Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]=[N:6][C:7]1([N:13]=[C:14]=[S:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[CH:16]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.[N-]=C=S>CCCCC>[C:1]([N:5]=[N:6][C:7]1([NH:13][C:14]([NH:22][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[S:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: NC1CCCCC1
Reactant: CC(C)(C)N=NC1(N=C=S)CCCCC1
Agent: [N-]=C=S
Solvent: CCCCC
Product: CC(C)(C)N=NC1(NC(=S)NC2CCCCC2)CCCCC1
Reaction time: 3 h

Procedure:
To 8.4 grams (0.0363 moles) of 1-t-butylazo-1-isothiocyanatocyclohexane stirred with a magnetic stirrer in a 50 ml erlenmeyer flask was added 3.6 grams (0.0363 moles) of cyclohexylamine at room temperature. A solid slowly started to form and pentane was added to keep the reaction mixture from solidifying and the reaction mixture was stirred for 3 hours and the pentane stripped off to leave a yellow solid weighing 11.4 grams (95% crude yield). The product melted at 100°-102° C. and the infrared spectrum of the product had a strong broad band at 1520-1540 cm-1 and a NH band at 3220 cm-1. The isothiocyanate band at 2040 cm-1 was absent.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][N:6]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH2:14][CH2:13][C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]1=2.Cl.[C:22](=[O:25])([O-])[O-:23].[K+].[K+].[CH2:28]([C:31](Cl)(Cl)Cl)[CH2:29]C>CN(C=O)C>[CH2:29]([O:23][C:22](=[O:25])[N:2]([CH2:3][CH2:4][CH2:5][N:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]1=2)[CH3:1])[CH2:28][CH3:31]
Reactant: CCCC(Cl)(Cl)Cl
Reactant: CNCCCN1c2ccccc2CCc2ccccc21
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOC(=O)N(C)CCCN1c2ccccc2CCc2ccccc21
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Desipramine hydrochloride (1 equivalent, 0.2 gram) was added drop wise to a stirred solution of potassium carbonate (5 equivalents, 0.45 gram) in dry DMF at 0° C. Propyl chloroform (1.5 equivalents, 0.1 ml) which had been dissolved in dry DMF was added drop wise to this mixture and stirred for 6 hours at room temperature. The reaction mixture was quenched with water, extracted with ethyl acetate, the organic layer separated, washed with brine solution and dried over anhydrous sodium sulfate. The dried material was concentrated and purified by column chromatography to provide a yellow liquid (yield: 0.12 gram) and by HPLC (purity 95.7%). The FTIR, MS and 1H NMR spectra were consistent with the assigned structure with the empirical formula of C22H28N2O2.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[C:13](=O)([O-:15])[O-:14].[K+].[K+].C(=O)=O>O>[OH:10][C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:9][C:8]=1[C:13]([OH:15])=[O:14]
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: O=C([O-])[O-]
Agent: O=C=O
Agent: [K+]
Solvent: O
Product: O=C(O)c1cc(OC(F)(F)F)ccc1O
Temperature: 200 °C

Procedure:
178 g (1 mol) of 4-trifluoromethoxyphenol and 345 g (2.5 mol) of potassium carbonate were initially introduced into an autoclave which was then pressurized to 60 bar with carbon dioxide and heated at 200° C. for 4 hours. After cooling and releasing the pressure, the residue was dissolved in 1.5 l of hot water, the solution was filtered hot, the cooled filtrate was extracted using methylene chloride and the extract was clarified using active carbon. The pH was then adjusted to 1 and the precipitated product was filtered off with suction. 192 g of product having a melting point of 129° C. were obtained, which corresponds to 86% of theory.
Reaction SMILES: [F:1][C:2]([F:50])([F:49])[C:3]1[CH:4]=[C:5]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][O:19][C@H:18]([CH2:22][O:23][CH3:24])[CH2:17]2)[CH2:10][C@H:9]1[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[C:28]([NH:33][CH2:34][N:35]2[C:39](=[O:40])[CH2:38][CH2:37][C:36]2=[O:41])[CH:27]=1)=[O:7].[BH4-].[Na+].O.C(OCC)(=O)C>CS(C)=O>[F:48][C:45]([F:46])([F:47])[C:43]1[CH:42]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:49])[F:50])[CH:44]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][O:19][C@H:18]([CH2:22][O:23][CH3:24])[CH2:17]2)[CH2:10][C@H:9]1[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[C:28]([NH:33][CH3:34])[CH:27]=1)=[O:7].[F:47][C:45]([F:46])([F:48])[C:43]1[CH:42]=[C:5]([CH:4]=[C:3]([C:2]([F:50])([F:49])[F:1])[CH:44]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][O:19][C@H:18]([CH2:22][O:23][CH3:24])[CH2:17]2)[CH2:10][C@H:9]1[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[C:28]([NH:33][CH2:34][N:35]2[CH:39]([OH:40])[CH2:38][CH2:37][C:36]2=[O:41])[CH:27]=1)=[O:7]
Reactant: COC[C@@H]1CN(CCN2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H](Cc3ccc(C)c(NCN4C(=O)CCC4=O)c3)C2)CCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CNc1cc(C[C@@H]2CN(CCN3CCO[C@H](COC)C3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)ccc1C
Product: COC[C@@H]1CN(CCN2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H](Cc3ccc(C)c(NCN4C(=O)CCC4O)c3)C2)CCO1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
A solution of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[4-methyl-3-[[(2,5-dioxopyrrolidino)methyl]amino]benzyl]-4-[2-[(2S)-2-(methoxymethyl)morpholino]ethyl]piperazine (0.14 g) in dimethylsulfoxide (0.42 ml) was added sodium borohydride (10 mg) and the whole was stirred at 80° C. for 15 hours. After cooling, water and ethyl acetate were added to the mixture. The organic layer was separated, washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of methylene chloride and methanol (30:1 to 10:1) as eluent to give (2R)-1-[3,5-bis(trifluoromethyl)-benzoyl]-2-[4-methyl-3-(methylamino)benzyl]-4-[2-[(2S)-2-(methoxymethyl)morpholino]ethyl]piperazine (37 mg) and (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[4-methyl-3-[[(5-hydroxy-2-oxopyrrolidino)methyl]amino]benzyl]-4-[2-[(2S)-2-(methoxymethyl)morpholino]ethyl]piperazine (45 mg), respectively. Each compound was converted to its trihydrochloride in a conventional manner.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH:7]=O.[CH3:9][NH:10][CH3:11].[C-:12]#[N:13].[K+].O>CCOCC>[CH3:9][N:10]([CH3:11])[CH:7]([C:2]1[N:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[C:12]#[N:13]
Reactant: O=Cc1ncccn1
Reactant: CNC
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: CN(C)C(C#N)c1ncccn1
Reaction time: 8 h

Procedure:
To 27.0 g. of 2-pyrimidinecarboxaldehyde and 11.3 g. of dimethylamine (neutralized with hydrochloric acid) is added, with stirring and cooling, 17.9 g. of potassium cyanide in a small amount of water. The mixture is allowed to stand overnight and ether is added. Concentrating and distilling the residue gives 2-dimethylamino-2-(2-pyrimidyl)acetonitrile.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[Cl:20][C:21]1[C:29]([F:30])=[CH:28][C:24]([C:25]([OH:27])=O)=[C:23]([F:31])[CH:22]=1.CCN=C=NCCCN(C)C.Cl.Cl.[C:45]1([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[CH:50]=[CH:49][C:48]([NH:51][C:52](=[O:62])[CH2:53][C:54](=[O:61])[N:55]2[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]2)=[CH:47][CH:46]=1>CN(C=O)C.O>[C:45]1([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[CH:46]=[CH:47][C:48]([NH:51][C:52](=[O:62])[CH2:53][C:54]([N:55]2[CH2:56][CH2:57][N:58]([C:25](=[O:27])[C:24]3[CH:28]=[C:29]([F:30])[C:21]([Cl:20])=[CH:22][C:23]=3[F:31])[CH2:59][CH2:60]2)=[O:61])=[CH:49][CH:50]=1
Reactant: O=C(O)c1cc(F)c(Cl)cc1F
Reactant: O=C(CC(=O)N1CCNCC1)Nc1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CC(=O)N1CCN(C(=O)c2cc(F)c(Cl)cc2F)CC1)Nc1ccc(-c2ccccc2)cc1
Temperature: 10 °C
Reaction time: 8 h
Yield: 24.1 %

Procedure:
HOBt (34 mg, 0.25 mmol) and DIPEA (67.9 mg, 0.51 mmol) were added to a stirred solution of 4-chloro-2,5-difluoro-benzoic acid (40 mg, 0.21 mmol) in DMF (1 mL). The reaction mixture was cooled to 10° C. and EDCI.HCl (48 mg, 0.25 mmol) followed by N-biphenyl-4-yl-3-oxo-3-piperazin-1-yl-propionamide.hydrochloride (75 mg, 0.2 mmol) were added. The mixture was stirred at room temperature overnight then diluted with water. The resulting precipitate was filtered then purified by column chromatography using silica gel 60-120 mesh and 60% ethyl acetate in hexane to afford 24 mg (23%) of N-biphenyl-4-yl-3-[4-(4-chloro-2,5-difluoro-benzoyl)-piperazin-1-yl]-3-oxo-propionamide. LCMS: 498.18 (M+1)+, 97.0%. 1H NMR: (CDCl3): δ 9.6 (d, 1H), 7.52 (m, 6H), 7.49 (t, 2H), 7.35 (t, 1H), 7.25 (t, 1H), 3.7 (m, 3H), 3.56 (d, 3H), 3.55 (d, 2H), 3.4 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.Cl[CH2:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:19][CH2:18]1)=[O:16]>C(OCC)C>[F:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][CH:20]2[CH2:21][CH2:22][N:17]([C:15](=[O:16])[CH2:14][NH:1][C:2]3[CH:3]=[CH:4][C:5]4[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=4[CH:12]=3)[CH2:18][CH2:19]2)=[CH:25][CH:26]=1
Reactant: Nc1ccc2c(c1)NC(=O)CO2
Reactant: O=C(CCl)N1CCC(Cc2ccc(F)cc2)CC1
Solvent: CCOCC
Product: O=C1COc2ccc(NCC(=O)N3CCC(Cc4ccc(F)cc4)CC3)cc2N1

Procedure:
The title compound is prepared from 6-amino-4H-benzo[1,4]oxazin-3-one and 2-chloro-1-[4-(4-fluoro-benzyl)-piperidin-1-yl]-ethanone (Example 197a) according to the method described in Example 142b. Melting Point: 220-223° C. (diethylether)
Reaction SMILES: [Si](Cl)(C(C)(C)C)(C)C.[CH2:9]([N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[CH3:10].ClCCl.C(#[N:21])C.CN(C=[O:26])C>CN(C)C1C=CN=CC=1>[NH:21]1[CH:13]=[CH:12][N:11]=[CH:9]1.[CH3:12][N:11]1[CH2:14][CH2:15][O:26][CH2:10][CH2:9]1
Reactant: CN(C)C=O
Reactant: CCN(CC)CC
Reactant: CC#N
Agent: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CN1CCOCC1
Product: c1c[nH]cn1
Temperature: 50 °C

Procedure:
More specifically, a glycine methyl ester (8) is reacted with 2-nitrobenznesulfonyl chloride in accordance with an already known method, thereby obtaining a 2-nitrobenzenesulofonylated compound (9). The above-described chloro-derivative (6) is reacted with the compound (9) under the same conditions as described above to obtain a compound (10). The compound (10) is treated by an already known method, thereby obtaining a compound (11). The compound (11) is reduced by lithium aluminum hydride under the same conditions as described above, thereby obtaining an alcohol (12). The compound (12) is reacted with tert-butyldimethylsilyl chloride (TBDMS-Cl) at 0° C. to reflux temperature, preferably 50° C. for 1 hour to several days, preferably a night in the presence of a base such as imidazole, triethylamine or 4-methylmorpholine and 4-(dimethylamino)pyridine in a solvent dichloromethane, acetonitrile or DMF to obtain a TBDMS-derivative (13). The compound (13) is reacted with 9-fluorenylmethoxycarbonyl-amino acid (Fmoc-amino acid) (14) at 0° C. to reflux temperature, preferably room temperature for 1 minute to several days, preferably 10 minutes in the presence of a dehydration-condensing agent such as dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (water-soluble carbodiimide hydrochloride) or O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU) in a solvent such as chloroform, dichloromethane, acetonitrile, THF, DMF or DMSO, thereby obtaining a compound (15). The compound (15) is reacted with piperidine in accordance with an already known method, thereby obtaining an amine derivative (16). The compound (16) is reacted with the above-described 2-nitrobenzenesulfonyl chloride under the same conditions as described above to obtain a 2-nitrobenzenesulfonylated compound (17). The compound (17) is treated by an already known method, thereby obtaining an alcohol (18). The compound (18) is dissolved in a solvent such as THF or dioxane and reacted with triphenylphosphine and diethyl azodicarboxylate (DEAD) at 0° C. to reflux temperature, preferably room temperature for 1 hour to several days, preferably a night, thereby obtaining a compound (19). The compound (19) is subjected to de-2-nitrobenzenesulfonylation by an already known method to obtain a compound (20). The above-described chloro-derivative (6) is reacted with the compound (20) under the same conditions as described above, thereby obtaining a compound (1b) according to the present invention.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1)[NH2:5].C(N(CC)CC)C.Cl[C:32](Cl)([O:34]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:43][C:44]1[O:48][N:47]=[C:46]([CH3:49])[CH:45]=1>C(Cl)(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:32]([NH:43][C:44]2[O:48][N:47]=[C:46]([CH3:49])[CH:45]=2)=[O:34])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1cc(N)on1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3Cl)c2cc1OC
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1cc2ncnc(Oc3ccc(NC(=O)Nc4cc(C)no4)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 58.6 %

Procedure:
3-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (84 mg) was dissolved in chloroform (2.5 ml) and triethylamine (0.25 ml) to prepare a solution. A solution of triphosgene (38 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 5 min. Next, 5-amino-3-methylisoxazole (27 mg) was added thereto, and the mixture was further stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was subjected to separatory extraction with chloroform. The organic layer was concentrated and was evaporated to dryness. Diethyl ether was added to the resultant solid, and the solid was collected by filtration and was further washed with methyl alcohol to give the title compound (34.2 mg, yield 30%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]=[CH:12][N:11]=[CH:10]1.[Br:14][CH2:15][CH2:16][CH3:17]>C1COCC1>[Br-:14].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N+:9]1[CH:13]=[CH:12][N:11]([CH2:15][CH2:16][CH3:17])[CH:10]=1
Reactant: COc1ccccc1-n1ccnc1
Reactant: CCCBr
Solvent: C1CCOC1
Product: CCCn1cc[n+](-c2ccccc2OC)c1
Product: [Br-]

Procedure:
According to the general synthesis procedure, 4.48 mmol (0.700 g) 1-(2-methoxyphenyl)imidazole and 4.93 mmol (0.606 g, 0.45 ml) 1-bromopropane are dissolved in 5 ml THF and heated for 5 h to 80° C.
Reaction SMILES: O[O:2][S:3]([O-:5])=O.[K+].[F:7][C:8]1[CH:9]=[C:10]([OH:16])[CH:11]=[CH:12][C:13]=1SC.[C:17](=O)(O)[O-].[Na+]>O.O1CCCC1>[F:7][C:8]1[CH:9]=[C:10]([OH:16])[CH:11]=[CH:12][C:13]=1[S:3]([CH3:17])(=[O:5])=[O:2]
Reactant: CSc1ccc(O)cc1F
Reactant: O=S([O-])OO
Reactant: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(O)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
A solution of oxone (19.6 g, 32 mmol) in water (50 mL) was added to a rapidly stirred solution of 3-fluoro-4-methylsulfanyl-phenol (2.47 g, 15.6 mmol) in tetrahydrofuran (100 mL). The mixture was stirred for 1 h at room temperature and then it was poured into aqueous sodium bicarbonate solution. The mixture was extracted three times with ethyl acetate, and the combined extracts were washed with brine, dried (magnesium sulfate), filtered, evaporated, and eluted through a short silica plug with 50% ethyl acetate/hexanes to give 3-fluoro-4-methanesulfonyl-phenol (2.31 g, 78%) as a light brown oil that solidified on standing.
Reaction SMILES: [NH:1]([CH:5](C)[CH2:6][CH2:7][CH2:8][C:9]([NH:11][C@H:12]([C:19]([OH:21])=[O:20])[CH2:13][C:14]1[N:18]=[CH:17][NH:16][CH:15]=1)=O)[C:2]([NH2:4])=[NH:3].C(SC(=N)N)C.OS(O)(=O)=O.NCCCCCC(N[C@H]([C:50]([OH:52])=[O:51])CC1N=CNC=1)=O>>[NH:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:50]([OH:52])=[O:51])[C:2]([NH2:4])=[NH:3].[NH2:11][C@H:12]([C:19]([OH:21])=[O:20])[CH2:13][C:14]1[N:18]=[CH:17][NH:16][CH:15]=1
Reactant: NCCCCCC(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O
Reactant: CC(CCCC(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O)NC(=N)N
Agent: CCSC(=N)N
Agent: O=S(=O)(O)O
Product: N=C(N)NCCCCCC(=O)O
Product: N[C@@H](Cc1c[nH]cn1)C(=O)O

Procedure:
ε-Guanidinohexanoyl-L-histidine (n=5) -- S-Ethylisothiourea. H2SO4 (1.4 g.) and εAhx-His (1.7 g.) were treated in the same way as Example 2; yield, 56.1%; mp, 102°-103° C., decomp. Hydrolysis as above gave ε-guanidinohexanoic acid and histidine (tlc).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[CH:19]=[CH:18][C:17]([C@@H:20]([NH:22][C:23](=[O:25])[CH3:24])[CH3:21])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:26][CH:27]1[CH2:29][CH:28]1[CH2:30]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC1CCCO1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[CH3:26][CH:27]1[CH2:29][CH:28]1[CH2:30][O:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[CH:15]=[CH:16][C:17]([C@@H:20]([NH:22][C:23](=[O:25])[CH3:24])[CH3:21])=[CH:18][CH:19]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC1CC1CO
Reactant: CC(=O)N[C@@H](C)c1ccc(C2CCN(c3ccc(O)cc3)CC2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC1CCCO1
Product: CC(=O)N[C@@H](C)c1ccc(C2CCN(c3ccc(OCC4CC4C)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
50 mg (0.15 mmol) (S)—N-{1-(4-[1-(4-Hydroxyphenyl)-piperidin-4-yl]-phenyl}-ethyl)-acetamide (compound 1.48), 14 mg (0.16 mmol) 2-methylcyclopropanemethanol and 38.8 mg (0.15 mmol) triphenylphosphine are added to 2 mL 2-methyl-tetrahydrofurane at 0° C. 30.5 μl (0.15 mmol) di-iso-propyl azodicarboxylate are added and the mixture is allowed to warm to rt. Stirring is continued over night followed by addition of 0.5 equivalents of triphenylphosphine and 0.5 equivalents of di-iso-propyl azodicarboxylate. Stirring is continued for one day and again additional triphenylphosphine and di-iso-propyl azodicarboxylate are added and stirring is continued for 16 h at 50° C. Then the mixture is filtered and purified using reversed phase HPLC (water/MeOH, 0.1% FA) to yield the desired product.
Reaction SMILES: CC1(C)[O:6][CH:5]([C:7]([NH:9][C:10]2[C:11]([I:33])=[C:12]([C:18]([I:32])=[C:19]([NH:22][C:23]([CH:25]3[CH2:29][O:28]C(C)(C)[O:26]3)=[O:24])[C:20]=2[I:21])[CH2:13]CC([O-])=O)=[O:8])[CH2:4][O:3]1.C([O-])([O-])=[O:36].[Cs+].[Cs+].[C:41](OCCBr)(=[O:43])[CH3:42].CCOCC>CC(N(C)C)=O.CS(C)=O>[OH:26][CH:25]([CH2:29][OH:28])[C:23]([N:22]([CH2:42][CH2:41][OH:43])[C:19]1[C:18]([I:32])=[C:12]([C:11]([I:33])=[C:10]([NH:9][C:7](=[O:8])[CH:5]([OH:6])[CH2:4][OH:3])[C:20]=1[I:21])[CH2:13][OH:36])=[O:24]
Reactant: O=C([O-])[O-]
Reactant: CC1(C)OCC(C(=O)Nc2c(I)c(CCC(=O)[O-])c(I)c(NC(=O)C3COC(C)(C)O3)c2I)O1
Reactant: CC(=O)OCCBr
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: CCOCC
Solvent: CS(C)=O
Product: O=C(Nc1c(I)c(CO)c(I)c(N(CCO)C(=O)C(O)CO)c1I)C(O)CO
Yield: 29.9 %

Procedure:
N,N'-Bis(2,2-dimethyl-1,3-dioxolane-4-carbonyl)-3,5-diamino-2,4,6-triiodobenzylacetate (204 mg, 0.25 mmol) was dissolved in a mixture of dimethylacetamide (4 ml) and DMSO (2.5 ml) containing Cs2CO3 (650 mg, 2.0 mmol) and 2-bromoethyl acetate (0.035 ml, 0.31 mmol). After stirring for 1 week, ether (150 ml) and a NaH2PO4 buffer (100 ml) were added, the organic phase was separated and the aqueous phase was extracted with ether (150 ml). The combined organic phases were then washed with water (6×100 ml), dried (Na2SO4) and evaporated. The residue was dissolved in a mixture of methanol (20 ml) and water (20 ml) and pH was adjusted to 12 with aqueous NaOH. After stirring for 1 h, the pH was adjusted to 1.5 with concentrated HCl and stirred for another 16 h. The solution was neutralized with aqueous NaH2PO4 and the solvents were evaporated. Preparative HPLC gave 55 mg (30%) of the pure product.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[C:6]1([C:12]2[C:21]3[N:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:15](=O)[NH:14][CH:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-].[Na+]>C1(C)C=CC=CC=1.CN(C)C1C=CC=CC=1>[C:6]1([C:12]2[CH:13]=[N:14][C:15]([Cl:3])=[C:16]3[C:21]=2[N:20]=[CH:19][CH:18]=[CH:17]3)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=c1[nH]cc(-c2ccccc2)c2ncccc12
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CN(C)c1ccccc1
Product: Clc1ncc(-c2ccccc2)c2ncccc12
Temperature: 0 °C

Procedure:
12.1 ml (130 mmol) of phosphoryl chloride are added dropwise at room temperature to a suspension of 22.2 g (100 mmol) of 8-phenyl-1,6-naphthyridin-5(6H)-one [173773-04-1] in 100 ml of toluene. After addition of 5 drops of N,N-dimethylaniline, the reaction mixture is heated under reflux for 5 h. After cooling, the reaction mixture is diluted with 300 ml of toluene, poured onto 1000 g of ice and rendered alkaline (pH about 9) by addition of 5 N NaOH. The organic phase is separated off, washed once with 300 ml of sat. sodium chloride solution, dried over magnesium sulfate, and the toluene is removed in vacuo. Yield: 22.9 g (95 mmol), 95%. Purity: >95% according to 1H-NMR.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:19][C:6]2=[C:7]([C:12]([N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)=[O:13])[S:8][C:9]([S:10][CH3:11])=[C:5]2[C:4](=[O:20])[C:3]1=[CH:21]O.Cl.[NH2:25]O>CCO.O>[CH3:1][C:2]1([CH3:23])[C:3]2[CH:21]=[N:25][O:20][C:4]=2[C:5]2=[C:9]([S:10][CH3:11])[S:8][C:7]([C:12]([N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)=[O:13])=[C:6]2[CH2:19]1
Reactant: NO
Reactant: CSc1sc(C(=O)N2CCCC2)c2c1C(=O)C(=CO)C(C)(C)C2
Agent: Cl
Solvent: CCO
Solvent: O
Product: CSc1sc(C(=O)N2CCCC2)c2c1-c1oncc1C(C)(C)C2
Temperature: 25 °C

Procedure:
To a solution of 6,6-dimethyl-5-hydroxymethylene-3-methylthio-1-(pyrrolidin-1-ylcarbonyl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one (173 mg, 0.49 mmol) in EtOH (4 mL) and water (0.7 mL) was added hydroxylamine hydrochloride (38 mg, 0.54 mmol). The solution was heated at reflux for 2 h then cooled to room temperature and the solvent evaporated. The residue was partitioned between EtOAc (20 mL) and water (20 mL), the organic layer separated, dried (Na2SO4) and evaporated. The residue was triturated with hexane/Et2O and the resultant yellow solid (131 mg, 77%) collected by filtration. mp 114-116° C. C17H2ON20N2S2O2.0.1(H2O) requires: C, 58.29; H, 5.81; N, 8.00%. Found: C, 58.05; H, 5.59; N, 7.65%. 1H NMR (360 MHz, CDCl3) δ1.26 (6H, s), 1.94-1.98 (4H, m), 2.63 (3H, s), 2.90 (2H, s), 3.56-3.67 (4H, m), 8.20 (1H, s). MS (ES+) 349 (M+1).
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[Cl:12][CH:13]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[Cl:24])[C:14](Cl)=[O:15]>ClCCl>[C:1]([O:5][C:14](=[O:15])[CH:13]([Cl:12])[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[Cl:24])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)C(Cl)c1ccc(Cl)cc1Cl
Reactant: CC(C)(C)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C(Cl)c1ccc(Cl)cc1Cl
Yield: 82.6 %

Procedure:
While stirring and with ice cooling, a solution of 17.6 g of t-butanol and 19.2 ml of pyridine in 60 ml of dichloromethane is dripped into a solution, cooled at 5° C., of 62 g of α-chloro-α-(2,4-dichlorophenyl)-acetyl chloride in 60 ml of dichloromethane in such a manner that the temperature of the reaction mixture stays below 10° C. After all the solution has been dripped in, the mixture is stirred overnight at room temperature, is then diluted with 100 ml of dichloromethane and extracted 5 times, each time with 100 ml of water. The organic phase is dried over magnesium sulfate and distilled after the solvent has been evaporated. There is obtained 58 g of α-chloro-α-(2,4-dichlorophenyl)-acetic acid t-butyl ester as a colorless oil; b.p. 98°-103° C./0.13 mbar.