Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C@H]([C@@H](C(O)=O)O)O)(O)=O.[NH2:11][C@@H:12]([C:15]1[CH:16]=[C:17]([CH:25]=[CH:26][N:27]=1)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH3:14].CN(C)C=O.C(N(CC)CC)C.[Cl:40][C:41]1[CH:42]=[CH:43][C:44]([O:80][CH3:81])=[C:45]([CH:79]=1)[CH2:46][C@H:47]1[C:53](=[O:54])[N:52]([C:55](OC2C=CC=CC=2Cl)=[O:56])[CH2:51][C:50](=[O:65])[N:49]([CH2:66][C:67]2[C:72]([O:73][CH3:74])=[CH:71][C:70]([O:75][CH3:76])=[CH:69][C:68]=2[O:77][CH3:78])[CH2:48]1>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[Cl:40][C:41]1[CH:42]=[CH:43][C:44]([O:80][CH3:81])=[C:45]([CH:79]=1)[CH2:46][C@H:47]1[C:53](=[O:54])[N:52]([C:55]([NH:11][C@@H:12]([C:15]2[CH:16]=[C:17]([CH:25]=[CH:26][N:27]=2)[C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:13][CH3:14])=[O:56])[CH2:51][C:50](=[O:65])[N:49]([CH2:66][C:67]2[C:68]([O:77][CH3:78])=[CH:69][C:70]([O:75][CH3:76])=[CH:71][C:72]=2[O:73][CH3:74])[CH2:48]1
Reactant: COc1cc(OC)c(CN2C[C@@H](Cc3cc(Cl)ccc3OC)C(=O)N(C(=O)Oc3ccccc3Cl)CC2=O)c(OC)c1
Reactant: CC[C@@H](N)c1cc(C(=O)OC(C)(C)C)ccn1
Agent: CN(C)c1ccncc1
Agent: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC[C@@H](NC(=O)N1CC(=O)N(Cc2c(OC)cc(OC)cc2OC)C[C@@H](Cc2cc(Cl)ccc2OC)C1=O)c1cc(C(=O)OC(C)(C)C)ccn1
Reaction time: 0.08 h
Yield: 71.5 %

Procedure:
To the compound 5105 described in WO 06-059801A, that is, tert-butyl 2-[(1R)-1-aminopropyl]-isonicotinate D-tartrate (157 mg) in an N,N-dimethylformamide (1.5 ml) solution, triethylamine (0.113 ml) was added under ice cooling, and the mixture was stirred at that temperature for 5 minutes. To the reaction solution, the compound S141C described in WO 06-059801A, that is, (6R)-2-chlorophenyl 6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-4-(2,4,6-trimethoxybenzyl)-1,4-diazepane-1-carboxylate (250 mg) and 4-dimethylaminopyridine (49 mg) were added, and the mixture was stirred at 0° C. for 18 hours. The reaction solution was diluted with ethyl acetate, then was successively washed with saturated aqueous ammonium chloride solution and brine. The organic layer was dried over anhydrous sodium sulfate, then was concentrated. The residue was purified by flash column chromatography (silica gel, hexane/ethyl acetate=1/1 to 1/2) to obtain tert-butyl 2-[(1R)-1-({[(6R)-6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-4-(2,4,6-trimethoxybenzyl)-1,4-diazepan-1-yl]carbonyl}amino)propyl]isonicotinate (compound S39a) (210 mg).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.[CH3:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH2:8][N:14]2[CH2:15][CH2:16][CH:11]([CH3:10])[CH2:12][CH2:13]2)[N:7]=1
Reactant: CC1CCNCC1
Reactant: O=Cc1cccc(Br)n1
Solvent: ClCCl
Product: CC1CCN(Cc2cccc(Br)n2)CC1

Procedure:
5] To 6-bromo-2-pyridinecarboxaldehyde (400 mg, 2.15 mmol) was added 4-methylpiperidine (0.4 mL, 3.22 mmol) in dry CH2Cl2 (10 mL) to give 2-bromo-6-[(4-methyl)piperidinylmethyl]pyridine as a white solid. MS m/z: 269.4 (M+H). Calc'd for C12H17BrN2: 269.18.
Reaction SMILES: O1CCCCC1[O:7][C:8](=O)[CH2:9][CH2:10][C@H:11]([C@@H:13]1[C@:30]2([CH3:31])[C@H:16]([C@H:17]3[C@H:27]([CH2:28][CH2:29]2)[C@:25]2([CH3:26])[C:20]([CH2:21][C@@H:22]([O:32][CH:33]4[CH2:38][CH2:37][CH2:36][CH2:35][O:34]4)[CH2:23][CH2:24]2)=[CH:19][CH2:18]3)[CH2:15][CH2:14]1)[CH3:12].[H-].[H-].[H-].[H-].[Li+].[Al+3].[O-]S([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[O:34]1[CH2:35][CH2:36][CH2:37][CH2:38][CH:33]1[O:32][C@H:22]1[CH2:23][CH2:24][C@@:25]2([CH3:26])[C:20](=[CH:19][CH2:18][C@@H:17]3[C@@H:27]2[CH2:28][CH2:29][C@@:30]2([CH3:31])[C@H:16]3[CH2:15][CH2:14][C@@H:13]2[C@H:11]([CH3:12])[CH2:10][CH2:9][CH2:8][OH:7])[CH2:21]1
Reactant: C[C@H](CCC(=O)OC1CCCCO1)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: C[C@H](CCCO)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 8 h
Yield: 92.3 %

Procedure:
Compound 2001 (16.1 g, 30 mmol) in dry tetrahydrofuran (THF, 150 ml) was added to a suspension of LiAlH4 (5.5 g, 145 mmol) in dry THF (200 ml). The suspension was stirred at 0° C. with a mechanical stirrer under argon overnight. The resultant gray slurry was quenched with EtOAc, followed by aqueous saturated Na2SO4 solution. During the addition of the Na2SO4 solution, a white precipitate formed and the solution became clear. Anhydrous Na2SO4 was added, the mixture was stirred for 15 minutes, and then filtered. The filter cake was washed well with ethyl acetate and the filtrate was concentrated in vacuo. The resulting solid was purified by flash chromatography (SiO2, hexanes:EtOAc 5:1) giving compound 2002 as a white solid (12.3 g, 27.7 mmol, 92%). 1H NMR (500 MHz, CDCl3) δ: 5.37-5.32 (m, 1H, C-6 H), 4.72 (brs, 1H, THP methine H), 3.95-3.88 (m, 1H, THP CH2O), 3.62-3.47 (m, 4H, THP CH2O & C-3 H & C-24 H), 1.01 (s, 3H, C-19 H), 0.93 (d, J=6.6 Hz, C-21 H), 0.68 (s, 3H, C-18 H); IR (CHCl3) 3610, 2900 cm-1 ; MS (CI/isobutane) m/z 445 (M+1, 2%), 343 (M+1-THPOH, 100%); m.p. 130°-131° C.
Reaction SMILES: [C:1]([C:3]1[S:7][CH:6]=[N:5][C:4]=1[CH2:8][OH:9])#[CH:2].[C:10]1([C:16]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[SH:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CC(C)([O-])C.[K+]>C1COCC1.[Cl-].[Na+].O>[OH:9][CH2:8][C:4]1[N:5]=[CH:6][S:7][C:3]=1/[CH:1]=[CH:2]\[S:17][C:16]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: C#Cc1scnc1CO
Reactant: SC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1ncsc1/C=C\SC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2.73 g of 5-ethynyl-4-hydroxymethylthiazole in 65 ml of THF was cooled in ice under an argon atmosphere, and 6.5 g of triphenylmethane thiol and 440 mg of potassium-t-butoxide were added to the cooled solution. The mixture was stirred at room temperature for 2 hr. Brine was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, were washed with brine, were then dried over anhydrous magnesium sulfate, were filtered, and were concentrated under the reduced pressure. Ethyl acetate (10 ml) and 10 ml of hexane were added to the residue, and the resultant precipitate was collected by filtration to give 7.26 of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([O:14][CH3:15])[C:8]([O:12][CH3:13])=[N:9]2)=[C:4](I)[CH:3]=1.[CH2:17]([OH:20])[C:18]#[CH:19].C(N(CC)CC)C.Cl>CN(C)C=O.[Cl-].[Na+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([O:14][CH3:15])[C:8]([O:12][CH3:13])=[N:9]2)=[C:4]([C:19]#[C:18][CH2:17][OH:20])[CH:3]=1
Reactant: COc1nc2cc(Cl)cc(I)c2nc1OC
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1nc2cc(Cl)cc(C#CCO)c2nc1OC
Temperature: 70 °C
Reaction time: 3.5 h
Yield: 10.7 %

Procedure:
12.9 g (36.8 mmol) of 7-chloro-2,3-dimethoxy-5-iodo-quinoxaline, 7.6 ml (128.4 mmol) of propargyl alcohol, 2.1 g (3 mmol) of bis(triphenylphosphine)-palladium dichloride, 6.6 ml (47.4 mmol) of triethylamine and 0.34 g (1.8 mmol) of cuprous iodide are placed in 125 ml of dimethylformamide and heated to a bath temperature of 70° C. The reaction mixture is then stirred for 3.5 hours at that temperature and then cooled to room temperature. Ethyl acetate is added to the reaction mixture and extraction is carried out with water, 1N hydrochloric acid and brine. The aqueous phases are washed with ethyl acetate. The organic phases are combined, dried over sodium sulfate, filtered with suction and concentrated. Chromatography of the crude product on silica gel with hexane/ethyl acetate (3:1) yields 1.1 g of 3-(7-chloro-2,3-dimethoxy-quinoxalin-5-yl)-prop-2-yn-1-ol in the form of brown crystals having a melting point of 137-140° C.
Reaction SMILES: [CH:1](/[CH:6]1[CH2:11][CH2:10][CH:9]([C:12]([OH:14])=[O:13])[CH2:8][CH2:7]1)=[CH:2]\[CH2:3][CH2:4][CH3:5].[OH-].[K+].Cl>C(O)COCCO>[CH:1](/[C@H:6]1[CH2:7][CH2:8][C@H:9]([C:12]([OH:14])=[O:13])[CH2:10][CH2:11]1)=[CH:2]\[CH2:3][CH2:4][CH3:5]
Reactant: CCC/C=C/C1CCC(C(=O)O)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Product: CCC/C=C/[C@H]1CC[C@H](C(=O)O)CC1

Procedure:
A mixture of 1.29 g of 4-(1E-pentenyl)cyclohexanecarboxylic acid and 20 ml of a 11 percent (wt./vol.) solution of potassium hydroxide in diethylene glycol was boiled at reflux for 20 hours while gassing with argon. The reaction mixture was subsequently made slightly acid with 25 percent hydrochloric acid and partitioned three times in water/ethylene chloride. The organic extracts were washed twice with water and the wash-water was back-extracted with methylene chloride. The organic phases were dried over magnesium sulphate and freed from solvent on a rotary evaporator. Recrystallization of the dark brown, crystallizing oil obtained (1.17 g) from 50 ml of petroleum ether at -78° C. gave 0.44 g of trans-4-(1E-pentenyl)cyclohexanecarboxylic acid as pale brown crystals. The mother liquor containing 0.695 g of crude cis/trans-4-(1-E-pentenyl)-cyclohexanecarboxylic acid was not worked-up.
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([N:20]([CH3:22])[CH3:21])=[O:19])[CH2:8][CH2:7]1)=[O:5].[N:31]1([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33][C@H:32]1[C:41](O)=[O:42].C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>>[CH3:21][N:20]([CH3:22])[C:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[N:9]1[CH2:8][CH2:7][N:6]([C:4](=[O:5])[C@H:3]([NH:2][C:41]([C@@H:32]2[CH2:33][C:34]3[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:40][N:31]2[C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[O:42])[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[CH2:11][CH2:10]1)=[O:19]
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)O
Reactant: CN(C)C(=O)c1ccccc1N1CCN(C(=O)[C@H](N)Cc2ccc(Cl)cc2)CC1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1ccccc1N1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)[C@@H]2Cc3ccccc3CN2C(=O)OC(C)(C)C)CC1

Procedure:
tert-Butyl 3-[N-((1R)-2-{4-[2-(N,N-dimethylcarbamoyl)-phenyl]piperazinyl}-1-[(4-chlorophenyl)methyl]-2-oxoethyl)carbamoyl](3S)-1,2,3,4-tetrahydro-isoquinoline-2-carboxylate was prepared according to the procedure described in Preparation V by using (2-{4-[(2R)-2-amino-3-(4-chlorophenyl)-propanoyl]-piperazinyl}phenyl)-N,N-dimethylcarboxamide HCl salt (Step 5) (230 mg, 0.50 mmol), Boc-L-Tic-OH (Bachem Company) (150 mg, 0.55 mmol), HOAT (Aldrich) (68 mg, 0. 50 mmol), EDC (Aldrich) (190 mg, 1.00 mmol) and DIEA (Aldrich) (87 μL, 0.50 mmol). The compound was isolated and purified by column chromatography (CH2Cl2: 1.5% 2M NH3 in MeOH). (255 mg). MS (ESI, pos. ion) m/z: 674 (M+H). Calc'd for C37H44ClN5O5: 674.23.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][CH2:39][CH2:40][C:41](=[O:49])[NH:42][C:43]([C:46](O)=[O:47])([CH3:45])[CH3:44])=[CH:33][CH:32]=2)=[C:28]([CH:50]([CH3:52])[CH3:51])[NH:27][N:26]=1)(=O)C.[CH3:53][N:54]1[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]1.NC(C)(C)C(N)=O>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([CH2:37][CH2:38][CH2:39][CH2:40][C:41](=[O:49])[NH:42][C:43]([C:46]([N:57]4[CH2:58][CH2:59][N:54]([CH3:53])[CH2:55][CH2:56]4)=[O:47])([CH3:45])[CH3:44])=[CH:35][CH:36]=3)=[C:28]([CH:50]([CH3:52])[CH3:51])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CN1CCNCC1
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(CCCCC(=O)NC(C)(C)C(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: CC(C)(N)C(N)=O
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(CCCCC(=O)NC(C)(C)C(=O)N2CCN(C)CC2)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Example 78 using 3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-[(4-{4-[1-carboxy-1-(methyl)-ethylcarbamoyl]butyl}phenyl)methyl]-5-isopropyl-1H-pyrazole and 1-methylpiperazine instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-carboxyethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole and 2-amino-2-methylpropionamide, respectively.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[C:13]([N:17]2[C:21](=[O:22])[NH:20][C:19]([C:23]3[CH:28]=[CH:27][C:26](I)=[CH:25][CH:24]=3)=[N:18]2)=[CH:12][C:3]=1[CH2:4][NH:5][C:6](=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8].[C:30]([CH:32]1[CH2:34][CH2:33]1)#[CH:31].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O>[Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[C:13]([N:17]2[C:21](=[O:22])[NH:20][C:19]([C:23]3[CH:28]=[CH:27][C:26]([C:31]#[C:30][CH:32]4[CH2:34][CH2:33]4)=[CH:25][CH:24]=3)=[N:18]2)=[CH:12][C:3]=1[CH2:4][NH:5][C:6](=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: C#CC1CC1
Reactant: CC(C)(C)C(=O)NCc1cc(-n2nc(-c3ccc(I)cc3)[nH]c2=O)c(Cl)cc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: CC(C)(C)C(=O)NCc1cc(-n2nc(-c3ccc(C#CC4CC4)cc3)[nH]c2=O)c(Cl)cc1Cl
Yield: 369.4 %

Procedure:
The title compound was prepared according to the procedure described in Example-111 using N-(2,4-dichloro-5-(4,5-dihydro-3-(4-iodophenyl)-5-oxo-1,2,4-triazol-1-yl)benzyl) pivalamide (Intermediate-84, 0.150 g, 0.028 mmol), ethynylcyclopropane (0.038 g, 0.56 mmol), TBAF (0.268 g, 0.85 mmol), bis(triphenylphosphine)palladium(II) chloride (catalytic) and DMSO (3.0 mL) to afford 0.050 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 0.77 (m, 2H), 0.93 (m, 2H), 1.21 (s, 9H), 1.58 (m, 1H), 4.32 (d, J=6.3 Hz, 2H), 7.50-7.53 (m, 3H), 7.82-7.91 (m, 2H), 7.95 (s, 1H), 8.21 (m, 1H)
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16](O)=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[N:25]=[C:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:23]=[N:22]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]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.[OH:68][C:69]1[CH:83]=[C:82]2[C:72]([NH:73][CH:74]=[C:75]2[CH2:76][C@@H:77]([C:79]([OH:81])=[O:80])[NH2:78])=[CH:71][CH:70]=1>CN(C=O)C>[CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([NH:78][CH:77]([CH2:76][C:75]4[C:82]5[C:72](=[CH:71][CH:70]=[C:69]([OH:68])[CH:83]=5)[NH:73][CH:74]=4)[C:79]([OH:81])=[O:80])=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[N:25]=[C:24]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:23]=[N:22]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N[C@@H](Cc1c[nH]c2ccc(O)cc12)C(=O)O
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)cnc3c1)n2C1CCCCC1
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: CN(C)C=O
Product: O=C(NC(Cc1c[nH]c2ccc(O)cc12)C(=O)O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)cnc3c1)n2C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compound 203 (100 mg, 0.22 mmol) was activated in 2 mL DMF with 92 mg (0.24 mmol) HBTU and 85 μL DIEA for 10 minutes at room temperature. 56 mg 5-hydroxy-L-tryptophane, dissolved in 1 mL DMF was added followed by 44 μL DIEA. The mixture was stirred at room temperature for 1 h, then evaporated to dryness. The oil was purified using RP-HPLC column to give Compound 234.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]#[N:16].[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28]>C(O)C.CO>[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28].[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([N:21]1[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]1)=[NH:16]
Reactant: N#CNc1ccccc1-c1ccccc1F
Reactant: CN1CCNCC1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CO
Solvent: CCO
Product: CN1CCN(C(=N)Nc2ccccc2-c2ccccc2F)CC1

Procedure:
A mixture of 2'-fluoro-2-biphenylylcyanamide (2.1 g) and N-methylpiperazine (1.5 g) in ethanol (25 ml) was heated at 90°-95° C. for 3 hours to yield the free base which was reacted with fumaric acid (1.78 g) in methanol (70 ml) to give N-(2'-fluoro-2-biphenylyl)-4-methylpiperazine-1-carboxamidine difumarate (m.p. 201°-202° C.) which was recrystallised from a 2:3 mixture of methanol and ether.
Reaction SMILES: [C:1]([CH2:3][CH:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[O:5][P:6](Cl)Cl)#[N:2].C[Si]([C:17]1[NH:18][CH:19]=[C:20]([CH3:22])[N:21]=1)(C)C>C1(C)C=CC=CC=1>[C:1]([CH2:3][CH:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[O:5][P:6]([C:17]1[NH:18][CH:19]=[C:20]([CH3:22])[N:21]=1)[C:17]1[NH:18][CH:19]=[C:20]([CH3:22])[N:21]=1)#[N:2]
Reactant: Cc1c[nH]c([Si](C)(C)C)n1
Reactant: CC(C)(C)C(CC#N)OP(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1c[nH]c(P(OC(CC#N)C(C)(C)C)c2nc(C)c[nH]2)n1
Reaction time: 0.08 h

Procedure:
To toluene (5 ml) there were added 0.332 g (1.46 mmol) of 2-cyano-1-tert-butylethoxydichlorophosphine and 0.495 g (3.21 mmol) of trimethylsilyl-4-methylimidazole under an argon atmosphere at room temperature, and reaction was conducted for 5 minutes. After by-product chlorotrimethylsilane and toluene were removed under reduced pressure for 10 minutes at room temperature, the residual toluene and excess trimethylsilyl-4-methylimidazole were removed under reduced pressure for 2 hours at 40° C. to obtain 2-cyano-1-tert-butylethoxybis(4-methylimidazolyl)phosphine as a colorless transparent oil. Under an argon atmosphere at room temperature, this 2-cyano-1-tert-butylethoxybis(4-methylimidazolyl)phosphine was dissolved in 2.9 ml of chloroform-d, and the solution (0.5 M) was added to 0.794 g (1.46 mmol) of 5′-O-(4,4′-dimethoxytrityl)thymidine that had been dried under reduced pressure for 2 hours. Upon reaching homogeneity, the mixture was allowed to stand overnight for reaction to obtain a nucleotide derivative represented by the formula (2-22) below. The 31P NMR of the obtained compound (external standard: (CH3O)3P=140 ppm, CDCl3) δ was 127.9, 128.2, 128.4, 130.8 ppm (measuring the 31P NMR spectrum with a 161.7 MHz NMR measuring apparatus).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][CH:8]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)[CH:10]=1)=[O:4]>CO.[Pd]>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][CH:8]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH:10]=1)=[O:4]
Reactant: COC(=O)c1cncc(Oc2ccc([N+](=O)[O-])cc2)c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cncc(Oc2ccc(N)cc2)c1

Procedure:
The mixture containing methyl-5-(4-nitrophenoxy)pyridine-3-carboxylate in methanol with catalytic amount of 10% Pd/C was hydrogenated to yield methyl5-[4-aminophenoxy]pyridine-3-carboxylate. MS: MH+=244.
Reaction SMILES: CS(C)=O.F[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]([CH3:15])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>O>[CH3:15][C:8]1[CH:7]=[C:6]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:11]=[CH:10][C:9]=1[N+:12]([O-:14])=[O:13]
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(N2CCOCC2)ccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
To a DMSO solution (8 ml) of 4-fluoro-2-methyl-1-nitro-benzene (500 mg), potassium carbonate (668 mg) and morpholine (0.42 ml) were added, followed by stirring at 80° C. for 18 hours. This was cooled to room temperature, and water (30 ml) was added, followed by extraction with ethyl acetate (50 ml×2). The organic layer was washed with saturated aqueous sodium chloride solution, followed by drying over magnesium sulfate. After the magnesium sulfate was filtered off, the solvent was distilled off under reduced pressure, to obtain the desired compound as a yellow solid (680 mg, 95%).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[CH3:14][CH2:15][CH2:16][CH:17]([NH2:21])[CH2:18][CH2:19][CH3:20]>>[CH2:16]([CH:17]([NH:21][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[O:1][CH2:2][CH2:3][O:4][C:5]=2[CH:10]=1)=[O:13])[CH2:18][CH2:19][CH3:20])[CH2:15][CH3:14]
Reactant: CCCC(N)CCC
Reactant: O=C(O)c1ccc2c(c1)OCCO2
Product: CCCC(CCC)NC(=O)c1ccc2c(c1)OCCO2

Procedure:
Prepared in a similar manner to example 4 using 2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid and heptan-4-amine. MS (M+H, 278.2).
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:47])[C@@H:6]([NH:25][C:26](=[O:46])[C:27]1[C:32]([Cl:33])=[CH:31][C:30]([O:34][Si](C(C)C)(C(C)C)C(C)C)=[CH:29][C:28]=1[Cl:45])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:24])[N:16]([CH3:23])[C:17](=[O:22])[N:18]([CH3:21])[C:19]=2[CH3:20])=[CH:10][CH:9]=1)[CH2:2][CH3:3].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[CH2:1]([O:4][C:5](=[O:47])[C@@H:6]([NH:25][C:26](=[O:46])[C:27]1[C:28]([Cl:45])=[CH:29][C:30]([OH:34])=[CH:31][C:32]=1[Cl:33])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:15](=[O:24])[N:16]([CH3:23])[C:17](=[O:22])[N:18]([CH3:21])[C:19]=2[CH3:20])=[CH:12][CH:13]=1)[CH2:2][CH3:3]
Reactant: CCCOC(=O)[C@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1)NC(=O)c1c(Cl)cc(O[Si](C(C)C)(C(C)C)C(C)C)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CCCOC(=O)[C@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1)NC(=O)c1c(Cl)cc(O)cc1Cl

Procedure:
The title compound was prepared using a similar procedure as described in Example 5, Step 4, starting from (S)-2-(2,6-dichloro-4-triisopropylsilanyloxy-benzoylamino)-3-[4-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)phenyl]propionic acid propyl ester (1.66 g, 2.35 mmol) and TBAF (3.5 mL, 3.5 mmol, 1M), and after ISCO column chromatography purification, resulted in a white solid (884 mg, 69%). ES(+)-LRMS m/e calcd. for C26H27Cl2N3O6 (M+H)+ 548, obsd. 548.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[NH2:26])[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[ClH:27]>ClCCl.O1CCOCC1>[ClH:27].[CH2:1]([O:3][C:4]([C:6]1([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[NH2:26])[CH2:7][CH2:8][NH:9][CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(Cc2ccccc2N)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOC(=O)C1(Cc2ccccc2N)CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 4-(2-amino-benzyl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (1.29 g, 4.102 mmol) in dichloromethane (15 mL) was added a 4.0M solution of hydrogen chloride in dioxane (5 mL). The resulting solution was stirred at room temperature overnight. The concentration of the solution under vacuum provided the title compound (1.23 g, 100%) as white solid, which was used in the next step without purification. Mass spec.: 263.40 (MH)+.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][N:9]1[C:13]2[C:14]([CH3:26])=[CH:15][C:16]([NH:18]C(=O)OC(C)(C)C)=[CH:17][C:12]=2[O:11][C:10]1=[O:27]>C(Cl)Cl>[NH2:18][C:16]1[CH:15]=[C:14]([CH3:26])[C:13]2[N:9]([CH3:8])[C:10](=[O:27])[O:11][C:12]=2[CH:17]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)cc2oc(=O)n(C)c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(N)cc2oc(=O)n(C)c12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
500 μL (6.58 mmol) TFA were added to 500 mg (1.80 mmol) tert-butyl (3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazol-6-yl)-carbamate in 10 mL DCM and the mixture was stirred for 1.5 h at RT. Then the reaction mixture was evaporated down, the residue was made alkaline and extracted with DCM. The organic phase was dried on sodium sulphate, filtered and evaporated down.