Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C@H:17]2[C@@H:12]([CH2:13][CH2:14][C:15](=O)[CH2:16]2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:20][OH:21]>C(O)C.N1C=CC=CC=1>[CH2:1]([N:8]1[C@H:17]2[C@@H:12]([CH2:13][CH2:14][C:15](=[N:20][OH:21])[CH2:16]2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C1CC[C@H]2CCCN(Cc3ccccc3)[C@@H]2C1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: ON=C1CC[C@H]2CCCN(Cc3ccccc3)[C@@H]2C1
Yield: 88 %

Procedure:
To (±)-1-benzyl-trans-decahydro-7-quinolinone (D.11) (1.17 g), dissolved in ethanol (20 ml) and pyridine (0.8 ml), was added hydroxylamine hydrochloride (0.4 g), and the mixture was heated under reflux for 1 hr. On cooling, the ethanol was removed under reduced pressure and the residue was treated with dilute potassium carbonate solution. The product was extracted with chloroform and dried (K2CO3). Removal of the solvent afforded crude (±)-1-benzyl-trans-decahydro-7-quinolinone oxime (D.12) (1.1. g, ca 88%).
Reaction SMILES: S([N:11]=[N+:12]=[N-])(C1C=CC(C)=CC=1)(=O)=O.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](=[O:30])[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:18][CH:17]=1.C(N(CC)CC)C>ClCCl>[N+:11](=[C:24]([C:23](=[O:30])[CH2:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH3:14])=[CH:21][CH:20]=1)[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N-:12]
Reactant: CCOC(=O)CC(=O)Cc1ccc(OC)cc1
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=[N+]=[N-])C(=O)Cc1ccc(OC)cc1
Temperature: 25 °C
Yield: 65 %

Procedure:
Synthesis of B can be performed in analogy to the protocol in J. Org. Chem. 2001, 66, 2509-2511. At 0° C. a solution of sodium azide (2.287 g, 35.2 mmol) in a minimum amount of water was added to a solution of tosylchloride (6.71 g, 35.2 mmol) in acetone (40 ml). The reaction mixture was stirred at 0° C. for 2 h. Acetone was evaporated and the remaining aqueous residue was extracted three times with Et2O, dried over MgSO4, filtrated and evaporated to provide the tosyl azide as a clear oil. The freshly prepared tosyl azide was dissolved in DCM (40.0 ml), a mixture of commercially available ethyl 4-(4-methoxyphenyl)-3-oxobutanoate (5.54 g, 23.45 mmol) and triethylamine (4.90 ml, 35.2 mmol) in DCM (dichloromethane) was added, and stirred at room temperature over night. The product as evaporated and purified by flash chromatography on 80 g SiO2 using 20% EtOAc in cyclohexane to obtain 4.03 g of the desired product (15.36 mM; yield: 65%).
Reaction SMILES: [CH3:1][C:2]([CH3:10])([CH3:9])[CH2:3][C@@H:4]([C:6]([OH:8])=[O:7])[NH2:5].S(=O)(=O)(O)O.[CH3:16][C:17](=[CH2:19])[CH3:18].[OH-].[Na+]>C(OCC)(=O)C.O1CCOCC1>[C:17]([O:7][C:6](=[O:8])[C@H:4]([CH2:3][C:2]([CH3:10])([CH3:9])[CH3:1])[NH2:5])([CH3:19])([CH3:18])[CH3:16]
Reactant: C=C(C)C
Reactant: CC(C)(C)C[C@H](N)C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)C[C@H](N)C(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 50.5 %

Procedure:
To a pressure bottle were added 1.5 gm (10.3 mMol) 4-methyl-(L)-leucine, 25 mL dioxane, 1.5 mL concentrated sulfuric acid and 25 mL isobutylene. The pressure bottle was stoppered and the reactants were shaken together for 18 hours. The reaction mixture was then treated with 60 mL cold 1N sodium hydroxide and 100 mL ethyl acetate. To this mixture was added sufficient 1N sodium hydroxide until the pH of the mixture was 8.5. The layers were separated and the aqueous phase was extracted well with ethyl acetate. The combined ethyl acetate phases were dried over sodium sulfate and concentrated under reduced pressure to provide an oil which gradually crystallized to provide 1.05 gm (50.5%) of the title compound.
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[O:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1>CN(C)C=O.C(O)C.C(N)C1C=CC=CC=1>[CH2:12]([NH:13][CH2:3][C@@H:2]([OH:1])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[O:14][N:13]=2)[CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:6][CH:7]=1
Reactant: c1cc(OC[C@H]2CO2)cc(-c2noc3ncccc23)c1
Solvent: CN(C)C=O
Solvent: CCO
Solvent: NCc1ccccc1
Product: O[C@H](CNCc1ccccc1)COc1cccc(-c2noc3ncccc23)c1

Procedure:
The title compound is prepared from a mixture of (R)-3-(3-oxiranylmethoxy-phenyl)-isoxazolo[5,4-b]pyridine in dimethylformamide and ethanol and benzylamine in ethanol essentially as described above in Example 102, except that 1.5 equivalents of benzylamine is used.
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:15](=[O:31])[NH:16][C@@H:17]1[CH2:23][CH2:22][CH2:21][CH2:20][N:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]1=[O:30])[C:9]([OH:11])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:39][C@H:40]1[CH2:46][CH2:45][S:44][C@H:43]2[CH2:47][CH2:48][CH2:49][C@@H:50]([C:51]#[N:52])[N:42]2[C:41]1=[O:53]>>[CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:15]([NH:16][C@H:17]1[CH2:23][CH2:22][CH2:21][CH2:20][N:19]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:18]1=[O:30])=[O:31])[C:9]([NH:39][C@H:40]1[CH2:46][CH2:45][S:44][C@H:43]2[CH2:47][CH2:48][CH2:49][C@@H:50]([C:51]#[N:52])[N:42]2[C:41]1=[O:53])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)[C@H](CC[C@H](Cc1ccccc1)C(=O)N[C@@H]1CCCCN(c2ccccc2)C1=O)Cc1ccccc1
Reactant: N#C[C@@H]1CCC[C@@H]2SCC[C@H](N)C(=O)N12
Product: N#C[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CCCCN(c4ccccc4)C3=O)Cc3ccccc3)C(=O)N12

Procedure:
(2R,5R)-2,5-Dibenzyl-N1-((4S,7S,10aS)-7-cyano-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-yl)-N6-((S)-2-oxo-1-phenylazepan-3-yl)hexanediamide was synthesized as described in General Procedure H using Intermediate 24 (10 mg, 0.020 mmol) and Intermediate 36 (6.1 mg, 0.023 mmol) to give a white solid (8.0 mg, 57% yield). Anal. Calcd. for C42H49N5O4S m/z 719.7. found: 720.7 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.40-7.32 (2H, m), 7.29-7.05 (13H, m), 7.00-6.91 (2H, m), 5.39-5.34 (1H, m), 5.31-5.25 (1H, m), 5.02-4.93 (1H, m), 4.85-4.76 (1H, m), 3.99-3.89 (1H, m), 3.63-3.54 (1H, m), 3.00-2.90 (1H, m), 2.89-2.68 (4H, m), 2.66-2.57 (1H, m), 2.45-2.31 (2H, m), 2.20-2.08 (2H, m), 2.03-1.62 (11H, m), 1.62-1.47 (3H, m), 1.43-1.26 (2H, m).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.C([N:9]([CH2:12][CH3:13])CC)C.Cl[C:15](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>CN(C)C=O>[CH3:1][C:2]1[N:3]([CH2:15][CH2:13][CH2:12][NH2:9])[CH:4]=[N:5][CH:6]=1
Reactant: Cc1c[nH]cn1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cncn1CCCN
Reaction time: 3.5 h

Procedure:
4-methyl-1H-imidazole (1) (36.53 mmol, 1 eq) of was dissolved in 120 mL of dimethylformamide, triethylamine (73.06 mmol, 2 eq.) and chlorotriphenylmethane (40.1 mmol, 1.1 eq) where added. The mixture was stirred for 3.5 h. The precipitate filtered off and was washed by means of ice-cooled dimethylformamide (2×50 mL) and water (2×50 mL). After removal of the solvent the remaining product was dried over P4O10.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][N:23]=1)[CH:19]=[O:20])([O-:3])=[O:2].[F:24][C:25]([F:35])([F:34])[C:26]1[CH:27]=[C:28]([Mg]Cl)[CH:29]=[CH:30][CH:31]=1.C([O-])(O)=O.[Na+]>C1COCC1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[C:16]1[CH:17]=[C:18]([CH:19]([C:30]2[CH:29]=[CH:28][CH:27]=[C:26]([C:25]([F:35])([F:34])[F:24])[CH:31]=2)[OH:20])[CH:21]=[CH:22][N:23]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccnc(-c2cc(N3CCCCC3)ccc2[N+](=O)[O-])c1
Reactant: FC(F)(F)c1cccc([Mg]Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(N2CCCCC2)cc1-c1cc(C(O)c2cccc(C(F)(F)F)c2)ccn1
Temperature: 0 °C

Procedure:
To a −78° solution of 110 mg of 2-(2-nitro-5-(piperidin-1-yl)phenyl)isonicotinaldehyde in 4 mL of THF was added 0.82 mL of a 1.0 M solution of 3-(trifluoromethyl)phenylmagnesium chloride in THF. After 5 min the solution was warmed to 0° C. and treated with 10 mL of a saturated aqueous solution of NaHCO3. The mixture was extracted with ethyl acetate and the organic extracts were washed with water and then with brine. The solution was dried (Na2SO4) and the solvent was evaporated. The residue was purified by silica gel chromatography eluting with 1:1 ethyl acetate/hexanes to give 123 mg of product. MS (ES, m/z) 458.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(N(CC)CC)C.Cl.[CH3:35][C:36]1([CH3:43])[CH2:41][CH2:40][CH:39]([NH2:42])[CH2:38][CH2:37]1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:17](=[O:19])[NH:42][CH:39]3[CH2:40][CH2:41][C:36]([CH3:43])([CH3:35])[CH2:37][CH2:38]3)=[CH:20][CH:21]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CC1(C)CCC(N)CC1
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NC4CCC(C)(C)CC4)cc3)c(Cl)cc21
Reaction time: 16 h
Yield: 47.2 %

Procedure:
To a solution of 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (0.0921 g, 0.244 mmol), N,N-dimethylpyridin-4-amine (0.00299 g, 0.0244 mmol), triethylamine (0.0511 ml, 0.367 mmol), and 4,4-dimethylcyclohexanamine hydrochloride (0.060 g, 0.367 mmol) in DMF (1.5 ml) was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.0562 g, 0.293 mmol), and the reaction was stirred for 16 hours. The reaction was diluted with EtOAc and washed with 1M hydrochloric acid, saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified on a Biotage SP1 system eluting with a linear gradient of 5-70% EtOAc in hexanes to yield 56 mg of the title compound (47.2% yield).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.OS(O)(=O)=O.O[CH2:19][NH:20][C:21](=[O:26])[C:22]([Cl:25])([Cl:24])[Cl:23].Cl[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29].Cl>>[CH2:31]([O:30][C:28]([NH:1][C@@H:2]([CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:19][NH:20][C:21](=[O:26])[C:22]([Cl:25])([Cl:24])[Cl:23])=[CH:6][CH:5]=1)[C:10]([OH:12])=[O:11])=[O:29])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=C(NCO)C(Cl)(Cl)Cl
Agent: Cl
Agent: O=S(=O)(O)O
Product: O=C(N[C@@H](Cc1ccc(CNC(=O)C(Cl)(Cl)Cl)cc1)C(=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
L-Phenylalanine (8, 8.26 g, 50.0 mmol) was added in portions to concentrated H2SO4 (35 mL) maintaining the temperature at 25° C. N-(hydroxymethyl)trichloroacetamide (1.05 eq., 52.5 mmol, 10.1 g) was added in portions while maintaining the temperature at 20-25° C. The cooling bath was removed and the light-brown cloudy solution was stirred at room temperature for 1 hour. The reaction mixture was added to ice (500 mL) and the pH was adjusted to pH 5.5 with 8 M aq. NaOH solution while maintaining the quench temperature at 15-20° C. The white solid was filtered off and washed with ice-cold H2O. The residue was dissolved in a 1:1 mixture of H2O/dioxane (100 mL) and the pH was adjusted to pH 9 by addition of Na2CO3. Next, benzyl chloroformate (7.32 mL, 50.0 mmol) was added and the mixture was stirred for 4 hours. Concentrated aq. HCl was added until pH 1 and the mixture was extracted twice with EtOAc. The combined organic layers were extracted with brine, dried (MgSO4) and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (25%->60% EtOAc/PE) and the title compound was obtained as a colourless solid (yield: 8.29 g, 17.5 mmol, 35%). 1H NMR (400 MHz, CDCl3): δ=10.16 (s, 1H), 7.31-7.21 (m, 6H), 7.13 (d, J=7.88 Hz, 2H), 7.09 (d, J=7.97 Hz, 2H), 5.58 (d, J=8.21 Hz, 1H), 5.05-4.97 (m, 2H), 4.60 (dd, J=13.68, 6.42 Hz, 1H), 4.40 (d, J=5.54 Hz, 2H), 3.14 (dd, J=13.57, 4.65 Hz, 1H), 3.01 (dd, J=13.81, 6.53 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ=174.70, 162.06, 155.85, 135.68, 135.31, 135.15, 129.57, 128.31, 128.28, 127.76, 127.57, 92.30, 66.91, 54.41, 44.54, 36.99 ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13](OCC)=O)[CH:9]=[CH:10][CH:11]=1.C([N-]C(C)C)(C)C.[Li+].CN(C)P(N(C)C)(N(C)C)=[O:34].ICC.[CH2:45]1[CH2:49][O:48][CH2:47][CH2:46]1>>[CH3:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:2]([CH3:1])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][CH2:13][CH2:46][C:47]([O:48][CH2:49][CH3:45])=[O:34])[CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)Cc1cccc(OCc2c(C)cccc2C)c1
Reactant: C1CCOC1
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCI
Product: CCOC(=O)CCCc1cccc(OCc2c(C)cccc2C)c1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of Ethyl 2-(3-(2,6-dimethylbenzyloxy)phenyl)acetate (Step A, 4.79 g, 16.0 mmol) in dry THF (60 ml) was added drop wise a solution of lithium diisopropylamide (1.0 M in THF, 25 ml) at −78° C. under argon followed by addition of hexamethylphosphoramide (HMPA, 15 ml). After 15 minutes of stirring at −78° C., Iodoethane (12.53 g, 80.3 mmol) was added rapidly. The reaction mixture was warmed to room temperature for 16 hours. The crude mixture was quenched with sat. NH4Cl and extracted with ether (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (ethyl acetate:hexane, 1:4) to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[CH2:6][CH:7]([C:9]([OH:11])=[O:10])[O:8][C:4]=2[C:3]=1[Cl:14].[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20](Cl)=[O:21].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[Cl:1][C:2]1[C:13]([C:20]([C:16]2[O:15][CH:19]=[CH:18][CH:17]=2)=[O:21])=[CH:12][C:5]2[CH2:6][CH:7]([C:9]([OH:11])=[O:10])[O:8][C:4]=2[C:3]=1[Cl:14]
Reactant: O=C(O)C1Cc2ccc(Cl)c(Cl)c2O1
Reactant: O=C(Cl)c1ccco1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1ccco1)c1cc2c(c(Cl)c1Cl)OC(C(=O)O)C2

Procedure:
To a well stirred mixture of 6,7-dichloro-2,3-dihydro-benzofuran-2-carboxylic acid (3.3 g.), furan-2-carbonyl-chlorine (3.6 g.) and 200 ml. methylene chloride, protected from the atmosphere with a calcium chloride tube is added anhydrous aluminum chloride (3.7 g.) over a one-half hour period. The reaction solution is stirred 18 hours at 25° C. and then refluxed for 1 hour. The solvent is removed and the residue added to ice water (200 ml.) and hydrochloric acid (20 ml.). The product is extracted into ether, washed with water, then extracted into aqueous sodium bicarbonate (200 ml.) from which the sodium salt of the product precipitates. The sodium salt of the product is placed in a separatory funnel with dilute hydrochloric acid (100 ml.) and ether (100 ml.) and shaken until the solid dissolves. The ether solution is washed with water, brine, dried over magnesium sulfate and the ether distilled at reduced pressure. The 6,7-dichloro-2,3-dihydro-5-(2-furoyl)-benzofuran-2-carboxylic acid melts at 166° C. after crystallization from acetonitrile/n-butyl chloride.
Reaction SMILES: C(OC(=O)[NH:7][C@@:8]([C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[C:29]([O:38][CH:39]3[CH2:44][CH2:43][CH:42]([CH:45]4[CH2:49][CH2:48][CH2:47][CH2:46]4)[CH2:41][CH2:40]3)[C:30]=2[C:34]([F:37])([F:36])[F:35])[CH:25]=1)([CH3:23])[CH2:9][O:10][P:11]([O:18]C(C)(C)C)([O:13]C(C)(C)C)=[O:12])(C)(C)C.Cl.O.C(O)(=O)C>>[NH2:7][C@@:8]([C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[C:29]([O:38][CH:39]3[CH2:44][CH2:43][CH:42]([CH:45]4[CH2:49][CH2:48][CH2:47][CH2:46]4)[CH2:41][CH2:40]3)[C:30]=2[C:34]([F:35])([F:36])[F:37])[CH:25]=1)([CH3:23])[CH2:9][O:10][P:11](=[O:12])([OH:13])[OH:18]
Reactant: CC(C)(C)OC(=O)N[C@@](C)(COP(=O)(OC(C)(C)C)OC(C)(C)C)c1ccc2c(C(F)(F)F)c(OC3CCC(C4CCCC4)CC3)ccc2c1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: C[C@](N)(COP(=O)(O)O)c1ccc2c(C(F)(F)F)c(OC3CCC(C4CCCC4)CC3)ccc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 103.5 %

Procedure:
[(R)-1-[6-(4-Cyclopentyl-cyclohexyloxy)-5-trifluoromethyl-naphthalen-2-yl]-2-(di-tert-butoxy-phosphoryloxy)-1-methyl-ethyl]-carbamic acid tert-butyl ester (11 mg, 0.000015 mol) was added 12 M of hydrogen chloride in water (1 mL, 0.01 mol; Supplier=Aldrich) and acetic acid (1 mL, 0.02 mol) and the solution was stirred for 1.5 h at RT. All solvent was then removed inder reduced pressure and the residue was dried on high-vac over night to give the desired product 8 mg was a white HCl salt (98%). ESI-MS: 499 (M-16)+. 1H NMR (400 MHz, DMSO-d6) δ=8.19-8.07 (m, 1 H), 7.84 (d, J=9.0 Hz, 1 H), 7.63-7.42 (m, 2 H), 7.22 (dd, J=5.0, 9.0 Hz, 1 H), 5.10 (br. s., 1 H), 4.32-4.11 (m, 1 H), 3.72 (m, 2 H), 2.18-1.98 (m, 2 H), 1.92-0.71 (m, 21 H)
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])=[CH:19][C:18]=3[CH3:29])=[C:13]([C:30]([O:32]CC)=[O:31])[C:12]2=[O:35])=[CH:2]1.[CH:36]1([CH2:39][OH:40])[CH2:38][CH2:37]1>CN(C)C(=O)C.[Zn]>[CH:30]([OH:32])=[O:31].[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])=[CH:19][C:18]=3[CH3:29])=[C:13]([C:30]([O:40][CH2:39][CH:36]3[CH2:38][CH2:37]3)=[O:31])[C:12]2=[O:35])=[CH:2]1
Reactant: OCC1CC1
Reactant: CCOC(=O)C1=C(Nc2ccc(OCCN(C)C)cc2C)OC(=Cc2c[nH]c3ncccc23)C1=O
Agent: [Zn]
Solvent: CC(=O)N(C)C
Product: Cc1cc(OCCN(C)C)ccc1NC1=C(C(=O)OCC2CC2)C(=O)C(=Cc2c[nH]c3ncccc23)O1
Product: O=CO
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 15.1 %

Procedure:
A solution of ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-({4-[2-(dimethylamino)ethoxy]-2-methylphenyl}amino)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.033 g, 0.070 mmol) which similarly prepared according to the procedure described in the Example 111, cyclopropyl carbinol (0.10 mL, 1.3 mmol) and zinc cluster catalyst (Zn4(OCOCF3)6O) (0.0033 g, 0.0035 mmol) in N,N-dimethylacetamide (0.9 mL) was stirred with the microwave synthesizer (Biotage Initiator™) at 150° C. for 30 min. Cooled to ambient temperature, the precipitate was removed by filtration. The filtrate was purified by preparative HPLC to afford the titled compound as solid (0.0029 g, y. 8%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[N:10]=[C:11]([N:20]3[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]3)[C:12]3[CH2:17][S:16](=[O:19])(=[O:18])[CH2:15][C:13]=3[N:14]=2)=[C:4]([F:27])[CH:3]=1.Cl[C:29]([O:31][C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1)=[O:30].N1C=CC=CC=1.[Cl-].[NH4+]>C(Cl)Cl>[C:29](=[O:30])([O:31][C:32]1[CH:33]=[CH:34][C:35]([N+:38]([O-:40])=[O:39])=[CH:36][CH:37]=1)[O:26][CH:23]1[CH2:24][CH2:25][N:20]([C:11]2[C:12]3[CH2:17][S:16](=[O:18])(=[O:19])[CH2:15][C:13]=3[N:14]=[C:9]([C:5]3[CH:6]=[C:7]([F:8])[C:2]([Cl:1])=[CH:3][C:4]=3[F:27])[N:10]=2)[CH2:21][CH2:22]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=S1(=O)Cc2nc(-c3cc(F)c(Cl)cc3F)nc(N3CCC(O)CC3)c2C1
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1CCN(c2nc(-c3cc(F)c(Cl)cc3F)nc3c2CS(=O)(=O)C3)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 112.1 %

Procedure:
A mixture of 571 mg of 1-[2-(4-chloro-2,5-difluorophenyl)-6,6-dioxido-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl]piperidin-4-ol, 0.30 g of 4-nitrophenyl chloroformate, 0.12 ml of pyridine, and 10 ml of methylene chloride was stirred at ambient temperature for 17 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted twice with chloroform. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to yield 894 mg of 1-[2-(4-chloro-2,5-difluorophenyl)-6,6-dioxido-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl]piperidin-4-yl 4-nitrophenyl carbonate as light yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.[C:18]12([CH2:28][NH2:29])[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:26][CH:20]([CH2:21]3)[CH2:19]1)[CH2:25]2.C(N(CC)C(C)C)(C)C>ClCCl.CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([NH:29][CH2:28][C:18]12[CH2:27][CH:22]3[CH2:21][CH:20]([CH2:26][CH:24]([CH2:23]3)[CH2:25]1)[CH2:19]2)=[O:9]
Reactant: NCC12CC3CC(CC(C3)C1)C2
Reactant: O=C(O)c1cc(Br)ccc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(Br)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.8 %

Procedure:
To a suspension of 5-bromo-2-chlorobenzoic acid (5.00 g) in dichloromethane (25 ml) at 0° C. was added oxalyl chloride (3.7 ml) and DMF (5 drops). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h, then concentrated under reduced pressure to yield a solid. The solid was dissolved in dichloromethane (20 ml) and added dropwise to a solution of 1-adamantanemethylamine (3.36 g) and N,N-diisopropylethylamine (5.55 ml) in dichloromethane (20 ml). The resulting solution was allowed to stir at room temperature under a nitrogen atmosphere for 20 hs. The reaction mixture was diluted with dichloromethane and washed with water, 10% aqueous potassium carbonate, 10% aqueous potassium hydrogen sulfate and saturated brine. The organic phase was then dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the subtitled compound as a solid (7.84 g).
Reaction SMILES: C([C:5]1([CH:13]=[CH:12][C:11](Br)=[CH:10][CH2:9]1)[C:6]([O-:8])=[O:7])(C)(C)C.[CH2:15]([C:18]1[CH:23]=[CH:22][C:21]([C:24]#[CH:25])=[CH:20][CH:19]=1)[CH2:16][CH3:17].[CH2:26]([C:29]1[CH:34]=CC(Br)=C[CH:30]=1)CC.C[Si](C#C)(C)C.Cl>O>[C:29]([O:8][C:6]([C:5]1[CH:9]=[CH:10][C:11]([C:25]#[C:24][C:21]2[CH:20]=[CH:19][C:18]([CH2:15][CH2:16][CH3:17])=[CH:23][CH:22]=2)=[CH:12][CH:13]=1)=[O:7])([CH3:34])([CH3:30])[CH3:26]
Reactant: CC(C)(C)C1(C(=O)[O-])C=CC(Br)=CC1
Reactant: C#Cc1ccc(CCC)cc1
Reactant: CCCc1ccc(Br)cc1
Agent: C#C[Si](C)(C)C
Agent: Cl
Solvent: O
Product: CCCc1ccc(C#Cc2ccc(C(=O)OC(C)(C)C)cc2)cc1

Procedure:
The reaction was conducted in the same manner as in the step (i) of the Example 31, except for using 1-tert-butyl-4-bromobenzoate synthesized in the step (i) of the Example 106 and 4-n-propylphenylacetylene synthesized in the step (ii) of the Example 31 instead of 1-n-propyl-4-bromobenzene and trimethylsilylacetylene, respectively. After completion of the reaction, the reaction mixture was poured into an iced water, and the resultant mixture was acidified by adding hydrochloric acid. The resultant solid was collected by filtration, washed with water, dried, and recrystallized from hexane to give 1-[4-(tert-butoxycarbonyl)phenyl]-2-(4-n-propylphenyl)acetylene.