Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][NH2:16])=[CH:11][N:10]=2)[CH:6]=[CH:5][N:4]=1.[N:19]1[CH:24]=[CH:23][N:22]=[CH:21][C:20]=1[C:25]1[CH:26]=[CH:27][C:28]([C:31]([OH:33])=O)=[N:29][CH:30]=1.[CH3:34]N(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:34][C:14]1[C:9]([C:7]2[CH:6]=[CH:5][N:4]=[C:3]([C:2]([F:1])([F:17])[F:18])[CH:8]=2)=[N:10][CH:11]=[C:12]([CH2:15][NH:16][C:31](=[O:33])[C:28]2[CH:27]=[CH:26][C:25]([C:20]3[CH:21]=[N:22][CH:23]=[CH:24][N:19]=3)=[CH:30][N:29]=2)[CH:13]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1ccc(-c2cnccn2)cn1
Reactant: NCc1ccc(-c2ccnc(C(F)(F)F)c2)nc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(CNC(=O)c2ccc(-c3cnccn3)cn2)cnc1-c1ccnc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of (2′-(trifluoromethyl)-2,4′-bipyridin-5-yl)methanamine 48-1 (27 mg, 0.10 mmol), 5-(pyrazin-2-yl)picolinic acid 41-4 (21 mg, 0.10 mmol) and HATU (38 mg, 0.10 mmol) in DMF (0.6 mL) was added DIEA (0.05 mL, 0.30 mmol). The mixture was stirred at room temperature for 2 hours. The solvent was removed by rotary evaporation. The crude product was purified by reverse phase HPLC to give N-((3-methyl-2′-(trifluoromethyl)-2,4′-bipyridin-5-yl)methyl)-5-(pyrazin-2-yl)picolinamide 55 as a white powder. MS m/z 451.20 (M+1); 1H NMR 400 MHz (DMSO-d6) δ 9.67 (t, 1H, J=6.0 Hz), 9.45 (d, 1H, J=1.2 Hz), 9.40 (d, 1H, J=0.8 Hz), 8.87-8.82 (m, 2H), 8.74-8.57 (m, 2H), 8.57 (m, 1H), 8.20 (d, 1H, J=8.4 Hz), 8.05 (m, 1H), 7.93 (dd, 1H, J1=9.6 Hz, J2=1.2 Hz), 7.77 (m, 1H), 4.59 (d, 2H, J=6.0 Hz), 2.38 (s, 3H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2.BrCCCN1C2C=CC=CC=2C2C1=CC=CC=2.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[C:43]1([OH:49])[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1.C([O-])([O-])=O.[K+].[K+]>CC(CC(C)C)=O>[ClH:1].[CH:16]1[C:17]2[N:5]([CH2:4][CH2:3][CH2:2][N:46]3[CH2:45][CH2:44][C:43]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=4[O:36][CH3:35])([OH:49])[CH2:48][CH2:47]3)[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12]=2[CH:13]=[CH:14][CH:15]=1
Reactant: COc1ccccc1C1(O)CCNCC1
Reactant: ClCCCn1c2ccccc2c2ccccc21
Agent: BrCCCn1c2ccccc2c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: COc1ccccc1C1(O)CCN(CCCn2c3ccccc3c3ccccc32)CC1
Product: Cl
Yield: 67.8 %

Procedure:
Compound 1 (0.879 g, 0.0036 mol ) was dissolved in methylisobutylketone (MIBK) (80 mL). 4-(2-Methoxyphenyl)piperidin-4-ol (1.123 g, 0.0054 mol) and K2CO3 (1.99 g, 0.0145 mol) were added. The resulting mixture was stirred at reflux temperature for 12 h. The reaction mixture was filtered and the solvent evaporated in vacuo. The residual oil was purified on a silica gel column (Eluent: CH2Cl2 /ethanol/25% NH4OH (aq) (92.75:7:0.25)). The product was acidified with 2M HCl(g) in diethylether, to give the title compound 1.1 g (68%). M.p. decomposes at 228° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10].[Br:11]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH2:10][Br:11]
Reactant: Cc1cc(C#N)ccc1Br
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(Br)c(CBr)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 36.4 %

Procedure:
To a solution of of 4-bromo-3-methylbenzonitrile (1.0 g, 5.0 mmol) in carbon tetrachloride (7.5 mL) was added N-bromosuccinimide (1.0 g, 5.6 mmol) followed by of benzoylperoxide (50 mg 0.2 mmol) and the mixture was refluxed. After 10 hours, the reaction was cooled to rt, filtered, and the filtrate was washed with 10% NaHSO3 (5 mL) followed by water (5 mL). The organic layer was dried (Na2SO4), filtered, volatiles removed, and the residue was purified by flash chromatography on silica gel. Elution with 10% Ethyl acetate in hexanes gave the title compound (0.5 g, 36%) as a white solid. 1H NMR (270 MHz, CDCl3) δ 4.55 (s, 2H), 7.38-7.42 (m, 1H), 7.65-7.77 (m, 2H).
Reaction SMILES: [NH3:1].O=O.C[CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:11].[CH3:12]O>>[C:5]([CH2:10][CH2:9][CH2:8][CH2:7][C:6](=[O:11])[CH3:12])#[N:1]
Reactant: CC1CCCCC1=O
Reactant: CO
Reactant: N
Agent: O=O
Product: CC(=O)CCCCC#N

Procedure:
A solution of 2 ml of NH3 in 50 ml of methanol is charged into a round bottom flask fitted with a gas inlet tube and a mechanical stirrer. Fitted to the gas inlet tube was an oxygen buret graduated in ml and containing oxygen gas. To this solution was added with stirring 0.015 g of CuCl2.H2O and 1.1 g of 2-methyl cyclohexanone. Stirring was continued until all solids had dissolved. A steady stream of oxygen was bubbled into the solution for approximately 20 hours, while the solution was stirred at room temperature. Total oxygen uptake was 190 ml. The methanol solvent was removed by rotary evaporator and the product extracted in ether. The ether layer was concentrated. IR analyses confirmed the presence of the desired compound and the lack of the oxazoline compound.
Reaction SMILES: [Cl-].[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[C:37]([O:41][C:42]([N:44]1[CH2:49][CH2:48][C:47](=O)[CH2:46][CH2:45]1)=[O:43])([CH3:40])([CH3:39])[CH3:38].O>C1COCC1>[C:37]([O:41][C:42]([N:44]1[CH2:49][CH2:48][C:47](=[CH:12][C:3]2[CH:4]=[CH:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:2]=2)[CH2:46][CH2:45]1)=[O:43])([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: c1ccc([P+](Cc2ccc3ccccc3n2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(=Cc2ccc3ccccc3n2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Under argon, 2-quinolylmethyltriphenylphosphonium chloride (8.72 g) was dissolved in anhydrous THF (60 ml), and a 1.6N solution (15 ml) of butyllithium was added dropwise over 20 minutes under cooling on ice. The mixture was then stirred for 10 minutes at room temperature. To the mixture, an anhydrous THF (24 ml) solution of 1-tert-butoxycarbonyl-4-ketopiperidine (4.29 g) was added dropwise over 15 minutes under cooling on ice. The mixture was stirred for 30 minutes under cooling on ice and further stirred overnight at room temperature. Water (200 ml) was added to the reaction mixture, then the resultant mixture was extracted with ether. The organic phase was back-extracted with 1N hydrochloric acid, and the aqueous phase was neutralized with a saturated solution of sodium hydrogencarbonate. The resultant mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate anhydrate, and concentrated under reduced pressure, to thereby obtain the title compound as a solid. This solid was used for subsequent reaction without further purification.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]([CH3:20])[C:3]1=[O:21].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[O:32])[CH:27]=[CH:28][CH:29]=1>O1CCCC1>[F:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:7]1[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]([CH3:20])[C:3](=[O:21])[CH:2]([NH:1][C:31]([NH:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([O:23][CH3:22])[CH:25]=2)=[O:32])[N:8]=1
Reactant: CN1C(=O)C(N)N=C(c2ccccc2F)c2ccccc21
Reactant: COc1cccc(N=C=O)c1
Solvent: C1CCOC1
Product: COc1cccc(NC(=O)NC2N=C(c3ccccc3F)c3ccccc3N(C)C2=O)c1
Reaction time: 8 h

Procedure:
Equimolar amounts of 3(R,S)-amino-1,3-dihydro-1-methyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one and 3-methoxyphenylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product: m.p. 271°-273° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[NH:14][C:13]([C:15]([C:50]4[C:55]([CH3:56])=[CH:54][C:53]([CH3:57])=[CH:52][C:51]=4[CH3:58])=[C:16]4[N:49]=[C:19]([C:20]([C:41]5[CH:46]=[CH:45][C:44]([CH2:47][OH:48])=[CH:43][CH:42]=5)=[C:21]5[NH:40][C:24](=[C:25]([C:31]6[C:36]([CH3:37])=[CH:35][C:34]([CH3:38])=[CH:33][C:32]=6[CH3:39])[C:26]6[CH:27]=[CH:28][C:29]=2[N:30]=6)[CH:23]=[CH:22]5)[CH:18]=[CH:17]4)=[CH:12][CH:11]=3)=[CH:5][CH:4]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl.C(Cl)(Cl)Cl>[CH:47]([C:44]1[CH:45]=[CH:46][C:41]([C:20]2[C:21]3[NH:40][C:24]([C:25]([C:31]4[C:32]([CH3:39])=[CH:33][C:34]([CH3:38])=[CH:35][C:36]=4[CH3:37])=[C:26]4[N:30]=[C:29]([C:9]([C:6]5[CH:7]=[CH:8][C:3]([CH:2]=[O:1])=[CH:4][CH:5]=5)=[C:10]5[NH:14][C:13](=[C:15]([C:50]6[C:51]([CH3:58])=[CH:52][C:53]([CH3:57])=[CH:54][C:55]=6[CH3:56])[C:16]6[CH:17]=[CH:18][C:19]=2[N:49]=6)[CH:12]=[CH:11]5)[CH:28]=[CH:27]4)=[CH:23][CH:22]=3)=[CH:42][CH:43]=1)=[O:48]
Reactant: Cc1cc(C)c(-c2c3nc(c(-c4ccc(CO)cc4)c4ccc([nH]4)c(-c4c(C)cc(C)cc4C)c4nc(c(-c5ccc(CO)cc5)c5ccc2[nH]5)C=C4)C=C3)c(C)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cc1cc(C)c(-c2c3nc(c(-c4ccc(C=O)cc4)c4ccc([nH]4)c(-c4c(C)cc(C)cc4C)c4nc(c(-c5ccc(C=O)cc5)c5ccc2[nH]5)C=C4)C=C3)c(C)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82.7 %

Procedure:
A solution of 15 (0.190 g, 0.250 mmol) in CH2Cl2 (25 mL) was treated with pyridinium chlorochromate (216 mg, 1.00 mmol). The reaction mixture was stirred at room temperature and monitored by TLC. After 90 min, the reaction mixture was poured on to a silica column (poured in CHCl3) and eluted with CHCl3/methanol (95:5) affording a purple solid (156 mg, 83%): 1H NMR δ −2.63 (brs, 2H), 1.84 (s, 12H), 2.63 (s, 6H), 7.29 (s, 4H), 8.28 (d, J=8.4 Hz, 4H), 8.41 (d, J=8.4 Hz, 4H), 8.71-8.78 (m, 8H), 10.39 (s, 2H); LD-MS obsd 755.24, calcd 754.3308 (C52H42N4O2); λabs 422, 515, 549, 594, 649 nm.
Reaction SMILES: [CH2:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)[CH2:2][CH3:3].[C:11]([C:13]1[CH:31]=[CH:30][C:16]([C:17]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([CH3:29])=[C:24]([CH:28]=2)[C:25](Cl)=[O:26])=[O:18])=[CH:15][CH:14]=1)#[N:12].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:25](=[O:26])[C:24]2[CH:28]=[C:20]([NH:19][C:17](=[O:18])[C:16]3[CH:30]=[CH:31][C:13]([C:11]#[N:12])=[CH:14][CH:15]=3)[CH:21]=[CH:22][C:23]=2[CH3:29])=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccc(N)cc1
Reactant: Cc1ccc(NC(=O)c2ccc(C#N)cc2)cc1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCc1ccc(NC(=O)c2cc(NC(=O)c3ccc(C#N)cc3)ccc2C)cc1
Yield: 16.4 %

Procedure:
4-n-Propylaniline (0.11 g) was added to a stirred suspension of 5-(4-cyanobenzamido)-2-methylbenzoyl chloride (0.224 g), triethylamine (0.21 ml) and methylene chloride (5 ml) and the resultant mixture was stirred at ambient temperature for 16 hours. The mixture was filtered and the filtrate was evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and methanol as eluent. There was thus obtained the title compound (0.049 g); NMR Spectrum: (DMSOd6) 0.87 (t, 3H), 1.56 (m, 2H), 2.33 (s, 3H), 2.48 (m, 2H), 7.13 (d, 2H), 7.28 (d, 1H), 7.63 (m, 2H), 7.83 (m, 3H), 8.01 (d, 1H), 8.1 (m, 2H); Mass Spectrum: M+H+ 398.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1CC[O:18][CH2:17][CH2:16]1.C(=O)C.C(N1CCC(N2CCOCC2)=CC1)C1C=CC=CC=1>O.C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([CH:17]([OH:18])[CH3:16])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: C1COCCN1
Agent: C1=C(N2CCOCC2)CCN(Cc2ccccc2)C1
Agent: CC=O
Solvent: O
Solvent: ClCCl
Product: CC(O)C1CN(Cc2ccccc2)CCC1=O
Reaction time: 8 h
Yield: 37.9 %

Procedure:
A 100 ml tolune solution of 10.0 g (52.9 mmol) of 1-benzyl-4-piperidone and 4.61 g (52.9 mmol) of morpholine was subjected to azeotropic dehydration for 5 hours under heating and reflux by using a water separator. After completion of the reaction, the solvent was distilled off under reduced pressure, whereby 13.7 g of 1-benzyl-4-morpholino-1,2,5,6-tetrahydropyridine were quantitatively obtained. In an argon atmosphere, a 20 ml methylene chloride solution of 1.52 g (34.6 mmol) of acetaldehyde was cooled to −40° C., followed by the dropwise addition of 5.3 ml (43 mmol) of a boron trifluoride-ether complex and 7.44 g (28.8 mmol) of the 1-benzyl-4-morpholino-1,2,5,6-tetrahydropyridine obtained above. After completion of the dropwise addition, the temperature was gradually raised and the reaction mixture was allowed to stand overnight at room temperature. Water was added to terminate the reaction, followed by extraction with methylene chloride. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to chromatography on a silica gel column (eluting solvent: toluene/ethyl acetate=4/1), whereby 4.68 g (yield: 69.7%) of 1-benzyl-3-(1-hydroxyethyl)-4-piperidone were obtained as a yellowish brown oil.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[CH3:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:15]1[CH:20]=[C:19]([CH:21]([F:23])[F:22])[N:18]=[C:17]([S:24][CH3:25])[N:16]=1.[H-].[Na+]>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C@@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:15]1[CH:20]=[C:19]([CH:21]([F:23])[F:22])[N:18]=[C:17]([S:24][CH3:25])[N:16]=1)[CH3:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CSc1nc(Cl)cc(C(F)F)n1
Reactant: C[C@@H](OC(C)(C)C)[C@H]1COC(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSc1nc(C(F)F)cc(N2C(=O)OC[C@@H]2[C@@H](C)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
A solution of (R)-4-((R)-1-tert-butoxyethyl)oxazolidin-2-one (0.100 g, 0.534 mmol) and 4-chloro-6-(difluoromethyl)-2-(methylthio)pyrimidine (0.124 g, 0.587 mmol, 1.10 equiv) in DMF (2.7 mL) was treated with NaH (60%, 0.026 g, 0.64 mmol, 1.20 equiv), then the resulting mixture (yellow) was stirred at room temperature for 30 min. The reaction mixture was diluted with EtOAc (20 mL), washed with saturated aqueous NaCl (2×20 mL), dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane 0 to 40%) provided (R)-4-((R)-1-tert-butoxyethyl)-3-(6-(difluoromethyl)-2-(methylthio)pyrimidin-4-yl)oxazolidin-2-one (0.164 g, white solid) in 85% yield. 1H NMR (400 MHz, CDCl3) δ 8.15 (s, 1H), 6.45 (t, J=54 Hz, 1H), 4.80-4.72 (m, 1H), 4.66 (dd, J=9.4, 3.0 Hz, 1H), 4.49-4.34 (m, 2H), 2.58 (s, 3H), 1.25 (s, 9H), 1.02 (d, J=6.5 Hz, 3H); MS m/z 362.3 (M+H)+; Rt-1.09 min.
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH3:15])[CH2:3][CH:4]([C:10]([O:12]CC)=[O:11])[C:5]([O:7]CC)=[O:6].CO.[OH-].[K+].C1(C)C=CC=CC=1>O>[CH3:1][C:2]([CH3:16])([CH3:15])[CH2:3][CH:4]([C:5]([OH:7])=[O:6])[C:10]([OH:12])=[O:11]
Reactant: CCOC(=O)C(CC(C)(C)C)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O
Product: CC(C)(C)CC(C(=O)O)C(=O)O

Procedure:
To a solution of the above-obtained diethyl (2,2-dimethylpropyl)malonate on 500 cm3 of methanol a solution of 125 g of KOH in 1000 cm3 of water was added. The obtained mixture was refluxed for 5 h, and then methanol and ethanol were distilled off at atmospheric pressure. To the residue ca. 3000 cm3 of water was added, the obtained solution was acidified by saturated HCl to pH 1. The formed product was extracted with 3×500 ml of ether. To the combined extract 200 ml of toluene was added, and the obtained solution was evaporated in vacuum to give a ca. 3 to 1 mixture of the title product and toluene (on the evidence of NMR spectroscopy). This mixture was further used without an additional purification.
Reaction SMILES: [F:1][C@H:2]1[CH2:6][NH:5][C@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.S(Cl)([Cl:12])=O.[CH3:14]O>>[ClH:12].[F:1][CH:2]1[CH2:6][NH:5][CH:4]([C:7]([O:9][CH3:14])=[O:8])[CH2:3]1
Reactant: O=C(O)[C@@H]1C[C@@H](F)CN1
Reactant: CO
Reactant: O=S(Cl)Cl
Product: COC(=O)C1CC(F)CN1
Product: Cl
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A round bottom flask was charged with (2S,4R)-4-fluoropyrrolidine-2-carboxylic acid (300 mg, 2254 μmol) and 22 mL MeOH. The heterogeneous mixture was cooled to 0° C. under nitrogen, and thionyl chloride (181 μl, 2479 μmol) was added dropwise. The reaction mixture was allowed to warm slowly to RT, and stirring was continued overnight at 65° C. The mixture was concentrated under high vacuum to provide methyl 4-fluoropyrrolidine-2-carboxylate hydrochloride as a mixture of the (2S,4R) and (2R,4R) diastereomers, confirmed by 1H and 13C NMR.
Reaction SMILES: [CH:1]1([C:4]2[S:8][C:7]([N:9]3[CH:14]([OH:15])[CH2:13][CH2:12][N:11]([CH3:16])[C:10]3=[O:17])=[N:6][N:5]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:25][O:26][CH2:27][C:28](Cl)=[O:29]>C1C=CC=CC=1>[CH:1]1([C:4]2[S:8][C:7]([N:9]3[CH:14]([O:15][C:28](=[O:29])[CH2:27][O:26][CH3:25])[CH2:13][CH2:12][N:11]([CH3:16])[C:10]3=[O:17])=[N:6][N:5]=2)[CH2:2][CH2:3]1
Reactant: CN1CCC(O)N(c2nnc(C3CC3)s2)C1=O
Reactant: COCC(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COCC(=O)OC1CCN(C)C(=O)N1c1nnc(C2CC2)s1

Procedure:
Tetrahydro-1-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2(1H)-pyrimidinone 0.05 mole), triethylamine (0.06 mole) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. Methoxyacetyl chloride (0.05 mole) is then added dropwise with stirring. After the addition is completed, the reaction mixture is heated at reflux with continued stirring for a period of about 30 minutes. After this time the reaction mixture is filtered and the filtrate is stripped of solvent under reduced pressure to yield the desired product tetrahydro-1-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-methoxyacetyloxy-2(1H)-pyrimidinone as the residue.
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]4=[O:25])=[CH:11][C:10]=3[F:26])[CH2:5][CH2:4]2)[CH2:2]1.OCC[CH2:30][SH:31]>>[O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]4=[O:25])=[CH:11][C:10]=3[F:26])[CH2:5][CH2:4]2)[CH2:30][S:31][CH2:2]1
Reactant: OCCCS
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)CO4)c(F)c2)C(=O)O1
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)CSCO4)c(F)c2)C(=O)O1

Procedure:
The title compound was prepared by reacting (S)—N-{3-[4-(1-oxa-6-aza-spiro[2.5]oct-6-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (0.275 mmol) and 3-hydroxypropanethiol (mmol) in at a temperature ° C. for hours in % yield. Mp; 114-116° C., Mass m/z 424.1 (ES+, 100%) for C20H26FN3O4S.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:24])[C:11]3[N:16]([CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)[N:15]=[C:14]([CH3:23])[C:12]=3[N:13]=2)=[C:4]([O:25][CH2:26][CH3:27])[CH:3]=1.Cl.[CH2:29]([N:31]([CH:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)[C:32](=[O:41])[O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH3:30]>>[CH:17]1([N:16]2[C:11]3[C:10](=[O:24])[NH:9][C:8]([C:5]4[CH:6]=[CH:7][C:2]([N:45]5[CH2:44][CH2:43][CH:42]([N:31]([CH2:29][CH3:30])[C:32](=[O:41])[O:33][CH2:34][C:35]6[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=6)[CH2:47][CH2:46]5)=[CH:3][C:4]=4[O:25][CH2:26][CH3:27])=[N:13][C:12]=3[C:14]([CH3:23])=[N:15]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCN(C(=O)OCc1ccccc1)C1CCNCC1
Reactant: CCOc1cc(Br)ccc1-c1nc2c(C)nn(C3CCCCC3)c2c(=O)[nH]1
Agent: Cl
Product: CCOc1cc(N2CCC(N(CC)C(=O)OCc3ccccc3)CC2)ccc1-c1nc2c(C)nn(C3CCCCC3)c2c(=O)[nH]1
Yield: 47 %

Procedure:
The same reaction procedure as in Example 16 was performed, except that the compound obtained in Example 116 was used in place of the compound obtained in Example 15, and benzyl ethyl(4-piperidinyl)carbamate monohydrochloride was used in place of N-methylpiperazine. In this manner, 134 mg (47%) of the captioned compound was obtained.
Reaction SMILES: [Br:1][C:2]([Br:5])(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([C@H:30]1[CH2:35][CH2:34][C@H:33]([CH2:36][CH2:37][C:38]2[CH:45]=[CH:44][C:41]([CH:42]=O)=[CH:40][CH:39]=2)[CH2:32][CH2:31]1)[CH2:26][CH2:27][CH2:28][CH3:29].CCCCC>C(Cl)Cl.[Zn]>[Br:1][C:2]([Br:5])=[CH:42][C:41]1[CH:44]=[CH:45][C:38]([CH2:37][CH2:36][C@H:33]2[CH2:32][CH2:31][C@H:30]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:35][CH2:34]2)=[CH:39][CH:40]=1
Reactant: CCCCC[C@H]1CC[C@H](CCc2ccc(C=O)cc2)CC1
Reactant: BrC(Br)(Br)Br
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCC
Solvent: ClCCl
Product: CCCCC[C@H]1CC[C@H](CCc2ccc(C=C(Br)Br)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 70.9 %

Procedure:
A mixture of 13.27 g of tetrabromomethane, 10.49 g of triphenylphosphine and 2.62 g of zinc dust in 100 ml of methylene chloride was stirred at room temperature for 24 hours in a sulphonation flask under argon gasification. In so doing, the heterogeneous mixture changed in colour via yellow-green to dark violet and pale violet. A solution of 2.86 g of p-[2-(trans-4-pentylcyclohexyl)ethyl]benzaldehyde in 10 ml of methylene chloride was subsequently added dropwise, the mixture was stirred at room temperature for 4 hours and then poured into 700 ml of pentane. The voluminous precipitate which separated was filtered off (rinsing with pentane), the concentrated filtrate (5.25 g) was digested with 300 ml of pentane, filtered and concentrated. Low-pressure chromatography (0.5 bar) of the residue (4.8 g) on silica gel with 3% ethyl acetate/petroleum ether gave 3.13 g (71%) of β,β-dibromo-p-[2-(trans-4-pentylcyclohexyl)ethyl]styrene as colourless crystals (purity 99.8%); m.p. 47.3° C.
Reaction SMILES: C[Si](C)(C)CCS([N:8]1[CH:13]=[CH:12][C:11](=[O:14])[CH2:10][CH:9]1[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)(=O)=O.[F-].[Cs+].C(O)(=O)C>CN(C=O)C.C(OCC)(=O)C>[NH:8]1[CH:13]=[CH:12][C:11](=[O:14])[CH2:10][CH:9]1[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: C[Si](C)(C)CCS(=O)(=O)N1C=CC(=O)CC1c1cccnc1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=C1C=CNC(c2cccnc2)C1
Temperature: 90 °C
Yield: 94.4 %

Procedure:
To a solution of 1-(2-trimethylsilyl-ethanesulfonyl)-2,3-dihydro-1H-[2,3′]bipyridinyl-4-one (106.1 mg, 0.31 mmol) in DMF (0.5 mL) was added cesium fluoride (153.5 mg, 1.0 mmol) under Ar atmosphere. The mixture was heated at 90° C. for 2 hours, then cooled to room temperature. Acetic acid (0.062 mL, 1.085 mmol) was added, and the mixture was diluted with ethyl acetate and filtered. The filtrate was taken to dryness under reduced pressure. Purification of the residue by flash chromatography (dichloromethane/methanol 95:5) gave 2,3-dihydro-1H-[2,3′]bipyridinyl-4-one (51 mg, 93.5%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[CH:3]=1.[NH2:12][CH2:13][CH2:14][NH:15][CH2:16][CH2:17][OH:18].C([O-])([O-])=O.[K+].[K+].CN1CCCC1=O>O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:12][CH2:13][CH2:14][NH:15][CH2:16][CH2:17][OH:18])=[CH:3][C:4]=1[CH3:11])([O-:10])=[O:9]
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: NCCNCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cc(NCCNCCO)ccc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 42.1 %

Procedure:
2 g of 4-fluoro-2-methyl-nitrobenzene, 1.61 g of 2-(2-aminoethylamino)ethanol and 2.14 g of K2CO3 were added to a solution of 20 ml of N-methylpyrrolidinone. The reaction medium was heated at 60° C. for 7 hours and, after cooling to room temperature, was then poured into a water and ice mixture. The yellow precipitate formed was filtered off, reslurried in water and then dried over P2O5. 1.3 g of 2-[2-(4-nitro-3-methylphenylamino)ethylamino]ethanol (7) were obtained.