Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:20][NH:21][O:22][CH3:23].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([N:21]([O:22][CH3:23])[CH3:20])=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)c1ccccc1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)[C@@H](NC(=O)OC(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-2-((tert-butoxycarbonyl)amino)-2-phenylacetic acid (1.0 g, 4.0 mmol) in dichloromethane (10 mL) were added N,O-dimethyl hydroxylamine hydrochloride (0.77 g, 8.0 mmol), EDCl (1.2 g, 6.0 mmol), HOBt (0.05 g, 0.4 mmol), Et3N (0.8 g, 8.0 mmol) and the contents were stirred at ambient temperature. After 2 hr, the reaction was quenched with ice cold H2O (10 mL), and the organic contents were extracted with CH2Cl2 (2×30 mL). The combined organic extracts were washed with brine (1×20 mL), dried over Na2SO4, concentrated and the residue thus obtained was purified by flash column chromatography to afford (S)-tert-butyl(2-(methoxy(methyl)amino)-2-oxo-1-phenylethyl)carbamate. 1H NMR (300 MHz, CDCl3) δ 7.39-7.29 (m, 5H), 5.77 (bs, 1H), 5.73 (bs, 1H), 3.47 (s, 3H), 3.20 (s, 3H), 1.42 (s, 9H).
Reaction SMILES: [CH2:1]([C:3]1([CH2:12][CH2:13][CH2:14]Br)[C:8](=[O:9])[NH:7][C:6](=[O:10])[NH:5][C:4]1=[O:11])[CH3:2].[N-:16]=[N+:17]=[N-:18].[Na+].O>CC(C)=O>[CH2:1]([C:3]1([CH2:12][CH2:13][CH2:14][N:16]=[N+:17]=[N-:18])[C:8](=[O:9])[NH:7][C:6](=[O:10])[NH:5][C:4]1=[O:11])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCC1(CCCBr)C(=O)NC(=O)NC1=O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCC1(CCCN=[N+]=[N-])C(=O)NC(=O)NC1=O

Procedure:
A solution of 30 g of 5-ethyl-5-(3-bromopropyl) barbituric acid and 13 g of sodium azide in 350 ml of acetone was added to 240 ml of water and refluxed for approximately 18 hours. Thereafter, the solution was cooled on ice, filtered, air dried, and dissolved in a minimal amount of hot 95% ethanol. Crystals appeared after cooling and were filtered and air-dried. The melting point was 182°-184° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[CH:2]1.[CH2:10](O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]C.CS(O)(=O)=O>C1(C)C=CC=CC=1>[CH2:9]([O:8][C:6]([C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)=[O:7])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH3:10]
Reactant: CCCCCCCCCCCCCCO
Reactant: COC(=O)c1ccsc1
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCOC(=O)c1ccsc1
Yield: 92.4 %

Procedure:
To a 200 mL round bottom flask were added 10 g (70 mmol) of methyl 3-thiophenecarboxylate, 17 g (79 mmol) of 1-tetradecanol, 1 mL methanesulfonic acid, and 50 mL of toluene. This mixture was heated to reflux for 17 hours. After the solvent was removed, the remaining methyl 3-thiophenecarboxylate was removed by kugelrohr distillation. The remaining residue was filtered through a silica gel pad with 10% ethyl acetate in hexane. The solvents were removed from the filtrate to provide 21 g of the desired compound. The NMR data were obtained and were consistent with those of the desired compound.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:5][C@H:4]([N:6]2[C:10]3=[N:11][CH:12]=[CH:13][N:14]=[C:9]3[C:8]([CH3:16])([CH3:15])[C:7]2=[O:17])[CH2:3]1.Cl[C:19]1[O:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1.C(N(C(C)C)CC)(C)C>CS(C)=O>[O:20]1[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=[C:19]1[NH:1][C@H:2]1[CH2:5][C@H:4]([N:6]2[C:10]3=[N:11][CH:12]=[CH:13][N:14]=[C:9]3[C:8]([CH3:15])([CH3:16])[C:7]2=[O:17])[CH2:3]1
Reactant: CC1(C)C(=O)N([C@H]2C[C@H](N)C2)c2nccnc21
Reactant: Clc1nc2ccccc2o1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)C(=O)N([C@H]2C[C@H](Nc3nc4ccccc4o3)C2)c2nccnc21
Temperature: 90 °C
Reaction time: 17 h

Procedure:
To a round bottomed flask was added 5-(trans-3-aminocyclobutyl)-7,7-dimethyl-5H-pyrrolo[2,3-b]pyrazin-6(7H)-one (Intermediate 30, 0.1663 g, 0.716 mmol, [00391]), 2-chlorobenzo[d]oxazole (0.132 g, 0.859 mmol, Sigma-Aldrich Chemical Company, Inc.), and diisopropylethylamine (0.249 ml, 1.432 mmol, Sigma-Aldrich Chemical Company, Inc.) in DMSO (2.386 ml) to stir at 90° C. for 17 hours. The crude product was purified by reverse-phase preparative HPLC using 0.1% TFA in CH3CN/H2O, gradient 10% to 90% over min. Product was taken up in DCM and loaded onto a Silicycle Si-carbonate cartridge to remove any salts to give 5-(trans-3-(benzo[d]oxazol-2-ylamino)cyclobutyl)-7,7-dimethyl-5H-pyrrolo[2,3-b]pyrazin-6(7H)-one (32.2 mg, 0.092 mmol, 12.87% yield). LCMS showed product peak at 1.625 min (m+1=350.0). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.34 (s, 6 H) 2.42-2.48 (m, 1 H) 3.18-3.29 (m, 2 H) 4.47-4.60 (m, 1 H) 5.17 (quin, J=8.31 Hz, 1 H) 6.95-7.04 (m, 1 H) 7.12 (td, J=7.63, 0.98 Hz, 1 H) 7.28 (d, J=7.24 Hz, 1 H) 7.37 (d, J=7.63 Hz, 1 H) 8.18 (d, J=3.33 Hz, 1 H) 8.23 (d, J=3.13 Hz, 1 H) 8.42 (d, J=6.65 Hz, 1 H).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6](C(OC(C)(C)C)=O)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][CH:22]=[CH:21][N:20]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:18][C:19]1[C:24]([C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][CH:2]=2)[NH:8][N:7]=[CH:6]3)=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: CC1(C)OB(c2cccnc2Cl)OC1(C)C
Reactant: CC(C)(C)OC(=O)c1n[nH]c2cc(Br)ccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: Clc1ncccc1-c1ccc2[nH]ncc2c1
Yield: 74.3 %

Procedure:
Analogous to the reaction conditions and work-up procedures used in the preparation of 5-(2-chloropyridin-3-yl)-1H-indazole, 5-(2-chloropyridin-3-yl)-1H-indazole was obtained by heating the mixture of tert-butyl 6-bromo-1H-indazole-carboxylate (7.3 g, 24.6 mmol), 2-chloro-3-pyridine boronic acid pinacol ester (7.0 g, 29.5 mmol), Pd(PPh3)4 (2 g, 1.7 mmol) and aq.Na2CO3 (44 mL, 88 mmol) in 1,4-dioxane (200 mL) under argon atmosphere. The crude concentrate that was obtained after the extractive work-up dissolved in CH2Cl2, adsorbed on to silica gel and dried. Subsequent purification by flash silica gel column chromatography (Combiflash® companion System® with RediSep® silica gel column 120 g, 30-70% EtOAC/hexanes eluting solvent gradient upon dry powder loading) provided 5-(2-chloropyridin-3-yl)-1H-indazole as a white solid (4.2 g, 74%). 1H NMR (DMSO-d6): δ 13.21 (s, 1H), 8.43 (dd, 1H, J=1.7 and 4.7 Hz), 8.12 (s, 1H), 7.93 (dd, 1H, J=1.7 and 7.6 Hz), 7.84 (d, 1H, J=8.5 Hz), 7.59 (s, 1H), 7.52 (dd, 1H, J=4.7 and 7.6 Hz), 7.17 (d, 1H, J=8.5 Hz).LCMS: rt 6.17 min (A), purity 98%, MS (m/e) 230 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][S:17][CH2:18][C@H:19]([O:35][C:36](=[O:48])[NH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:20][O:21][C:22](=[O:34])[NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:82][CH2:83][CH2:84][O:85][CH2:86][CH2:87][O:88][CH2:89][CH2:90][O:91][CH2:92][CH2:93][P:94](=[O:101])([O:98][CH2:99][CH3:100])[O:95][CH2:96][CH3:97]>C(Cl)Cl>[CH2:99]([O:98][P:94]([CH2:93][CH2:92][O:91][CH2:90][CH2:89][O:88][CH2:87][CH2:86][O:85][CH2:84][CH2:83][NH:82][C:13](=[O:14])[C@@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])[CH2:16][S:17][CH2:18][C@H:19]([O:35][C:36](=[O:48])[NH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:20][O:21][C:22](=[O:34])[NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])(=[O:101])[O:95][CH2:96][CH3:97])[CH3:100]
Reactant: CCOP(=O)(CCOCCOCCOCCN)OCC
Reactant: CCCCCCCCCCNC(=O)OC[C@H](CSC[C@H](NC(=O)OCc1ccccc1)C(=O)O)OC(=O)NCCCCCCCCCC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCCCCCCNC(=O)OC[C@H](CSC[C@H](NC(=O)OCc1ccccc1)C(=O)NCCOCCOCCOCCP(=O)(OCC)OCC)OC(=O)NCCCCCCCCCC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (R)-2-(benzyloxycarbonylamino)-3-((R)-2,3-bis(decylcarbamoyloxy)propylthio) propanoic acid (15, 1 eq) and HBTU (1.2 eq) in DCM (0.06 M) was added DIEA (2.4 eq), followed by diethyl 2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethylphosphonate (1.2 eq, from example 18, step 4). The reaction was stirred at room temperature for 4 hours. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using a gradient of 0-10% MeOH/DCM to afford the title compound as a clear viscous oil.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([CH2:13][CH2:14][CH2:15][OH:16])(=[O:12])[CH3:11].Cl[CH2:18][O:19][CH3:20]>ClCCl>[CH3:18][O:19][CH2:20][O:16][CH2:15][CH2:14][CH2:13][C:10](=[O:12])[CH3:11]
Reactant: COCCl
Reactant: CC(=O)CCCO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOCCCC(C)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.2 %

Procedure:
Compound 27 intermediates: To diisopropylethyl amine (18.48 g, 143 mmol) in 200 mL of dichloromethane was added 3-acetyl-1-propanol (13.28 g, 130 mmol) at 0° C. After the solution was stirred for 0.5 hour, chloromethylmethyl ether (13.08 g, 162.5 mmol) was added while the temperature was maintained at 0° C. The resulting solution was stirred for another 1 hour, brought to room temperature and stirred overnight. Organic solvent was removed via rotary evaporation. The residue was treated with 100 mL of brine and extracted with 3×150 mL of diethyl ether. The organic layers were combined, dried over Na2SO4 and concentrated via rotary evaporation. The crude product was purified via a flash chromatography with dichloromethane as eluent to afford 5-methoxymethoxy-2-pentanone (14.3 g, yield: 75) as a pale oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:21]2[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=2)[C:5]2[O:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:7]3[C:17](=[O:20])[NH:18][C:19]=1[C:6]=23.[Cl-].[CH3:28][Zn+]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:28][C:2]1[CH:3]=[C:4]([C:21]2[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=2)[C:5]2[O:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:7]3[C:17](=[O:20])[NH:18][C:19]=1[C:6]=23
Reactant: Cn1nccc1-c1cc(Br)c2[nH]c(=O)n3c2c1OCC3c1ccccc1
Reactant: C[Zn+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1cc(-c2ccnn2C)c2c3c1[nH]c(=O)n3C(c1ccccc1)CO2

Procedure:
A reaction mixture of 9-bromo-7-(1-methyl-1H-pyrazol-5-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one (17 mg, 0.04 mmol), a solution of 2.0 M methylzinc chloride in THF (0.10 mL) and tetrakis(triphenylphosphine)palladium(0) (2 mg, 0.002 mmol) in THF (0.5 mL) under nitrogen was heated in a microwave at 130° C. for 5 min. The title compound was purified by preparative LCMS using a pH10 buffer. LCMS calc. for C20H19N4O2 (M+H)+: m/z=347.1. found: 347.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9](#[N:12])[CH:10]=[CH2:11]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:11][CH2:10][C:9]#[N:12])=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: C=CC#N
Product: N#CCCOc1ccc(F)cc1
Yield: 85 %

Procedure:
A mixture of 11.2 g of 4-fluorophenol, 26.5 g of acrylonitrile and 4.9 g of cupric hydroxide was refluxed for 8 hours with stirring, and then acrylonitrile and 4-fluorophenol were removed from the mixture under reduced pressure. After diluting the obtained residue with ether and filtering solid, the ether layer was successively washed with 10% aqueous solution of sodium hydroxide and 2N hydrochloric acid and dehydrated with anhydrous magnesium sulfate. Ether was distilled away to give 14.02 g of colorless liquid of 3-(4-fluorophenoxy)propionitrile (yield: 85%).
Reaction SMILES: [CH:1]1([N:4]=[C:5]=[O:6])[CH2:3][CH2:2]1.[CH:7]1([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:30])=[C:17]([N:22]4[CH2:27][CH:26]([CH3:28])[NH:25][CH:24]([CH3:29])[CH2:23]4)[C:18]=3[O:20][CH3:21])[C:13](=[O:31])[C:12]([C:32]([NH:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][C:37]=3[Cl:43])=[O:33])=[CH:11]2)[CH2:9][CH2:8]1>ClCCl>[CH:7]1([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:30])=[C:17]([N:22]4[CH2:23][CH:24]([CH3:29])[N:25]([C:5]([NH:4][CH:1]5[CH2:3][CH2:2]5)=[O:6])[CH:26]([CH3:28])[CH2:27]4)[C:18]=3[O:20][CH3:21])[C:13](=[O:31])[C:12]([C:32]([NH:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][C:37]=3[Cl:43])=[O:33])=[CH:11]2)[CH2:9][CH2:8]1
Reactant: O=C=NC1CC1
Reactant: COc1c(N2CC(C)NC(C)C2)c(F)cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3Cl)cn(C3CC3)c12
Solvent: ClCCl
Product: COc1c(N2CC(C)N(C(=O)NC3CC3)C(C)C2)c(F)cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3Cl)cn(C3CC3)c12
Temperature: 25 °C

Procedure:
30 μl (24.3 mg, 0.29 mmol) of cyclopropylisocyanate are dissolved in dichloromethan, 80.0 mg (0.146 mmol) of the compound of Example 12 are added and the mixture is stirred over night at room temperature. For the work-up the solvent is removed completely and after fine purification by preparative RP-HPLC (Method 6) 55 mg of the target compound are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([NH:13][C:14](=[O:25])[O:15][CH:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[CH3:17])=[CH:11][O:10][N:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][CH2:34][CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38].O>CN(C)C=O>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH:16]([O:15][C:14]([NH:13][C:12]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:7][CH:6]=2)=[N:9][O:10][CH:11]=1)=[O:25])[CH3:17]
Reactant: CCOC(=O)CCCCBr
Reactant: CC(OC(=O)Nc1conc1-c1ccc(O)cc1)c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCCOc1ccc(-c2nocc2NC(=O)OC(C)c2ccccc2Cl)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 54.3 %

Procedure:
To a solution (2 ml) of 1-(2-chlorophenyl)ethyl 3-(4-hydroxyphenyl)-4-isoxazolylcarbamate (80 mg, 0.223 mmol) in N,N-dimethylformamide were added potassium carbonate (60 mg, 0.435 mmol) and ethyl 5-bromovalerate (60 mg, 0.287 mmol), and the mixture was stirred at 100° C. for 1 hour. Water was added, the mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give the title compound (59 mg, 55%).
Reaction SMILES: [OH:1][CH:2]1[C:13]2=[C:14]3[C:9](=[CH:10][CH:11]=[CH:12]2)[CH:8]=[CH:7][CH:6]=[C:5]3[CH2:4][CH:3]1[NH:15][C:16](=[O:18])[CH3:17].[H-].[Na+].[CH3:21]I>CN(C=O)C>[CH3:21][O:1][CH:2]1[C:13]2=[C:14]3[C:9](=[CH:10][CH:11]=[CH:12]2)[CH:8]=[CH:7][CH:6]=[C:5]3[CH2:4][CH:3]1[NH:15][C:16](=[O:18])[CH3:17]
Reactant: CI
Reactant: CC(=O)NC1Cc2cccc3cccc(c23)C1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1c2cccc3cccc(c23)CC1NC(C)=O

Procedure:
The N-(1-hydroxy-2,3-dihydro-1H-phenalen-2-yl)acetamide obtained is stage C of Example 1 (1 mmol, 290 mg) is dissolved in 10 cm3 of anhydrous DMF. Under an inert atmosphere, NaH (1 mmol, 0.05 g of 60% in oil suspension) and then methyl iodide (0.09 cm3, 1.2 eq) are added in the reaction mixture. Stirring is maintained at ambiant temperature for 4h30 and the solvent is evaporated. The residue is taken up in CH2 Cl2 and the solution is flitrated. The filtrate is evaporated and purified by chromatography on silica gel (particle size 60-200 μm); eluent: CH2Cl2 : MeOH 99 :-1 v/v. The title product is isolated. This is and amorphous product, which is a diastereoisomer mixture.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:15][CH2:16][OH:17].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:15][CH2:16][OH:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: OCCN1CCC(Cc2ccccc2)CC1
Temperature: 110 °C
Yield: 40.7 %

Procedure:
To a solution of 4-benzylpiperidine (0.50 mL, 2.8 mmol) in DMF (15 mL) were added 2-chloroethanol (0.25 mL, 3.70 mmol) and K2CO3 (0.79 g, 5.70 mmol). The heterogeneous mixture was heated at 110° C. for 2 h. It was then cooled to 25° C. and was diluted with water (100 mL) and extracted with ether (2×70 mL). The collected organic phase was washed with water (2×100 mL), dried and concentrated in vacuo. The crude compound was purified by filtration on silica gel using CH2Cl2/MeOH as eluant to afford the title compound as a colorless solid (0.25 g, 40%): mp 62-64° C.; 1H NMR (CDCl3) δ1.15-1.35 (m, 2H), 1.45-1.60 (m, 1H), 1.63 (bd, J=13.8 Hz, 2H), 1.99 (t, J=11.7 Hz, 2H), 2.48 (t, J=5.7 Hz, 2H), 2.53 (d, J=6.9 Hz, 2H), 2.87 (bd, J=11.7 Hz, 2H), 2.9 (bs, 1H), 3.574 (t, J=5.4 Hz, 2H), 7.14 (d, J=7.2 Hz, 2H), 7.20 (d, J=6.9 Hz, 1H), 7.28 (t, J=6.2 Hz, 2H); MS (m/z) 219, 188, 91. Anal. Calcd for C14H21NO: C, 76.71; H 9.65; N, 6.40. Found: C, 74.49; H 9.29; N, 6.08.
Reaction SMILES: [OH-].[K+].[CH:3]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)=O.Br[C:12]1[S:13]C=[N:15][N:16]=1>>[S:13]1[CH:12]=[N:16][N:15]=[C:3]1[N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1
Reactant: O=CN1CCNCC1
Reactant: Brc1nncs1
Agent: [K+]
Agent: [OH-]
Product: c1nnc(N2CCNCC2)s1

Procedure:
The starting 1-(1,3,4-thiadiazol-2-yl)-piperazine was prepared by hydrolyzing with alcoholic potassium hydroxide the crude formyl derivative, itself prepared by condensing 1-formyl piperazine with 2-bromo-1,3,4-thiadiazole melting at 74° C. (Goerdeler and al., Ber 89 1534 (1956)).
Reaction SMILES: C[O-].[Na+].[CH3:4][C:5]1([CH3:32])[CH2:14][CH2:13][C:12]([CH3:16])([CH3:15])[C:11]2[CH:10]=[C:9]([C:17]([CH2:19][O:20][C:21]3[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=3[I:31])=O)[CH:8]=[CH:7][C:6]1=2.[Br-].[CH3:34]P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[I:31][C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][C:21]=1[O:20][CH:19]=[C:17]([C:9]1[CH:8]=[CH:7][C:6]2[C:5]([CH3:4])([CH3:32])[CH2:14][CH2:13][C:12]([CH3:15])([CH3:16])[C:11]=2[CH:10]=1)[CH3:34])[C:25]([O:27][CH3:28])=[O:26]
Reactant: C[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccc(OCC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)c(I)c1
Agent: C[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC=C(C)c2ccc3c(c2)C(C)(C)CCC3(C)C)c(I)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
30% sodium methoxide solution (2.67 g, 14.83 mmol) is added over 8 hours to a mixture of methyl 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthoyl)methoxy]-3-iodobenzoate (7.50 g, 14.8 mmol) and methyltriphenylphosphine bromide (7.30 g, 20.42 mmol) in THF (80 ml). The mixture is stirred for 18 hours at room temperature. The mixture is concentrated on a rotary evaporator under vacuum at 40° C. This is extracted with 90 ml of ethyl ether and 90 ml of water. After separation of the phases by settling, the organic phase is washed twice with 90 ml of water, dried over anhydrous magnesium sulphate and concentrated on a rotary evaporator under vacuum at 40° C. The product is purified by flash chromatography on a column of silica (70% CH2Cl2, 30% heptane).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23](O)=[O:24])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].O[N:27]=[C:28]([NH2:34])[CH2:29][S:30]([CH3:33])(=[O:32])=[O:31]>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:10][CH:11]([C:23]3[O:24][N:34]=[C:28]([CH2:29][S:30]([CH3:33])(=[O:32])=[O:31])[N:27]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[O:16])[CH2:14]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CS(=O)(=O)CC(N)=NO
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCOCC3)C2)cc1
Product: CCc1ccc(C2CC(c3nc(CS(C)(=O)=O)no3)CN(C(=O)N3CCOCC3)C2)cc1

Procedure:
60 mg (0.17 mmol) of the compound from Example 38A and 40 mg (0.26 mmol) of N′-hydroxy-2-(methylsulphonyl)ethanimidamide were reacted according to the General Method 2. Yield: 15 mg (18% of theory)
Reaction SMILES: [CH3:1][C:2]([N:6]([CH2:19][CH2:20][CH:21]=[O:22])[C:7]([NH:9][C:10]1[S:11][C:12]([C:15]([F:18])([F:17])[F:16])=[N:13][N:14]=1)=[O:8])([CH3:5])[C:3]#[CH:4].Cl>O>[F:16][C:15]([F:18])([F:17])[C:12]1[S:11][C:10]([N:9]2[CH:21]([OH:22])[CH2:20][CH2:19][N:6]([C:2]([CH3:1])([CH3:5])[C:3]#[CH:4])[C:7]2=[O:8])=[N:14][N:13]=1
Reactant: C#CC(C)(C)N(CCC=O)C(=O)Nc1nnc(C(F)(F)F)s1
Agent: Cl
Solvent: O
Product: C#CC(C)(C)N1CCC(O)N(c2nnc(C(F)(F)F)s2)C1=O

Procedure:
The diethyl acetal of 3-[1-(1,1-dimethylprop-2-ynyl)-3-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)ureido]-propionaldehyde (15 grams), water (400 ml) and hydrochloric acid (4 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. The reaction mixture is then filtered while hot and the filtrate is cooled to form a precipitate. The precipitate is recovered by filtration, is dried and is recrystallized to yield the desired product tetrahydro-1-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)-3-(1,1-dimethylprop-2-ynyl)-6-hydroxy-2(1H)-pyrimidinone.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:4]([C:13]([F:16])([F:15])[F:14])[CH:3]=1.[Cl:17][CH2:18][CH2:19][CH2:20]I.[H-].[Na+].C(OCC)(=O)C>O1CCCC1>[Cl:17][CH2:18][CH2:19][CH2:20][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[C:13]([F:14])([F:15])[F:16])[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)Cc1ccc(Cl)cc1C(F)(F)F
Reactant: ClCCCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)C(CCCCl)c1ccc(Cl)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of methyl (4-chloro-2-trifluoromethylphenyl)acetate (5.5 g) and 3-chloro-1-iodopropane (4.6 mL) in tetrahydrofuran (15 mL) was added dropwise to a suspension of sodium hydride (containing 60% in mineral oil, 955 mg) in tetrahydrofuran (50 mL) under ice-cooling. The reaction solution was stirred at the same temperature for 10 minutes and then at room temperature for three hours and 20 minutes. Ice water and ethyl acetate were added to the reaction solution, and the organic layer was separated. The aqueous layer was reextracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (carrier: Wakogel™ C-200; elution solvent:heptane:ethyl acetate=19:1) to obtain 5.30 g of the title compound. The property values of the compound are as follows.