Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([N:16]3[CH:20]=[C:19]([CH2:21][CH3:22])[CH:18]=[N:17]3)[C@@H:13]([OH:23])[C@H:12]2[OH:24])=[C:4]([NH:25][CH2:26][CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:3]=1.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].C1(C(C2C=CC=CC=2)CNC2N=C(NCCN3CCCCC3)N=C3C=2N=CN3[C@@H]2C[C@H](N3C=C(CO)C=N3)[C@@H](O)[C@H]2O)C=CC=CC=1.[CH2:94]([N:96]1[CH:100]=[C:99]([CH2:101][CH2:102][NH2:103])[N:98]=[CH:97]1)[CH3:95]>>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[C:34]1([CH:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:26][NH:25][C:4]2[N:3]=[C:2]([NH:103][CH2:102][CH2:101][C:99]3[N:98]=[CH:97][N:96]([CH2:94][CH3:95])[CH:100]=3)[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][N:8]3[C@@H:11]2[CH2:15][C@H:14]([N:16]3[CH:20]=[C:19]([CH2:21][CH3:22])[CH:18]=[N:17]3)[C@@H:13]([OH:23])[C@H:12]2[OH:24])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CCn1cnc(CCN)c1
Reactant: CCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(Cl)nc43)[C@H](O)[C@@H]2O)c1
Agent: OCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(NCCN5CCCCC5)nc43)[C@H](O)[C@@H]2O)c1
Solvent: O=C(O)C(F)(F)F
Product: CCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(NCCc5cn(CC)cn5)nc43)[C@H](O)[C@@H]2O)c1

Procedure:
This compound is prepared from (1R,2S,3R,5S)-3-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(4-ethyl-pyrazol-1-yl)-cyclopentane-1,2-diol (Intermediate BA8) using a procedure analogous to that of (1R,2S,3R,5S)-3-[6-(2,2-diphenyl-ethylamino)-2-(2-piperidin-1-yl-ethylamino)-purin-9-yl]-5-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentane-1,2-diol trifluoro-acetate (Example 461 by replacing 1-(2-amino-ethyl)piperidine with 2-(1-ethyl-1H-imidazol-4-yl)-ethylamine (intermediate CD). MS (ES+) m/e 647.42 (MH+).
Reaction SMILES: I.[Cl:2][C:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](SC)=[NH:16])=[CH:10][C:9]=2[O:19][CH3:20])[CH:7]=1.[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1[F:37])[C:27](O)=O.[NH2:38][NH2:39]>>[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([C:27]1[NH:39][N:38]=[C:15]([NH:14][C:11]2[CH:12]=[CH:13][C:8]([N:6]3[CH:7]=[C:3]([Cl:2])[N:4]=[CH:5]3)=[C:9]([O:19][CH3:20])[CH:10]=2)[N:16]=1)[C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1[F:37]
Reactant: O=C(O)C(CCCCCl)c1ccc(F)cc1F
Reactant: NN
Reactant: COc1cc(NC(=N)SC)ccc1-n1cnc(Cl)c1
Agent: I
Product: COc1cc(Nc2n[nH]c(C(CCCCCl)c3ccc(F)cc3F)n2)ccc1-n1cnc(Cl)c1
Yield: 100 %

Procedure:
Methyl 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylcarbamimidothioate, hydroiodide (500 mg, 1.685 mmol, from preparation A) and 6-chloro-2-(2,4-difluorophenyl)hexanoic acid (443 mg, 1.69 mmol, from preparation AG) were coupled and then reacted with hydrazine (0.211 mL, 6.74 mmol) using a procedure analogous to Step A of Example 13. The crude product, 5-(5-chloro-1-(2,4-difluorophenyl)pentyl)-N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-1H-1,2,4-triazol-3-amine (1.03 g, 100% yield), was used in the subsequent step without purification. LC-MS (M+H)+ 507.3.
Reaction SMILES: [O:1]1[CH:5]=[N:4][N:3]=[C:2]1[C@H:6]([NH2:9])[CH2:7][CH3:8].[C:10]1(=O)[CH2:14][CH2:13][CH2:12][CH2:11]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C1COCC1>[O:1]1[CH:5]=[N:4][N:3]=[C:2]1[C@H:6]([NH:9][CH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)[CH2:7][CH3:8]
Reactant: CC[C@@H](N)c1nnco1
Reactant: O=C1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC[C@@H](NC1CCCC1)c1nnco1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74.1 %

Procedure:
(1R)-1-(1,3,4-oxadiazol-2-yl)propan-1-amine (610 mg, 4.798 mmol) in THF (6.972 mL) was treated with cyclopentanone (407.6 mg, 428.6 μL, 4.846 mmol) then acetic acid (288.1 mg, 272.8 μL, 4.798 mmol). The reaction was stirred at ambient temperature for 20 minutes then treated with sodium triacetoxyborohydride (1.485 g, 7.005 mmol). The reaction was stirred at ambient temperature for 5 hours then basified with aqueous NaHCO3. The mixture was extracted with DCM (×10), dried over MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography (50% EtOAc/petrol) to give the sub-title compound as a colourless solid (694 mg, 74%); 1H NMR (400.0 MHz, CDCl3) d 0.81 (3H, t), 1.10-1.87 (10H, m), 2.85 (1H, m), 3.95 (1H, t), 8.33 (1H, s); MS ES (+) 196.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][CH2:12][O:13][P:14]([CH2:19][N:20]1[CH:23](SC)[CH:22]([N:26]=[N+:27]=[N-:28])[C:21]1=[O:29])([O:16][CH2:17][CH3:18])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrN[C:32](=O)C.[S:35]([O-:39])([O-])(=[O:37])=S.[Na+].[Na+].[Cl-].[Na+]>CO>[CH2:1]([O:8][C:9]([CH2:11][CH2:12][O:13][P:14]([CH2:19][N:20]1[CH:23]([S:35]([CH3:32])(=[O:39])=[O:37])[CH:22]([N:26]=[N+:27]=[N-:28])[C:21]1=[O:29])([O:16][CH2:17][CH3:18])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S([O-])([O-])=S
Reactant: CCOP(=O)(CN1C(=O)C(N=[N+]=[N-])C1SC)OCCC(=O)OCc1ccccc1
Reactant: CC(=O)NBr
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CCOP(=O)(CN1C(=O)C(N=[N+]=[N-])C1S(C)(=O)=O)OCCC(=O)OCc1ccccc1
Reaction time: 0.08 h

Procedure:
1-(Benzyloxycarbonyldiethylphosphono)methyl-3-azido-4-(methylthio)-2-azetidinone (0.44 g.) is dissolved in methanol (20 ml.) and treated with N-bromoacetamide (0.52 g.) for two hours. Sodium thiosulfate (10 ml.; 0.1N) is then added and the mixture is allowed to stir for five minutes. At the end of this time, the reaction mixture shows no positive reaction to starch iodide paper. The reaction mixture is saturated with sodium chloride and extracted with methylene chloride. The methylene chloride extract is dried and evaporated. The residue is chromatographed to afford 1-(benzyloxycarbonyldiethylphosphono)methyl-3-azido-4-methylsulfonyl-2-azetidinone.
Reaction SMILES: Br[CH2:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([O:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH2:7][N:6]1[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)=[O:16])=O.[C:28]([O:32][C:33]([NH:35][CH2:36][C:37]([NH2:39])=[S:38])=[O:34])([CH3:31])([CH3:30])[CH3:29].C(OCC)(=O)C>CO.ClCCl>[C:28]([O:32][C:33]([NH:35][CH2:36][C:37]1[S:38][CH:2]=[C:3]([C@@H:5]2[CH2:9][C@@H:8]([O:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH2:7][N:6]2[C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=2)=[O:16])[N:39]=1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)NCC(N)=S
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)CBr)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1nc([C@@H]2C[C@@H](OS(C)(=O)=O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)cs1
Temperature: 25 °C
Reaction time: 12 h
Yield: 40.5 %

Procedure:
To a solution of (2S,4R)-2-bromoacetyl-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (20 g) in a mixture of methanol (200 ml) and dichloromethane (200 ml) was added 2-(N-t-butoxycarbonylamino)thioacetamide (20 g) at room temperature. After stirring at ambient temperature for 12 hours, the mixture was poured into ethyl acetate, washed with saturated sodium bicarbonate and brine successively. The dried organic layer was evaporated, and the obtained oil was subjected to a column chromatography on silica gel and eluted with a mixture of acetone and dichloromethane (1:5, V/V) to give (2S,4R)-2-[2-(N-t-butoxycarbonylamino)methylthiazol-4-yl]-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (9.7 g).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([Cl:8])=[C:5](C)[CH:6]=1.C=O.[ClH:11].[C:12](O)(=O)[CH3:13]>>[CH3:1][C:2]1[S:3][C:4]([Cl:8])=[C:12]([CH3:13])[C:6]=1[CH2:5][Cl:11]
Reactant: CC(=O)O
Reactant: Cc1cc(C)c(Cl)s1
Reactant: Cl
Agent: C=O
Product: Cc1sc(Cl)c(C)c1CCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.04 G. of 2,4-dimethyl-5-chloro-thiophene are dissolved in 60 ml. of acetic acid and 2.1 g. of formalin and 32 ml. of concentrated hydrochloric acid are added. The mixture is stirred at room temperature for 2 hours, then poured into ice water and extracted with hexane. The organic solution is washed with 5% sodium bicarbonate solution, dried, filtered and evaporated to yield 2,4-dimethyl-3-chloromethyl-5-chloro-thiophene.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=C[C:5](N)=[CH:4][C:3]=1N.[C:10](#[N:12])[CH3:11].[CH2:13]1COCC1>>[CH3:11][C:10]1([CH3:13])[CH2:5][CH2:4][CH2:3][C:2]([CH3:7])([CH3:1])[NH:12]1
Reactant: C1CCOC1
Reactant: Cc1ccc(N)cc1N
Reactant: CC#N
Product: CC1(C)CCCC(C)(C)N1

Procedure:
Four amine bases were examined (Table 2) in THF or acetonitrile. Of the 4 amines examined, 2,2,6,6-tetramethylpiperidine gave the best results in both acetonitrile and THF (72%, 65%). Piperidine, which was used in the previous method, gave a low yield.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)=[CH:7][CH:6]=1)[NH2:4].CCN(C(C)C)C(C)C.[Br:28][CH2:29][CH2:30][CH2:31][C:32](Cl)=O>C(Cl)Cl>[Br:28][CH2:29][CH2:30][CH2:31][C:32]1[O:1][N:2]=[C:3]([C:5]2[CH:6]=[CH:7][C:8]([CH2:11][O:12][CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)=[CH:9][CH:10]=2)[N:4]=1
Reactant: NC(=NO)c1ccc(COC2CCCCO2)cc1
Reactant: O=C(Cl)CCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: BrCCCc1nc(-c2ccc(COC3CCCCO3)cc2)no1
Temperature: 0 °C
Reaction time: 8 h
Yield: 61.8 %

Procedure:
To a solution of N′-hydroxy-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]benzenecarboximidamide (Intermediate 27; 211 mg, 0.84 mmol) in DCM (3 mL) was added DIEA (0.176 mL, 1.01 mmol). The mixture was cooled to 0° C. and a solution of 4-bromobutanoyl chloride (0.108 mL, 0.88 mmol) in DCM (1 mL) was added dropwise. The mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure and the crude obtained was purified by column chromatography with silica gel, eluting with a mixture of Hexane:ether give the title compound as a solid (198 mg, 53%).
Reaction SMILES: F[C:2]1[CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Cl[C:20]1[CH:25]=[C:24]([S:26][CH3:27])[N:23]=[C:22]([NH2:28])[N:21]=1.C([O-])(O)=O.[Na+].O.[NH2:35][NH2:36]>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.O1CCOCC1>[NH2:28][C:22]1[N:21]=[C:20]([C:8]2[CH:9]=[C:2]3[C:3]([C:4]([NH2:5])=[N:35][NH:36]3)=[CH:6][CH:7]=2)[CH:25]=[C:24]([S:26][CH3:27])[N:23]=1
Reactant: NN
Reactant: CC1(C)OB(c2ccc(C#N)c(F)c2)OC1(C)C
Reactant: CSc1cc(Cl)nc(N)n1
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: C1COCCO1
Solvent: O
Product: CSc1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 24.8 %

Procedure:
To 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (16.5 g, 66.6 mmol) and 4-chloro-6-(methylthio)-2-pyrimidinamine (11.7 g, 66.6 mmol) were added 1,4-dioxane (300 mL) and saturated aqueous NaHCO3 (150 mL) and the mixture was degassed with nitrogen gas for 15 minutes into a sealable tube. Pd(Ph3P)4 (2.3 g, 2.0 mmol) was added, the tube was sealed, and the reaction mixture was stirred overnight at 100° C. The mixture was cooled to room temperature and poured onto water where a precipitate was formed. The mixture was filtered and the solid was transferred to a sealable tube. Dioxane (300 mL) was added followed by hydrazine monohydrate (32.7 mL, 666 mmol) and the reaction mixture was stirred overnight at 100° C. into the sealed tube. The reaction mixture was allowed to cool to room temperature and filtered. The filtrate was poured onto water and filtered again. The aqueous filtrate was poured onto a separatory funnel and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated. To the resulting residue was added 1,4-dioxane (100 mL) and the mixture was sonicated for 30 minutes. The solids were filtered affording the crude title compound (11.5 g) as a yellow solid. The filtrate was concentrated and the resulting residue was dissolved in dioxane and purified via flash chromatography on SiO2 (gradient: 99:1:0.1 CHCl3/CH3OH/NH4OH to 90:10:1 CHCl3/CH3OH/NH4OH) to afford the title compound (4.5 g) as a pale yellow solid. LC-MS (ES) m/z=273 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 2.53 (s, 3H), 5.41 (s, 2H), 6.70 (s, 2H), 7.06 (s, 1H), 7.58 (dd, J=8.5, 1.1 Hz, 1H), 7.74 (d, J=8.6 Hz, 1H), 7.98 (s, 1H), 11.60 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:32])=[C:5]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[C:6]=1[C:7]([NH:9][C@H:10]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1)[CH3:11])=[O:8].[CH3:33][S:34]([NH2:37])(=[O:36])=[O:35].Cl.CN(C)CCCN=C=NCC>C1COCC1.CN(C=O)C.CN(C)C1C=CN=CC=1>[CH3:1][C:2]1[S:3][C:4]([CH3:32])=[C:5]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:30])([F:31])[F:29])=[CH:26][CH:27]=2)[C:6]=1[C:7]([NH:9][C@H:10]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH:37][S:34]([CH3:33])(=[O:36])=[O:35])=[O:18])=[CH:14][CH:13]=1)[CH3:11])=[O:8]
Reactant: CS(N)(=O)=O
Reactant: Cc1sc(C)c(C(=O)N[C@@H](C)c2ccc(C(=O)O)cc2)c1Cc1ccc(C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1sc(C)c(C(=O)N[C@@H](C)c2ccc(C(=O)NS(C)(=O)=O)cc2)c1Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-{(1S)-1-[({2,5-dimethyl-4-[4-(trifluoromethyl)benzyl]-3-thienyl}carbonyl)amino]ethyl}benzoic acid from Example 12 (200 mg, 0.433 mmol) in a mixture of THF (5 mL) and DMF (2.5 mL), were successively added methanesulfonamide (52.0 mg, 0.542 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (166 mg, 0.866 mmol) and 4-dimethylaminopyridine (66.0 mg, 0.542 mmol). The mixture was stirred overnight at r.t. and quenched with acetic acid. After 10 min., the mixture was diluted with water and partitioned between 1N HCl and EtOAc. The organic layer was washed with 1N HCl (2×) and brine, dried and concentrated. The residue was purified by Combi Flash chromatography system (50% THF/CHCl3 in 13 min.) to afford the desired product as a white solid. MS (−APCI): m/z 537 (M−1)−.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[C:5](=[N:16][N:17]([CH3:19])[N:18]=2)[NH:6][C:7]2[CH:13]=[C:12]([Cl:14])[C:11]([Cl:15])=[CH:10][C:8]=2[N:9]=1.CS(C)=O.[CH3:24][N:25]1[CH2:30][CH2:29]N[CH2:27][CH2:26]1>C1(C)C=CC=CC=1>[Cl:14][C:12]1[C:11]([Cl:15])=[CH:10][C:8]2[N:9]=[C:3]([N:2]3[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]3)[C:4]3[C:5](=[N:16][N:17]([CH3:19])[N:18]=3)[NH:6][C:7]=2[CH:13]=1
Reactant: Cn1nc2c(n1)C(N)=Nc1cc(Cl)c(Cl)cc1N2
Reactant: CN1CCNCC1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: CN1CCN(C2=Nc3cc(Cl)c(Cl)cc3Nc3nn(C)nc32)CC1
Temperature: 125 °C

Procedure:
10-Amino-6,7-dichloro-2-methyl-2,4-dihydro-1,2,3-triazolo[4,5-b][1,5]benzodiazepine hydrochloride (0.84 g) was added to a mixture of dry dimethylsulphoxide (5 ml), toluene (5 ml) and N-methylpiperazine (1 ml), which had been purged with nitrogen for 20 minutes. The stirred solution was then heated at 125° C. (oil bath) under nitrogen for 16 hours, cooled to room temperature, and distilled water (10 ml) added, keeping the temperature below 25° C. After stirring at 5° C. for half an hour, the suspension obtained was filtered off and dried at 70° C. under reduced pressure to leave a yellow-brown solid which was recrystallised from ethyl acetate/n-hexane to give a yellow crystalline solid, melting point 217.5°-218.5° C.
Reaction SMILES: [C:1]12([N:11]=[C:12]=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15]1.CCN(CC)CC>C(Cl)Cl>[C:1]12([NH:11][C:12]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH2:16][CH2:15]3)=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: c1ccc2c(c1)CCN2
Reactant: O=C=NC12CC3CC(CC(C3)C1)C2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC12CC3CC(CC(C3)C1)C2)N1CCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 35.7 mg (0.2 mmol) 1-adamantyl isocyanate, 20 mg (0.168 mmol) indoline and 51 mg (0.5 mmol) NEt3 in 2 mL DCM was shaken at room temperature overnight and evaporated to dryness. The residue was taken up in DMF and subjected to column chromatography on reversed phase eluting with a gradient formed from acetonitrile, water and formic acid to yield after evaporation of the product containing fractions 15.2 mg (30%) of the title compound as white solid. MS(m/e): 297.4 (MH+).
Reaction SMILES: [CH2:1]1[O:3][CH2:2]1.[NH2:4][C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[C:16](O)(=[O:18])[CH3:17]>>[OH:18][CH2:16][CH2:17][N:4]([C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2][CH2:1][OH:3]
Reactant: CC(=O)O
Reactant: CCOC(=O)c1ccccc1N
Reactant: C1CO1
Product: CCOC(=O)c1ccccc1N(CCO)CCO
Reaction time: 1 h
Yield: 53 %

Procedure:
Ethylene oxide (12 ml; 242 mmol) was added dropwise under ice cooling to a solution of 4.1 g (25 mmol) of ethyl 2-aminobenzoate in 25 ml of a 30% suspension of acetic acid, followed by stirring for 1 hour. After the resultant mixture was stirred at room temperature for 2 nights, the mixture was stirred for 2 hours while bubbling nitrogen gas therethrough. Sodium hydrogencarbonate was added to the mixture to neutralized the same. Sodium chloride was then added until saturation, followed by extraction with ethyl acetate. The extract was dried over magnesium sulfate and the solvent was distilled out under reduced pressure. The residue was purified by chromatography on a silica gel column (n-hexane/ethyl acetate=1:1→0:1), whereby 3.4 g of a pale yellow oil were obtained (yield: 53%).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]#[N:13])(=O)OCC)C.[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28](C(=O)C)[CH:29]=3)[C:24]([CH3:35])([CH3:34])[CH2:23][CH:22]=2)=[CH:17][CH:16]=1.[CH2:36]1COC[CH2:37]1>CCOCC>[CH3:34][C:24]1([CH3:35])[CH2:23][CH:22]=[C:21]([C:18]2[CH:17]=[CH:16][C:15]([CH3:14])=[CH:20][CH:19]=2)[C:30]2[CH:29]=[C:28]([C:11](=[CH:36][CH3:37])[C:12]#[N:13])[CH:27]=[CH:26][C:25]1=2
Reactant: CC(=O)c1ccc2c(c1)C(c1ccc(C)cc1)=CCC2(C)C
Reactant: CCOP(=O)(CC#N)OCC
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: CC=C(C#N)c1ccc2c(c1)C(c1ccc(C)cc1)=CCC2(C)C
Reaction time: 0.67 h

Procedure:
To a slurry of NaH (48.0 mg, 2.00 mmol) in THF (6 ml), was added diethylcyanomethylphosphonate (450.0 mg, 2.50 mmol). After 40 mins, a solution of 3,4-dihydro-1-(4-methylphenyl)-4,4-dimethyl-7-acetylnaphthalene (Compound V) 95.0 mg, (0.33 mmol) in THF (4 ml) was added, The mixture was stirred for 16 hours, diluted with ether (100 ml), and washed with water, and saturated aqueous NaCl before being dried over MgSO4. Removal of the solvents under reduced pressure, and column chromatography (3% EtOAc/hexanes) afforded the title compound as a solid. 1 H NMR (CDCl3): δ 7.39 (1H, d, J=1H), 7.32 (1H, dd, J=2.0, 8.1 Hz), 7.20-7.25 (4H, brs), 7.15 (1H, d, J=2.0 Hz), 6.03 (1H, t, J=6.0 Hz), 5.44 (1H, s), 2.42 (3H, s), 2.36 (2H, d, J=6.0 Hz), 2.35 (3H, s), 1.35 (6H, s).
Reaction SMILES: [Na:1].[NH2:2][C:3]([NH2:5])=[O:4].[C:6]([O:12]COC)(=O)[CH2:7][C:8]([O-:10])=O.[CH2:16]([OH:18])C>>[OH:10][C:8]1[NH:5][C:3](=[O:4])[NH:2][C:6](=[O:12])[C:7]=1[O:18][CH3:16].[Na:1]
Reactant: NC(N)=O
Reactant: CCO
Reactant: COCOC(=O)CC(=O)[O-]
Agent: [Na]
Product: COc1c(O)[nH]c(=O)[nH]c1=O
Temperature: 100 °C

Procedure:
Under an atmosphere of nitrogen, sodium metal (1.15 g, 0.05 moles) was added portionwise to ethanol (dried over 4 Å molecular sieves, 50 mL) at 40° C. and the mixture stirred until a solution was formed. Urea (3.0 g, 0.05 moles) was added and the mixture heated at 100° C. for 15 minutes until complete dissolution was achieved. The reaction mixture was allowed to cool slightly and methoxymethyl malonate (8.1 g, 0.05 moles) added, a pink/white precipitate forming almost immediately. Further dry ethanol (10 mL) was added to maintain a stirrable mixture. The resultant suspension was heated at 100° C. (reflux) for 4 hours. The reaction mixture was concentrated in vacuo and the residue dried under high vacuum to give 6-Hydroxy-5-methoxy-1H-pyrimidine-2,4-dione, sodium salt as a pink/white solid, used in the subsequent step without analysis or purification.
Reaction SMILES: BrC1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[CH:16][N:15]=1)[CH2:6][CH2:5]2.[CH2:27]([OH:31])[CH2:28][C:29]#[CH:30].[CH2:32](NCC)C>CCOC(C)=O>[OH:31][CH:27]([CH3:32])[C:28]#[C:29][C:30]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)=[CH:16][N:15]=1)[CH2:6][CH2:5]2
Reactant: CCNCC
Reactant: O=C1c2ccc(Br)cc2CCN1Cc1ccc(-c2ccc(F)cc2)cn1
Reactant: C#CCCO
Solvent: CCOC(C)=O
Product: CC(O)C#Cc1ccc2c(c1)CCN(Cc1ccc(-c3ccc(F)cc3)cn1)C2=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 6-bromo-2-{[5-(4-fluorophenyl)-2-pyridyl]methyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline (500 mg, 1.22 mmol) and 3-butyn-1-ol (170 mg, 0.19 mL, 2.44 mmol) in diethylamine (20 mL) is de-gassed with argon. After 20 minutes, pallasium bis(diphenylphosphino) chloride (85 mg, 0.12 mmol) and cuprous iodide (13 mg, 0.12 mmol) are added and the resulting solution is stirred at ambient temperature for 12 hours. The reaction mixture is then diluted with EtOAc (20 mL), dried over MgSO4, filtered through celite and concentrated in vacuo. The residue is chromatographed (silica gel, 1:1 then 2:1 EtOAc/hexanes) to afford 6-[3-hydroxy-1-butyn-1-yl]-2-{[5-(4-fluorophenyl)-2-pyridyl]-methyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline as yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([CH2:18][N:19]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[O:43][CH3:44])C(OCC3C4C=CC=CC=4C4C3=CC=CC=4)=O)=[C:16]3[C:11]([NH:12][C:13]([CH3:48])([CH3:47])[C:14](=[O:46])[N:15]3[CH3:45])=[CH:10][CH:9]=2)=[C:4]([O:49][CH3:50])[CH:3]=1.[CH2:51]([N:53](CC)[CH2:54]C)C.Cl.[Cl-].[O:60]1[CH2:64][CH2:63][CH2:62][CH2:61]1>ClCCl>[CH3:44][O:43][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=1[NH:19][CH2:18][C:17]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][C:64]([C:63]3[CH:51]=[N:53][CH:54]=[CH:61][CH:62]=3)=[O:60])=[CH:3][C:4]=2[O:49][CH3:50])=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]([CH3:45])[C:14](=[O:46])[C:13]([CH3:48])([CH3:47])[NH:12]2
Reactant: CCN(CC)CC
Reactant: COc1cc(O)ccc1-c1ccc2c(c1CN(C(=O)OCC1c3ccccc3-c3ccccc31)c1ccccc1OC)N(C)C(=O)C(C)(C)N2
Reactant: C1CCOC1
Agent: Cl
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccccc1NCc1c(-c2ccc(OC(=O)c3cccnc3)cc2OC)ccc2c1N(C)C(=O)C(C)(C)N2
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 52 %

Procedure:
7-(4-Hydroxy-2-methoxyphenyl)-8-[N-(2-methoxyphenyl)-N-(9-fluorenylmethoxycarbonyl)aminomethyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Compound No. 13-1, 30.0 mg, 0.0448 mmol) was dissolved in mixed solvent of tetrahydrofuran (1 mL) and dichloromethane (1 mL), and triethylamine (25 μL, 0.18 mmol) and nicotynoyl chloride hydrochloride (12.0 mg, 0.0674 mmol) were added successively. After the reaction mixture was stirred for 40 minutes at room temperature, it was purified by silica gel column chromatography (hexane-ethyl acetate). The obtained colorless amorphous product was dissolved in N,N-dimethylformamide (1 mL) and piperidine (50 μL) was added thereto. After the reaction mixture was stirred for 20 minutes at room temperature, it was diluted with ethyl acetate (50 mL). The mixture was washed with water (50 mL) and saturated brine (50 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (13.0 mg) as a colorless solid. (Yield 52%)