Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH3:34][NH:35][CH2:36][CH2:37][CH2:38][CH:39]=[CH2:40].[CH2:41]([O:45][C:46]1[CH:47]=[C:48]([C:56]2[NH:60][C:59](=[O:61])[C:58]3([CH2:66][CH2:65][N:64]([S:67]([CH2:70][CH2:71][C:72]4[CH:80]=[CH:79][C:75]([C:76](O)=[O:77])=[CH:74][C:73]=4[CH3:81])(=[O:69])=[O:68])[CH2:63][CH2:62]3)[N:57]=2)[CH:49]=[C:50]([C:52]([F:55])([F:54])[F:53])[CH:51]=1)[CH2:42][CH:43]=[CH2:44].[Cl-].[NH4+]>CN(C=O)C>[CH2:41]([O:45][C:46]1[CH:47]=[C:48]([C:56]2[NH:60][C:59](=[O:61])[C:58]3([CH2:66][CH2:65][N:64]([S:67]([CH2:70][CH2:71][C:72]4[CH:80]=[CH:79][C:75]([C:76]([N:35]([CH3:34])[CH2:36][CH2:37][CH2:38][CH:39]=[CH2:40])=[O:77])=[CH:74][C:73]=4[CH3:81])(=[O:68])=[O:69])[CH2:63][CH2:62]3)[N:57]=2)[CH:49]=[C:50]([C:52]([F:53])([F:55])[F:54])[CH:51]=1)[CH2:42][CH:43]=[CH2:44]
Reactant: C=CCCCNC
Reactant: C=CCCOc1cc(C2=NC3(CCN(S(=O)(=O)CCc4ccc(C(=O)O)cc4C)CC3)C(=O)N2)cc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=CCCCN(C)C(=O)c1ccc(CCS(=O)(=O)N2CCC3(CC2)N=C(c2cc(OCCC=C)cc(C(F)(F)F)c2)NC3=O)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.4 %

Procedure:
HATU (194 mg, 0.510 mmol), N,N-diisopropylethylamine (143 μL) and methyl-pent-4-enyl-amine (80 mg) were added to a solution of 4-{2-[2-(3-but-3-enyloxy-5-trifluoromethyl-phenyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl]-ethyl}-3-methyl-benzoic acid (200 mg, 0.337 mmol) in DMF (3 ml), and the mixture was stirred at room temperature overnight. A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 4-{2-[2-(3-but-3-enyloxy-5-trifluoromethyl-phenyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl]-ethyl}-3,N-dimethyl-N-pent-4-enyl-benzamide (192 mg, 84%).
Reaction SMILES: Br[CH:2]([CH3:8])[CH:3]([O:6][CH3:7])[O:4][CH3:5].O.[NH2:10][NH2:11]>>[CH3:5][O:4][CH:3]([O:6][CH3:7])[CH:2]([NH:10][NH2:11])[CH3:8]
Reactant: NN
Reactant: COC(OC)C(C)Br
Solvent: O
Product: COC(OC)C(C)NN
Temperature: 140 °C

Procedure:
6.25 g (34.1 mmol) of 2-bromo-1,1-dimethoxypropane and 6.65 ml (137 mmol) of hydrazine hydrate were stirred under reflux in an oil bath at 140° C. for 6 h. After cooling, the two-phase reaction mixture was extracted with 50 ml of tert-butyl methyl ether. The organic phase was filtered, the filtrate was concentrated on a rotary evaporator and the residue was dried under high vacuum. This gave 1.89 g (21% of theory) of a pale yellow oil which was reacted directly, without further purification, in the subsequent reaction.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:9]=[C:10]2[C:22](=[O:23])[NH:21][N:20]=[CH:19][C:12]3=[C:13]([CH:17]=[O:18])[NH:14][C:15]([CH:16]=1)=[C:11]23)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:9]=[C:10]2[C:22](=[O:23])[NH:21][N:20]=[CH:19][C:12]3=[C:13]([CH2:17][OH:18])[NH:14][C:15]([CH:16]=1)=[C:11]23)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc2c3c(c(C=O)[nH]c3c1)C=NNC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cc2c3c(c(CO)[nH]c3c1)C=NNC2=O
Yield: 49.8 %

Procedure:
A solution of intermediate 230(a) of Example 230 (26 mg, 0.079 mmol) in methanol (2 mL) was treated with NaBH4 (6 mg, 0.16 mmol) at 0° C. for 15 min. The solution was quenched with saturated aqueous NH4Cl and diluted with ethyl acetate. After extraction, the organic phase was washed with brine, dried (Na2SO4), filtered, and concentrated. Silica gel chromatography of the residue (3:1 ethyl acetate:hexane) gave intermediate 241(a) (13 mg) in 50% yield.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:34]=[CH:33][C:9]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]#[C:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[H][H]>C(O)(=O)C.O=[Pt]=O>[CH2:1]([O:3][C:4]([C:6]1[CH:34]=[CH:33][C:9]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=2)=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)c1ccc(OCCCCCCCCC#CCCCCOc2ccc(Cl)cc2)cc1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(OCCCCCCCCCCCCCCOc2ccc(Cl)cc2)cc1
Yield: 80.3 %

Procedure:
1-(4-ethoxycarbonylphenoxy)-14-(4-chlorophenoxy)-tetradec 9-yne (2.00 g.; 0.0041 M.) in acetic acid (15 ml.) was reduced in the presence of hydrogen and PtO2 (0.05 g.) at 60° C. and atmospheric pressure. When hydrogen absorption was complete the solution was filtered, the catalyst washed well with ethanol and the solvents evaporated under reduced pressure to yield a colourless oil. 1-(4-ethoxycarbonylphenoxy)-14-(4-chlorophenoxy)-tetradecane (1.62 g.; 80%) M.P. 72.5°-73.5° C. was obtained as a pure crystalline compound by chromatography of this oil on silica-gel (100 g.).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1[CH:10]=[C:11]([O:16][CH3:17])[CH:12]=[CH:13][C:14]=1[CH3:15].[N:18]([O-:20])=[O:19].[Na+]>O>[CH3:15][C:14]1[C:9]([CH3:8])=[CH:10][C:11]([O:16][CH3:17])=[C:12]([N+:18]([O-:20])=[O:19])[CH:13]=1
Reactant: COc1ccc(C)c(C)c1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1cc(C)c(C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 14 h
Yield: 55 %

Procedure:
Trifluoroacetic acid(250 ml) was added into 3,4-dimethylanisole(17.1 g, 0.13 mol), successively sodium nitrite(16.6 g, 0.24 mol) was added slowly in water bath, and stirred at room temperature for 14 hrs. After trifluoroacetic acid was removed and water was added thereto, the resulting mixture was extracted with ether, and purified by column chromatography to obtain the titled compound.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[C:4]([NH:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=O)([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]>C(Cl)Cl>[C:7]([O:6][C:4](=[O:5])[NH:11][CH2:12][CH2:13][CH2:14][C:15](=[O:17])[NH:3][CH2:1][CH3:2])([CH3:8])([CH3:9])[CH3:10]
Reactant: CCN
Reactant: CC(C)(C)OC(=O)NCCCC(=O)O
Solvent: ClCCl
Product: CCNC(=O)CCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
An aqueous solution of ethylamine (70%, 41 ml) was added into an ice cold solution of benzotriazole derivative 2 (50 g, 156 mmol) in CH2Cl2 (500 ml), stirred for 1 h at room temperature, diluted 2 times with CH2Cl2, washed with H2O, then brine, dried (Na2SO4), concentrated and dried in vacuo. Yield 32.845 g (91%). mp: 82-83° C. 1H NMR (CDCl3): 1.15 (t, J=7.27, 3H), 1.44 (s, 9H), 1.75-1.85 (m, 2H), 2.20 (t, J=7.10, 2H), 3.17 (q, J=6.49, 2H), 3.24-3.34 (m, 2H), 4.82 (s, 1H), 6.13 (bs, 1H). 13C NMR (CDCl3): 14.72, 24.91, 26.33, 28.35, 33.66, 33.92, 34.32, 39.78, 79.21, 156.44, 172.43. ESI-MS: 483.4 (M2Na+), 461.4 (M2H+), 321.2 (MH+).
Reaction SMILES: [N:1]1([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[O:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl.[O-:17][C:18]#[N:19].[K+].[OH-].[Na+]>O>[NH2:19][C:18]([N:4]1[CH2:3][CH2:2][N:1]([CH2:7][C:8]([N:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)=[O:9])[CH2:6][CH2:5]1)=[O:17]
Reactant: N#C[O-]
Reactant: O=C(CN1CCNCC1)N1CCOCC1
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: NC(=O)N1CCN(CC(=O)N2CCOCC2)CC1
Reaction time: 8 h
Yield: 54.1 %

Procedure:
9.1 g of piperazin-1-yl-acetic acid morpholide are dissolved in 30 ml of water and 4.4 ml of concentrated hydrochloric acid and the solution is cooled to 20° C. A solution of 3.1 g of potassium cyanate in 15 ml of water is slowly added dropwise, with cooling. A further 4.4 ml of concentrated hydrochloric acid are then added and the mixture is left to stand overnight at 20° C. The solution is rendered neutral with 2N sodium hydroxide solution and concentrated. Boiling up of the solid residue with isopropanol and cooling of the solution gives 5.3 g of colourless crystals, which are recrystallised from ethanol.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[N:3]=1.[OH:12][C:13]1[C:14]([C:19]([O:21][CH3:22])=[O:20])=[N:15][CH:16]=[CH:17][CH:18]=1.CS([O-])=O.[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:11][O:10][C:4]1[CH:5]=[C:6]([O:8][CH3:9])[N:7]=[C:2]([O:12][C:13]2[C:14]([C:19]([O:21][CH3:22])=[O:20])=[N:15][CH:16]=[CH:17][CH:18]=2)[N:3]=1
Reactant: COC(=O)c1ncccc1O
Reactant: COc1cc(OC)nc(Cl)n1
Agent: CS(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ncccc1Oc1nc(OC)cc(OC)n1
Reaction time: 5 h

Procedure:
1.75 g (10 mmol) of 2-chloro-4,6-dimethoxypyrimidine, 1.53 g (10 mmol) of methyl 3-hydroxy-2-pyridinecarboxylate and 0.104 g (1.0 mmol) of sodium methanesulfinate were heated in the presence of 2.17 g (15 mmol) of potassium carbonate in 6 ml of N,N-dimethylformamide to 100° C. with stirring. After 5 hours, the solvent was removed in a rotary evaporator at 60° C./20 mbar. The residue was purified by chromatography on a silica gel column (eluent hexane/ethyl acetate 4:1). The title product was obtained from the product fraction in the form of a yellowish oil in a yield of 1.94 g (61 percent of theory) (GC content 92.3 percent). Other data concerning the title compound was:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[C:13]([F:16])([F:15])[F:14])[C:7]([OH:9])=O)[CH3:2].Cl.[CH3:18][NH:19][O:20][CH3:21].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>CN(C1C=CN=CC=1)C.C(Cl)Cl.CN(C=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[C:13]([F:16])([F:15])[F:14])[C:7]([N:19]([O:20][CH3:21])[CH3:18])=[O:9])[CH3:2]
Reactant: CCOc1cc(C(=O)O)ccc1C(F)(F)F
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)N(C)OC)ccc1C(F)(F)F
Temperature: 23 °C
Reaction time: 18 h

Procedure:
To a mixture of 3-ethoxy-4-trifluoromethyl-benzoic acid from step 6 (13.76 g, 59 mmol), N,O-dimethylhydroxylamine hydrochloride (9.17 g, 94 mmol), N-methylmorpholine (9.51 mL, 94 mmol) and 4-DMAP (718 mg, 6 mmol) in DCM (185 mL) and DMF (38 mL) at 0° C. was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (13.52 g, 70 mmol), and the mixture was stirred at 23° C. for 18 h. Poured onto ice cold 1 N HCl, extracted with TBME, washed with sat. NaHCO3-sol. and brine, dried over Na2SO4. Removal of the solvent in vacuum left the title compound as a light brown oil (16.15 g, 100%, which was used without further purification. MS (ISP) 278.4 [M+H].
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]1[N:21]=[C:20]([NH:22][CH2:23][CH2:24][NH2:25])[N:19]2[CH:26]=[CH:27][N:28]=[C:18]2[CH:17]=1.F[C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][N:31]=1.C(=O)(O)[O-].[K+]>CS(C)=O>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]1[N:21]=[C:20]([NH:22][CH2:23][CH2:24][NH:25][C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][N:31]=2)[N:19]2[CH:26]=[CH:27][N:28]=[C:18]2[CH:17]=1
Reactant: NCCNc1nc(-c2ccc(Cl)cc2Cl)cc2nccn12
Reactant: Fc1ccc(C(F)(F)F)cn1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1ccc(NCCNc2nc(-c3ccc(Cl)cc3Cl)cc3nccn23)nc1
Temperature: 130 °C

Procedure:
50 mg (0.155 mmol) of the amine (Example 8A) are introduced into 3 ml of dry DMSO, 51.2 mg (0.31 mmol) of 2-fluoro-5-(trifluoromethyl)pyridine and 31.1 mg (0.31 mmol) of potassium bicarbonate are added, and the mixture is heated at 130° C. under argon for 16 h. Purification by preparative HPLC results in 22 mg (30% of theory) of the product as a solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15]Cl)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[C:6]=2[CH:24]=1.[CH2:25]([NH:27][CH2:28][CH:29]1[CH2:31][CH2:30]1)[CH3:26]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][N:27]([CH2:28][CH:29]4[CH2:31][CH2:30]4)[CH2:25][CH3:26])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[C:6]=2[CH:24]=1
Reactant: CCNCC1CC1
Reactant: Fc1ccc2c(c1)C(c1ccccc1F)=NCc1nnc(CCl)n1-2
Product: CCN(Cc1nnc2n1-c1ccc(F)cc1C(c1ccccc1F)=NC2)CC1CC1

Procedure:
In the manner given in Preparation 29, 8-fluoro-1-(chloromethyl)-6-(o-fluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine is treated with ethyl(cyclopropylmethyl)amine to give 8-fluoro-1-[[(cyclopropylmethyl)ethylamino]methyl]-6-(o-fluorophenyl)-4-H-s-triazolo[4,3-a][1,4]benzodiazepine. Preparation 36 9-(Trifluoromethyl)-1-[[(cyclopropylmethyl)methylamino]methyl]-6-phenyl-4-H-s-triazolo[4,3-a][1,4]benzodiazepine
Reaction SMILES: [C:1]([O:5][C:6](=[O:49])[CH2:7][N:8]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([S:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=2)(=[O:35])=[O:34])[NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21](B3OC(C)(C)C(C)(C)O3)=[CH:20][CH:19]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:51]1[S:52][CH:53]=[C:54]([C:56]([F:59])([F:58])[F:57])[N:55]=1>>[C:1]([O:5][C:6](=[O:49])[CH2:7][N:8]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([S:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=2)(=[O:35])=[O:34])[NH:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:51]3[S:52][CH:53]=[C:54]([C:56]([F:59])([F:58])[F:57])[N:55]=3)=[CH:22][CH:23]=2)[N:10]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: FC(F)(F)c1csc(Br)n1
Reactant: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1cccc(C(NCc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)S(=O)(=O)c2ccccn2)n1
Product: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1cccc(C(NCc2ccc(-c3nc(C(F)(F)F)cs3)cc2)S(=O)(=O)c2ccccn2)n1
Yield: 90 %

Procedure:
Reaction and post-treatment were carried out in the same manner as in Example 22-(c) except for using tert-butyl[tert-butoxycarbonyl(6-{(pyridin-2-ylsulfonyl)[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzyl]aminomethyl}pyridin-2-yl)amino]acetate (490 mg, containing 0.700 mmol of a pure content) obtained in Example 22-(b), and using 2-bromo-4-trifluoromethylthiazole (see WO 2005/077912A) (341 mg, 1.47 mmol) in place of 2-bromo-5-methylthiazole to afford the title compound (454 mg) as a white foam. (Yield: 90%)
Reaction SMILES: C(OC(C(F)(F)F)C(F)(F)F)(=O)C(C)=C.O=C=NC1CC(C)(C)CC(C)(CN=C=O)C1.[C:32]([C:35]1[CH:36]=[C:37]([CH:44]=[CH:45][CH:46]=1)C(N=C=O)(C)C)([CH3:34])=[CH2:33]>>[CH3:34][C:32]([C:35]1[CH:36]=[CH:37][CH:44]=[CH:45][CH:46]=1)=[CH2:33]
Reactant: C=C(C)c1cccc(C(C)(C)N=C=O)c1
Agent: C=C(C)C(=O)OC(C(F)(F)F)C(F)(F)F
Agent: CC1(C)CC(N=C=O)CC(C)(CN=C=O)C1
Product: C=C(C)c1ccccc1

Procedure:
9.045 g (5.53 m equiv. amine) of an α,ω-di-propylamino-poly-(dimethyl siloxane) of MW 1636 (Shin Etsu Corp. No. X-22-161A) are placed in a 1 oz. jar; 4.56 g of hexafluoroisopropyl methacrylate (F6MA) are added and the mixture is stirred and cooled in an ice-water bath. 0.21 g (0.9546 m moles) of isophorone diisocyanate (IPDI) are added and the mixture is stirred for 2 hours at room temperature until all isocycanate has disappeared (by IR). Then 1.85 g (9.22 m moles) m-isopropenyl-α,α-dimethylbenzyl isocyanate (TMI) are added and the mixture is stirred for 2 more hours to yield a clear viscous liquid of a 70.90% solution of α-methyl styrene capped, chain extended poly(dimethyl siloxane) of MW 2426 (calculated) in F6MA.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([C@H:13]([OH:23])[CH2:14][O:15]CC2C=CC=CC=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1.CN(C=O)C.[H-].[Na+]>[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([C@H:13]([O:23][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)[CH2:14][OH:15])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Fc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]([C@H](O)COCc2ccccc2)C1
Agent: [Pd]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@H]([C@@H](CO)Oc2ccc(C(F)(F)F)cc2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62.8 %

Procedure:
(S)-3-((S)-2-Benzyloxy-1-hydroxyethyl)-pyrrolidine-1-carboxylic acid t-butyl ester (4.6 g, 14 mmol, 10. eq.) was combined with 4-fluorobenzotrifluoride (5.5 mL, 42.9 mmol, 3.0 eq.) in DMF (30 mL, 400 mmol). The mixture was degassed under nitrogen, and NaH (481 mg, 20.0 mmol) was added in small portions. The resulting mixture was stirred for 10 minutes at room temperature, followed by stirring at 90° C. for 3 hours. The mixture was then cooled to room temperature, extracted with hexanes (50 mL), and washed with water (50 mL) then 2M aqueous NaCl (50 mL). The organic layer was collected, stirred in activated carbon (460 mg) for 5 minutes, dried over Na2SO4, filtered, and concentrated. The resulting crude oil was dissolved in MeOH (50 mL), and 10% Pd/C (0.1:0.9, Palladium:carbon black, 670 mg, 630 μmol) was added under nitrogen. The mixture was stirred under hydrogen (1 atm) overnight. The mixture was filtered and the filtrate was concentrated. The resulting crude oil was dissolved in hexanes (˜30 mL) and EtOAc (˜15 ml), then concentrated until precipitate formed. Additional hexanes was added and the precipitate was stirred for 15 minutes. The precipitate was filtered and dried to give the title compound as a white solid (3.3 g).
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5]([NH2:6])=[N:4][C:2]1=[O:3].[O:9]1[C:11]2[CH2:12][CH2:13][CH2:14][C:10]1=2.O1CCCC1>[Pd].CS(C)=O>[OH:9][CH:10]1[CH2:14][CH:13]([N:1]2[CH:8]=[CH:7][C:5]([NH2:6])=[N:4][C:2]2=[O:3])[CH:12]=[CH:11]1
Reactant: Nc1cc[nH]c(=O)n1
Reactant: C1CC2=C(C1)O2
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: Nc1ccn(C2C=CC(O)C2)c(=O)n1
Temperature: 25 °C
Reaction time: 90 h
Yield: 79.1 %

Procedure:
52.5 g (0.47 mol) of cytosine are reacted with 38.5 g (0.47 mol) of epoxycyclopentene at 0° C., by slow addition, in a mixture of in each case 220 ml of dry tetrahydrofuran and dimethylsulfoxide with 1 mol % of the palladium(0) catalyst prepared in situ as described above under an inert argon atmosphere. The reaction mixture is stirred at room temperature for 90 hours and then freed from the solvent and the residue is chromatographed over silica gel using methylene chloride/methanol 7/3. 71.8 g (79.2% of theory) of 1-[(1RS,4SR)-4-hydroxycyclopent-2-en-1-yl]cytosine of melting point 241°-242° C. are obtained. 1H-NMR (270 MHz, d6 -DMSO), δ[ppm]: 7.42 (d, 1H), 7.02 (s, 2H), 6.09 (m, 1H), 5.75 (m, 1H), 5.72 (d, 1H), 5.44 (m, 1H), 5.18 (d, 1H), 4.63 (m, 1H), 2.72 (m, 1H), 1.27 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:29])[C:5]([CH3:28])=[C:6]([CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4](=[O:29])[C:5]([CH3:28])=[C:6]([CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([N:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)=[O:18])=[C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(C(=O)O)c(-c3ccccc3)c2)=C(C)C1=O
Reactant: C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(C(=O)N3CCCCC3)c(-c3ccccc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 56.9 %

Procedure:
4-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-phenylbenzoic acid (18 mg, 0.0459 mmol) and piperidine (5.9 mg, 0.0692 mmol) were dissolved in methylene chloride (3 ml), then WSC-HCl (22 mg, 0.1147 mmol) was added thereto and the mixture was stirred at room temperature for 6 hours. The reaction solution was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by preparative thin layer chromatography (hexane:ethyl acetate=1:1) to give the title compound (12 mg, 0.0261 mmol, 57%).
Reaction SMILES: [OH-].[Li+].[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]1[C:18]([O:20]C)=[O:19]>CO>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]1[C:18]([OH:20])=[O:19]
Reactant: COC(=O)[C@@H]1CCCCN1c1nc2ccccc2o1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)[C@@H]1CCCCN1c1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.1 %

Procedure:
Aqueous lithium hydroxide solution (1N, 51 ml) was added to a solution of methyl (2S)-1-(1,3-benzoxazol-2-yl)-2-piperidinecarboxylate (8.987 g) [see Preparation 2] in methanol (306 ml) at 0° C. The reaction mixture was stirred at room temperature for 18 hours, after which time the solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and water. The aqueous layer was separated and acidified to pH 2 with 2N aqueous hydrochloric acid, the product was extracted with ethyl acetate, dried over magnesium sulphate and the solvent removed under reduced pressure to afford (2S)-1-(1,3-benzoxazol-2-yl)-2-piperidinecarboxylic acid (8.17 g) as a white solid.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Br:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]=[CH:10][N+:11]([O-])=[CH:12]2>C(Cl)(Cl)Cl>[Cl:3][C:12]1[C:13]2[C:8](=[C:7]([Br:6])[CH:16]=[CH:15][CH:14]=2)[CH:9]=[CH:10][N:11]=1
Reactant: [O-][n+]1ccc2c(Br)cccc2c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Clc1nccc2c(Br)cccc12
Temperature: 50 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
Phosphorus oxychloride (5 ml) was added to a suspension of compound (1a) (7.83 g) in chloroform (120 ml), and the mixture was stirred overnight at 50° C. The solvent was distilled off under reduced pressure, and chloroform was added to the residue. The reaction solution was neutralized with an aqueous sodium hydroxide solution with cooling in an ice bath and partitioned into organic and aqueous layers. The organic layer was washed with brine. The organic layer thus washed was dried over anhydrous sodium sulfate. Then, the solvent was distilled off, and small amounts of chloroform and diethyl ether were added to the residue. The deposit was filtrated to obtain compound (1b) (5.83 g, 65%) as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([NH2:10])[CH2:8][NH2:9].[Cl:11][C:12]1[S:13][C:14]([CH2:17]Cl)=[CH:15][N:16]=1>C(#N)C>[Cl:11][C:12]1[S:13][C:14]([CH2:17][NH:9][CH2:8][CH2:7][NH2:10])=[CH:15][N:16]=1
Reactant: NCCN
Reactant: ClCc1cnc(Cl)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NCCNCc1cnc(Cl)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
To a stirred solution of 0.03 mol of potassium carbonate and 10 ml (0.15 mol) of ethylenediamine in a 50 ml of flask placed in an ice bath, 0.03 mol of 2-chloro-5-(chloromethyl)thiazole dissolved in 15 ml of acetonitrile was added dropwise and slowly. After addition, the ice bath was removed and then the mixture was stirred for 8 hours at room temperature. After the reaction was stopped, a large amount of water was added to dissolve potassium carbonate and ethylenediamine, and the mixture was extracted with dichlormethane. The lower organic phase was collected, dried, and evaporated to dryness. The obtained product was yellow oily liquid in 70% yield.