2 (10 mL) to afford benzo[1,3]dioxole-5-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-amide as a white solid (0.8 g, 85%): mp, 231-233° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=2.7 (99%); 1H NMR (DMSO-d6): δ 2.06-2.10 (m, 1H), 2.53-2.64 (m, 2H), 2.86-2.97 (m, 1H), 4.92 (d, J=5.6 Hz, 2H), 5.14-5.20 (dd, J=5, 12 Hz, 1H), 6.11 (s, 2H), 7.03 (d, J=8.1 Hz, 1H), 7.45-7.85 (m, 5H), 9.00 (t, J=6 Hz, 1H), 11.15 (s, 1H). 13C NMR (DMSO-d6) δ: 21.97, 30.92, 38.33, 48.85, 101.68, 107.34, 107.90, 121.81, 122.35, 127.08, 127.88, 131.50, 133.01, 134.77, 139.44, 147.36, 149.87, 165.70, 166.96, 167.52, 169.82, 172.74. Anal Calcd for C22H17N3O7+0.2H2O: C, 60.19; H, 4.00; N, 9.57. Found: C, 60.15; H, 3.71; N, 9.46.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH:12]1([CH2:15][N:16]([CH2:38][CH:39]2[CH2:41][CH2:40]2)[C:17]2[C:18]([S:36][CH3:37])=[N:19][N:20]3[C:25]([C:26]4[C:31]([CH3:32])=[CH:30][C:29]([CH3:33])=[CH:28][C:27]=4[O:34][CH3:35])=[CH:24][CH:23]=[CH:22][C:21]=23)[CH2:14][CH2:13]1.O.C(OCC)(=O)C>ClCCl>[CH:12]1([CH2:15][N:16]([CH2:38][CH:39]2[CH2:41][CH2:40]2)[C:17]2[C:18]([S:36]([CH3:37])=[O:9])=[N:19][N:20]3[C:25]([C:26]4[C:31]([CH3:32])=[CH:30][C:29]([CH3:33])=[CH:28][C:27]=4[O:34][CH3:35])=[CH:24][CH:23]=[CH:22][C:21]=23)[CH2:13][CH2:14]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cc(C)cc(C)c1-c1cccc2c(N(CC3CC3)CC3CC3)c(SC)nn12
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: COc1cc(C)cc(C)c1-c1cccc2c(N(CC3CC3)CC3CC3)c(S(C)=O)nn12
Reaction time: 2 h
Yield: 78 %

Procedure:
m-Chloroperbenzoic acid (234 mg) was added to a solution of N,N-dicyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine (200 mg) in dichloromethane (10 mL) at 0° C., and the mixture was stirred for 2 hours. Water was added to the reaction mixture, extraction was performed with ethyl acetate, the extract washed with saturated aqueous sodium hydrogencarbonate and brine and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (20 g), and the title compound (162 mg) was obtained from the n-hexane:ethyl acetate (1:1) fraction as a light yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13](CO)=[C:14]([CH:17]([CH3:19])[CH3:18])[CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]([O:28][Si](C)(C)C)=[C:25]([CH3:27])[CH3:26].[CH2:33](Cl)Cl>Cl[Ti](Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH2:26][C:25]([CH3:33])([CH3:27])[C:24]([O:23][CH3:22])=[O:28])=[C:14]([CH:17]([CH3:19])[CH3:18])[CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COC(O[Si](C)(C)C)=C(C)C
Reactant: CC(C)c1cc2c(cnn2-c2ccc(F)cc2)cc1CO
Reactant: ClCCl
Agent: Cl[Ti](Cl)(Cl)Cl
Product: COC(=O)C(C)(C)Cc1cc2cnn(-c3ccc(F)cc3)c2cc1C(C)C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
(1-(4-Fluorophenyl)-6-isopropyl-1H-indazol-5-yl)methanol (145 mg, 0.51 mmol) was dissolved in 5 mL of dry DCM and TiCl4 (60 mL of 1.0 M DCM solution, 60 mmol) was added portionwise and then stirred 30 min. Then the reaction was treated with 1-methoxy-2-methyl-1-(trimethylsiloxy)propene (0.2 mL, 1.0 mmol). The reaction was quenched with aqueous sodium bicarbonate and extracted 2×EtOAc, the organic layers dried over MgSO4, filtered, and concentrate. The residue was purified on SiO2 by MPLC using a 5:95 to 10:90 EtOAc/hexane gradient to give 87 mg (47% yield) of methyl 3-(1-(4-fluorophenyl)-6-isopropyl-1H-indazol-5-yl)-2,2-dimethylpropanoate. MS found: (M+H)+=369.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20]([CH3:21])=[N:19][N:18]=[C:17]2[CH2:22][NH:23][C:24](=[O:27])[CH2:25]Cl)=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].[CH3:28][NH:29][CH3:30]>CO.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20]([CH3:21])=[N:19][N:18]=[C:17]2[CH2:22][NH:23][C:24](=[O:27])[CH2:25][N:29]([CH3:30])[CH3:28])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: CNC
Reactant: Cc1nnc(CNC(=O)CCl)n1-c1ccc(Cl)cc1C(=O)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1nnc(CNC(=O)CN(C)C)n1-c1ccc(Cl)cc1C(=O)c1ccccc1

Procedure:
To a solution of 5-chloro-2-[3-(2-chloroacetamidomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]-benzophenone (0.4 g) in methanol (4 ml) and chloroform (8 ml), 40% aqueous dimethylamine (0.5 g) is added, and the resultant mixture is stirred at room temperature for 24 hours. The reaction mixture is evaporated under reduced pressure, and the residue is shaken with methylene chloride (20 ml). The methylene chloride layer is washed with aqueous sodium bicarbonate and water in order, dried over sodium sulfate and evaporated under reduced pressure to remove the solvent. The residue is chromatographed on a column of silica gel, whereby 5-chloro-2-[3-(2-dimethylaminoacetamidomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]-benzophenone is obtained as a colorless oil.
Reaction SMILES: [I:1]I.[I-].[K+].[CH3:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1[CH3:15].[CH3:16][N:17]1[CH2:22][CH2:21][CH2:20][N:19]=[C:18]1[SH:23]>O.CO>[IH:1].[CH3:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([S:23][C:18]2[N:17]([CH3:16])[CH2:22][CH2:21][CH2:20][N:19]=2)=[C:7]1[CH3:15]
Reactant: CN1CCCN=C1S
Reactant: Cc1cc2ccccc2n1C
Reactant: II
Agent: [I-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1c(SC2=NCCCN2C)c2ccccc2n1C
Product: I
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 12.7 g of iodine and 20 g of potassium iodide in 100 ml water was added dropwise to a mixture of 7.25 g of 1,2-dimethylindole and 6.5 g of 1-methyl-1,4,5,6-tetrahydro-2-pyrimidinethiol in 120 ml methanol. The reaction mixture is stirred at room temperature for 2 hours. The crystalline precipitate formed was filtered and recrystallized from a mixture of methanol and ethyl acetate to yield 1,2-dimethyl-3-(1-methyl-1,4,5,6-tetrahydro-2-pyrimidinylthio)-indole hydriodide which melts at 239°-240° (with decomposition).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([S:14](=[O:17])(=[O:16])[NH2:15])=[CH:8][C:4]=1[C:5]([OH:7])=O.C(N(CC)CC)C.ClC(OCC)=O.[CH:31]1([CH2:37][N:38]2[CH2:42][CH2:41][CH2:40][CH:39]2[CH2:43][NH2:44])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>CC(C)=O.O>[CH:31]1([CH2:37][N:38]2[CH2:42][CH2:41][CH2:40][CH:39]2[CH2:43][NH:44][C:5](=[O:7])[C:4]2[CH:8]=[C:9]([S:14](=[O:17])(=[O:16])[NH2:15])[CH:10]=[C:11]([O:12][CH3:13])[C:3]=2[O:2][CH3:1])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]1
Reactant: NCC1CCCN1CC1CCCCC1
Reactant: COc1cc(S(N)(=O)=O)cc(C(=O)O)c1OC
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(C)=O
Product: COc1cc(S(N)(=O)=O)cc(C(=O)NCC2CCCN2CC2CCCCC2)c1OC
Reaction time: 1 h

Procedure:
26.1 g of 2,3-dimethoxy-5-sulphamoyl-benzoic acid (0.10 mole), 40 ml of water, 200 ml of acetone and 10.1 g of triethylamine (0.10 mole) are placed in a 500 ml flask fitted with an agitator, a thermometer and a dropping funnel. The solution is cooled to between 0° and +5° C. and 10.9 g of ethyl chloroformate (0.10 mole) is added drop by drop. It is agitated for 1 hour 30 with the temperature kept at about +5° C., then 19.6 g of 1-cyclohexylmethyl-2-aminomethyl pyrrolidine (0.10 mole) is added drop by drop. A precipitate forms progressively as more and more is added. The reaction medium is then agitated at room temperature, after which it is left to stand. The crystals are filtered, washed three times with water then with 100 ml of 10% ammonia and dried in an oven at 50° C. 50 g is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[C:6]([CH3:9])[N:5]=[C:4]([NH2:10])[N:3]=1.[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[C:7]([C:16]#[C:15][Si:12]([CH3:14])([CH3:13])[CH3:11])=[C:6]([CH3:9])[N:5]=[C:4]([NH2:10])[N:3]=1
Reactant: Cc1nc(N)nc(Cl)c1I
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(N)nc(Cl)c1C#C[Si](C)(C)C

Procedure:
The title compound is synthesized according to general procedure GP2 starting from 5.0 g (19 mmol) 4-chloro-5-iodo-6-methyl-pyrimidin-2-ylamine (GP3) and 3.6 mL (26 mmol) trimethylsilylethyne using 352 mg (1.9 mmol) CuI, 485 mg triphenylphosphine (1.9 mmol), 1.3 g (1.9 mmol) PdCl2(PPh3)2 and 26 mL (185 mmol) triethylamine in 100 mL dry DMF. For the work-up the solvent is removed in vacuo and the product is purified by RP-MPLC (ACN/H2O gradient). Yield: 1.6 g (38%).