Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:3]=[C:4](SC)[NH:5][CH2:6][CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]2[C:19](=[O:34])[NH:20][C:21](=[O:33])[C:22]=2[C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]([CH3:32])[CH:24]=2)=[CH:10]1)#[N:2].[CH3:37][NH2:38]>CN(C=O)C.C(O)C>[C:1]([N:3]=[C:4]([NH:38][CH3:37])[NH:5][CH2:6][CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]2[C:19](=[O:34])[NH:20][C:21](=[O:33])[C:22]=2[C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]([CH3:32])[CH:24]=2)=[CH:10]1)#[N:2]
Reactant: CN
Reactant: CSC(=NC#N)NCCCn1cc(C2=C(c3cn(C)c4ccccc34)C(=O)NC2=O)c2ccccc21
Solvent: CN(C)C=O
Solvent: CCO
Product: CNC(=NC#N)NCCCn1cc(C2=C(c3cn(C)c4ccccc34)C(=O)NC2=O)c2ccccc21
Reaction time: 16 h

Procedure:
A solution of 50 mg of the product of Example 50 in 10 ml of DMF was treated with 4 ml of a 33% solution of methylamine in ethanol. The mixture was stirred for 16 hours and the solvents were then removed under reduced pressure. The residue was chromatographed on silica gel with ethyl acetate to give 46 mg of 3-[1-[3-(2-cyano-3-methylguanidino)propyl]-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione, m.p. 190°-193° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[C:6]([CH:19]=O)[C:5]2=[O:21].OS(O)(=O)=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]1=[N:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH:19]=[C:6]1[C:5]2=[O:21]
Reactant: O=Cc1c(Nc2ccccc2)oc2ccc(Br)cc2c1=O
Agent: O=S(=O)(O)O
Product: O=c1c2cc(Br)ccc2oc2nc3ccccc3cc12
Yield: 76.7 %

Procedure:
To the product of Step A (1 g; 2.92 mmol) concentrated H2SO4 (1 ml) was gently added with stirring. The mixture was kept in sealed vial for 24 h, at room temperature, than poured onto ice water and extracted with CH2Cl2 (50 ml). The organic layer was washed with NaHCO3 solution, H2O, dried over MgSO4 and filtered. The filtrate was distilled off and the residue was crystallized from CH3CN to give the title compound (0.73 g, 77%), as green yellow solid. 1H-NMR (CDCl3) 9.28 (s, 1H); 8.44 (d, 1H, J=2.1 Hz); 8.1-8.06 (m, 2H); 7.94-7.84 (m, 2H); 7.63 (t, 1H, J=7.88 Hz); 7.51 (d, 1H, J=8.83 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([O:13]CC2C=CC=CC=2)[CH:10]=[C:9]([Cl:21])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][OH:8].[H][H]>[Pd].C(O)C>[Cl:1][C:2]1[CH:12]=[C:11]([OH:13])[CH:10]=[C:9]([Cl:21])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][OH:8]
Reactant: OCCCOc1c(Cl)cc(OCc2ccccc2)cc1Cl
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: OCCCOc1c(Cl)cc(O)cc1Cl
Yield: 93.7 %

Procedure:
This compound was prepared in a manner analogous to that of Step B of Example 1, by the treatment of 11.8 grams (0.036 mole) of 3-[2,6-dichloro-4-(phenylmethoxy)phenoxy]propan-1-ol with hydrogen gas in the presence of a catalytic amount of 10% palladium on carbon in ethanol using a Parr hydrogenation apparatus. Following the theoretical uptake of hydrogen, the reaction mixture was and filtered and concentrated under reduced pressure to a residue, yielding 8.0 grams of the subject compound.
Reaction SMILES: [CH3:1][C@@H:2]1[C@@H:9]2[C@@H:5]([CH2:6][N:7]([S:10]([CH3:13])(=[O:12])=[O:11])[CH2:8]2)[CH2:4][C@H:3]1[NH:14][C:15]1[C:16]2[N:17]([CH:24]=[C:25]([C:27]3[NH:31][N:30]=[N:29][N:28]=3)[CH:26]=2)[N:18]=[CH:19][C:20]=1[C:21]([NH2:23])=[O:22].IC.[C:34](=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[CH3:1][C@@H:2]1[C@@H:9]2[C@@H:5]([CH2:6][N:7]([S:10]([CH3:13])(=[O:12])=[O:11])[CH2:8]2)[CH2:4][C@H:3]1[NH:14][C:15]1[C:16]2[N:17]([CH:24]=[C:25]([C:27]3[N:28]=[N:29][N:30]([CH3:34])[N:31]=3)[CH:26]=2)[N:18]=[CH:19][C:20]=1[C:21]([NH2:23])=[O:22]
Reactant: O=C([O-])[O-]
Reactant: C[C@@H]1[C@H]2CN(S(C)(=O)=O)C[C@H]2C[C@H]1Nc1c(C(N)=O)cnn2cc(-c3nnn[nH]3)cc12
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CI
Product: C[C@@H]1[C@H]2CN(S(C)(=O)=O)C[C@H]2C[C@H]1Nc1c(C(N)=O)cnn2cc(-c3nnn(C)n3)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of the crude 4-(((3aS,4R,5R,6aS)-4-methyl-2-(methylsulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)amino)-6-(1H-tetrazol-5-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide from Step 2, iodomethane (6.8 μl, 0.109 mmol) and potassium carbonate (23.2 mg, 0.168 mmol) in 1-methyl-2-pyrrolidinone (1 mL) was stirred at room temperature for 2 h. Attempted purification by RP-HPLC gave impure product. The mixture was further purified by silica gel chromatography, eluting with 0 to 10% methanol in dichloromethane to give the title compound (4 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.92 (d, J=7.3 Hz, 1H), 8.30 (s, 1H), 8.20 (d, J=1.5 Hz, 1H), 7.40 (d, J=1.5 Hz, 1H), 5.91-5.90 (m, 1H), 4.40 (s, 3H), 4.28-4.05 (m, 1H), 3.35-3.13 (m, 4H), 2.93 (s, 3H), 2.90-2.75 (m, 1H), 2.62-2.55 (m, 1H), 2.46-2.30 (m, 1H), 1.66-1.54 (m, 1H), 1.39-1.29 (m, 1H), 1.08 (d, J=6.6 Hz, 3H); MS (ES+) m/z: 460.3 (M+H); LC retention time: 6.988 min (analytical HPLC Method E).
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[CH:3]([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])[CH:4]=[O:5].[BH4-].[Na+].C(OCC)(=O)C>C1COCC1.C(O)C>[CH3:1][CH:2]([CH3:14])[CH:3]([O:6][Si:7]([C:10]([CH3:11])([CH3:13])[CH3:12])([CH3:8])[CH3:9])[CH2:4][OH:5]
Reactant: CC(C)C(C=O)O[Si](C)(C)C(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)C(CO)O[Si](C)(C)C(C)(C)C
Reaction time: 0.33 h

Procedure:
A stirred, ice-cooled solution of 3-methyl-2-(tert-butyldimethylsilyloxy)butanal (Preparation 7) (0.5 g) in THF (4 ml) and ethanol (8 ml) was treated with sodium borohydride (0.1 g). After 20 minutes, the reaction mixture was worked-up (ethyl acetate) to give the intermediate 3-methyl-2-(tert-butyldimethylsilyloxy)-1-butanol as an oil. This was dissolved in dichloromethane (5 ml), cooled to 0° C., and treated with pyridine (0.5 ml) and trifluoromethansulphonic anhydride (0.5 ml). After stirring for 1 hour, the reaction mixture was worked-up (ether) to give the title compound as an oil.
Reaction SMILES: C[Mg]Br.CC([N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][N:20]2[C:28]3[C:23](=[C:24]([C:29](=[O:31])[CH3:30])[CH:25]=[CH:26][CH:27]=3)[C:22]([NH:32][S:33]([C:36]3[S:37][C:38]([Cl:41])=[CH:39][CH:40]=3)(=[O:35])=[O:34])=[N:21]2)[CH:14]=1)C(=O)[O-])(C)C.O1CCOC[CH2:43]1>C1COCC1.Cl>[NH2:8][CH2:12][C:13]1[CH:14]=[C:15]([CH2:19][N:20]2[C:28]3[C:23](=[C:24]([C:29]([OH:31])([CH3:30])[CH3:43])[CH:25]=[CH:26][CH:27]=3)[C:22]([NH:32][S:33]([C:36]3[S:37][C:38]([Cl:41])=[CH:39][CH:40]=3)(=[O:35])=[O:34])=[N:21]2)[CH:16]=[CH:17][CH:18]=1
Reactant: CC(=O)c1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CN(C(=O)[O-])C(C)(C)C)c1
Reactant: C1COCCO1
Agent: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(O)c1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CN)c1
Reaction time: 2 h
Yield: 76 %

Procedure:
Methylmagnesium bromide (3M solution in diethyl ether) (0.730 mL, 2.191 mmol) was added slowly dropwise to a stirring solution of 1,1-dimethylethyl({3-[(4-acetyl-3-{[(5-chloro-2-thienyl)sulfonyl]amino}-1H-indazol-1-yl)methyl]phenyl}methyl)carbamate (for a preparation see Intermediate 76) (210 mg, 0.365 mmol) in THF (3 mL) at room temp. The reaction was stirred for 2 h and then more methylmagnesium bromide (3M solution in diethyl ether) (0.730 mL, 2.191 mmol) was added and stirred overnight. LCMS indicated molecular ion 592 [M+1] corresponding to the desired alcohol and that the starting material co-eluted with the product. 1N HCl (5 mL) was added and the product was extracted with EtOAc (15 mL×3). The combined organic layers were dried by passing through a hydrophobic frit and concentrated in vacuo. The residue was dissolved in 4N HCl in Dioxane (2 mL, 8.00 mmol) and the reaction was stirred at room temp over 1 h. The reaction mixture was loaded on an SCX-2 ion-exchange 20 g cartridge eluting with methanol and 2M ammonia in methanol. The appropriate ammoniacal fractions were combined and evaporated in vacuo to give the title compound (168 mg, 76%) as a brown oil. LCMS (System A) RT=0.79 min, ES+ve m/z 491/493 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:32])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=2[O:23][CH3:24])(=[O:14])=[O:13])[C:3]1=[O:25].[CH3:33][S:34](Cl)(=[O:36])=[O:35]>N1C=CC=CC=1>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]([S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=1[O:23][CH3:24])(=[O:14])=[O:13])[C:3](=[O:25])[C:2]2([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[Cl:32])[NH:1][S:34]([CH3:33])(=[O:36])=[O:35]
Reactant: COc1ccc(S(=O)(=O)N2C(=O)C(N)(c3ccccc3Cl)c3cc(Cl)ccc32)c(OC)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)N2C(=O)C(NS(C)(=O)=O)(c3ccccc3Cl)c3cc(Cl)ccc32)c(OC)c1
Reaction time: 18 h

Procedure:
A solution of 0.4 g of the compound obtained in EXAMPLE 3 in 5 ml of pyridine is cooled to 0° C. and 0.1 g of methanesulfonyl chloride is added. The mixture is stirred for 18 hours, the temperature being allowed to rise to RT, and evaporated under vacuum. The residue is extracted with AcOEt, washed with a 5% solution of potassium hydrogensulfate, dried over sodium sulfate and evaporated under vacuum. The residue is chromatographed on silica using a DCM/AcOEt mixture (98/2; v/v) as the eluent to give the expected product after crystallization from a DCM/iso ether mixture. m=0.22 g. M.p.=252° C.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[CH:10][C:9]2[C:8](=[O:14])[CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.[C:15]1([C:21]2[S:25][C:24](B(O)O)=[CH:23][CH:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].CCCCCC.CCOC(C)=O>O1CCOCC1.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.O>[O:14]=[C:8]1[CH2:7][CH2:6][CH2:5][C:4]2[N:3]=[C:2]([C:24]3[S:25][C:21]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)=[CH:22][CH:23]=3)[C:11]([C:12]#[N:13])=[CH:10][C:9]1=2
Reactant: OB(O)c1ccc(-c2ccccc2)s1
Reactant: N#Cc1cc2c(nc1Cl)CCCC2=O
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: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1cc2c(nc1-c1ccc(-c3ccccc3)s1)CCCC2=O
Yield: 45.6 %

Procedure:
To a solution of 2-chloro-5-oxo-5,6,7,8-tetrahydro-quinoline-3-carbonitrile (300 mg, 1.46 mmol) and 5-phenyl-thiophen-2-yl-boronic acid (446 mg, 2.19 mmol) in dioxane (3 ml) under an argon atmosphere was added tetrakis(triphenylphosphine)palladium (85 mg, 0.073 mmol) and 2M aqueous K2CO3 (0.7 ml). The mixture was stirred at reflux till complete (TLC; hexane-EtOAc, 2:1) consumption of 2-chloro-5-oxo-5,6,7,8-tetrahydro-quinoline-3-carbonitrile. Then water was added and the mixture was extracted by dichloromethane. The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (CH2Cl2-Hexane, 1:1), then heated under reflux in ethyl alcohol and filtered to give the title compound (220 mg, 46%) as a dark yellow solid.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][C:13]=2[CH2:20][N:21]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]([CH:24]2[CH2:26][CH2:25]2)=[O:23])[CH:11]=1)C.[Li+].[OH-]>CO>[CH2:27]([N:21]([CH2:20][C:13]1[CH:14]=[C:15]([C:18]#[N:19])[CH:16]=[CH:17][C:12]=1[C:10]1[CH:11]=[C:6]([CH2:5][C:4]([OH:34])=[O:3])[CH:7]=[N:8][CH:9]=1)[C:22]([CH:24]1[CH2:26][CH2:25]1)=[O:23])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)Cc1cncc(-c2ccc(C#N)cc2CN(Cc2ccccc2)C(=O)C2CC2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: N#Cc1ccc(-c2cncc(CC(=O)O)c2)c(CN(Cc2ccccc2)C(=O)C2CC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(5-{2-[(N-Benzyl-N-cyclopropanecarbonyl-amino)-methyl]-4-cyano-phenyl}-pyridin-3-yl)-acetic acid ethyl ester (0.1 g, 0.22 mmol) was dissolved in MeOH (10 mL) and treated with 1N aqueous LiOH (1 mL) dropwise. The reaction was stirred at room temperature for 1 hour, and then quenched with 1N aqueous HCl (1 ml) and extracted with EtOAc. The combined organic layers were dried and concentrated to give Compound 3.
Reaction SMILES: C[O:2][C:3](=[O:36])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][C:9]2[O:26][C:13]3([CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[N:12]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:11](=[O:34])[C:10]=2[CH:35]=1.[OH-].[Na+]>>[C:22]([O:21][C:19]([N:16]1[CH2:17][CH2:18][C:13]2([N:12]([CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:11](=[O:34])[C:10]3[CH:35]=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:36])=[O:2])[CH:7]=[CH:8][C:9]=3[O:26]2)[CH2:14][CH2:15]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)N(Cc1ccccc1)C1(CCN(C(=O)OC(C)(C)C)CC1)O2
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)N1CCC2(CC1)Oc1ccc(/C=C/C(=O)O)cc1C(=O)N2Cc1ccccc1
Yield: 96.2 %

Procedure:
(E)-3-{1′-tert-butoxycarbonyl-3,4-dihydro-3-benzyl-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-acrylic acid methyl ester (800 mg, 1.63 mmol, Intermediate 6, Step A) was hydrolyzed with NaOH following the procedure described in Example 1, Step A, to give (E)-3-{1′-tert-butoxycarbonyl-3,4-dihydro-3-benzyl-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-acrylic acid as a white solid (750 mg, 96%). The resulting product was treated with NH2OTHP according to the procedure described in Example 1, Step B, obtaining (E)-3-{1′-tert-butoxycarbonyl-3,4-dihydro-3-benzyl-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide as a white solid (430 mg, 48%). Finally, removal of the THP and BOC protecting groups (420 mg, 0.73 mmol) following the procedure described in Example 1, Step C gave (E)-3-{3,4-dihydro-3-benzyl-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-N-hydroxy-acrylamide (208 mg, trifluoroacetate salt) after purification by preparative HPLC.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[F:17][C:18]1[CH:19]=[CH:20][C:21]([CH:24]=O)=[N:22][CH:23]=1>C1COCC1.O>[F:17][C:18]1[CH:19]=[CH:20][C:21](/[CH:24]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:22][CH:23]=1
Reactant: O=Cc1ccc(F)cn1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1ccc(F)cn1
Reaction time: 0.5 h
Yield: 84.5 %

Procedure:
To a suspension of sodium hydride (55 wt %, 1.97 g) in THF (200 ml) was added at 0° C. ethyl (diethoxyphosphoryl)acetate (9.3 g), and the mixture was stirred at 30 min. To this mixture was added a solution of the compound (4.7 g) obtained in step 1 in THF (200 mL) at 0° C., and the mixture was stirred at room temperature for 12 hr. The mixture was diluted with water (500 mL), extracted with ethyl acetate (500 mL), dried and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (25% ethyl acetate/hexane) to give ethyl (2E)-3-(5-fluoropyridin-2-yl)prop-2-enoate (6.2 g, 85%) as a white powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[N:7]([CH2:9][C:10]1[CH:15]=[C:14]([CH:16]=[O:17])[CH:13]=[CH:12][C:11]=1[O:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].[OH-].[Na+]>CO>[C:1]([O:5][C:6](=[O:27])[N:7]([CH2:9][C:10]1[CH:15]=[C:14]([CH2:16][OH:17])[CH:13]=[CH:12][C:11]=1[O:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(Cc1cc(C=O)ccc1Oc1ccc(Cl)c(Cl)c1)C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(Cc1cc(CO)ccc1Oc1ccc(Cl)c(Cl)c1)C(=O)OC(C)(C)C
Reaction time: 24 h

Procedure:
To a solution of [2-(3,4-dichloro-phenoxy)-5-formyl-benzyl]-methyl-carbamic acid tert-butyl ester (816 mg, 1.98 mmol) in MeOH (40 mL), was added NaBH4 (75 mg, 1.98 mmol). After 24 h, the mixture was treated with 1 N NaOH, was stirred an additional 1 h, and then partially concentrated. The resulting aqueous mixture was extracted with DCM and the combined organic layers were dried (Na2SO4) and concentrated. The crude material was carried forward without further purification (784 mg, 96%). MS (ESI): mass calcd. for C20H23Cl2NO4, 411.10; m/z found, 434.7 [M+Na]+.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][O:12][CH:13]([CH2:24][O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:14][O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:4](Cl)[N:3]=1.C(O)C.O1CCCC1>[Pd].C(N(CC)CC)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][O:12][CH:13]([CH2:24][O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:14][O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:4][N:3]=1
Reactant: Nc1nc(Cl)c2ncn(COC(COC(=O)c3ccccc3)COC(=O)c3ccccc3)c2n1
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ncc2ncn(COC(COC(=O)c3ccccc3)COC(=O)c3ccccc3)c2n1
Reaction time: 24 h

Procedure:
A mixture of 3.393 g (7.04 mM) of 2-amino-9-[(2-benzoyloxy-1-(benzoyloxymethyl)ethoxy)methyl]-6-chloro-9H-purine, 100 ml ethanol, 100 ml tetrahydrofuran, 1.9 ml triethylamine was added to 0.6 g Pd-C catalyst in a Parr bottle. The mixture was shaken under 50 P.S.I. of H2 for 24 hours. The Pd-C was filtered through a Celite pad and 0.65 g fresh Pd-C was added to the reaction mixture and the hydrogenation was continued for 4 days. Column chromatography using 100% CH2Cl2, 4:1 CH2Cl2 /acetone, and 100% acetone produced the title compound, mpt. 132°-133° C.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH3:15])[N:13]=2)[N:8]=[CH:7][C:6]=1[C:16]#[N:17])([CH3:3])[CH3:2].[O:18]1CCOCC1>>[CH:15]([C:12]1[N:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:16]#[N:17])=[C:5]2[O:4][CH:1]([CH3:3])[CH3:2])=[O:18]
Reactant: Cc1ccc2ncc(C#N)c(OC(C)C)c2n1
Reactant: C1COCCO1
Product: CC(C)Oc1c(C#N)cnc2ccc(C=O)nc12
Temperature: 25 °C

Procedure:
To a solution of 4-isopropoxy-6-methyl-[1,5]naphthyridine-3-carbonitrile (260.0 mg, 1.14 mmol) in 1,4-dioxane was added SeO2 (165.0 mg, 1.48 mmol) and the reaction mixture was refluxed for 3.5 hrs, when the TLC showed no starting material left, then cooled to room temperature and filtered through celite. The solid was washed with hot AcOEt and the filtrate was then concentrated to give 6-formyl-4-isopropoxy-[1,5]naphthyridine-3-carbonitrile as a light yellow solid (270.3 mg, 98.3). HR-MS-EI (+) m/e calcd for C13H11N3O2 (M+) 241.0851. found 241.0854.
Reaction SMILES: Cl.[NH2:2][N:3]1[CH2:8][C:7]([CH3:9])=[N:6][NH:5][C:4]1=[O:10].[OH-].[Na+].[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=O)[CH:14]=1>CO.O>[CH3:9][C:7]1[CH2:8][N:3]([N:2]=[CH:19][C:15]2[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=2)[C:4](=[O:10])[NH:5][N:6]=1
Reactant: O=Cc1cccnc1
Reactant: CC1=NNC(=O)N(N)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1=NNC(=O)N(N=Cc2cccnc2)C1
Temperature: 5 °C
Reaction time: 2 h

Procedure:
To a suspension of 164 g of 4-amino-6-methyl-3-oxo-2,3,4,5-tetrahydro-1,2,4-triazine hydrochloride in 500 ml methanol a 50% NaOH solution is added until a pH of 6 is reached. Now 486 g of a solution containing 22% 3-pyridinaldehyde in water is added maintaining a temperature below 70° C. After the addition is completed the reaction mixture is kept at 65° C. for two hours. Then the suspension is cooled to about 5° C., filtered and dried to yield the title compound.
Reaction SMILES: CC(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)=[CH:11][C:10]=1[NH:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:38])[CH2:30][CH2:31][P:32]([CH3:37])(=[O:36])[O:33][CH2:34][CH3:35])=[CH:25][CH:24]=1)=[O:22])=O)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)=[CH:11][C:10]=1[NH:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:38])[CH2:30][CH2:31][P:32]([CH3:37])(=[O:36])[O:33][CH2:34][CH3:35])=[CH:25][CH:24]=1)=[O:22]
Reactant: CCOP(C)(=O)CCC(=O)c1ccc(C(=O)Nc2cc(-c3cccs3)ccc2NC(=O)OC(C)(C)C)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOP(C)(=O)CCC(=O)c1ccc(C(=O)Nc2cc(-c3cccs3)ccc2N)cc1
Reaction time: 3 h

Procedure:
Ethyl {3-[4-({[2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-5-(2-thienyl)phenyl]amino}carbonyl)phenyl]-3-oxopropyl}methylphosphinate (125 mg, 0.225 mmol) was taken up in DCM (5 mL)/TFA (2 mL). After 3 hours, saturated NaHCO3 was added and the products extracted into EtOAc (×2). The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo to give ethyl {3-[4-({[2-amino-5-(2-thienyl)phenyl]amino}carbonyl)phenyl]-3-oxopropyl}methylphosphinate as an orange solid.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13](I)[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4].I[C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[CH2:25]N(C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:23]2>>[F:1][C:2]([F:18])([F:17])[C:3]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([C:23]#[C:22][CH2:21][CH2:20][CH2:28][CH2:27][CH2:26][CH3:25])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: Ic1ccc2c(c1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Reactant: O=C(N1CCc2ccc(I)cc2CC1)C(F)(F)F
Product: CCCCCCC#Cc1ccc2c(c1)CCN(C(=O)C(F)(F)F)CC2
Yield: 73 %

Procedure:
When the product of Step B was substituted for 5-iodo-2-tritylisoindoline in Example 2, Step D, the similar process afforded the title compound in 73% yield, as a pale oil. 1H-NMR (CDCl3) 0.9 (tr, 3H), 1.28-1.33 (m, 10H); 1.42-1.46 (m, 2H); 2.88-2.96 (m, 4H); 3.64-3.67 (m, 2H); 3.71-3.75 (m, 2H); 7.05 (tr, 1H, J=7.92 Hz), 7.13-7.2 (m, 2H).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[C:9]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH:21]=[CH:20][CH:19]=[C:18]2[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:13]([CH3:29])[CH:12]=1)#[N:10].O>CN(C=O)C>[Br:8][C:21]1[N:17]([C:14]2[CH:15]=[CH:16][C:11]([C:9]#[N:10])=[CH:12][C:13]=2[CH3:29])[C:18]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:19][CH:20]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)CCc1cccn1-c1ccc(C#N)cc1C
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1ccc(Br)n1-c1ccc(C#N)cc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
NBS (4.76 g, 1 equiv) was added portionwise to a solution of ethyl 3-(1-(4-cyano-2-methylphenyl)-1H-pyrrol-2-yl)propanoate in DMF at 0° C. during 45 min. After addition, the mixture was stirred at room temperature for 30 min, then poured into water, and extracted with ethyl acetate for three times. The combined organic layers were washed with brine, dried over Na2SO4, concentrated and purified by silica gel column chromatography (PE:EA=15:1) to afford ethyl 3-(5-bromo-1-(4-cyano-2-methylphenyl)-1H-pyrrol-2-yl)propanoate as a white solid.