Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.CN([CH:9]=[O:10])C.[CH3:11][C:12](=O)[C:13]([CH3:16])([CH3:15])[CH3:14].N>>[Cl:3][C:12]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:11][CH:9]=[O:10]
Reactant: CC(=O)C(C)(C)C
Reactant: CN(C)C=O
Reactant: O=P(Cl)(Cl)Cl
Agent: N
Product: CC(C)(C)C(Cl)=CC=O
Reaction time: 2 h
Yield: 79.8 %

Procedure:
Phosphorous oxychloride (18.77 mL, 200 mmol) was added dropwise to DMF (30.8 mL, 400 mmol) at 0-5° C. for 30 min. Pinacolone (10 g, 100 mmol) was added dropwise to the reaction mixture at the same temperature for 30 min. The mixture was allowed to rt and stirred for 2 h. The reaction mixture was poured into ice cold water and basified with ammonia solution. The solution was extracted with chloroform (3×200 mL) and the combined chloroform layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using hexane-EtoAc (97:3) as eluents to give the product as a pale green color oil (11.7 g, 80%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:3]([N:5]1[CH2:10][CH2:9][N:8]([CH:11]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)=[O:4].[C:30]([C:34]1[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=1)([CH3:33])([CH3:32])[CH3:31].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.CCOC(C)=O>[F:18][C:15]1[CH:14]=[CH:13][C:12]([CH:11]([C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[N:8]2[CH2:7][CH2:6][N:5]([C:3](=[O:4])[C@@H:2]([NH:1][CH2:38][C:37]3[CH:40]=[CH:41][C:34]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:35][CH:36]=3)[CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:10][CH2:9]2)=[CH:17][CH:16]=1
Reactant: CC(C)C[C@H](N)C(=O)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reactant: CC(C)(C)c1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)C[C@H](NCc1ccc(C(C)(C)C)cc1)C(=O)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.4 %

Procedure:
(S)-2-Amino-1-{4-[bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}-4-methyl-pentan-1-one (0.500 g, 1.25 mmol, Example 53) and 4-(tert-butyl)benzaldehyde (0.208 mL, 1.25 mmol, Aldrich, Milwaukee, Wis.) were mixed in CH2Cl2 (6 mL). After stirring at ambient temperature under nitrogen atmosphere for 30 minutes, the solution was cooled to 0° C. in an ice-water bath. To this solution was added sodium triacetoxyborohydride (0.396 g, 1.87 mmol). The resulting reaction mixture was stirred for, in succession, 30 minutes at 0° C. and 12 hours at ambient temperature. Twenty milliliters of saturated aqueous NaHCO3 solution was added to the reaction mixture and the resulting mixture was stirred for 15 minutes. The two layers were separated and the aqueous layer was extracted with CH2Cl2 (2×20 mL). The combined organic solution was dried over Na2SO4. TLC (50% EtOAc in Hexanes as the eluant) showed two spots with Rf values 0.93 and 0.63. The solution was concentrated in vacuo affording a viscous oil. The lower spot on TLC (Rf=0.63) was isolated by flash chromatography (30% EtOAc in hexanes). 0.496 g (73%) of the pure titled compound was obtained as a white foam: mp 57-62° C. APCI-MS m/z 548.5 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C@H:16]3[CH2:21][CH2:20][C@H:19]([CH2:22][CH2:23][CH:24]=[O:25])[CH2:18][CH2:17]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.O.O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C@H:16]3[CH2:21][CH2:20][C@H:19]([CH2:22][CH2:23][CH2:24][OH:25])[CH2:18][CH2:17]3)=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=CCC[C@H]1CC[C@H](C#Cc2ccc(-c3ccc(F)cc3)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: OCCC[C@H]1CC[C@H](C#Cc2ccc(-c3ccc(F)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 81.3 %

Procedure:
A solution of 0.44 g of 3-[trans-4-[(4'-fluoro-4-biphenylyl)ethynyl]cyclohexyl]propanal in 20 ml of methanol/water (vol. 4:1) and 15 ml of dioxan is treated portionwise with 0.10 g of sodium borohydride. The reaction mixture is stirred at room temperature for 0.75 hour and concentrated. The residue is treated with water and extracted with diethyl ether. The ether phase is washed with water, dried over sodium sulphate, filtered and evaporated. 0.36 g of 3-[trans-4-[(4'-fluoro-4-biphenylyl)ethynyl]cyclohexyl]propanol is obtained.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C@@H:15]3[NH:19][C@H:18]([C:20]([O:22]C)=[O:21])[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[O:26](C(OC(C)(C)C)=O)[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=O>C1COCC1.O>[CH3:31][C:30]([O:29][C:27]([N:19]1[C@@H:15]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:14][CH:13]=2)[CH2:16][CH2:17][C@H:18]1[C:20]([OH:22])=[O:21])=[O:26])([CH3:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: COC(=O)[C@@H]1CC[C@H](c2ccc(OCc3ccccc3)cc2)N1
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1[C@@H](c2ccc(OCc3ccccc3)cc2)CC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 90.7 %

Procedure:
To a solution of methyl (5R)-5-{4-[(phenylmethyl)oxy]phenyl}-L-prolinate (D4, 120 mg, 0.38 mmol) in THF (2.3 ml) was added LiOH monohydrate (26 mg, 0.61 mmol) dissolved in water (1.1 ml), followed by methanol (1.1 ml). The resulting solution was stirred at room temperature for 2.5 hours, then left overnight at −18° C. Then the organic solvent was evaporated under reduced pressure maintaining the temperature at 38° C. and the aqueous residue containing the acid intermediate (D6, Rt (HPLC)=3.63 min. MS: (ES/+) m/z: 298 [MH+]. C18H19NO3 requires 297) was treated with BOC2O (168 mg, 0.77 mmol) dissolved in THF (1.1 ml). The reaction mixture was stirred at room temperature for 3.5 hours. The organic solvent was evaporated and the basic aqueous solution was acidified at 0° C. with aqueous 1N HCl solution to pH=3, this acidic aqueous solution was extracted with ethyl acetate (2×10 ml). The organic phase dried over Na2SO4 and evaporated under reduced pressure gave a solid, which was titurated in n-hexanes (3×6 ml) affording the title compound as a white powder (D7, 137 mg, 90% for two steps); Rt (HPLC): 5.81 min; Rf (cyclohexane:ethyl acetate=1:1): 0.34; MS: (ES/+) m/z: 420 [M+Na+] C23H27NO5 requires 397; MS: (ES/−) m/z: 396 [M−H] C23H27NO5 requires 397; 1H NMR (300 MHz, CDCl3) δ (ppm): 7.5-7.3 (m, 5H), 7.10 (bm, 2H), 6.90 (d, 2H), 5.08 (s, 2H), 4.65 (bm, 1H), 4.50 (bm, 1H), 2.58 (bm, 1H), 2.31 (bm, 1H), 2.11-1.90 (m, 2H), 1.16 (s, 9H).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH2:8][O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[C:14](=[O:22])[C:15](=[O:21])[NH:16]2>>[O:7]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:14]3([OH:22])[C:13]4[C:17](=[CH:18][CH:19]=[CH:20][C:12]=4[Cl:11])[NH:16][C:15]3=[O:21])[C:10]=2[O:9][CH2:8]1
Reactant: O=C1Nc2cccc(Cl)c2C1=O
Reactant: Brc1cccc2c1OCO2
Product: O=C1Nc2cccc(Cl)c2C1(O)c1cccc2c1OCO2
Yield: 43.9 %

Procedure:
With 9.00 g of 4-bromo-1,3-benzodioxol and 1.81 g of 4-chloroisatin as starting materials, 1.33 g of the title compound was obtained by a similar method to Step 21-1.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:10]([F:13])([F:12])[F:11])=[C:5]([C:7]([OH:9])=O)[N:6]=1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:25][C:26]1[CH:27]=[C:28]([CH:45]=[CH:46][C:47]=1[F:48])[O:29][C:30]1[CH:31]=[CH:32][C:33]2[N:34]([N:36]=[C:37]([NH:39][C:40]([CH:42]3[CH2:44][CH2:43]3)=[O:41])[N:38]=2)[CH:35]=1>CN(C)C=O.CN(C)C(=O)C>[CH:42]1([C:40]([NH:39][C:37]2[N:38]=[C:33]3[CH:32]=[CH:31][C:30]([O:29][C:28]4[CH:45]=[CH:46][C:47]([F:48])=[C:26]([NH:25][C:7]([C:5]5[N:6]=[C:2]([CH3:1])[O:3][C:4]=5[C:10]([F:13])([F:12])[F:11])=[O:9])[CH:27]=4)=[CH:35][N:34]3[N:36]=2)=[O:41])[CH2:43][CH2:44]1
Reactant: Cc1nc(C(=O)O)c(C(F)(F)F)o1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)ccc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Product: Cc1nc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)ccc2F)c(C(F)(F)F)o1
Yield: 89.6 %

Procedure:
In the same manner as in Example 18-4 and using 2-methyl-5-(trifluoromethyl)-1,3-oxazole-4-carboxylic acid (238 mg, 1.22 mmol), tetrahydrofuran (7 mL), oxalyl chloride (160 μL, 1.83 mmol), N-[6-(3-amino-4-fluorophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 0.611 mmol), N,N-dimethylformamide (1 drop) and N,N-dimethylacetamide (3 mL) as starting materials, the title compound (276 mg, 90%) was obtained as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][C:3]=1[I:11].[C:12]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:17])[CH2:13][C:14]([CH3:16])=O>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:19]([O:18][C:12](=[O:17])/[CH:13]=[C:14](/[NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][C:3]=1[I:11])\[CH3:16])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1ccc(CCO)cc1I
Reactant: CC(=O)CC(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: C/C(=C\C(=O)OCc1ccccc1)Nc1ccc(CCO)cc1I
Yield: 99.9 %

Procedure:
To a solution of 4-amino-3-iodophenethyl alcohol from Step A (10 g, 38 mmol) and benzyl acetoacetate (7.3 g, 38 mmol) in benzene (150 mL) was added p-toluenesulfonic acid (361 mg, 1.9 mmol). The mixture was heated at reflux overnight using a Dean Stark condenser. The mixture was washed with water and brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to give 16.6 g (99%) of the crude desired product as a light brown oil: MS(APCI+): m/z 438.1 (MH+). The compound was taken to Step C without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12]([CH3:34])([CH3:33])[C:13](=[O:32])[N:14]([CH:16]3[CH2:21][CH2:20][N:19]([C:22]([C:24]4[CH:29]=[C:28]([OH:30])[CH:27]=[CH:26][C:25]=4[CH3:31])=[O:23])[CH2:18][CH2:17]3)[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Br[CH2:36][CH:37]1[CH2:39][CH2:38]1.COC1C=C(C2C(C)(C)C(=O)N(C3CCN(S(C4C=C(OC)C=CC=4OC)(=O)=O)CC3)N=2)C=CC=1OC.[OH-].[Na+]>C(O)C>[CH:37]1([CH2:36][O:30][C:28]2[CH:27]=[CH:26][C:25]([CH3:31])=[C:24]([C:22]([N:19]3[CH2:20][CH2:21][CH:16]([N:14]4[C:13](=[O:32])[C:12]([CH3:34])([CH3:33])[C:11]([C:5]5[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=5)=[N:15]4)[CH2:17][CH2:18]3)=[O:23])[CH:29]=2)[CH2:39][CH2:38]1
Reactant: BrCC1CC1
Reactant: COc1ccc(C2=NN(C3CCN(C(=O)c4cc(O)ccc4C)CC3)C(=O)C2(C)C)cc1OC
Agent: COc1ccc(OC)c(S(=O)(=O)N2CCC(N3N=C(c4ccc(OC)c(OC)c4)C(C)(C)C3=O)CC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cc(OCC5CC5)ccc4C)CC3)C(=O)C2(C)C)cc1OC
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A solution of 0.35 g of 5-(3,4-dimethoxyphenyl)-2-{1-[(5-hydroxy-2-methylphenyl)carbonyl]piperidin-4-yl}-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (compound described in example 85) and 0.11 ml (bromomethyl)cyclopropane in 8 ml ethanol is treated with 0.11 ml 10 n aqueous sodium hydroxide solution and stirred under a blanket of nitrogen for about 16 h at 80° C. until the reaction is completed largely according to TLC analysis. The solvent is evaporated under reduced pressure, and the resulting crude product is purified by chromatography (amino phase silica gel and DCM) to yield the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:25])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[CH:13]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:26][O:27][S:28]([C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=1)(=[O:30])=[O:29]>CN(C=O)C>[CH3:37][C:34]1[CH:33]=[CH:32][C:31]([S:28]([O-:30])(=[O:29])=[O:27])=[CH:36][CH:35]=1.[CH3:26][N+:22]1[CH:21]=[CH:20][C:19]([NH:18][C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([C:11]([NH:10][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)=[O:25])[CH:13]=2)=[CH:24][CH:23]=1
Reactant: O=C(Nc1ccc([N+](=O)[O-])cc1)c1cccc(Nc2ccncc2)c1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Solvent: CN(C)C=O
Product: C[n+]1ccc(Nc2cccc(C(=O)Nc3ccc([N+](=O)[O-])cc3)c2)cc1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97 %

Procedure:
Compound C4 (1.92 g, 5.73 mmol) was suspended in DMF (10 mL), methyl-p-toluenesulfonate (15 mL) was added, and the mixture was stirred at room temperature for 18 h. Solvent was removed under reduced pressure and the residue was dissolved in warm MeOH (10 mL), then diluted with EtOAc. Some of the MeOH was boiled off, and the solution was then refrigerated for 18 h. The resulting precipitate was filtered, and washed with EtOAc to give essentially pure C5 (2.90 g, 97%), which was used without further purification. 1H NMR [(CD3)2SO] δ10.85 (s, 1 H, CONH), 10.60 (s, 1 H, NH), 8.33-8.27 (m, 4 H, H-3′,5′ & py H-2,6), 8.08-8.30 (m, 2 H, H-2′,6′), 7.94-7.89 (m, 2 H, H-2″ 4″), 7.69 (t, J=7.9 Hz, 1 H, H-5″), 7.60-7.57 (m, 1 H, H-6″), 7.48-7.45 (m, 2 H, H-3, 5), 7.22 (d, J=7.5 Hz, 2 H, p-tol H-2,6), 7.20 (d, J=8.1 Hz, 2 H, p-tol H-3,5), 3.99 (s, 3 H, N+CH3), 1.99 (s, 3 H, CH3).
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.[N-:11]=[N+:12]=[N-:13].[Na+]>CN(C=O)C.C(OCC)(=O)C.O>[N:11]([CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1)=[N+:12]=[N-:13]
Reactant: O=Cc1ccc(CBr)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NCc1ccc(C=O)cc1
Temperature: 60 °C
Yield: 92.2 %

Procedure:
Bromide 3 (180 mg, 0.90 mmol) was dissolved in DMF (10 ml). Sodium azide (88 mg, 1.35 mmol) was added. The reaction mixture was then heated at 60° C. for an hour. The reaction mixture was allowed to cool and was dissolve in ethyl acetate (150 ml) and H2O (150 ml). The phases were separated and the organic phase was washed again with water (2×150 ml). The organic phase was dried over sodium sulphate, and evaporated under reduced pressure to yield 4 as an oil (134 mg, 0.83 mmol, 92%). Rf=0.70 (DCM); νmax=2094, 1694, 1607, 1207, 1167, 812, 773 cm−1; 1H NMR (300 MHz, CDCl3) δ=10.02 (s, 1H, CHO), 7.90 (d, 3J(H,H)=7.9 Hz, 2H, ArCH α to CHO), 7.48 (d, 3J(H,H)=7.9 Hz, 2H, ArCH α to CH2N3), 4.45 (s, 2H, CH2N3); 13C NMR (75 MHz, CDCl3) δ=191.6 (CHO), 142.1 (ArCCH2N3), 136.2 (ArCCHO), 130.2 (ArCH α to ArCCHO), 128.4 (ArCH α to ArCCH2N3), 54.2 (CH2N3); HRMS (ESI+): m/z calculated for C8H7N3ONa [M+Na]+: 184.0481, found 184.0497.
Reaction SMILES: N1C=CC=CC=1.[O:7]1[CH2:12][CH2:11][C:10]2([C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH2:13]2)[CH2:9][CH2:8]1.Cl.CN(C)CCCN=C=NCC.[CH3:33][N:34]1[C:39](=[O:40])[CH:38]=[C:37]([N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)[N:36]=[C:35]1[CH2:47][C:48]([O-])=[O:49].[Na+]>CN(C)C=O>[CH3:33][N:34]1[C:39](=[O:40])[CH:38]=[C:37]([N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)[N:36]=[C:35]1[CH2:47][C:48](=[O:49])[N:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:10]2([CH2:11][CH2:12][O:7][CH2:8][CH2:9]2)[CH2:13]1
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Reactant: c1ccc2c(c1)NCC21CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cn1c(CC(=O)N2CC3(CCOCC3)c3ccccc32)nc(N2CCOCC2)cc1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 5.3 %

Procedure:
3.8 ml of pyridine, 378 mg of 1,2,2′,3′,5′,6′-hexahydrospiro[3H-indole-3,4′-[4H]pyran] and 575 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride are successively added to a solution of 770 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate (example 4d, step 2d) in 11.3 ml of N,N-dimethylformamide. The reaction mixture is stirred at ambient temperature for 16 hours, and then concentrated under reduced pressure. The residue is taken up in 15 ml of water and 20 ml of ethyl acetate, and then left to stir at ambient temperature for 1 hour. The precipitate formed is filtered off, and then rinsed successively with water and diethyl ether. 45 mg of 3-methyl-6-(morpholin-4-yl)-2-[2-oxo-2-(2′,3′,5′,6′-tetrahydrospiro[indole-3,4′-pyran]-1(2H)-yl)ethyl]pyrimidin-4(3H)-one are thus obtained in the form of an off-white powder, the characteristics of which are the following:
Reaction SMILES: C([N:8]1[C:16]2([CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:29])C1C=CC=CC=1.[Na].N.[Cl-:32].[NH4+]>CO>[ClH:32].[NH:19]1[CH2:20][CH2:21][C:16]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:29])[NH:8]2)[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)c1ccccc1C(=O)N2Cc1ccccc1
Reactant: [Cl-]
Agent: N
Agent: [NH4+]
Agent: [Na]
Solvent: CO
Product: Cl
Product: O=C1NC2(CCNCC2)c2ccccc21
Reaction time: 0.5 h

Procedure:
2-Benzyl-1′-tert-butoxycarbonylspiro[1H-isoindole-1,4′-piperidine]-3(2H)-one (200 mg) was added to metallic sodium (235 mg) in liquid ammonia (10 mL) and the mixture was stirred for 30 minutes. To the reaction mixture was added methanol, neutralized with a saturated ammonium chloride aqueous solution and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue dissolved in methanol was stirred together with 4M hydrogen chloride/ethyl acetate at 50° C. for 1 hour. The reaction solution was concentrated to give the subject compound (591 mg).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[O:19]1[C:24]2[C:25]([NH2:29])=[CH:26][CH:27]=[CH:28][C:23]=2[NH:22][CH2:21][CH2:20]1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[O:19]1[C:24]2[C:25]([NH:29][C:15](=[O:17])[CH2:14][C:9]3[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[N:8]=3)=[CH:26][CH:27]=[CH:28][C:23]=2[NH:22][CH2:21][CH2:20]1
Reactant: Nc1cccc2c1OCCN2
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1cccc2c1OCCN2
Yield: 26.9 %

Procedure:
The product is prepared according to the procedure described in example 5, using 261 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 166 mg of 3,4-dihydro-2H-1,4-benzoxazin-8-ylamine and 249 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 162 μl of pyridine and 4.0 ml of N,N-dimethylformamide. 100 mg of N-(3,4-dihydro-2H-1,4-benzoxazin-8-yl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white powder, the characteristics of which are the following:
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:16]1([N+:22]#[C-:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.Cl(O)(=O)(=O)=O.[C:29](Cl)(=[O:31])[CH3:30]>C(Cl)Cl>[CH2:9]([O:8][C:7]1[C:2]2[N:3]([C:23]([N:22]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[C:29](=[O:31])[CH3:30])=[C:9]([CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[N:1]=2)[CH:4]=[CH:5][CH:6]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Nc1ncccc1OCc1ccccc1
Reactant: CC(=O)Cl
Reactant: [C-]#[N+]C1CCCCC1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: ClCCl
Product: CC(=O)N(c1c(C2CCCCC2)nc2c(OCc3ccccc3)cccn12)C1CCCCC1

Procedure:
Compound (35) was prepared from 1.0 ml of 2-amino-3-benzyloxypyridine solution (0.1 M, DCM), 0.575 ml of cyclohexyl isocyanide solution (0.2 M, DCM), 0.500 ml of cyclohexylcarbaldehyde solution (0.3 M, DCM), and 10 μl of perchloric acid (w=20%), and reaction with acetyl chloride. Excess acetyl chloride was removed under reduced pressure.
Reaction SMILES: S(=O)(=O)(O)O.[OH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:8]=1[CH2:15][CH2:16][OH:17].[CH2:18]([OH:20])[CH3:19].C1(C)C=CC=CC=1>C(O)(=O)C.O>[C:18]([O:17][CH2:16][CH2:15][C:8]1[C:9]([O:13][CH3:14])=[CH:10][CH:11]=[CH:12][C:7]=1[OH:6])(=[O:20])[CH3:19]
Reactant: COc1cccc(O)c1CCO
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cccc(O)c1CCOC(C)=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 47.6 %

Procedure:
1.0 mL (1.8 g, 18 mmol) of concentrated sulfuric acid was added dropwise to a solution of 0.27 g (1.6 mmol) of 2-(2-hydroxy-6-methoxyphenyl)ethanol in 5.0 mL of acetic acid while being cooled on an ice-water bath. This mixture was stirred under room temperature for 5 minutes and 6.0 mL (4.7 g, 102 mmol) of ethanol was added dropwise thereto. 20 mL of toluene and 20 mL of water were added to this mixture and after stirred for 5 minutes, the mixture was transferred to a separatory funnel and settled. The aqueous layer was separated and discarded and after the organic layer was washed with 100 mL of water twice, the solvent was evaporated to obtain 0.16 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([C@H:13]([CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[C:14]([O:16][CH3:17])=[O:15])[C:7]2=[O:12].CN(C)C=O.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[Cl:65][C:66]1[CH:71]=[CH:70][C:69]([CH:72]([CH3:76])[C:73](O)=[O:74])=[CH:68][CH:67]=1>>[Si:20]([O:19][CH2:18][C@@H:13]([N:6]1[CH:5]=[CH:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][C:73](=[O:74])[CH:72]([C:69]2[CH:70]=[CH:71][C:66]([Cl:65])=[CH:67][CH:68]=2)[CH3:76])[C:7]1=[O:12])[C:14]([O:16][CH3:17])=[O:15])([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: CC(C(=O)O)c1ccc(Cl)cc1
Reactant: COC(=O)[C@@H](CO[Si](C)(C)C(C)(C)C)n1ccc2c(N)cccc2c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H](CO[Si](C)(C)C(C)(C)C)n1ccc2c(NC(=O)C(C)c3ccc(Cl)cc3)cccc2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A round bottom flask was charged with (R)-methyl 2-(5-amino-1-oxoisoquinolin-2(1H)-yl)-3-(tert-butyldimethylsilyloxy)propanoate (500 mg, 0.001 mol), N,N-dimethylformamide (2 mL, 0.03 mol), N,N-diisopropylethylamine (0.5 mL, 0.003 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (1 g, 0.003 mol) and 2-(4-chlorophenyl)propanoic acid (340 mg, 0.0018 mol) and the reaction stirred at room temperature overnight then for another 12 h. The solvent was removed and the residue purified by flash chromatography to yield the product as a white solid. MS m/z=545.4 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([OH:12])[C:9]2[CH2:8][CH2:7][CH2:6][C:5]3([CH2:16][CH2:15][CH2:14][CH2:13]3)[C:4]=2[N:3]=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl.O>[CH3:27][C:17]1[CH:22]=[CH:21][C:20]([S:23]([O:12][C:10]2[C:9]3[CH2:8][CH2:7][CH2:6][C:5]4([CH2:13][CH2:14][CH2:15][CH2:16]4)[C:4]=3[N:3]=[C:2]([NH2:1])[N:11]=2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: Nc1nc(O)c2c(n1)C1(CCCC1)CCC2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(S(=O)(=O)Oc2nc(N)nc3c2CCCC32CCCC2)cc1
Reaction time: 3 h
Yield: 15.1 %

Procedure:
A solution of Example 1C (2.91 g, 13.27 mmol), p-toluenesulfonyl chloride (3.79 g, 19.91 mmol), and DMAP (324 mg, 2.65 mmol) in CH2Cl2 (60 mL) was treated with TEA (3.7 ml, 4.40 mmol) at ambient temperature, and the resulting solution was stirred for 3 hours. It was then diluted with CH2Cl2 (100 mL) and H2O (50 mL), and the layers were separated. The organic layer was dried with MgSO4 and concentrated under reduced pressure, then the residue was chromatographed on silica gel (1:2:2 EtOAc/CH2Cl2/hexane, eluant) to provide the title product (750 mg). 1H NMR (300 MHz, CD3OD) δ 7.95 (d, 2 H), 7.44 (d, 2 H), 2.45-2.47 (m, 3 H), 2.40-2.45 (m, 2 H), 1.99-2.10 (m, 2 H), 1.79-1.90 (m, 2 H), 1.65-1.75 (m, 6 H), 1.52-1.62 (m, 2 H). MS (DCI+) m/z 374 (M+H).