Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[C:18](OC(=O)C)(=[O:20])[CH3:19]>CN(C=O)C>[C:18]([NH:15][C:14]1[CH:16]=[CH:17][N:10]([C@@H:1]2[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]2[OH:3])[C:11](=[O:12])[N:13]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n1
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n1
Yield: 100.3 %

Procedure:
To a solution of cytidine (1.22 g, 5.00 mmol) in DMF(40 mL) is added acetic anhydride (0.94 mL, 10.00 mmol). The solution is treated with microwave radiation (Panasonic, 1000 Watts) at full power for 40 seconds. The solution is concentrated in vacuo and the residue is co-evaporated with methanol (2×20 mL) to give 4-N-acetyl-cytidine (1.43 g, 95.0%) as a white powder. MS (FAB):m/z 286 (MH+).
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:14]([NH:16][C@H:17]([C:21]([OH:23])=O)[CH:18]([CH3:20])[CH3:19])=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)(=[O:3])[CH3:2].[C:24]([O:28][C:29](=[N:56][NH:57][C:58]([NH2:60])=[O:59])[CH2:30][CH:31]([NH:34][C:35](=[O:55])[C@@H:36]1[CH2:40][CH:39]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH2:38][N:37]1C(OCC=C)=O)[CH:32]=[O:33])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([O:28][C:29](=[N:56][NH:57][C:58]([NH2:60])=[O:59])[CH2:30][CH:31]([NH:34][C:35](=[O:55])[C@@H:36]1[CH2:40][CH:39]([O:41][CH2:42][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH2:38][N:37]1[C:21](=[O:23])[C@H:17]([CH:18]([CH3:19])[CH3:20])[NH:16][C:14](=[O:15])[C@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1)[NH:4][C:1](=[O:3])[CH3:2])[CH:32]=[O:33])([CH3:27])([CH3:25])[CH3:26]
Reactant: C=CCOC(=O)N1CC(OCc2ccccc2)C[C@H]1C(=O)NC(C=O)CC(=NNC(N)=O)OC(C)(C)C
Reactant: CC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@H](C(=O)O)C(C)C
Product: CC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@H](C(=O)N1CC(OCc2ccccc2)C[C@H]1C(=O)NC(C=O)CC(=NNC(N)=O)OC(C)(C)C)C(C)C

Procedure:
The title compound was prepared by reaction of N-acetyl-tyrosinyl-valine and N-(N-allyloxycarbonyl-4-benzyloxyprolinyl)-3-amino-4-oxobutanoic acid tert-butyl ester semicarbazone by reaction conditions reported for compound 1, step A.
Reaction SMILES: [N:1]1[C:10]2[CH:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:26])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl[CH2:28][C:29]1[NH:33][C:32]2[CH:34]=[C:35]([C:38]([F:41])([F:40])[F:39])[CH:36]=[CH:37][C:31]=2[N:30]=1.C(N(CC)C(C)C)(C)C.[I-].[K+]>C(#N)C>[N:1]1[C:10]2[CH:9]([N:11]([CH2:28][C:29]3[NH:30][C:31]4[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:39])[F:40])=[CH:34][C:32]=4[N:33]=3)[CH2:12][CH2:13][CH2:14][CH2:15][N:16]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:26])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: FC(F)(F)c1ccc2nc(CCl)[nH]c2c1
Reactant: O=C1c2ccccc2C(=O)N1CCCCNC1CCCc2cccnc21
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1c2ccccc2C(=O)N1CCCCN(Cc1nc2cc(C(F)(F)F)ccc2[nH]1)C1CCCc2cccnc21
Yield: 75.4 %

Procedure:
2-[4-(5,6,7,8-tetrahydro-quinolin-8-ylamino)-butyl]-isoindol-1,3-dione (160 mg, 0.46 mmol) and 2-chloromethyl-6-trifluoromethyl-1H-benzoimidazole (129 mg, 0.55 mmol), N,N-diisopropylethylamine (100 μL, 0.60 mmol), and potassium iodide (8 mg, 0.05 mmol) in acetonitrile were stirred at 40° C. for 3 days. Then the reaction mixture was cooled and the solvent was removed under reduced pressure to afford a red oil. Purification by flash column chromatography on silica gel using NH4OH/CH3OH/CH2Cl2 (1:2:97) afforded the product as an orange foam (190 mg, 76%). 1H NMR (CDCl3) δ 1.37-1.45 (m, 5H), 1.56-1.70 (m, 2H), 2.18-2.20 (m, 1H), 2.57-2.61 (m, 1H), 2.72-2.80 (m, 3H), 3.49-3.54 (m, 2H), 3.98-4.16 (m, 3H), 7.13-7.15 (m, 1H), 7.40-7.45 (m, 2H), 7.62-7.74 (m, 5H), 7.86 (br m, 1H), 8.62 (br m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[N:12]=[N:11][C:10]([CH2:13][C:14](O)=[O:15])=[N:9]2)=[CH:5][CH:4]=1.S(Cl)([Cl:21])=O>>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[N:12]=[N:11][C:10]([CH2:13][C:14]([Cl:21])=[O:15])=[N:9]2)=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(Cn2nnc(CC(=O)O)n2)cc1
Product: COc1ccc(Cn2nnc(CC(=O)Cl)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
The 2-[2-(4-methoxybenzyl)-2H-1,2,3,4-tetrazol-5-yl]acetic acid (262.0 mg, 1.05 mmol) obtained in (B) was added dropwise with thionyl chloride (615.9 μl, 8.44 mmol) under ice cooling and stirred at room temperature for 30 minutes. Excessive regents were evaporated to obtain the title compound (0.27 g, quantitative) as pale yellow oil.
Reaction SMILES: [K].Cl[C:3]1[N:8]=[C:7](Cl)[C:6]([F:10])=[CH:5][N:4]=1.[CH2:11]([OH:15])[CH2:12][CH2:13][CH3:14]>>[CH2:11]([O:15][C:3]1[N:8]=[C:7]([O:15][CH2:11][CH2:12][CH2:13][CH3:14])[C:6]([F:10])=[CH:5][N:4]=1)[CH2:12][CH2:13][CH3:14]
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: CCCCO
Agent: [K]
Product: CCCCOc1ncc(F)c(OCCCC)n1
Reaction time: 5 h
Yield: 85.1 %

Procedure:
A 9.8 g quantity of metal potassium is dissolved in 300 ml of absolute n-butanol, 16.7 g of 2,4-dichloro-5-fluoropyrimidine is added to the solution and the mixture is stirred at 60° to 70° C for 5 hours. After the reaction, the solvent is distilled off, 50 ml of water is added to the residue and the mixture is extracted with 300 ml of toluene. The toluene layer is washed with water, dried and concentrated. The concentrate is distilled at reduced pressure to give 20.6 g of colorless oily 2,4-di(n-butoxy)-5-fluoropyrimidine in a yield of 85.1 %, b.p. 125°-126° C/3-4 mm Hg.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1)[NH2:17].N1C2C(C(=O)C)CCCC=2C=CC=1>[Cu]I.CN(C=O)C>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:14]2[CH:20]=[C:19]([C:21]([F:22])([F:24])[F:23])[CH:18]=[C:16]([NH2:17])[CH:15]=2)[CH:6]=1
Reactant: Cc1c[nH]cn1
Reactant: Nc1cc(Br)cc(C(F)(F)F)c1
Agent: [Cu]I
Agent: CC(=O)C1CCCc2cccnc21
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Cc1cn(-c2cc(N)cc(C(F)(F)F)c2)cn1
Temperature: 110 °C
Reaction time: 18 h
Yield: 90.8 %

Procedure:
In a pressure tube with one end sealed, add 190 mg CuI (1 mmol), 1.64 g 4-methyl-1H-imidazole (20 mmol), 3.25 g Cs2CO3 (10 mmol), and after Nitrogen replacement, add 2.40 g 3-bromo-5-(trifluoromethyl)aniline (10 mmol), 350 mg 1-(5,6,7,8-tetrahydroquinolin-8-yl)ethanone (2 mmol) and 30 mL DMF was added into a flask. The mixture was stirred at 110° C. for 18 h under sealing. After cooling to room temperature, the solvent was removed under vacuum and the residue was purified by column chromatography to afford 2.19 g desired product (91%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH2:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH:14]1[CH2:18][NH2:19])[CH3:12].C(=O)([O-])[O-].[Na+].[Na+]>O>[CH2:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH:14]1[CH2:18][NH:19][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=1)[CH3:12]
Reactant: CCN1CCCC1CN
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCN1CCCC1CNC(=O)c1ccc(F)cc1
Reaction time: 20 h

Procedure:
Add 5.05 g (31.8 mmol) of p-fluorobenzoyl chloride drop-wise to a 0° C. solution of 4.08 g (31.8 mmol) of 1-ethyl-2-(aminomethyl)pyrrolidine and 3.85 (35.0 mmol) of sodium carbonate in 50 mL of water. Stir the resultant solution at 0° C. for about 30 minutes, then at room temperature for about 20 hr. Extract the resultant solution with methylene chloride (2×100 mL). Dry the combined extracts with Na2SO4 and evaporate the solvent to give the title compound.
Reaction SMILES: C([O-])(=O)C.[Na+].Cl.[NH2:7][CH2:8][C:9](=O)[CH2:10][CH3:11].F[B-](F)(F)F.[NH:18]=[C:19](SC)[C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(O)(=O)C>[CH2:10]([C:9]1[NH:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:7][CH:8]=1)[CH3:11]
Reactant: CCOC(=O)C(=N)SC
Reactant: CCC(=O)CN
Agent: CC(=O)[O-]
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CC(=O)O
Product: CCOC(=O)c1ncc(CC)[nH]1
Temperature: 100 °C
Reaction time: 4 h
Yield: 72.2 %

Procedure:
Sodium acetate (9.3 g, 113.4 mmol) was added to a solution of 1-amino-butan-2-one hydrochloride (3.41 g, 27.60 mmol) and ethyl imino(methylthio)acetate tetrafluoroborate (7.45 g, 31.84 mmol) synthesized according to the method described in the document (J. Med. Chem., 38, 1995, 2196-2201) in acetic acid (120 mL), and the mixture was stirred at 100° C. for four hours. The reaction solution was concentrated under reduced pressure and then saturated aqueous sodium bicarbonate solution was added to the reaction solution, followed by extraction with ethyl acetate. Then, the organic layer was washed with brine and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=5/1, 2/1, 1/2) to obtain 3.35 g of the title compound as a pale yellow solid (72%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:20]3[C:21]4[CH:36]=[C:35]([Br:37])[CH:34]=[N:33][C:22]=4[N:23]([S:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)(=[O:26])=[O:25])[C:19]=3[CH:18]=[N:17][C:16]=2[C:38]#[N:39])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[C:27]1([S:24]([N:23]2[C:19]3[CH:18]=[N:17][C:16]([C:38]#[N:39])=[C:15]([O:14][CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[C:20]=3[C:21]3[CH:36]=[C:35]([Br:37])[CH:34]=[N:33][C:22]2=3)(=[O:25])=[O:26])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2c(C#N)ncc3c2c2cc(Br)cnc2n3S(=O)(=O)c2ccccc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ncc2c(c1OC1CCNCC1)c1cc(Br)cnc1n2S(=O)(=O)c1ccccc1
Yield: 83.4 %

Procedure:
To a solution of 4-(9-benzenesulfonyl-3-bromo-6-cyano-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-5-yloxy)piperidine-1-carboxylic acid tert-butyl ester (12.6 g, 20.6 mmol) in dichloromethane (36 mL) was added TFA (36 mL). After 1 hour at ambient temperature the reaction mixture was concentrated in-vacuo and the residue partitioned between saturated aqueous sodium carbonate solution (800 mL) and dichloromethane (2 L). The organic phase was separated, dried (Na2SO4), filtered and evaporated in-vacuo to afford the title compound as an off-white solid (8.8 g, 84%) which was used without further purification. 1H NMR (300 MHz, DMSO-d6): 9.46 (s, 1H), 8.90 (d, J=2.3 Hz, 1H), 8.64 (d, J=2.3 Hz, 1H), 8.23-8.22 (m, 2H), 7.78 (t, J=7.4 Hz, 1H), 7.64 (t, J=7.8 Hz, 2H), 4.85-4.85 (m, 1H), 3.17 (s, 1H), 3.00 (dt, J=13.0, 4.1 Hz, 2H), 2.50-2.49 (m, 2H obscured by solvent peak), 2.15-1.97 (m, 2H), 1.75-1.75 (m, 2H).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1.OOS([O-])=O.[K+].O>CN(C=O)C>[Br:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]2[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:14]=2)=[CH:18][CH:17]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: Nc1ccccc1Nc1ccccc1
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc(-c2nc3ccccc3n2-c2ccccc2)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 35.5 %

Procedure:
N-Phenyl-o-phenylenediamine (50 g, 0.27 mol) is dissolved in anhydrous DMF (400 ml) under N2, and 4-bromobenzaldehyde (45.5 g, 0.25 mol) is added dropwise. The reaction mixture is warmed to 40° C., and Oxone (potassium hydrogen monopersulfate, 98.1 g, 0.16 mol) is added in portions. After the mixture has been stirred at room temperature for 120 min., 1 l of water is added. The precipitated product is filtered off, washed with water and dried in vacuo. Recrystallisation from acetonitrile gives a cream-coloured solid (31 g, 35%).
Reaction SMILES: [C:1]1([C:7]2OC(=O)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][O:14][C:15]([C:17]#[C:18][C:19]([O:21][CH3:22])=[O:20])=[O:16]>ClC1C=CC=CC=1>[CH3:13][O:14][C:15]([C:17]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:8][S:9][C:18]=1[C:19]([O:21][CH3:22])=[O:20])=[O:16]
Reactant: COC(=O)C#CC(=O)OC
Reactant: O=c1oc(-c2ccccc2)ns1
Solvent: Clc1ccccc1
Product: COC(=O)c1snc(-c2ccccc2)c1C(=O)OC
Reaction time: 6 h
Yield: 59.5 %

Procedure:
A solution of 5-phenyl-[1,3,4]oxathiazol-2-one (30.33 mmol) and dimethylacetylenedicarboxylate (60.67 mmol) in chlorobenzene (17.8 mL) was refluxed with stirring for 6 h before it was concentrated in vacuo. The residue was crystallized from cold MeOH to give the title compound (5.0 g) as a slightly yellow solid: MS (m/z) 278.1 (M+1).
Reaction SMILES: O(P(O[C:18]1[C@H:19]([CH3:42])[C@H:20]2[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:41])[N:21]2[C:22]=1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:24])(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[SH:43][C@@H:44]1[CH2:48][N:47]([C:49]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][C:56]([N+:59]([O-:61])=[O:60])=[CH:55][CH:54]=2)=[O:50])[C@H:46]([CH:62]2[CH2:67][CH2:66][N:65]([C:68]([O:70][CH2:71][C:72]3[CH:77]=[CH:76][C:75]([N+:78]([O-:80])=[O:79])=[CH:74][CH:73]=3)=[O:69])[CH2:64][CH2:63]2)[CH2:45]1>>[OH:40][C@@H:38]([C@H:37]1[C:36](=[O:41])[N:21]2[C:22]([C:23]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=3)=[O:24])=[C:18]([S:43][C@@H:44]3[CH2:48][N:47]([C:49]([O:51][CH2:52][C:53]4[CH:54]=[CH:55][C:56]([N+:59]([O-:61])=[O:60])=[CH:57][CH:58]=4)=[O:50])[C@H:46]([CH:62]4[CH2:67][CH2:66][N:65]([C:68]([O:70][CH2:71][C:72]5[CH:73]=[CH:74][C:75]([N+:78]([O-:80])=[O:79])=[CH:76][CH:77]=5)=[O:69])[CH2:64][CH2:63]4)[CH2:45]3)[C@H:19]([CH3:42])[C@H:20]12)[CH3:39]
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CCC([C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(Oc3ccccc3)Oc3ccccc3)[C@H](C)[C@@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C4CCN(C(=O)OCc5ccc([N+](=O)[O-])cc5)CC4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Yield: 78.5 %

Procedure:
The same procedure as in Example 1-1 was carried by using p-nitrobenzyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (245 mg, 0.41 mmol) and (2S,4S)-4-mercapto-N-(p-nitrobenzyloxycarbonyl)-2-[N-(p-nitrobenzyloxycarbonyl)piperidin-4-yl]pyrrolidine (216 mg, 0.40 mmol, compound of Reference Example 32) to obtain p-nitrobenzyl (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-N-(p-nitrobenzyloxycarbonyl)-2-[N-(p-nitrobenzyloxycarbonyl)piperidin-4-yl]pyrrolidin-4ylthio]-1-carbapen-2-em-3-carboxylate (279 mg, yield: 76.2%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH:36]([F:38])[F:37])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25]/[CH:26]=[CH:27]/[CH2:28][N:29]3[CH2:34][CH2:33]O[CH2:31][CH2:30]3)[N:9]=2)[CH:7]=1.[CH3:39][N:40]1CCNCC1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH:36]([F:38])[F:37])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25]/[CH:26]=[CH:27]/[CH2:28][N:29]3[CH2:30][CH2:31][N:40]([CH3:39])[CH2:33][CH2:34]3)[N:9]=2)[CH:7]=1
Reactant: O=C(Nc1cn(C/C=C/CN2CCOCC2)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Reactant: CN1CCNCC1
Product: CN1CCN(C/C=C/Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1

Procedure:
Using synthetic method analoguous to that of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[(2E)-4-(morpholin-4-yl)but-2-en-1-yl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide, the title compound was prepared from 1-methylpiperazine. LCMS (Method 23) [M+H]+=557.1, RT=1.76 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.74 (s, 1H), 9.34 (d, 1H, J=5.2 Hz), 8.68-8.66 (m, 2H), 8.31 (s, 1H), 7.62 (d, 1H, J=8.8 Hz), 7.58 (d, 1H, J=2.4 Hz), 7.47 (d, 1H, J=8.8 Hz), 7.28 (dd, 1H, J=4.0, 6.8 Hz), 7.06 (t, 1H, J=73.2 Hz), 5.92-5.80 (m, 1H), 5.78-5.66 (m, 1H), 4.81 (d, 2H, J=6.0 Hz), 2.94 (d, 2H, J=6.4 Hz), 2.45-2.20 (m, 8H), 2.13 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[CH2:12][CH2:11][C@H:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:9]1[C:19](=[O:36])[CH2:20][NH:21][C:22](=[O:35])[NH:23][C:24]1[CH:25]=[C:26]([CH2:30][C:31]([O:33]C)=[O:32])[CH:27]=[CH:28][CH:29]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+]>CO.O>[C:1]([O:5][C:6]([C@@H:8]1[CH2:12][CH2:11][C@H:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:9]1[C:19](=[O:36])[CH2:20][NH:21][C:22](=[O:35])[NH:23][C:24]1[CH:25]=[C:26]([CH2:30][C:31]([OH:33])=[O:32])[CH:27]=[CH:28][CH:29]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)Cc1cccc(NC(=O)NCC(=O)N2[C@@H](c3ccccc3)CC[C@H]2C(=O)OC(C)(C)C)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)[C@@H]1CC[C@H](c2ccccc2)N1C(=O)CNC(=O)Nc1cccc(CC(=O)O)c1
Yield: 35.2 %

Procedure:
The operation is carried out as in Example 9, but starting from 1.9 g of methyl (2S,5R)-3-{3-[2-(2-tert-butoxycarbonyl-5-phenyl-1-pyrrolidinyl)-2-oxoethyl]ureido}phenylacetate in solution in 60 cm3 of methanol and 0.22 g of potassium hydroxide dissolved in 30 cm3 of water. After treatment, 0.65 g of (2S,5R)-3-{3-[2-(2-tert-butoxycarbonyl-5-phenyl-1-pyrrolidinyl)-2-oxoethyl]ureido}phenylacetic acid, melting at 112° C., [α]D20 =+30.6°±0.8° (c=1; methanol) is obtained.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6]1[C:10](=[O:11])[CH2:9][CH2:8][CH2:7]1)=[O:5].Cl[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:16][CH:15]=1.[OH-].[K+]>CN(C)C=O.C(O)(=O)C>[CH2:2]([O:3][C:4]([C:6]1([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:18][CH:19]=2)[CH2:7][CH2:8][CH2:9][C:10]1=[O:11])=[O:5])[CH3:1]
Reactant: CCOC(=O)Cc1ccc(CCl)cc1
Reactant: CCOC(=O)C1CCCC1=O
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(CC2(C(=O)OCC)CCCC2=O)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 72.4 %

Procedure:
A mixture of 9.4 g of ethyl 2-cyclopentanonecarboxylate, 10.6 g of ethyl p-chloromethylphenylacetate, 3.58 g of potassium hydroxide and 60 ml of dimethyl formamide was stirred at room temperature for 5 hours, at 50° C. for 1 hour and thereafter at room temperature overnight. The reaction mixture was acidified by addition of acetic acid, dimethyl formamide was removed by distillation, water was added to the residue, and the mixture was extracted with ether. The extract was washed with water, dried over anhydrous sodium sulfate, and the solvent evaporated to give an oily substance, which was subjected to a vacuum distillation affording 12 g of the desired compound, b.p. 180°-190° C. at 0.8 mm Hg.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[C:27][Si](C)(C)C)=[CH:22][N:21]=1>C1COCC1>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[CH:27])=[CH:22][N:21]=1
Reactant: C[Si](C)(C)C#Cc1ccc(Cl)nc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1ccc(Cl)nc1
Reaction time: 8 h
Yield: 73.3 %

Procedure:
A 1 M solution of TBAF in THF (12 mL) was added to 500 mg (2.38 mmol) of 2-chloro-5-trimethylsilanylethynyl-pyridine and the black solution was stirred overnight. The mixture was concentrated, the resulting residue was stirred in 50 mL of Et2O for 1 h, and the liquid was decanted from the solids. This washing procedure was repeated twice, and the combined washes were concentrated and chromatographed to provide 240 mg of 2-chloro-5-ethynylpyridine as a colorless solid.
Reaction SMILES: ClC1C=C(C=CC=1)C([O:7][CH:8]1[C:13](=[O:14])[NH:12][C:11]([CH3:15])=[C:10]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[S:9]1)=O.O>CC(C)=O>[OH:7][CH:8]1[C:13](=[O:14])[NH:12][C:11]([CH3:15])=[C:10]([C:16]2[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=2)[S:9]1
Reactant: CC1=C(c2ccncc2)SC(OC(=O)c2cccc(Cl)c2)C(=O)N1
Solvent: O
Solvent: CC(C)=O
Product: CC1=C(c2ccncc2)SC(O)C(=O)N1
Temperature: 70 °C
Reaction time: 44 h
Yield: 19 %

Procedure:
2-(3-Chlorobenzoyloxy)-5-methyl-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one (1.37 g) and water (1 ml) were dissolved in acetone (20 ml) and the mixture was stirred at 70° C. for 44 hours. The mixture was chromatographed on silica gel (Wakogel C-200) column, using chloroform-methanol (=30:1) as an eluant to give the titled compound (0.16 g, yield 19.1%) as red needles.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=O.[NH2:16][C:17]1[NH:21][N:20]=[C:19]([C:22]([OH:24])=[O:23])[CH:18]=1>C(O)(=O)C>[N:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:5]1[CH:4]=[C:3]([C:2]([F:15])([F:14])[F:1])[N:21]2[N:20]=[C:19]([C:22]([OH:24])=[O:23])[CH:18]=[C:17]2[N:16]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccccn1
Reactant: Nc1cc(C(=O)O)n[nH]1
Solvent: CC(=O)O
Product: O=C(O)c1cc2nc(-c3ccccn3)cc(C(F)(F)F)n2n1
Yield: 71.5 %

Procedure:
4,4,4-Trifluoro-1-pyridin-2-yl-butane-1,3-dione (3.00g, 13.8 mmol) and 5-amino-1H-pyrazole-3-carboxylic acid (1.76 g, 13.8 mmol) in acetic acid (100 ml) was heated at reflux overnight. The reaction mixture was concentrated under reduced pressure and the crude product was purified by column chromatography on silica gel to give 5-pyridin-2-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (3.04 g, 71%).
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[NH2:16][C@@H:17]([C:34]1[CH:39]=[CH:38][C:37]([F:40])=[C:36]([Br:41])[CH:35]=1)[CH2:18][N:19]([CH2:32][CH3:33])S(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O>>[Br:41][C:36]1[CH:35]=[C:34]([C@H:17]([NH:16][C:2]2[C:3]3[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:18][NH:19][CH2:32][CH3:33])[CH:39]=[CH:38][C:37]=1[F:40]
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Reactant: CCN(C[C@@H](N)c1ccc(F)c(Br)c1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: CCNC[C@@H](Nc1ncnc2c(C(N)=O)ccnc12)c1ccc(F)c(Br)c1

Procedure:
Compound 30 was prepared following general synthesis scheme 8 wherein 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with N—[(S)-2-Amino-2-(3-bromo-4-fluoro-phenyl)-ethyl]-N-ethyl-4-nitro-benzenesulfonamide hydrochloride to give the title compound as a white solid. LC/MS [434 (M+H)]; 1H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 9.36 (s, 1H), 9.02 (d, J=4.5 Hz, 1H), 8.60 (s, 1H), 8.40 (d, J=4.4 Hz, 1H), 8.18 (s, 1H), 7.87 (d, J=4.9 Hz, 1H), 7.53 (d, J=5.5 Hz, 1H), 7.35 (t, J=8.7 Hz, 1H), 5.78-5.51 (m, 1H), 3.55-3.36 (m, 1H), 3.23-3.10 (m, 1H), 2.93-2.69 (m, 2H), 1.08 (t, J=7.0 Hz, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7]2)[CH2:3][CH2:2]1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>>[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([S:23]([N:1]2[CH2:6][CH2:5][C:4]3([C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH:8]=[CH:7]3)[CH2:3][CH2:2]2)(=[O:25])=[O:24])=[CH:21][CH:22]=1
Reactant: C1=CC2(CCNCC2)c2ccccc21
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Product: COc1ccc(S(=O)(=O)N2CCC3(C=Cc4ccccc43)CC2)cc1

Procedure:
The procedure of example 3 was carried out using 20 mg (0.108 mmol) of spiro(1H-indene-1,4'-piperidine), and substituting p-methoxybenzenesulfonyl chloride (21 mg, 0.1 mmol) for the p-bromo derivative. The title compound was obtained as a solid: (m.p. 181°-183°).