Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-])=O)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>O1CCCC1.[C].[Pd]>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H](CNc1ccccc1[N+](=O)[O-])C(=O)O
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CNc1ccccc1N)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
To a solution of (R)-(−)-2-tert-butoxycarbonylamino-3-(2-nitrophenylamino)propionic acid (7.6 g) in tetrahydro-furan (100mL), 10% palladium carbon (1 g) was added, followed by stirring at room temperature for 3 hours under a hydrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure, whereby (R)-2-tert-butoxycarbonylamino-3-(2-aminophenylamino)-propi onic acid was obtained. It was dissolved in toluene (100 mL). The solution was refluxed overnight. The reaction mixture was allowed to cool down and then concentrated under reduced pressure. The residue was purified by silica gel colomn chromatography (ethyl acetate:n-hexane=1:1), whereby the title compound (5.16 g) was obtained. Yield: 80%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.[CH3:10][CH2:11][O:12][C:13]([CH:15]([C:19]([CH3:21])=O)[C:16]([CH3:18])=O)=[O:14]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:19]([CH3:21])=[C:15]([C:13]([O:12][CH2:11][CH3:10])=[O:14])[C:16]([CH3:18])=[N:9]2)=[CH:4][CH:3]=1
Reactant: NNc1ccc(F)cc1
Reactant: CCOC(=O)C(C(C)=O)C(C)=O
Solvent: CCO
Product: CCOC(=O)c1c(C)nn(-c2ccc(F)cc2)c1C
Yield: 96.2 %

Procedure:
4-Fluorophenylhydrazine (7.75 g) and ethyl diacetoacetate (10.6 g) were added to ethanol (30 ml) and the mixture was refluxed for 3 h. The solvent was evaporated under reduced pressure and diisopropyl ether was added to the residue to allow crystallization. The crystals were recrystallized from a mixed solvent of ethyl acetate-diisopropyl ether to give ethyl 1-(4-fluorophenyl)-3,5-dimethylpyrazole-4-carboxylate (15.5 g), melting point: 59–60° C.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:14])[O:4][CH2:5][C@@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1>ClCCl.O=[Pt]=O>[CH3:1][C@@H:2]1[NH:7][C@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][O:4][C:3]1=[O:14]
Reactant: CC1=N[C@H](c2ccccc2)COC1=O
Agent: O=[Pt]=O
Solvent: ClCCl
Product: C[C@@H]1N[C@H](c2ccccc2)COC1=O
Reaction time: 5 h
Yield: 79.6 %

Procedure:
To a solution of (5R)-3-methyl-5-phenyl-5,6-dihydro-2H-1,4-oxazin-2-one (1.70 g, 9.0 mmol, 1.0 equiv.) in anhydrous dichloromethane (60 mL) under an atmosphere of nitrogen was added PtO2 (170 mg, 0.1 equiv.). The mixture was consecutively degassed and purged three times with hydrogen and then stirred for 5 hours under an atmosphere of hydrogen. Filtration through a short pad of CELITE® diatomaceous earth and removal of solvent from the filtrate in vacuo yielded the crude product which was purified by recrystalisation in dichloromethane, diethyl ether and hexane to furnish the title compound as white needles (1.37 g, 80%); m.p. 82.0-83.0° C. (lit. m.p. 81.0-82.0° C.); v(max)(KBr) 3314 (N—H), 2981 (C—H), 1739 (C═O), cm−1, δH (250 MHz, CDCl3) 7.44-7.33 (5H, m, Ph); 4.42-4.23 (3H, m, CHCH2), 3.88 (1H, q, /6.76 Hz, CHCH3), 1.86 (1H, br, NH), 1.50 (3H, d, J 6.16 Hz, CH3); δc (62.5 MHz, CDCl3) 170.7, 138.0, 129.3, 127.5, 127.2, 75.4, 58.2, 55.4, 19.0 m/z (CL, NH3), 191 (M+, 7%), 147 (20%), 131 (65%), 104 (100%), 91 (20%), and 77 (12%); HRMS for C11H13NO2 requires 191.0943 found 191.0940. [α]D20 −92.9 (c 1.02 CHCl3) (lit. for the enantiomer [α]D20 +92.3 (c 0.84 CHCl3)).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C@@H:13]([C:15]2[CH:27]=[CH:26][C:18]([C:19](OC(C)(C)C)=[O:20])=[CH:17][CH:16]=2)[CH3:14])(=[O:11])=[O:10])=[CH:5][CH:4]=1.FC(F)(F)C(O)=O.CN(C([O:44][N:45]1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[Si](ON)(C(C)(C)C)(C)C.Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C)C=O.C1(C)C=CC=CC=1.ClCCCl>[OH:44][NH:45][C:19](=[O:20])[C:18]1[CH:26]=[CH:27][C:15]([C@H:13]([NH:12][S:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:29])([F:28])[F:1])=[CH:4][CH:5]=2)(=[O:11])=[O:10])[CH3:14])=[CH:16][CH:17]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: C[C@@H](NS(=O)(=O)c1ccc(C(F)(F)F)cc1)c1ccc(C(=O)OC(C)(C)C)cc1
Agent: CC(C)(C)[Si](C)(C)ON
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: C[C@@H](NS(=O)(=O)c1ccc(C(F)(F)F)cc1)c1ccc(C(=O)NO)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 15 %

Procedure:
To a 2-dram vial containing (R)-tert-butyl 4-(1-(4-(trifluoromethyl)phenylsulfonamido)ethyl)benzoate was added 1,2-dichloroethane (2 mL), and trifluoroacetic acid (0.246 mL, 3.20 mmol). After shaking at rt for 4 h, the mixture was evaporated to dryness to give a residue which was azetroped with toluene (2×5 mL). To the solid residue in another vial was added HATU (0.091 g, 0.24 mmol), N,N-dimethylformamide (1.5 mL), triethylamine (0.18 mL, 1.28 mmol). The mixture was stirred for 10 min then O-(tert-butyldimethylsilyl)hydroxylamine (0.047 g, 0.32 mmol) in DCM (0.5 mL) was added. The solution was shaken at rt for 2 h, after which the solvent was then completely removed to afford a brown oil. To this oil in another vial was added hydrochloric acid (3.5 mL, 1% in IPA). After shaking at rt for 30 min, solid NaHCO3 was added to quench the excess acid, and the solvent was then removed. To the solid residue was added DMSO (1.2 mL). After filtration, the DMSO solution was purified by Gilson prep-HPLC to give the title compound (0.091 g, 15%) as a white solid. LC-MS: (FA) ES− 387; 1H NMR (Methanol-d4, 400 MHz) δ7.79 (d, J=8.3 Hz, 2H), 7.66 (d, J=8.3 Hz, 2H), 7.51 (d, J=8.5 Hz, 2H), 7.19 (d, J=8.5 Hz, 2H), 4.53 (q, J=7.0 Hz, 1H), 1.36 (d, J=7.0 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:17][CH:18]([O:35]C(=O)CCl)[C:19](=[O:34])[NH:20][CH2:21][C:22]1[C:27]([O:28][CH3:29])=[CH:26][C:25]([O:30][CH3:31])=[CH:24][C:23]=1[O:32][CH3:33])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].NC(N)=S.C([O-])(O)=O.[Na+]>CCO.C1COCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:17][CH:18]([OH:35])[C:19](=[O:34])[NH:20][CH2:21][C:22]1[C:27]([O:28][CH3:29])=[CH:26][C:25]([O:30][CH3:31])=[CH:24][C:23]=1[O:32][CH3:33])[C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1cc(OC)c(CNC(=O)C(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)OC(=O)CCl)c(OC)c1
Agent: NC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(OC)c(CNC(=O)C(O)C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(OC)c1
Temperature: 50 °C

Procedure:
To a stirred solution of 9 (0.678 g, 1.18 mmol) in EtOH/THF (5/5 mL) was added thiourea (0.269 g, 3.54 mmol) and NaHCO3 (0.297 g, 3.54 mmol). The reaction mixture was stirred and heated to 50° C. for 1.5 h. The solvent was then removed under the reduced pressure and the residue was submitted to FC on silica gel (EtOAc/Hexanes, 45/55 to 60/40, V/V) to give 10 as a mixture of C(4) diastereomers as a waxy white solid (0.543 g, 91%): 1H NMR (200 MHz, CDCl3) δ 7.26 (br s, 1H), 6.13 (s, 1H), 6.12 (s, 1H), 5.45 (d, 1H, J=5.6 Hz), 4.63-4.03 (m, 5H), 3.82, 3.81 (s, s, total 9H), 2.43-1.84 (m, 2H), 1.45 (d, 9H, J=1.2 Hz), 1.43 (s, 9H); 13C NMR (50 MHz, CDCl3) δ 172.6, 172.0, 171.5, 171.3, 161.0, 159.5, 157.3, 156.1, 106.7, 90.8, 82.7, 82.4, 80.8, 80.3, 69.6, 68.5, 55.9, 55.4, 52.0, 51.0, 39.1, 38.5, 32.2, 31.9, 28.3, 28.0; HRMS calcd for C24H39N2O9 (M+H)+: 499.2656. found: 499.2669, 499.2662.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][O:28][CH:29]([CH3:31])[CH3:30])=[O:24])[C:5]1=[O:32].C(N(C(C)C)CC)(C)C.Cl[C:43]([O:45][CH3:46])=[O:44]>CN(C=O)C>[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][C:11]2[CH:12]=[C:13]3[C:8]([C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][O:28][CH:29]([CH3:30])[CH3:31])=[O:24])[C:5](=[O:32])[N:4]3[CH2:3][CH2:2][NH:1][C:43](=[O:44])[O:45][CH3:46])=[N:9][CH:10]=2)=[CH:20][CH:19]=1
Reactant: COC(=O)Cl
Reactant: CC(C)OCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN)c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)NCCn1c(=O)c(C(=O)NCCOC(C)C)c(O)c2ncc(Cc3ccc(F)cc3)cc21

Procedure:
A solution of 1-(2-aminoethyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-{2-[(1-methylethyl)oxy]ethyl}-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (0.020 g, 0.045 mmol) and diisopropyl ethylamine (0.04 mL, 0.23 mmol) in DMF (5 mL) under nitrogen was treated with methyl chloroformate (0.0036 mL, 0.047 mmol) at ambient temperature. The reaction was concentrated in vacuo and the resulting residue was treated with 1N NaHSO4. The resulting suspension was filtered, washed with EtOH and Et2O, and dried in vacuo to provide the title compound as an beige solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.12 (d, J=6.18 Hz, 6 H), 3.22-3.31 (m, 2 H), 3.45 (s, 3 H), 3.49-3.56 (m, 4 H), 3.61 (dt, J=12.07, 6.04 Hz, 1 H), 4.14 (s, 2 H), 4.29 (t, J=6.32 Hz, 2 H), 7.11-7.19 (m, 2 H), 7.26 (t, J=5.62 Hz, 1 H), 7.39 (dd, J=8.56, 5.48 Hz, 2 H), 8.12 (s, 1 H), 8.53 (s, 1 H), 10.38 (t, J=5.48 Hz, 1 H), 17.12 (s, 1 H); ES+ MS: 501 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:8](C(O)=O)[C:7](O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C1C=CC2N([OH:23])N=NC=2C=1.CC(C)N=C=NC(C)C>>[N+:1]([C:4]1[CH:12]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:23])([O-:3])=[O:2]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1O
Reactant: On1nnc2ccccc21
Agent: CC(C)N=C=NC(C)C
Product: O=[N+]([O-])c1ccccc1O

Procedure:
This material was prepared from 5-nitrosalicylic acid (1c) (1 g, 5.46 mmol), HOBt (1 g, 7.4 mmol), DIC (1,3-diisopropylcarodiimide, 1 mL, 6.4 mmol), and an amino macroporous resin (1 g, 0.99 mmol) using a procedure similar to polystyrene resin (PS-2a).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:11]([CH3:12])=[CH:10][CH:9]=[N:8][C:6]=2[N:7]=1.[OH-:14].[Na+].Cl>>[ClH:1].[Cl:1][C:2]1[NH:3][C:4](=[O:14])[C:5]2[C:11]([CH3:12])=[CH:10][CH:9]=[N:8][C:6]=2[N:7]=1
Reactant: Cc1ccnc2nc(Cl)nc(Cl)c12
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: Cc1ccnc2nc(Cl)[nH]c(=O)c12
Reaction time: 1 h

Procedure:
2,4-Dichloro-5-methyl-pyrido[2,3-d]pyrimidine (302 mg, 1.4 mmol) was suspended at ambient temperature in aqueous 1N NaOH solution (6 ml) and stirred for 1 h. The pH was adjusted to 7 with aqueous 25% HCl solution and the mixture was washed two times with dichloromethane. The aqueous layer was brought to dryness under reduced pressure to give 344 mg (1.48 mmol; quant.) 2-chloro-5-methyl-3H-pyrido[2,3-d]pyrimidin-4-one hydrochloride as off-white solid which was used in the next step without further purification. MS: m/e=195.9 [M+H+].
Reaction SMILES: [Cl-].COC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC([O-])(C)C.[K+].[CH2:30]([C@H:34]1[CH2:39][CH2:38][C@H:37]([C@H:40]2[CH2:45][CH2:44][C@H:43](CC=O)[CH2:42][CH2:41]2)[CH2:36][CH2:35]1)[CH2:31][CH:32]=[CH2:33].[CH2:49]1[CH2:53][O:52][CH2:51][CH2:50]1>>[CH3:51][O:52][CH2:53][CH:49]=[CH:50][C@H:43]1[CH2:44][CH2:45][C@H:40]([C@H:37]2[CH2:36][CH2:35][C@H:34]([CH2:30][CH2:31][CH:32]=[CH2:33])[CH2:39][CH2:38]2)[CH2:41][CH2:42]1
Reactant: C=CCC[C@H]1CC[C@H]([C@H]2CC[C@H](CC=O)CC2)CC1
Reactant: C1CCOC1
Agent: CC(C)(C)[O-]
Agent: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Product: C=CCC[C@H]1CC[C@H]([C@H]2CC[C@H](C=CCOC)CC2)CC1
Temperature: -50 °C
Reaction time: 1 h

Procedure:
A mixture of 25.2 g (73.5 mmol) of methoxymethyltriphenyl phosphonium chloride and 300 ml of THF was cooled to −50° C. under a gas stream of nitrogen. To the mixture, 7.6 g (67.8 mmol) of t-BuOK was added and stirred for 1 hour. To the mixture, a solution of 14.8 g (56.5 mmol) of trans-4-(trans-4-(3-butenyl)cyclohexyl)cyclohexyl acetaldehyde in 150 ml of THF was added dropwise with maintaining the temperature below −50° C. After dropwise addition, the reaction temperature was increased gradually to the room temperature, and stirring was carried out further for 5 hours. The solvent was distilled off under a decresed pressure, 150 ml of water was added and the mixture was extracted with 200 ml of toluene. The organic layer was washed with 100 ml of water for three times and dried with anhydrous magnesium sulphate. The solvent was distilled off under a decreased pressure, and the residue was subjected to silica gel column chromatography (eluent: a mixed solvent of toluene/heptane=3/7), to obtain 12.8 g of crude 1-(3-methoxypropenyl)-trans-4-(trans-4-(3-butenyl)cyclohexyl)cyclohexane.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([O:13][S:14]([C:17]([F:20])([F:19])[F:18])(=[O:16])=[O:15])[CH:8]=[CH:9][C:10]=1[CH:11]=[CH2:12])C=C>ClCCl>[O:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([O:13][S:14]([C:17]([F:18])([F:19])[F:20])(=[O:15])=[O:16])[CH:6]=2)[CH:11]=[CH:12][CH2:1]1
Reactant: C=CCOc1cc(OS(=O)(=O)C(F)(F)F)ccc1C=C
Solvent: ClCCl
Product: O=S(=O)(Oc1ccc2c(c1)OCC=C2)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of trifluoro-methanesulfonic acid 3-allyloxy-4-vinyl-phenyl ester (0.68 g, 2.2 mmol) in dichloromethane (5 ml) was added Ru-catalyst (Grubb's catalyst) (36 mg, 2 mol %), and the reaction mixture was stirred for 2 h at room temperature. After that period the reaction was complete (GC) and the reaction mixture was used in the next step without any work-up. Analytical sample was obtained after removal of the solvent by silica gel column chromatography (EA:Hex, 1:20).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].C([O-])([O-])=O.[Na+].[Na+].[CH:12]1[CH:17]=[CH:16][C:15]([CH2:18][O:19][C:20](Cl)=[O:21])=[CH:14][CH:13]=1.C(Cl)Cl>C1COCC1.O>[OH:5][CH2:4][CH2:3][CH2:2][NH:1][C:20](=[O:21])[O:19][CH2:18][C:15]1[CH:16]=[CH:17][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCCCO)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.9 %

Procedure:
To a mixture of 3-aminopropan-1-ol (5.0 g, 67 mmol), Na2CO3 (8.8 g, 83 mmol) in THF (40 mL) and H2O (130 mL) at 0° C. was added Cbz-Cl (14.8 g, 87 mmol). The reaction mixture was stirred (RT, 1 h). Water (500 mL) and CH2Cl2 (500 mL) were added, and the layers were separated. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica chromatography (PE:EA, 5:1) to afford benzyl 3-hydroxypropylcarbamate as a white solid (12.6 g, 90.5%).
Reaction SMILES: [OH:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]3[C:19]([N:18]=[C:17]4[C:12]([CH:13]=[CH:14][CH:15]=[C:16]4[C:20]([OH:22])=[O:21])=[N:11]3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.[Br:23]Br>C(Cl)(Cl)Cl>[Br:23][C:3]1[CH:4]=[CH:5][C:6]2=[C:19]3[C:10](=[CH:9][CH:8]=[C:7]2[C:2]=1[OH:1])[N:11]=[C:12]1[C:17]([C:16]([C:20]([OH:22])=[O:21])=[CH:15][CH:14]=[CH:13]1)=[N:18]3
Reactant: O=C(O)c1cccc2nc3ccc4c(O)cccc4c3nc12
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: O=C(O)c1cccc2nc3ccc4c(O)c(Br)ccc4c3nc12

Procedure:
A mixture of 4-hydroxy-benzo[a]phenazine-11-carboxylic acid (see Reference Example 1K, 102 mg) and bromine (0.04 mL) was stirred in chloroform (3 mL) at room temperature for 20 hours. The solvent was removed in vacuo and the residue was purified using flash chromatography (10% methanol in dichloromethane) to yield the title compound (24 mg) as a yellow-brown solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:15]=[C:14]([CH:16]=O)[CH:13]=[CH:12][C:4]=1[O:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:2].[CH2:18]([NH2:22])[CH2:19][CH2:20][CH3:21]>C(O)C>[CH2:18]([NH:22][CH2:16][C:14]1[CH:13]=[CH:12][C:4]([O:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:3]([CH2:1][CH3:2])[CH:15]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CCOC(=O)COc1ccc(C=O)cc1CC
Reactant: CCCCN
Solvent: CCO
Product: CCCCNCc1ccc(OCC(=O)OCC)c(CC)c1
Reaction time: 0.5 h
Yield: 56.4 %

Procedure:
To a solution of ethyl (2-ethyl-4-formylphenoxy)acetate (0.52 g, 2.2 mmol) in anhydrous ethanol (10 mL) was added butylamine (0.26 mL, 2.6 mmol). The resulting solution was stirred at room temperature under N2 for 18 h over 4A molecular sieves. The reaction was quenched by cautious addition of sat. NaHCO3 aq. (30 mL) and the mixture stirred for 30 mins. The mixture was then extracted EtOAc (2×100 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. Purification by SPE (SCX, 20 g) conditioning the cartridge with ethanol and then loading the compound and washing with CH2Cl2, then ethanol before eluting the title compound using 10% NH3 in ethanol, evaporation of the 10% NH3 in ethanol extract afforded the title compound as a pale yellow oil (0.364 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1)#[N:2].Br[C:13]1[CH:18]=[CH:17][C:16]([O:19][C@H:20]([C@H:24]([OH:33])[CH2:25][CH2:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[CH:21]([CH3:23])[CH3:22])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.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>[OH:33][C@H:24]([CH2:25][CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)[C@H:20]([CH:21]([CH3:23])[CH3:22])[O:19][C:16]1[CH:17]=[CH:18][C:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=2)=[CH:14][CH:15]=1
Reactant: CC(C)[C@H](Oc1ccc(Br)cc1)[C@H](O)CCc1cccnc1
Reactant: N#Cc1cccc(B(O)O)c1
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: CCO
Product: CC(C)[C@H](Oc1ccc(-c2cccc(C#N)c2)cc1)[C@H](O)CCc1cccnc1
Temperature: 90 °C
Yield: 56.6 %

Procedure:
Prepared according to the method described in Example 12b) from 3-cyanobenzeneboronic acid (0.40 g), (3S,4R)-3-(4-bromophenyloxy)-2-methyl-6-(3-pyridyl)hexan-4-ol (0.90 g, Example 61d)), 2M aqueous sodium carbonate (2.72 ml) and tetrakis(triphenylphosphine)palladium(0) (0.160 g) in ethanol (4 ml). The reaction mixture was heated at 90° C. for 4 hours. After cooling, the solution was poured onto water, and extracted with ethyl acetate. The combined extracts were washed with brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, dissolved in dichloromethane, filtered and purified by normal-phase HPLC eluting with a gradient of 0-25% ethanol in dichloromethane to give the title compound as a gum (0.54 g).
Reaction SMILES: [C@@H:1]1([N:8]2[CH:15]=[CH:14][C:12]([NH2:13])=[N:11][C:9]2=[O:10])[O:7][C@H:4]([CH2:5][OH:6])[CH2:3][CH2:2]1.[I:16]I>CO.ClCCl>[I:16][C:14]1[C:12]([NH2:13])=[N:11][C:9](=[O:10])[N:8]([CH:15]=1)[C@@H:1]1[O:7][C@H:4]([CH2:5][OH:6])[CH2:3][CH2:2]1
Reactant: II
Reactant: Nc1ccn([C@H]2CC[C@@H](CO)O2)c(=O)n1
Solvent: CO
Solvent: ClCCl
Product: Nc1nc(=O)n([C@H]2CC[C@@H](CO)O2)cc1I
Reaction time: 4 h
Yield: 82.8 %

Procedure:
A solution of 2',3'-dideoxycytidine (2.11 g, 10 mmol, Raylo) and mercuric acetate (3.35 g, 10.5 mmol, Fisher) in 50 mL of methanol was refluxed for 19 h. The resulting white suspension was diluted with methanol (50 mL) and dichloromethane (100 mL). Iodine (3.05 g, 12 mmol) was added and the suspension was stirred at 25° until a clear purple solution was present. After 4 h, the free base form of AG3 X4A resin (20 mL, 38 meq, Bio-Rad; a weakly basic polystyrene resin) was added and hydrogen sulfide was bubbled into the reaction for 15 min. Complete precipitation of mercury(II) was verified by TLC. The reaction was filtered though filter aid and the filter aid was washed with 1:1 methanol-dichloromethane. The filtrate was evaporated onto silica gel 10 g) and the loaded silica gel was placed on top of a 150 g silica gel column. Elution with 5%, 10% and 20% methanol in dichloromethane afforded 2.79 g (83%) of iodide 44 as a colorless crystalline solid. Two recrystallizations from boiling water afforded, after vacuum-drying at 50°, large, analytically-pure prisms (mp: d 178°).
Reaction SMILES: CN(C)[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][C:13](=[O:15])[CH2:12][C:11](=O)[CH2:10]2)=CC=1.C1C2(CC(=O)CC(=O)C2)CCC1.C([O-])(=O)C.[NH4+:34]>>[NH2:34][C:11]1[CH2:10][C:9]2([CH2:6][CH2:7][CH2:8][CH2:3]2)[CH2:14][C:13](=[O:15])[CH:12]=1
Reactant: CN(C)c1ccc(C2CC(=O)CC(=O)C2)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: O=C1CC(=O)CC2(CCCC2)C1
Product: NC1=CC(=O)CC2(CCCC2)C1

Procedure:
In analogy to (Baraldi, P. G.; Simoni, D.; Manfredini, S.; Synthesis 1983, (11) 902-903 spiro[4.5]decane-7,9-dione was reacted with ammonium acetate to give the title compound as a colorless solid.
Reaction SMILES: [OH:1][CH:2]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[CH:11]=[CH:10][CH:9]=1)[CH2:3][NH:4][C:5](=[O:7])[CH3:6].C([O-])(=O)C.[K+].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[CH3:19][O:18][C:15]1[CH:16]=[C:17]2[C:12]([CH:11]=[CH:10][CH:9]=[C:8]2[C:2](=[O:1])[CH2:3][NH:4][C:5](=[O:7])[CH3:6])=[CH:13][CH:14]=1
Reactant: COc1ccc2cccc(C(O)CNC(C)=O)c2c1
Agent: O=[Cr](=O)([O-])Cl
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Product: COc1ccc2cccc(C(=O)CNC(C)=O)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound obtained in Step F (7.7 mmol) is dissolved in 200 ml of anhydrous dichloromethane. The resulting solution is added to a suspension of potassium acetate (0.23 g) and pyridinium chlorochromate (11.6 mmol) in 50 ml of dichloromethane. The reaction mixture is stirred at ambient temperature for 2 hours. It is then filtered over Celite. The filtrate is washed with water, decolourised on vegetable carbon and evaporated under reduced pressure. The residue obtained is triturated in diethyl ether, filtered off under suction and recrystallised from diisopropyl ether to yield the title product in the form of a white solid.
Reaction SMILES: [CH2:1]([N:4]([CH2:32][CH2:33][CH3:34])[CH2:5][CH2:6][CH2:7][CH2:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:18][N:19]3C(=O)C4C(=CC=CC=4)C3=O)[CH:15]=2)[CH:10]1[O:30][CH3:31])[CH2:2][CH3:3].O.NN>CO>[NH2:19][CH2:18][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[CH:10]([O:30][CH3:31])[CH:9]([CH2:8][CH2:7][CH2:6][CH2:5][N:4]([CH2:32][CH2:33][CH3:34])[CH2:1][CH2:2][CH3:3])[CH2:17]2
Reactant: CCCN(CCC)CCCCC1Cc2cc(CN3C(=O)c4ccccc4C3=O)ccc2C1OC
Agent: NN
Solvent: CO
Solvent: O
Product: CCCN(CCC)CCCCC1Cc2cc(CN)ccc2C1OC
Yield: 65.4 %

Procedure:
The compound (95.7 mg) obtained in Example 127-12 was dissolved in methanol (4.79 ml) and added with hydrazine monohydrate (0.0957 ml), followed by thermal reflux for 1 hour. The reaction solution was concentrated under reduced pressure. Then, the residue was added with water and subjected to separation/extraction with chloroform, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (45.0 mg) as a yellow oily substance.
Reaction SMILES: ClC1C(CCCl)=C(C2C=CC=C(OC)C=2)N=C(N2CCOCC2)N=1.C(C1C=CC(N)=CC=1)(C)C.[CH:35]([C:38]1[CH:43]=[CH:42][C:41]([N:44]2[C:48]3[N:49]=[C:50]([N:61]4[CH2:66][CH2:65][O:64][CH2:63][CH2:62]4)[N:51]=[C:52]([C:53]4[CH:58]=[CH:57][CH:56]=[C:55]([O:59]C)[CH:54]=4)[C:47]=3[CH2:46][CH2:45]2)=[CH:40][CH:39]=1)([CH3:37])[CH3:36]>>[CH:35]([C:38]1[CH:39]=[CH:40][C:41]([N:44]2[C:48]3[N:49]=[C:50]([N:61]4[CH2:66][CH2:65][O:64][CH2:63][CH2:62]4)[N:51]=[C:52]([C:53]4[CH:54]=[C:55]([OH:59])[CH:56]=[CH:57][CH:58]=4)[C:47]=3[CH2:46][CH2:45]2)=[CH:42][CH:43]=1)([CH3:37])[CH3:36]
Reactant: COc1cccc(-c2nc(N3CCOCC3)nc3c2CCN3c2ccc(C(C)C)cc2)c1
Agent: CC(C)c1ccc(N)cc1
Agent: COc1cccc(-c2nc(N3CCOCC3)nc(Cl)c2CCCl)c1
Product: CC(C)c1ccc(N2CCc3c(-c4cccc(O)c4)nc(N4CCOCC4)nc32)cc1

Procedure:
In the same manner as Example 1-A-01, from 4-[4-chloro-5-(2-chloroethyl)-6-(3-methoxyphenyl)-pyrimidin-2-yl]-morpholine and 4-isopropylaniline, 7-(4-isopropyl-phenyl)-4-(3-methoxy-phenyl)-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine was obtained, and subsequently, further in the same manner as Example 1-A-09, the desired compound was obtained.