Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.Cl.CN(CCCN=C=NCC)C.[O:20]=[C:21]1[NH:25][CH:24]([C:26]([OH:28])=O)[CH:23]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[S:22]1.[N+]([O-])(O)=O.[N+:39]([O:42][CH2:43][CH2:44][NH2:45])([O-:41])=[O:40]>CN(C)C=O>[N+:39]([O:42][CH2:43][CH2:44][NH:45][C:26]([CH:24]1[CH:23]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[S:22][C:21](=[O:20])[NH:25]1)=[O:28])([O-:41])=[O:40]
Reactant: NCCO[N+](=O)[O-]
Reactant: O=C1NC(C(=O)O)C(c2ccccc2)S1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O=[N+]([O-])O
Product: O=C1NC(C(=O)NCCO[N+](=O)[O-])C(c2ccccc2)S1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.2 %

Procedure:
0.07 ml of triethylamine and 90 mg of 1-(N,N-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added, whilst ice-cooling and stirring, to a solution of 105 mg of 2-oxo-5-phenylthiazolidine-4-carboxylic acid and 79.5 mg of N-(2-nitrooxyethyl)amine nitrate in 10 ml of dry N,N-dimethylformamide, and the resulting mixture was stirred at room temperature overnight. At the end of this time, the solvent was removed by distillation under reduced pressure, and the residue was mixed with ethyl acetate. The resulting mixture was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The solvent was distilled off and the residual yellow oil was triturated with diethyl ether. The crystals which precipitated were collected by filtration and purified by column chromatography through silica gel, using a 40:1 by volume mixture of methylene chloride and methanol as the eluent, to give 34 mg of the title compound as pale yellow crystals, melting at 139°-140° C.
Reaction SMILES: [CH:1](N1CCCCC1)=[O:2].[CH2:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([Li])=[C:14]([F:19])[C:13]=1[F:20])[CH3:10]>C1COCC1.C1COCC1.CCCCCC>[CH2:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([CH:1]=[O:2])=[C:14]([F:19])[C:13]=1[F:20])[CH3:10]
Reactant: O=CN1CCCCC1
Reactant: [Li]c1ccc(OCC)c(F)c1F
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOc1ccc(C=O)c(F)c1F
Temperature: -20 °C

Procedure:
A solution of 0.1 mol of N-formylpiperidine in 10 ml of THF is added dropwise at -60° C. to the solution of 4-ethoxy-2,3-difluorophenyllithium in THF/hexane prepared according to 1b). The mixture is then warmed to -20° C. in the course of 1 hour. Customary working up (recrystallization from petroleum ether (boiling range 40°-60° C.) gives colourless crystals, m.p. 70° C.
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][C:12]([N+:19]([O-:21])=[O:20])=[CH:13][CH:14]=3)[C:9](=[O:22])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[C:23]([C:27]1[CH:33]=[CH:32][C:30](N)=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24].[N+](C1C=CC2C(=O)C3C(=CC=CC=3)C(=O)C=2C=1[N+]([O-])=O)([O-])=O>COCCO>[C:23]([C:27]1[CH:33]=[CH:32][C:30]([NH:1][C:4]2[C:17]3[C:16](=[O:18])[C:15]4[C:10](=[CH:11][C:12]([N+:19]([O-:21])=[O:20])=[CH:13][CH:14]=4)[C:9](=[O:22])[C:8]=3[CH:7]=[CH:6][CH:5]=2)=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: O=C1c2cc([N+](=O)[O-])ccc2C(=O)c2c1cccc2[N+](=O)[O-]
Agent: O=C1c2ccccc2C(=O)c2c1ccc([N+](=O)[O-])c2[N+](=O)[O-]
Solvent: COCCO
Product: CC(C)(C)c1ccc(Nc2cccc3c2C(=O)c2ccc([N+](=O)[O-])cc2C3=O)cc1

Procedure:
The product employed in a) can be obtained as follows: 15 g of 1,6-dinitro-anthraquinone and 30 ml of p-tert.-butylaniline are stirred at 125° C until no further dinitro-anthraquinone is detectable (approx. 6 hours being required). The warm mixture is diluted with 30 ml of ethylene glycol monomethyl ether, stirred until cold and filtered, and the residue is successively washed with ethylene glycol monomethyl ether and water. 13.9 g of 1-(p-tert.-butyl-anilino)-6-nitro-anthraquinone are obtained.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:13][CH2:14]OC)[CH2:11][CH2:10][NH:9][C:8](=[O:12])[CH2:7]1)=[O:5])C.[F:17][C:18]([F:28])([F:27])[O:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1.[Cl-].C[Al+]C>C1(C)C=CC=CC=1.CCCCCC.CCOC(C)=O>[F:17][C:18]([F:27])([F:28])[O:19][C:20]1[CH:21]=[CH:22][C:23]([N:24]2[CH2:14][CH2:13][C:6]3([CH2:11][CH2:10][NH:9][C:8](=[O:12])[CH2:7]3)[C:4]2=[O:5])=[CH:25][CH:26]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)C1(CCOC)CCNC(=O)C1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C1CC2(CCN1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O
Temperature: 25 °C

Procedure:
4-(2-Methoxy-ethyl)-2-oxo-piperidine-4-carboxylic acid ethyl ester (2 g) and 4-(trifluormethoxy)aniline (3.09 g) were dissolved in toluene (100 ml) under an argon atmosphere at RT, dimethylaluminium chloride in hexane (1 molar, 39.25 ml) was added and the mixture was refluxed for 8 hours. The reaction mixture was then cooled to RT, diluted with AcOEt, quenched with water (9 ml), dried over MgSO4, filtered and the solvent was evaporated off. The residue was adsorbed on silica gel and purified by flash chromatography on silica gel (acetone/CH2Cl2, gradient from 0 to 40%) to give 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decane-1,7-dione as light brown solid. MS (ESI): 329.1 (MH+).
Reaction SMILES: [OH:1][C:2]12[CH2:16][CH:15]([CH3:17])[CH2:14][C:13](=[O:18])[CH:12]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2.[CH3:19][C:20](OC(C)=O)=[O:21].CC1C=CC(S(O)(=O)=O)=CC=1.O>[NH4+].[Cl-]>[C:20]([O:1][C:2]12[CH2:16][CH:15]([CH3:17])[CH2:14][C:13](=[O:18])[CH:12]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)(=[O:21])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: CC1CC(=O)C2CCCCCCCCCC2(O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: CC(=O)OC12CCCCCCCCCC1C(=O)CC(C)C2
Temperature: 0 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
2.5 g (10 mmol) of (16) were added to a mixture of 4 g (40 mmol) Ac2O and 95 mg (0.5 mmol) pTsOH.H2O at 0° C. After stirring for 1 hour at 0° C. the mixture was warmed up to room temperature. After 60 minutes, the reaction mixture was poured into 10 g of ice and 10 ml of a saturated aqueous NH4Cl solution. After extraction with 150 ml diethyl ether the combined organic phases were washed (saturated aqueous NaHCO3 and NaCl solution), dried (Na2SO4) and 1 ml Et3N were added. The solvent was evaporated. Flash chromatography, using SiO2 (300 g) and n-pentane/EtOAc/Et3N=95/4/1 as eluent, afforded 1.31 g (4.4 mmol, yield: 44%) of (28).
Reaction SMILES: C([S:4][CH2:5][S:6][C:7]1[N:8]=[N:9][NH:10][CH:11]=1)(=O)C.C[O-].[Na+].[C:15]1([CH:21]([O:28][C:29]([C:31]2[N:36]3[C:37](=[O:61])[C@@H:38](NC(=O)/C(/C4N=C(NC(OC(C)(C)C)=O)SC=4)=N\OCC=C)[C@H:35]3[S:34][CH2:33][C:32]=2OS(C)(=O)=O)=[O:30])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C)C=O.CO.Cl.O>[C:15]1([CH:21]([O:28][C:29]([C:31]2[N:36]3[C:37](=[O:61])[CH2:38][C@H:35]3[S:34][CH2:33][C:32]=2[S:4][CH2:5][S:6][C:7]2[N:8]=[N:9][NH:10][CH:11]=2)=[O:30])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: C=CCO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(OS(C)(=O)=O)CS[C@H]12)c1csc(NC(=O)OC(C)(C)C)n1
Reactant: CC(=O)SCSc1c[nH]nn1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: O=C(OC(c1ccccc1)c1ccccc1)C1=C(SCSc2c[nH]nn2)CS[C@@H]2CC(=O)N12
Temperature: -78 °C
Reaction time: 0.42 h
Yield: 83.6 %

Procedure:
To a solution of 4-acetylthiomethylthio-1,2,3-triazole (230 mg : 1.22 mMol.) in dimethylformamide (6 ml) is dropwise added a 1.26N-sodium methoxide in methanol (1.9 ml) at -60° C., and the mixture is stirred at the same temperature for 25 minutes, and cooled to -78° C. To the reaction mixture is dropwise added a solution of 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol -4-yl)-2-(2-propenyloxyimino)acetamido]-3 methanesulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester (770 mg : 1 mMol.) in dimethylformamide (3 ml), and the mixture is stirred at the same temperature for 40 minutes. The reaction mixture is diluted with 1N-hydrochloric acid (2 ml) and water (50 ml), and extracted with ethyl acetate. The extract is washed with water, dried over sodium sulfate, and purified by silica gel chromatography (toluene : ethyl acetate=2:1). The eluted material is crystallized from toluene to give 7β-](Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl) 2-(2propentyloxyimino)acetamido]-3-(1,2,3-triazol-4-ylthiomethylthio) -3-cephem-4- carboxylic acid diphenylmethyl ester (415 mg) as colorless crystals. Yield : 51%. mp. 167° to 170° C. (decomposition).
Reaction SMILES: CC([O-])(C)C.[Na+].[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8]1.Br[C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH3:23][C:20]1[CH:21]=[CH:22][C:17]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)=[CH:18][CH:19]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: Cc1ccc(Br)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1ccc(-n2ccc3ccccc32)cc1
Temperature: 100 °C
Reaction time: 21 h
Yield: 94 %

Procedure:
An oven-dried resealable Schlenk tube was purged with argon and charged with Pd2(dba)3 (11.2 mg, 0.012 mmol, 2.5 mol % Pd), 2 [Example 1] (14.4 mg, 0.036 mmol, 7.5 mol %), NaOt-Bu (130 mg, 1.35 mmol) and indole (115 mg, 0.98 mmol). The tube was purged with argon then toluene (1.0 mL) and 4-bromotoluene (120 μL, 0.98 mmol) were added through a rubber septum. The septum was removed, the tube was sealed with a teflon screw cap and the mixture was stirred at 100° C. for 21 h. The reaction was then diluted with ether (20 mL), filtered through celite and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel to afford 191 mg (94%) of a colorless oil.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][C:11]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:28][C@H:27]([CH2:29][NH:30][C:31](=[O:33])[CH3:32])[O:26][C:25]3=[O:34])=[CH:20][C:19]=2[F:35])([OH:15])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>CO>[F:35][C:19]1[CH:20]=[C:21]([N:24]2[CH2:28][C@H:27]([CH2:29][NH:30][C:31](=[O:33])[CH3:32])[O:26][C:25]2=[O:34])[CH:22]=[CH:23][C:18]=1[O:17][CH2:16][C:11]1([OH:15])[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(OCC3(O)CCCN(C(=O)OC(C)(C)C)CC3)c(F)c2)C(=O)O1
Agent: Cl
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2ccc(OCC3(O)CCCNCC3)c(F)c2)C(=O)O1

Procedure:
A solution of 334 mg 4-{4-[(5S)-5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenoxymethyl}-4-hydroxy-azepane-1-carboxylic acid tert-butyl ester (MW: 495.55, 0.674 mmol) in 3 ml of a 1.25 M anhydrous hydrogen chloride solution in methanol was stirred at 35° C. for four hours. The solvent was evaporated under reduced pressure. The residue was dissolved in 4 ml water and the water layer neutralized to pH 7 with a saturated sodium bicarbonate solution. The water was evaporated and the residue dissolved in 30 ml of a 9/1 dichloromethane/methanol mixture. The unsoluble salt were filtered and the filtrate evaporated to dryness to afford off white solid. Yield 266 mg, quant. MS: 395.8 (M+H)+, 440.6 (M+HCOO−), Method ESI+, ESI−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:40]=[CH:41][CH:42]=1)[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([CH:27]5[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]5)=[CH:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH:9]=[N:8]1>C(O)(C(F)(F)F)=O.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:40]=[CH:41][CH:42]=1)[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([CH:27]5[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]5)=[CH:25][CH:26]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH:9]=[N:8]1
Reactant: COc1cccc(Cn2cc(-c3c[nH]c4ncc(-c5ccc(C6CCN(C(=O)OC(C)(C)C)CC6)cc5)cc34)cn2)c1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(Cn2cc(-c3c[nH]c4ncc(-c5ccc(C6CCNCC6)cc5)cc34)cn2)c1
Yield: 15.8 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(4-(3-(1-(3-methoxybenzyl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperidine-1-carboxylate (85 mg, 0.150 mmol) was deprotected in TFA/toluene (2.5/5 ml). This afforded 11 mg (16.2% yield) of the titled compound. 1H NMR (CD3OD, 300 MHz): δ 8.458-8.451 (d, 1H), 8.327-8.321 (d, 1H), 8.14 (s, 1H), 7.90 (s, 1H), 7.65-7.61 (m, 3H), 7.38-7.35 (d, 2H), 7.29-7.23 (m, 1H), 6.87-6.85 (m, 2H), 5.38 (s, 2H), 3.25-3.76 (s, 3H), 3.25-3.20 (d, 2H), 2.87-2.73 (m, 3H), 1.93-1.72 (m, 4H). MS: m/z=464.6 (M+1), HPLC: 90.63% in method A.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([NH:6][CH:7]2[CH2:12][CH2:11][N:10](C(OCC)=O)[CH2:9][CH2:8]2)=[C:4]([C:20](=[O:28])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[F:27])[CH:3]=1.Cl.O>>[ClH:1].[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([NH:6][CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[C:4]([C:20](=[O:28])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[F:27])[CH:3]=1
Reactant: CCOC(=O)N1CCC(Nc2ccc(Cl)cc2C(=O)c2ccccc2F)CC1
Agent: Cl
Solvent: O
Product: O=C(c1ccccc1F)c1cc(Cl)ccc1NC1CCNCC1
Yield: 190.3 %

Procedure:
A mixture of said product (6.35 g) obtained in Step (a) and conc.hydrochloric acid-water (1:1) mixture (50 ml) is refluxed over a period of 20 hours. The reaction mixture is concentrated in vacuo to give 4-[4-chloro-2-(2-fluorobenzoyl)anilino]piperidine hydrochloride (5.51 g) as crystals melting at 225° to 228° C.
Reaction SMILES: [C:1]([O:18][CH:19]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:20][C:21]([OH:23])=O)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[NH2:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44]([OH:46])=[O:45]>>[C:1]([O:18][CH:19]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:20][C:21]([NH:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44]([OH:46])=[O:45])=[O:23])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)O
Reactant: NCCCCC(=O)O
Product: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)NCCCCC(=O)O
Yield: 89.5 %

Procedure:
Starting from 3-hexadecanoyloxyoctadecanoic acid (5.38 g) prepared by the method described in Preparation A-2 (5) and 5-aminopentanoic acid (5 g), N-(3-hexadecanoyloxyoctadecanoyl)-5-aminopentanoic acid (5.7 g) was obtained as crystals according to a similar manner to that of Preparation B-1. M.p. 66°-67°.
Reaction SMILES: CC(OC1CCCCO1)(C)C#C[C:5](=[O:11])[C:6]([O:8]CC)=[O:7].[C:20]1([CH:26]2[CH2:30][S:29][C:28](=[S:31])[S:27]2)[CH:25]=CC=C[CH:21]=1.C(Cl)Cl>C1(C)C(C)=CC=CC=1>[CH3:25][C:20]1([CH3:21])[C:26]2[S:27][C:28](=[S:31])[S:29][C:30]=2[C:5](=[O:11])[C:6](=[O:7])[O:8]1
Reactant: CCOC(=O)C(=O)C#CC(C)(C)OC1CCCCO1
Reactant: S=C1SCC(c2ccccc2)S1
Solvent: ClCCl
Solvent: Cc1ccccc1C
Product: CC1(C)OC(=O)C(=O)c2sc(=S)sc21
Temperature: 130 °C

Procedure:
Ethyl 5-methyl-2-oxo-5-(tetrahydro-2H-pyran-2-yloxy)hex-3-ynoate (2) (1.0 g, 3.7 mmol) and 4-phenyl-1,3-dithiolane-thione (2.0 g, 9.3 mmol) were dissolved in xylene (15 mL). The deep yellow solution was heated to 130° C. for ca. 4 h under Ar (the reaction was followed by TLC, eluent: CH2Cl2). The solvent was removed under reduced pressure and purification of the residue by chromatography (silica gel, CH2Cl2) provided 4,4-dimethyl-2-thioxo-4H-[1,3]dithiolo[4,5-c]pyran-6,7-dione (4) as a yellow solid. Yield: 0.44 g (48%). 1H-NMR spectrum in CDCl3 (ppm): 1.88 (s, 6H). 13C-NMR spectrum in CDCl3 (ppm): 205.3, 167.7, 162.6, 157.8, 153.6, 83.2, 31.9. Selected IR (neat, cm−): 1747, 1681, 1557, 1460. MS-ESI calculated for C7H8O4S2Na [M+Na]+ 268.96. found 268.79.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([S:9][CH3:10])=[C:4](Cl)[N:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]([S:9][CH3:10])=[C:6]([Cl:8])[N:7]=1
Reactant: C1COCCN1
Reactant: CSc1c(Cl)nc(Cl)nc1Cl
Solvent: C1CCOC1
Product: CSc1c(Cl)nc(Cl)nc1N1CCOCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2,4,6-trichloro-5-methylsulfanyl-pyrimidine (4.0 g, 17.4 mmol.), morpholine (2.3 g, 26.1 mmol, 1.5 eq.) and THF (20 ml) was stirred at room temperature for 2.0 hr. The reaction mixture was dried and the solvent was evaporated. Thereafter, a 0.1 N HCl washing free morpholine was added to the solution. The solution was extracted with EA and the EA in the solution was removed by evaporation. A crude product was obtained. Purification of the crude by flash chromatography on silica gel (Hexane/EtOAc 6:1) gave a gray solid of 2.34 g (48.2%).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[C:8](=[O:12])[N:7]3[N:13]=[CH:14][CH:15]=[C:6]3[NH:5][C:4]=2[CH:3]=1.[H][H]>C(N(CC)CC)C.[Pd].CN(C)C=O>[N:13]1[N:7]2[C:8](=[O:12])[C:9]3[CH:10]=[N:11][CH:2]=[CH:3][C:4]=3[NH:5][C:6]2=[CH:15][CH:14]=1
Reactant: [H][H]
Reactant: O=c1c2cnc(Cl)cc2[nH]c2ccnn12
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=c1c2cnccc2[nH]c2ccnn12
Temperature: 25 °C

Procedure:
22 g. of 6-chloropyrazolo[1,5-a]pyrido[4,3-d]pyrimidin-9(4H)-one of Example 1 are hydrogenated in 200 ml. of dimethylformamide in the presence of 15 g. of triethylamine and 10% palladium on charcoal as catalyst at 80° and 3 atmospheres hydrogen pressure. When the theoretical amount of hydrogen has been absorbed, the reaction is stopped and the mixture is filtered after cooling to room temperature. After evaporation of the solvent, the crystalline residue, pyrazolo[1,5-a]pyrido[4,3-d]pyrimidin-9(4H)-one, is recrystallized from dimethylformamide, yield: 13 g. (70%); m.p. >300°.
Reaction SMILES: [C:1]([S@:5]([NH2:7])=[O:6])([CH3:4])([CH3:3])[CH3:2].[Br:8][C:9]1[N:14]=[C:13]([C:15](=O)[CH3:16])[C:12]([F:18])=[C:11]([Si:19]([CH2:24][CH3:25])([CH2:22][CH3:23])[CH2:20][CH3:21])[CH:10]=1>C1COCC1.[Cl-].[Na+].O>[Br:8][C:9]1[N:14]=[C:13](/[C:15](=[N:7]/[S@@:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[O:6])/[CH3:16])[C:12]([F:18])=[C:11]([Si:19]([CH2:22][CH3:23])([CH2:20][CH3:21])[CH2:24][CH3:25])[CH:10]=1
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC[Si](CC)(CC)c1cc(Br)nc(C(C)=O)c1F
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)c1cc(Br)nc(/C(C)=N/[S@](=O)C(C)(C)C)c1F
Yield: 82 %

Procedure:
A mixture of titantetraethoxide (4.26 g, 18.69 mmol), (R)-tert.-butylsulfinamide (1.246 g, 10.28 mmol) and 1-(6-bromo-3-fluoro-4-triethylsilanyl-pyridin-2-yl)-ethanone (3.45 g, 9.34 mmol, 90% pure) in THF (25 ml) was refluxed under a nitrogen atmosphere for 6 hours. The cold reaction mixture was poured onto icecold brine (200 ml) with gentle stirring. The precipitate was filtered through a pad of hyflo and washed with ethyl acetate. The filtrate was diluted with ethyl acetate and washed with brine, dried over sodium sulfate, filtered and evaporated. The crude yellow oil (4.55 g) was chromatographed over silica gel (cyclohexane/ethyl acetate 94:6) to give the title compound as a yellow oil. 3.35 g (82% yield).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:10](C(=O)C)[N:9]=[CH:8][C:6]=2[N:7]=1.[OH-].[Na+].Cl>C(#N)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:10][N:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CC(=O)n1ncc2nc(Cl)ncc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: Clc1ncc2[nH]ncc2n1
Reaction time: 2 h
Yield: 75.4 %

Procedure:
27 mg of 1-(5-chloro-pyrazolo[4,3-d]pyrimidin-1-yl)-ethanone was dissolved in 1.5 mL of acetonitrile, added with 1.5 mL of 5N sodium hydroxide aqueous solution, and stirred for 2 hours. After adding 2N hydrochloric acid to the reaction solution to render it acidic, the solution was extracted with ethyl acetate, and the resultant organic layer was washed with saturated brine, then dried over magnesium sulfate, and the solvent was evaporated, to afford 16 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:15][C@@H:14]([C:16]([OH:18])=O)[N:13]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[C:12]1=[O:26])(=[O:10])=[O:9].[CH3:27][C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][C:29]=1[N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:15][C@@H:14]([C:16]([N:38]2[CH2:39][CH2:40][N:35]([C:29]3[CH:30]=[C:31]([CH3:34])[CH:32]=[CH:33][C:28]=3[CH3:27])[CH2:36][CH2:37]2)=[O:18])[N:13]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[C:12]1=[O:26])(=[O:9])=[O:10]
Reactant: O=C(O)[C@@H]1CN(S(=O)(=O)c2ccccc2Cl)C(=O)N1c1ccccc1Cl
Reactant: Cc1ccc(C)c(N2CCNCC2)c1
Product: Cc1ccc(C)c(N2CCN(C(=O)[C@@H]3CN(S(=O)(=O)c4ccccc4Cl)C(=O)N3c3ccccc3Cl)CC2)c1

Procedure:
Steps 4 and 5: In analogy to example 1, (S)-1-(2-chloro-benzenesulfonyl)-3-(2-chloro-phenyl)-2-oxo-imidazolidine-4-carboxylic acid methyl ester was hydrolyzed using sodium hydroxide solution to give (S)-1-(2-chloro-benzenesulfonyl)-3-(2-chloro-phenyl)-2-oxo-imidazolidine-4-carboxylic acid. Finally, (S)-1-(2-chloro-benzenesulfonyl)-3-(2-chloro-phenyl)-2-oxo-imidazolidine-4-carboxylic acid was coupled with 1-(2,5-dimethylphenyl)piperazine to give the title compound as a colorless solid. MS: 587.2 ([M+H]+)
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:14]([NH:15][S:16]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:18])=[O:17])[CH2:13][CH:12]=[CH:11][CH2:10][N:9]1[S:26]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)(=[O:28])=[O:27])=[O:7])(C)(C)C.C(OC(C1C(NC(OCC2C=CC=CC=2)=O)CC=CCN1S(C1C=CC(OC)=CC=1)(=O)=O)=O)(C)(C)C>>[CH3:36][O:35][C:32]1[CH:33]=[CH:34][C:29]([S:26]([N:9]2[CH2:10][CH:11]=[CH:12][CH2:13][CH:14]([NH:15][S:16]([CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)(=[O:18])=[O:17])[CH:8]2[C:6]([OH:7])=[O:5])(=[O:28])=[O:27])=[CH:30][CH:31]=1
Reactant: COc1ccc(S(=O)(=O)N2CC=CCC(NS(=O)(=O)Cc3ccccc3)C2C(=O)OC(C)(C)C)cc1
Agent: COc1ccc(S(=O)(=O)N2CC=CCC(NC(=O)OCc3ccccc3)C2C(=O)OC(C)(C)C)cc1
Product: COc1ccc(S(=O)(=O)N2CC=CCC(NS(=O)(=O)Cc3ccccc3)C2C(=O)O)cc1

Procedure:
1-(4-Methoxy-benzenesulfonyl)-3-(phenylmethanesulfonyl amino)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid tert-butyl ester (29 mg, 0.054 mmol) is reacted in the same manner as 3-Benzyloxycarbonylamino-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid tert-butyl ester: Cal. 479.5 found (M−H)+ 478.6. Cal. 498.6, found (MNH4)+ 498.1; 1H NMR (DMSO, 400 MHz), ppm: 7.85 (d, 2H), 7.38 (m, 5H) 7.01 (d, 2H), 5.5 (m, 2H) 4.45 (d, 2H), 4.30 (d, 2H), 4.15 (m, 2H), 4.00 (m, 1H), 3.90 (dd, 1H), 3.83 (s, 3H), 2.18 (m, 2H).