Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[C@@H:2]1([N:11]2[C:20]3[C:14](=[C:15]([N+:17]([O-])=[CH:18][N:19]=3)[NH2:16])[N:13]=[CH:12]2)[O:10][C@H:7]([CH2:8][OH:9])[C@@H:5]([OH:6])[C@H:3]1[OH:4].[OH-].[Na+].CO.C(=S)=[S:27]>>[CH:12]1[N:11]([C@@H:2]2[O:10][C@H:7]([CH2:8][OH:9])[C@@H:5]([OH:6])[C@H:3]2[OH:4])[C:20]2[C:14](=[C:15]([NH2:16])[NH:17][C:18]([N:19]=2)=[S:27])[N:13]=1
Reactant: Nc1c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2nc[n+]1[O-]
Reactant: S=C=S
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Nc1[nH]c(=S)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 97 %

Procedure:
8.0 g of adenosine 1-oxide monohydrate (26.67 mmol) was refluxed in 5 ml of a 5N sodium hydroxide aqueous solution for 15 minutes. The resulting liquid was neutralized to a pH of 9.0 using Amberlite IRC-50 (H+-type) and then concentrated to a small volume to prepare 5-amino-1-β-D-ribofuranosylimidazole-4-carboxamide oxime. To this was added 200 ml of an aqueous solution containing 175 ml of methanol. The pH of the resulting solution was 9. 50 ml of carbon disulfide was further added to the solution, and the mixture was allowed to react in an autoclave at 120° C for 5 hours under autogenous pressure (about 10 Kg/cm2). The orange colored substance formed in the autoclave was removed and concentrated to dryness. The residue was dissolved in 63 ml of 2.5N aqueous ammonia, and any impurities were filtered out. A mixture of n-butanol and acetic acid (125 ml:63 ml) was added to the above filtrate to crystallize the product to obtain 8.20 g of 2-thioadenosine having a melting point of 199° C (with decomposition) in a 97% yield.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10].[N-:15]=[N+:16]=[N-:17].[Na+]>CCO.O>[N:15]([CH2:2][CH2:3][O:4][CH2:5][CH2:6][P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[N+:16]=[N-:17]
Reactant: CCOP(=O)(CCOCCBr)OCC
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOP(=O)(CCOCCN=[N+]=[N-])OCC

Procedure:
To a solution of diethyl 2-(2-bromoethoxy)ethylphosphonate (1 eq) in EtOH (0.3 M) was added sodium azide (5 eq) in water (2 M). The reaction mixture was heated at reflux overnight. The mixture was then diluted with water, extracted with ethyl acetate. The organic layer was washed with 5% citric acid, saturated NaHCO3, water and brine, dried over anhydrous Na2SO4, and concentrated en vaccuo. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 80-100% EtOAc/Hex to give the product as colorless oil.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][C:10]([OH:18])([C:12]#[C:13][Si](C)(C)C)[CH2:9][CH2:8][O:7]1)=O)C.[NH3:19]>CO>[C:12]([C:10]1([OH:18])[CH2:9][CH2:8][O:7][CH:6]([C:4]([NH2:19])=[O:3])[CH2:11]1)#[CH:13]
Reactant: CCOC(=O)C1CC(O)(C#C[Si](C)(C)C)CCO1
Reactant: N
Solvent: CO
Product: C#CC1(O)CCOC(C(N)=O)C1
Reaction time: 0.17 h
Yield: 97 %

Procedure:
4-Hydroxy-4-trimethylsilanylethynyl-tetrahydro-pyran-2-carboxylic acid ethyl ester (2.50 g, 9.25 mmol) was dissolved in MeOH (20 mL) in a pressure reaction tube and NH3 gas was passed through the solution for 10 minutes with stirring. The tube was tightly capped and the reaction was stirred for 3 days. After solvent removal, 1.53 g (97%) of yellow oil was obtained: 1H NMR (CD3OD) δ 1.48 (t, 1H), 1.70 (td, 1H), 1.85 (d, 1H), 2.30 (d, 1H), 3.04 (s, 1H), 3.29 (s, 1H), 3.71(t, 1H), 3.98 (d, 1H), 4.06 (dt, 1H).
Reaction SMILES: N=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=3)=[CH:11][CH:10]=2)[S:3]1.Cl.C(=O)([O-])[OH:27].[Na+]>C(O)C>[CH3:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([CH2:8][CH:4]3[S:3][C:2](=[O:27])[NH:6][C:5]3=[O:7])=[CH:10][CH:11]=2)=[N:19][CH:20]=1
Reactant: O=C([O-])O
Reactant: Cc1ccc(CCOc2ccc(CC3SC(=N)NC3=O)cc2)nc1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(CCOc2ccc(CC3SC(=O)NC3=O)cc2)nc1
Yield: 87.5 %

Procedure:
A mixture of 2-imino-5-{4-[2-(5-methyl-2-pyridyl)ethoxy]benzyl}-4-thiazolidinone (8.0 g), 2N HCl (80 ml) and ethanol (80 ml) was refluxed for 16 hours. The reaction solution was neutralized with a saturated aqueous solution of sodium hydrogencarbonate to yield crystals. The crystals were collected by filtration and recrystallized from ethanol to give 5-{4-[2-(5-methyl-2pyridyl)ethoxy]benzyl}-2,4-thiazolidinedione as colorless prisms (7.0 g, 87.5%), m.p. 192°-193° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[CH2:6][O:7][C:8]1[CH:16]=[CH:15][C:14]2[NH:13][C:12]3[CH:17]([CH2:20][C:21]([O:23]CC)=[O:22])[CH2:18][CH2:19][C:11]=3[C:10]=2[CH:9]=1)#[N:2].[Li+].[OH-]>O1CCOCC1>[C:1]([C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[CH2:6][O:7][C:8]1[CH:16]=[CH:15][C:14]2[NH:13][C:12]3[CH:17]([CH2:20][C:21]([OH:23])=[O:22])[CH2:18][CH2:19][C:11]=3[C:10]=2[CH:9]=1)#[N:2]
Reactant: CCOC(=O)CC1CCc2c1[nH]c1ccc(OCc3ccc(C4CCCCC4)c(C#N)c3)cc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: N#Cc1cc(COc2ccc3[nH]c4c(c3c2)CCC4CC(=O)O)ccc1C1CCCCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 56.8 %

Procedure:
To a solution of ethyl 2-(7-(3-cyano-4-cyclohexylbenzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (185.3 mg, 0.406 mmol) in 1,4-dioxane (5.0 mL) was added 1 M aqueous LiOH solution (1.22 mL, 1.22 mmol). The mixture was stirred at room temperature for 5 h. The mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and then acidified with 1 N aqueous HCl acid solution to pH 4. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was triturated with dichloromethane to provide the title compound as a pink solid (98.9 mg). LCMS m/z=429.6 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.21-1.31 (m, 1H), 1.33-1.54 (m, 4H), 1.68-1.74 (m, 1H), 1.74-1.88 (m, 4H), 2.08 (dd, J=4.93, 3.54 Hz, 1H), 2.34 (dd, J=16.04, 8.97 Hz, 1H), 2.61-2.76 (m, 4H), 2.81-2.89 (m, 1H), 3.45 (bs, 1H), 5.07 (s, 2H), 6.70 (dd, J=8.78, 2.46 Hz, 1H), 6.91 (d, J=2.40 Hz, 1H), 7.19 (d, J=8.72 Hz, 1H), 7.52 (d, J=8.08 Hz, 1H), 7.72 (dd, J=8.15, 1.71 Hz, 1H), 7.81 (d, J=1.52 Hz, 1H), 10.46 (s, 1H), 12.18 (bs, 1H).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([Cl:47])=[C:43]([Cl:48])[CH:42]=3)[C:19]([N:21]3[CH2:26][CH2:25][N:24]([CH:27]4[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:49]=[CH:50][CH:51]=[CH:52][C:4]=2[NH:3]1>Cl>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([Cl:47])=[C:43]([Cl:48])[CH:42]=3)[C:19](=[O:20])[N:21]3[CH2:26][CH2:25][N:24]([CH:27]4[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]4)[CH2:23][CH2:22]3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:49]=[CH:50][CH:51]=[CH:52][C:4]=2[NH:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCN(C(=O)[C@@H](Cc3ccc(Cl)c(Cl)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Agent: Cl
Product: O=C(O[C@H](Cc1ccc(Cl)c(Cl)c1)C(=O)N1CCN(C2CCNCC2)CC1)N1CCC(N2CCc3ccccc3NC2=O)CC1

Procedure:
A solution of 30 mg (0.04 mmol) of (R)-1-(3,4-dichloro-benzyl)-2-[4-(1-tertbutoxycarbonyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 25) in 5 mL 4 M HCl was stirred overnight at RT. The reaction mixture was lyophilised, and the product was obtained as the HCl salt.
Reaction SMILES: C([O:5][C:6]([C:8]1[S:9][C:10]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:12]=1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:18]([O:17][C:15]([CH2:14][CH2:13][C:10]1[S:9][C:8]([C:6]([OH:7])=[O:5])=[CH:12][CH:11]=1)=[O:16])[CH3:19]
Reactant: CCOC(=O)CCc1ccc(C(=O)OC(C)(C)C)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CCc1ccc(C(=O)O)s1
Temperature: 25 °C
Reaction time: 5 h
Yield: 98.6 %

Procedure:
0.564 g (2 mmol) of 5-(2-ethoxycarbonyl-ethyl)-thiophene-2-carboxylic acid tert-butyl ester were dissolved in 10 ml of dichloromethane. 2.5 ml of trifluoroacetic acid were added dropwise with stirring at room temperature. Stirring was continued for 5 hours until the starting compound was no more detectable by thin layer chromatography (TLC). The solvents were evaporated in vacuo to give 0.45 g of a crystalline residue which was sufficiently pure for use in the subsequent step.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH2:7]([O:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1)[CH2:8][CH2:9][CH3:10].Br[C:22]1[C:23]([NH2:28])=[N:24][CH:25]=[CH:26][CH:27]=1>COCCOC.O.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>[CH2:7]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:22]2[C:23]([NH2:28])=[N:24][CH:25]=[CH:26][CH:27]=2)=[CH:14][CH:13]=1)[CH2:8][CH2:9][CH3:10]
Reactant: Nc1ncccc1Br
Reactant: CCCCOc1ccc(B(O)O)cc1
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: COCCOC
Solvent: O
Product: CCCCOc1ccc(-c2cccnc2N)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 61.7 %

Procedure:
A mixture of sodium carbonate (0.978 g), tetrakis(triphenylphosphine)palladium(0) (0.267 g), 4-butoxyphenylboronic acid (1.16 g) and 3-bromopyridin-2-amine (0.799 g,) in DME (23 mL) and water (4.6 mL) was stirred at 80° C. overnight. The mixture was added with silica gel, concentrated in vacuo, and purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (0.690 g) as a pale yellow solid.
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH2:7][N:8]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:9]2=[O:14].[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[O:22]=[C:16]1[CH:15]([N:8]2[CH2:7][C:6]3[C:10](=[CH:11][CH:12]=[CH:13][C:5]=3[CH2:4][N:3]([CH3:2])[C:32]([NH:31][C:28]3[CH:27]=[CH:26][C:25]([O:24][CH3:23])=[CH:30][CH:29]=3)=[O:33])[C:9]2=[O:14])[CH2:20][CH2:19][C:18](=[O:21])[NH:17]1
Reactant: CNCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reactant: COc1ccc(N=C=O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(NC(=O)N(C)Cc2cccc3c2CN(C2CCC(=O)NC2=O)C3=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.8 %

Procedure:
To a suspension of 3-(4-methylaminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.60 g, 1.86 mmol) and 4-methoxy-phenyl-isocyanate (0.29 mL, 2.23 mmol) in dry CH2Cl2 (80 ml), was added diisopropylethylamine (0.45 mL g, 2.60 mmol). The mixture was stirred at room temperature overnight. The mixture was quenched with MeOH and filtered. The resulting solid was rinsed with CH2Cl2 (5 mL) to give 1-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-3-(4-methoxy-phenyl)-1-methyl-urea (0.38 g, 46%): mp 245-247° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=1.91 (98%); 1H NMR (DMSO-d6): δ 1.99-2.04 (m, 1H), 2.30-2.37 (m, 1H), 2.56-2.63 (m, 1H), 2.85-2.87 (m, 1H), 2.95 (s, 3H), 3.70 (s, 3H), 4.37 (d, J=17.3 Hz, 1H), 4.44 (d, J=17.4 Hz, 1H), 4.63 (s, 2H), 5.11-5.18 (dd, J=4.9, 13.1 Hz, 1H), 6.84 (d, J=8.9 Hz, 2H), 7.32 (d, J=8.9 Hz, 2H), 7.45 (d, J=7.4 Hz, 1H), 7.53 (t, J=7.4 Hz, 1H), 7.64 (d, J=7.3 Hz, 1H), 8.31 (s, 1H), 11.02 (s, 1H). 13C NMR (DMSO-d6) δ: 22.58, 31.17, 34.64, 46.26, 48.36, 51.57, 55. 10, 113.46, 121.69, 122.01, 128.41, 129.91, 131.91, 133.29, 133.98, 140.13, 154.64, 155.91, 168.02, 171.02, 172.85. Anal Calcd for C23H24N4O5+0.1H2O: C, 63.03; H, 5.57; N, 12.78. Found: C, 62.96; H, 5.48; N, 12.49.
Reaction SMILES: [CH2:1]([N:4]1[C:9](=[O:10])[C:8]2[CH:11]=[CH:12][NH:13][C:7]=2[N:6]=[CH:5]1)[CH2:2][CH3:3].[H-].[Na+].[Cl:16][C:17]1[CH:32]=[CH:31][C:20]([C:21]([C:23]2[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=2)=[O:22])=[CH:19][CH:18]=1>COCCOC>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([C:23]2[CH:30]=[CH:29][C:26]([CH2:27][N:13]3[C:7]4[N:6]=[CH:5][N:4]([CH2:1][CH2:2][CH3:3])[C:9](=[O:10])[C:8]=4[CH:11]=[CH:12]3)=[CH:25][CH:24]=2)=[O:22])=[CH:31][CH:32]=1
Reactant: CCCn1cnc2[nH]ccc2c1=O
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCCn1cnc2c(ccn2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c1=O
Yield: 88.9 %

Procedure:
Under argon gas, 3-propyl-7H-pyrrolo[2,3-d]pyrimidin-4-one (249 mg) was dissolved in anhydrous DME (6 ml) and, under ice-cooling and stirring, 60% sodium hydride-oil (62 mg) was added. The mixture was stirred for 30 minutes, after which a solution of 4-(4-chlorobenzoyl)benzyl bromide (564 mg) in anhydrous DME (2 ml) was added. The mixture was further stirred at room temperature for 2 hours. The solvent was then distilled off under reduced pressure and the residue was dissolved in ethyl acetate, washed with saturated aqueous NaCl solution, and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure and the residue was purified by flash column chromatography (silica gel, 21 g; hexane: ethyl acetate =4:1-3:2) to provide the title compound as colorless powder (507 mg).
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:23]=[CH:22][C:7]2[CH:8]=[C:9]([C:11]([NH:13][C@@H:14]3[CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)=[O:12])[S:10][C:6]=2[CH:5]=1.C(N(CC)CC)C.[C:31]([C:33]1[CH:34]=[C:35]([N:39]=[C:40]=[O:41])[CH:36]=[CH:37][CH:38]=1)#[N:32]>C1COCC1>[ClH:1].[N:16]12[CH2:21][CH2:20][CH:19]([CH2:18][CH2:17]1)[C@@H:14]([NH:13][C:11]([C:9]1[S:10][C:6]3[CH:5]=[C:4]([NH:3][C:40]([NH:39][C:35]4[CH:36]=[CH:37][CH:38]=[C:33]([C:31]#[N:32])[CH:34]=4)=[O:41])[CH:23]=[CH:22][C:7]=3[CH:8]=1)=[O:12])[CH2:15]2
Reactant: N#Cc1cccc(N=C=O)c1
Reactant: Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#Cc1cccc(NC(=O)Nc2ccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc3c2)c1
Reaction time: 18 h

Procedure:
A solution of 40 mg (0.11 mmol) of 6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide dihydrochloride in 2 ml of THF is mixed with 29.8 μl (0.21 mmol) of triethylamine and 30.8 mg (0.21 mmol) of 3-cyanophenyl isocyanate. After 18 h at room temperature, the product is purified by preparative HPLC. The concentrated product fraction is dissolved in a mixture of acetonitrile and 1 N hydrochloric acid (5:1), again concentrated and dried under high vacuum. 32 mg (62.1% of theory) of the title compound are obtained.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[F:11][C:12]([F:27])([F:26])[C:13]1[CH:14]=[C:15]([CH:23]=[CH:24][CH:25]=1)/[CH:16]=[CH:17]/[C:18](OCC)=[O:19].O>C1COCC1>[F:11][C:12]([F:26])([F:27])[C:13]1[CH:14]=[C:15]([CH:23]=[CH:24][CH:25]=1)/[CH:16]=[CH:17]/[CH2:18][OH:19]
Reactant: CCOC(=O)/C=C/c1cccc(C(F)(F)F)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: OC/C=C/c1cccc(C(F)(F)F)c1
Yield: 50.7 %

Procedure:
12.29 ml of 1M diisobutylaluminum hydride solution in THF diluted with 20 ml of THF are introduced under argon and a solution of 1.00 g (4.095 mmol) of ethyl E-3-trifluoromethylcinnamate in 20 ml of THF is added dropwise. The mixture is subsequently stirred for 30 min. hydrolyzed with water, then extracted with dichloromethane, and the combined extracts are dried and concentrated. Column chromatography on silica gel (mobile phase: cyclohexane:ethylacetate:=7:3) yields in the first fraction 420 mg (50.7% of theory) of E-3-trifluoromethylcinnamyl alcohol which is employed further for the oxidation.
Reaction SMILES: F[B-](F)(F)F.C([O+](CC)CC)C.[Cl:13][C:14]1[C:19]([F:20])=[C:18]([Cl:21])[CH:17]=[CH:16][C:15]=1[C:22]([N:24]1[CH2:29][CH2:28][NH:27][C:26](=O)[CH2:25]1)=[O:23].[S:31]1[CH:35]=[CH:34][N:33]=[C:32]1[C:36]([NH:38][NH2:39])=O>ClCCl.C(OCC)(=O)C>[Cl:13][C:14]1[C:19]([F:20])=[C:18]([Cl:21])[CH:17]=[CH:16][C:15]=1[C:22]([N:24]1[CH2:29][CH2:28][N:27]2[C:36]([C:32]3[S:31][CH:35]=[CH:34][N:33]=3)=[N:38][N:39]=[C:26]2[CH2:25]1)=[O:23]
Reactant: O=C1CN(C(=O)c2ccc(Cl)c(F)c2Cl)CCN1
Reactant: NNC(=O)c1nccs1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(c1ccc(Cl)c(F)c1Cl)N1CCn2c(nnc2-c2nccs2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triethyloxonium tetrafluoroborate (144 mg, 0.756 mmol) was added to a suspension of 4-[(2,4-dichloro-3-fluorophenyl)carbonyl]-2-piperazinone (I37) (200 mg, 0.687 mmol) in dry dichloromethane (DCM) (1.7 ml). The reaction was stirred at room temperature 1 h—everything dissolved. 1,3-thiazole-2-carbohydrazide (I50)(118 mg, 0.824 mmol) was added and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and 1-butanol (1.700 ml) was added to the residue. The resulting reaction mixture was stirred at reflux for 9 h. The reaction mixture was diluted with ethyl acetate (I25 mL) and washed with water (2×25 mL), sat. NaHCO3 (25 mL) and brine (2×25 mL). The resulting organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by MDAP (acidic method). The resulting residue was triturated with Et2O and dried 3 days at 50° C. under vacuum to afford desired product in 30.5 mg as a white solid.
Reaction SMILES: C(N)(C)C.[BH4-].[Na+].[Cl:7][C:8]1[CH:9]=[C:10]([CH:14]([OH:28])[CH2:15][CH2:16][N:17]([CH:25]([CH3:27])[CH3:26])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:11]=[CH:12][CH:13]=1.[H-].[Na+].CS(O[CH2:36][CH2:37][CH2:38][O:39][CH3:40])(=O)=O>C1COCC1>[Cl:7][C:8]1[CH:9]=[C:10]([CH:14]([O:28][CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH2:15][CH2:16][N:17]([CH:25]([CH3:26])[CH3:27])[C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:23])[CH3:21])[CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)N(CCC(O)c1cccc(Cl)c1)C(=O)OC(C)(C)C
Reactant: COCCCOS(C)(=O)=O
Agent: [BH4-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)N
Product: COCCCOC(CCN(C(=O)OC(C)(C)C)C(C)C)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
tert-butyl 3-(3-chlorophenyl)-3-hydroxypropyl(isopropyl)carbamate was obtained using procedures analogous to Preparation A, Steps 1-6, using isopropylamine in Step 1 and NaBH4 in Step 6. To a 0° C. solution of tert-butyl 3-(3-chlorophenyl)-3-hydroxypropyl(isopropyl)carbamate (158 mg, 0.48 mmol) in THF (5 mL) was added NaH (60 mg, 1.45 mmol) and the reaction was allowed to stir for 5 minutes. 3-methoxypropyl methanesulfonate (810 mg, 4.8 mmol) was then added and the reaction was heated to reflux for 2.5 hrs. After cooling to room temperature, the reaction was quenched with saturated ammonium chloride solution at 0° C. The aqueous layer was extracted with EtOAc (2×). The combined organic layers were dried over MgSO4, filtered, evaporated and purified via ISCO to afford tert-butyl 3-(3-chlorophenyl)-3-(3-methoxypropoxy)propyl(isopropyl)carbamate. MS ESI+ve m/z 422 (M+Na).
Reaction SMILES: [C:1]([C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])=[N:21][N:22]=3)[CH:19]=2)=[CH:10][CH:9]=1)=[O:6])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:34]>C1COCC1>[CH3:34][N:7]([C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[O:6])[C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])=[N:21][N:22]=3)[CH:19]=2)=[CH:12][CH:13]=1
Reactant: COc1ccccc1-c1nnc2ccc(-c3ccc(NC(=O)C(C)(C)C)cc3)cn12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccccc1-c1nnc2ccc(-c3ccc(N(C)C(=O)C(C)(C)C)cc3)cn12
Temperature: 0 °C
Reaction time: 2 h
Yield: 31.6 %

Procedure:
To a mixture of 6-(4-t-butylcarbonylaminophenyl)-3-(2-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine (120 mg, 0.29 mmol) in dry THF (20 mL) cooled at 0° C. was added NaH (12 mg, 0.32 mmol), and it was stirred for 2 h. To the mixture was added iodomethane (164 mg, 1.5 mmol) in THF (8 mL) dropwise, and the mixture was stirred at room temperature overnight. The reaction mixture was quenched with saturated NH4Cl (20 mL) and extracted with ethyl acetate (100 mL×3). The combined organic phase was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the residue was purified by preparative TLC to give the title compound (38 mg, 31% yield) as yellow solids. MS: m/z 431.3 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:6](=O)[CH2:7][CH2:8][C:9]=2[CH:10]=1.[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([F:27])=[C:17]([C@@:19]2([CH3:26])[NH:24][C:23](=[O:25])[CH2:22][O:21][CH2:20]2)[CH:18]=1.[B][B][B][B][B][B][B][B][B][B].C(=O)([O-])O.[Na+]>CO.ClCCl>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([NH:12][C:13]3[CH:14]=[CH:15][C:16]([F:27])=[C:17]([C@@:19]4([CH3:26])[NH:24][C:23](=[O:25])[CH2:22][O:21][CH2:20]4)[CH:18]=3)[CH2:7][CH2:8][C:9]=2[CH:10]=1
Reactant: O=C1CCc2cc(Cl)cnc21
Reactant: C[C@@]1(c2cc(N)ccc2F)COCC(=O)N1
Agent: O=C([O-])O
Agent: [B][B][B][B][B][B][B][B][B][B]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: C[C@@]1(c2cc(NC3CCc4cc(Cl)cnc43)ccc2F)COCC(=O)N1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A solution of 3-chloro-5,6-dihydro-[1]pyrindin-7-one (34.5 mg, 0.21 mmol) and (R)-5-(5-amino-2-fluoro-phenyl)-5-methyl-morpholin-3-one (50.1 mg, 0.22 mmol) in a mixture of methanol (7.3 ml) and dichloromethane (0.9 ml) was treated with decaborane (6.9 mg, 0.21 mmol). The reaction mixture was stirred at room temperature for 22 hours. For the workup, the mixture was poured into a saturated aqueous solution of sodium hydrogen carbonate, thereafter extracted with ethyl acetate. The combined organic layers were dried over sodium sulphate, then evaporated at reduced pressure. The crude material was purified by flash chromatography on silica gel using a gradient of heptane/ethyl acetate=100:0 to 20:80 as the eluent. The (R)-5-[5-((RS)-3-chloro-6,7-dihydro-5H-[1]pyrindin-7-ylamino)-2-fluoro-phenyl]-5-methyl-morpholin-3-one was obtained as an orange solid (50 mg, 71%); (calculated) C19H19ClFN3O2 [375.83]; (found) [M]+=376, [M+2]+=378.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7]([C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])[CH2:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[N:41]([C:44]1[CH:54]=[CH:53][C:47]([C:48]([O:50][CH2:51][CH3:52])=[O:49])=[CH:46][CH:45]=1)=[C:42]=[O:43].C(=O)([O-])O.[Na+]>C1COCC1>[C:1]([O:5][C:6]([N:7]([CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:42]([NH:41][C:44]2[CH:54]=[CH:53][C:47]([C:48]([O:50][CH2:51][CH3:52])=[O:49])=[CH:46][CH:45]=2)=[O:43])[CH2:11][CH:10]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])=[O:33])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)c1ccc(N=C=O)cc1
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCNCC1c1ccccc1)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(NC(=O)N2CCC(CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)C(c3ccccc3)C2)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 137.9 %

Procedure:
To a solution of 181 mg of the crude tert-butyl[(1R)-1-(1-naphthyl)ethyl][(3-phenylpiperidin-4-yl)methyl]carbamate and 0.114 mL of triethylamine and 2.7 mL of THF was added 117 mg of ethyl 4-isocyanatobenzoate at room temperature. The reaction vessel was tightly sealed, followed by stirring at 100° C. overnight. The reaction mixture was cooled to room temperature, and a saturated aqueous sodium hydrogen carbonate solution was then added thereto, followed by extraction with chloroform. Then, the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 357 mg of ethyl 4-({[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]carbonyl}amino)benzoate as a crude product. ESI+: 636