Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=1[N:20]=[C:21]=[O:22]>ClCCCl>[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=1[NH:20][C:21]([NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([I:1])[CH:3]=1)=[O:22]
Reactant: Nc1cccc(I)c1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Solvent: ClCCCl
Product: O=C(Nc1cccc(I)c1)Nc1cc(C(F)(F)F)ccc1F
Yield: 71 %

Procedure:
To a solution of 3-iodoaniline (438 mg, 2.0 mmol) in 15.0 mL 1,2-dichloroethane at rt was added 2-fluoro-5-(trifluoromethyl)phenyl isocyanate (0.304 mL, 2.1 mmol). After 4 hours the precipitant was filtered and rinsed with 10% EtOAc/hexane to give the title compound as a white solid (602 mg, 71%). 1H NMR (DSMO-d6) δ: 9.25 (br. s, 1H), 8.91 (br. s, 1H), 8.57 (dd, J=7.3, 2.1 Hz, 1H), 8.04 (t, J=1.9 Hz, 1H), 7.46-7.54 (m, 1H), 7.42 (dd, J=4.5, 2.2 Hz, 1H), 7.35-7.40 (m, 1H), 7.28-7.33 (m, 1H), 7.06-7.14 (m, 1H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]23[N:23]([C:24]([C:26]4[C:27]([CH3:31])=[N:28][O:29][CH:30]=4)=[O:25])[CH2:22][CH2:21][N:10]2[C:11](=[O:20])[C:12]2[N:13]([CH:15]=[C:16]([C:18]#[N:19])[CH:17]=2)[CH2:14]3)=[CH:5][CH:4]=1.Cl>CO.[Pd]>[NH2:19][CH2:18][C:16]1[CH:17]=[C:12]2[C:11](=[O:20])[N:10]3[CH2:21][CH2:22][N:23]([C:24]([C:26]4[C:27]([CH3:31])=[N:28][O:29][CH:30]=4)=[O:25])[C:9]3([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH2:14][N:13]2[CH:15]=1
Reactant: COc1ccc(C23Cn4cc(C#N)cc4C(=O)N2CCN3C(=O)c2conc2C)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1ccc(C23Cn4cc(CN)cc4C(=O)N2CCN3C(=O)c2conc2C)cc1
Temperature: 25 °C

Procedure:
To a stirred suspension of 10a-(4-methoxyphenyl)-1-[(3-methyl-1,2-oxazol-4-yl)carbonyl]-5-oxo-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazine-7-carbonitrile (89) (220 mg, 0.53 mmol) in methanol (22 mL) was added Pd/C and conc. HCl (1.1 mL). The reaction was placed under an atmosphere of hydrogen and stirred at room temperature. Analysis by tlc and LCMS indicated a new product was forming. The crude material was purified by preparative HPLC to give 7-(aminomethyl)-10a-(4-methoxyphenyl)-1-[(3-methyl-1,2-oxazol-4-yl)carbonyl]-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one; trifluoroacetate salt (147) as an oil (44 mg, 16%).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH:15]([CH3:17])[CH3:16])=[N:5][CH:4]=[C:3]1[C:18]([O:20]CC)=[O:19].Cl>[OH-].[Na+]>[O:1]=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH:15]([CH3:17])[CH3:16])=[N:5][CH:4]=[C:3]1[C:18]([OH:20])=[O:19]
Reactant: CCOC(=O)c1cnc(-c2ccccc2OC(C)C)[nH]c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)Oc1ccccc1-c1ncc(C(=O)O)c(=O)[nH]1

Procedure:
A solution of ethyl 1,6-dihydro-6-oxo-2-(2-isopropoxyphenyl)pyrimidine-5-carboxylate (3.02 g.) in 1N NaOH (25 ml.) was heated on a steam bath for 15 minutes. The solution was acidified with 1N HCl (26 ml.) to precipitate 2.7 g. of the title acid, m.p. 191°-193°. Recrystallization from methanol gave pale yellow crystals of the acid, m.p. 193°-195°.
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]([CH3:12])[C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1.O=P(Cl)(Cl)Cl.[C:18](=O)(O)[O-:19].[Na+]>CN(C=O)C>[F:1][CH2:2][CH2:3][N:4]([CH3:12])[C:5]1[CH:10]=[CH:9][C:8]([CH:18]=[O:19])=[C:7]([OH:11])[CH:6]=1
Reactant: O=C([O-])O
Reactant: CN(CCF)c1cccc(O)c1
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CN(CCF)c1ccc(C=O)c(O)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 66 %

Procedure:
169 mg (1 mmol) 3-[(2-Fluoro-ethyl)-methyl-amino]-phenol are dissolved in 4 mL DMF and cooled below 10° C. 0.101 mL (1.1 eq.) POCl3 are added dropwise over the course of one minute, the reaction mixture is stirred 10 minutes at room temperature, then heated to 90° C. for 30 minutes. The reaction mixture is allowed to cool to 30° C. and cautiously treated with a slow addition of 8 mL saturated aqueous sodium bicarbonate solution. The desired product is extracted with ethyl acetate and saline, the organic phase dried over sodium sulfate and evaporated to yield 130 mg (66%) crude product as a slightly brownish oil. This compound is used without further purification.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][CH:21]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:29][CH3:30])C1C=CC=CC=1.C(O[K])=O>CO.O.CCOC(C)=O.[Pd]>[NH2:26][C:23]1[CH:24]=[CH:25][C:20]([O:19][C:13]2[C:12]3[C:17](=[CH:18][C:9]([OH:8])=[C:10]([O:29][CH3:30])[CH:11]=3)[N:16]=[CH:15][CH:14]=2)=[CH:21][CH:22]=1
Reactant: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3)ccnc2cc1OCc1ccccc1
Agent: [Pd]
Agent: O=CO[K]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: COc1cc2c(Oc3ccc(N)cc3)ccnc2cc1O
Temperature: 25 °C
Yield: 85 %

Procedure:
A suspension of 7-(benzyloxy)-6-methoxy-4-(4-nitrophenoxy)quinoline (43.00 g, 120 mmol), 10% Pd/C (4.30 g) and HCOOK (89.93 g, 600 mmol) in MeOH/H2O (345 mL/200 mL) was refluxed overnight. The mixture was cooled to room temperature, diluted with EtOAc (300 mL) and filtered through a celite pad. The filtrate was concentrated in vacuo and the residue was washed with water, dried in vacuo at 60° C. overnight to give the title compound as a yellow solid (28.8 g, 95.5%).
Reaction SMILES: C=[C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:3]1.C(N(C1C(Br)=NC=CC=1)C(=O)[O:23]C(C)(C)C)C=C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])=O.[K+]>CN(C=O)C.O.[Cl-].C([N+](CC)(CC)CC)C.CCOC(C)=O.C([O-])(O)=O.[Na+].CC([O-])=O.CC([O-])=O.[Pd+2]>[O:23]=[C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:3]1
Reactant: C=C1CN(C(=O)OC(C)(C)C)c2cccnc21
Reactant: C=CCN(C(=O)OC(C)(C)C)c1cccnc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC[N+](CC)(CC)CC
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC(=O)c2ncccc21
Temperature: 110 °C
Reaction time: 16 h

Procedure:
tert-butyl 3-methylene-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate. To a solution of tert-butyl allyl(2-bromopyridin-3-yl)carbamate (1 eq.) in DMF (0.2 M), PPh3 (0.25 eq.), Pd(OAc)2 (0.1 eq), and KOAc (5 eq.), is added, under an argon atmosphere, tetraethyl ammonium chloride hydrate (2 eq.). The flask is purged with argon for 15 min, and the resulting reaction mixture is stirred at 110° C. for 16 h. The reaction progress is monitored by TLC. The reaction mixture is diluted with EtOAc and saturated NaHCO3 solution. The organic layer is separated and dried over Na2SO4, and concentrated. The product that may be thus obtained is purified by column chromatography to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[N:8]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[C:9]3[C:14]([C:15]=2[S:16][C:17]#[N:18])=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:5]([CH3:26])[O:4][N:3]=1.[NH2:27][OH:28].C([O-])(O)=O.[Na+]>CS(C)=O.O.CCOC(C)=O.C(OCC)C>[OH:28][N:27]=[C:17]([S:16][C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:19]2[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=2)[C:7]=1[C:6]1[C:2]([CH3:1])=[N:3][O:4][C:5]=1[CH3:26])[NH2:18]
Reactant: NO
Reactant: Cc1noc(C)c1-c1c(SC#N)c2ccccc2n1-c1ccc(O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1noc(C)c1-c1c(SC(N)=NO)c2ccccc2n1-c1ccc(O)cc1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
4-(2-(3,5-Dimethylisoxazol-4-yl)-3-thiocyanato-1H-indol-1-yl)phenol was dissolved in DMSO and 10 eq 2 M hydroxylamine/NaHCO3 (aq) stock solution was added. The reaction was stirred at 65° C. overnight and then diluted with H2O. A precipitation was formed after stirring for 5 min. The mixture was diluted with EtOAc and diethylether, washed with NH4Cl (aq) and phases were partitioned. Organic phase was evaporated to dryness in vacuo and subjected to purification on reverse phase preparative HPLC to provide the title compound 2-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indol-3-yl N′-hydroxycarbamimidothioate (E32). ES/MS m/z: 395.17 (M+H), 393.19 (M−H); 1H NMR (acetone-d6, 500 MHz): 8.88 (broad s, 1H), 8.73 (broad s, 1H), 7.80-7.78 (m, 1H), 7.29-7.24 (m, 3H), 7.18 (d, 2H), 6.95 (d, 2H), 5.11 (broad s, 2H), 2.28 (s, 3H), 2.00 (s, 3H)
Reaction SMILES: [CH3:1][CH:2]1[N:9]([C:10]#N)[CH:8]2[CH2:12][C:4]([CH3:17])([C:5]3[CH:16]=[CH:15][CH:14]=[CH:13][C:6]=3[CH2:7]2)[CH2:3]1.Cl.N>O>[CH3:10][N:9]1[CH:2]([CH3:1])[CH2:3][C:4]2([CH3:17])[CH2:12][CH:8]1[CH2:7][C:6]1[CH:13]=[CH:14][CH:15]=[CH:16][C:5]=12
Reactant: CC1CC2(C)CC(Cc3ccccc32)N1C#N
Agent: Cl
Agent: N
Solvent: O
Product: CC1CC2(C)CC(Cc3ccccc32)N1C
Temperature: 25 °C

Procedure:
A mixture of 4,6-dimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carbonitrile (one diastereomer, 925 mg), water (30 mL), and 4 M hydrochloric acid (30 mL) is stirred at reflux temperature for 9 h. After cooling to ambient temperature, the solution is basified using concentrated aqueous ammonia solution and the resulting mixture is extracted with EtOAc (2×50 mL). The combined organic extracts are washed with brine and dried (MgSO4). Removal of the solvent under reduced pressure affords the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[Br:9]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][Br:9])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccnc(Br)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccnc(Br)c1

Procedure:
A mixture of 2-bromo-4-methylpyridine (12.2 g), N-bromosuccinimide (30 g) and 2,2'-azobis(2-methylpropionitrile) (100 mg) in carbon tetrachloride (200 ml) was heated at reflux for 2.5 hours. The mixture was allowed to cool and the insoluble material removed by filtration. The solvent was removed from the filtrate by evaporation and the residue was purified by filtration through a silica pad eluting with ethyl acetate/hexane (10/1) to give 2-bromo-4-bromomethylpyridine.
Reaction SMILES: [C:1]([C:5]1[C:6]([NH2:15])=[N:7][N:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:3])[CH3:2].[CH:16]1([CH2:21][CH2:22][C:23](Cl)=[O:24])[CH2:20][CH2:19][CH2:18][CH2:17]1>>[C:1]([C:5]1[C:6]([NH:15][C:23](=[O:24])[CH2:22][CH2:21][CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[N:7][N:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cnc2c(C(C)(C)C)c(N)nn2c1
Reactant: O=C(Cl)CCC1CCCC1
Product: Cc1cnc2c(C(C)(C)C)c(NC(=O)CCC3CCCC3)nn2c1

Procedure:
The product from Example 178A and 3-cyclopentylpropionyl chloride were processed using the method analogous to that described in Example 105C to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.04-1.15 (m, 2H), 1.43-1.81 (m, 18H), 2.26-2.30 (m, 5H), 8.38 (d, J=2.0 Hz, 1H), 8.75 (s, 1H), 9.62 (br s, 1H); MS (DCI) m/z 329 (M+H)+.
Reaction SMILES: [NH3:1].[C:2]([O:5][C:6]1[C:7]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:8][C:9]2[O:13][C:12]([CH2:15][N:16]=[C:17]=[S:18])([CH3:14])[CH2:11][C:10]=2[C:19]=1[C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:4])[CH3:3]>C(O)C>[C:2]([O:5][C:6]1[C:7]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:8][C:9]2[O:13][C:12]([CH2:15][NH:16][C:17]([NH2:1])=[S:18])([CH3:14])[CH2:11][C:10]=2[C:19]=1[C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:4])[CH3:3]
Reactant: N
Reactant: CC(=O)Oc1c(C(C)(C)C)cc2c(c1C(C)(C)C)CC(C)(CN=C=S)O2
Solvent: CCO
Product: CC(=O)Oc1c(C(C)(C)C)cc2c(c1C(C)(C)C)CC(C)(CNC(N)=S)O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of 4.16 g of a 28% aqueous ammonia solution in 10 ml of ethanol was added dropwise a solution of 5.15 g of (5-acetoxy-4,6-di-t-butyl-2-methyl-2,3-dihydrobenzofuran-2-yl)methyl isothiocyanate in 20 ml of ethanol at room temperature. The mixture was stirred at room temperature for 2 hours, and then heated under reflux for further 1 hour. After cooling, ethanol was removed using an evaporator, and the mixture was combined with water and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated. The concentrate was purified by silica gel column chromatography eluting with chloroform containing 10% methanol to give 5.3 g of 1-[(5-acetoxy-4,6-di-t-butyl-2-methyl-2,3-dihydrobenzofuran-2-yl)methyl]thiourea (rotamer mixture) as a white solid (yield 99%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](C(N=[N+]=[N-])CC)=[CH:5]2>[Pd].C(O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([NH:7][CH2:6][CH2:5][CH3:4])=[CH:5]2
Reactant: CCC(N=[N+]=[N-])c1cc2cc(F)ccc2[nH]1
Agent: [Pd]
Solvent: CCO
Product: CCCNc1cc2cc(F)ccc2[nH]1
Yield: 121.8 %

Procedure:
A solution of 5-fluoro-indolyl-3-propylazide (8 g, 0.037 mol) and 10% palladium on carbon in ethanol was hydrogenated at 50 psi for 16 hours. The catalyst was filtered and the solvent removed under vacuum. The celite was washed with methanol (300 ml) and the solvent was removed under vacuum. Chromatography (15% methanol-methylene chloride plus ammonium hydroxide) afforded 4.33 g (61%) of product as a yellow solid: mp 82-84.5° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:18]([CH2:21][O:22][C:23]4[C:32]5[C:27](=[CH:28][C:29]([O:33][CH3:34])=[CH:30][CH:31]=5)[N:26]=[CH:25][CH:24]=4)=[N:19][N:20]=3)[N:17]=2)[CH:9]=[CH:8][C:3]=1[C:4](OC)=[O:5].O.[OH-].[Li+].Cl.[CH3:39][O:40][CH2:41][CH2:42][NH2:43].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.FC1C=C(C2C=CC3N(C(COC4C5C(=CC(OC)=CC=5)N=CC=4)=NN=3)N=2)C=CC=1C(O)=O>C1COCC1.O.CO.CN(C=O)C>[F:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:18]([CH2:21][O:22][C:23]4[C:32]5[C:27](=[CH:28][C:29]([O:33][CH3:34])=[CH:30][CH:31]=5)[N:26]=[CH:25][CH:24]=4)=[N:19][N:20]=3)[N:17]=2)[CH:9]=[CH:8][C:3]=1[C:4]([NH:43][CH2:42][CH2:41][O:40][CH3:39])=[O:5]
Reactant: COC(=O)c1ccc(-c2ccc3nnc(COc4ccnc5cc(OC)ccc45)n3n2)cc1F
Reactant: COCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: COc1ccc2c(OCc3nnc4ccc(-c5ccc(C(=O)O)c(F)c5)nn34)ccnc2c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: COCCNC(=O)c1ccc(-c2ccc3nnc(COc4ccnc5cc(OC)ccc45)n3n2)cc1F
Temperature: 40 °C
Reaction time: 1 h

Procedure:
A mixture of methyl 2-fluoro-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)benzoate (0.488 g, 1.06 mmol) (prepared according to General Method A) and lithium hydroxide hydrate (0.223 g, 5.31 mmol) in THF (20 mL), water (5 mL) and MeOH (5 mL) was heated to 40° C. for 3 h. Brought to near neutral pH with 1M HCl. Concentrated. Azeotroped with MeCN (20 mL) and PhMe (20 mL). Used without further purification. A mixture of 2-methoxyethylamine (0.033 ml, 0.38 mmol), HATU (0.24 g, 0.62 mmol), Hunig'sBase (0.24 ml, 1.4 mmol), 2-fluoro-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)benzoic acid (0.153 g, 0.34 mmol) in DMF was allowed to stir at room temperature for 1 h. Concentrated. Purified on RPHPLC. Took fractions containing product and made basic with 9% sodium carbonate. The volatiles were removed in vacuo and the product was isolated by filtration. Dried under vacuum. MS m/z=503.2 [M+1]+. Calc'd for C26H23FN6O4: 502.5.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Br[CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[C:15]([O:34][CH3:35])=[CH:16][CH:17]=[C:18]2[C:23]=1[O:22][C:21](=[O:24])[CH:20]=[C:19]2[NH:25][C:26]1[C:31]([Cl:32])=[CH:30][N:29]=[CH:28][C:27]=1[Cl:33]>>[Cl:33][C:27]1[CH:28]=[N:29][CH:30]=[C:31]([Cl:32])[C:26]=1[NH:25][C:19]1[C:18]2[C:23](=[C:14]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[C:15]([O:34][CH3:35])=[CH:16][CH:17]=2)[O:22][C:21](=[O:24])[CH:20]=1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCBr
Reactant: CN1CCNCC1
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCN1CCN(C)CC1

Procedure:
The title compound was prepared from 1-methylpiperazine and 8-(4-bromobutoxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2H-chromen-2-one (Example 25) following the procedure outlined in Example 52. 1H NMR (400 MHz, DMSO-d6; bis HCl salt): δ 11.74 (br, 2H), 9.66 (s, 1H), 8.82 (s, 2H), 8.02 (d, 1H), 7.22 (d, 1H), 4.63 (s, 1H), 4.01 (t, 2H), 3.94 (s, 3H), 3.84-3.18 (br m, 10H), 2.81 (s, 3H), 1.97 (m, 2H), 1.75 (m, 2H); MS (ESI): 507.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([C:12]([NH:14]C(=O)C1C=CC=CC=1)=[O:13])[CH2:7][CH2:6][C:5]2=[O:23].[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([C:12]([NH2:14])=[O:13])[CH2:7][CH2:6][CH:5]2[OH:23]
Reactant: O=C(NC(=O)N1CCC(=O)c2cc(Br)cnc21)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)N1CCC(O)c2cc(Br)cnc21
Reaction time: 0.5 h
Yield: 59.9 %

Procedure:
To the N-(6-bromo-4-oxo-3,4-dihydro-2H-[1,8]naphthyridine-1-carbonyl)-benzamide (188 mg, 0.50 mmol) in 2 mL of MeOH is added NaBH4 (38.0 mg, 1.00 mmol) in one portion. The mixture is stirred for 30 min. and concentrated to dryness. The residue is dissolved in 40 mL EtOAc/H2O, diluted with 10 mL EtOAc and quenched with 20 mL of saturated aqueous NH4Cl. The organic phase is washed with 2×20 mL of H2O and 1×20 mL of brine, dried with MgSO4, filtered and concentrated. The crude material is applied to a silica preparative TLC plate and eluted with 100% EtOAc to give 81.5 mg of 6-bromo-4-hydroxy-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide. This is converted to the titled product using the procedure of Step 5 of Example 22.
Reaction SMILES: [C:1]([Si:5]([CH3:20])([CH3:19])[O:6][C@@H:7]1[CH2:14][N:13]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:12][CH2:11][C:8]21[CH2:10][CH2:9]2)([CH3:4])([CH3:3])[CH3:2].[CH3:21][O:22][CH:23]([O:26][CH3:27])[CH:24]=O.[BH4-].[Na+]>CO>[C:1]([Si:5]([CH3:20])([CH3:19])[O:6][C@@H:7]1[CH2:14][N:13]([CH2:15][CH2:16][CH2:17][NH:18][CH2:24][CH:23]([O:26][CH3:27])[O:22][CH3:21])[CH2:12][CH2:11][C:8]21[CH2:10][CH2:9]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(C=O)OC
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CN(CCCN)CCC12CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(CNCCCN1CCC2(CC2)[C@H](O[Si](C)(C)C(C)(C)C)C1)OC
Yield: 69.6 %

Procedure:
A solution of 3-[(S)-4-(tert-butyl-dimethyl-silanyloxy)-6-aza-spiro[2.5]oct-6-yl]-propylamine (234 mg, 0.78 mmol) and dimethoxyacetaldehyde (45% solution in TBME, 0.20 mL, 0.78 mmol) in MeOH (3 mL) was stirred for 5 h at RT, then sodium borohydride (47 mg, 1.25 mmol) was added, then after 15 min the reaction mixture was partitioned between EtOAc and sat. aq. NaHCO3 solution. The organic layer was washed with brine, dried (MgSO4), filtered, and evaporated. Chromatography (IST Isolute® Flash NH2; EtOAc) afforded the title compound (210 mg, 69%). Light yellow gum, MS: 387.4 (M+H)+.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][S:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]([C:21]2[S:22][C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=3[N:25]=2)[O:13][CH:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[CH:7]=1.O.[NH2:32][NH2:33]>C(O)C>[S:22]1[C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=[C:21]1[CH:12]([O:13][CH:14]1[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]1)[C:8]1[CH:7]=[C:6]([S:5][CH2:4][C:3]([NH:32][NH2:33])=[O:2])[CH:11]=[CH:10][CH:9]=1
Reactant: NN
Reactant: COC(=O)CSc1cccc(C(OC2CCN(C)CC2)c2nc3ccccc3s2)c1
Solvent: CCO
Solvent: O
Product: CN1CCC(OC(c2cccc(SCC(=O)NN)c2)c2nc3ccccc3s2)CC1
Temperature: 80 °C

Procedure:
To a solution of {3-[(benzothiazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}acetic acid methyl ester (30 mg) in absolute ethanol (1 mL) is added hydrazine hydrate (0.1 mL). The reaction mixture is heated at 80° C. for 18 hours. Solvent and volatiles are removed under reduced pressure. The residue is purified by chromatography (gradient dichloromethane/methanol from 95/5 to 80/20) to give {3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}acetic acid hydrazide.
Reaction SMILES: [H-].[Na+].[CH2:3](Br)[CH:4]=[CH2:5].[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([O:17][CH2:18][CH:19]2[CH2:23][C:22]3[CH:24]=[C:25]([Cl:32])[CH:26]=[C:27]([O:28]CC=C)[C:21]=3[O:20]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1.C(OCC=C)C=C>C1(C)C=C(C)C=C(C)C=1>[CH3:7][C:8]1[CH:9]=[CH:10][C:11]([S:14]([O:17][CH2:18][CH:19]2[CH2:23][C:22]3[CH:24]=[C:25]([Cl:32])[C:26]([CH2:5][CH:4]=[CH2:3])=[C:27]([OH:28])[C:21]=3[O:20]2)(=[O:15])=[O:16])=[CH:12][CH:13]=1
Reactant: C=CCOc1cc(Cl)cc2c1OC(COS(=O)(=O)c1ccc(C)cc1)C2
Reactant: C=CCBr
Agent: C=CCOCC=C
Agent: [H-]
Agent: [Na+]
Solvent: Cc1cc(C)cc(C)c1
Product: C=CCc1c(Cl)cc2c(c1O)OC(COS(=O)(=O)c1ccc(C)cc1)C2
Yield: 19 %

Procedure:
Treatment of (±)-(5-chloro-7-methoxy-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (22.1 g, 0.06 mol) with hydrogen bromide (30 wt. % in acetic acid, 400 mL) followed by potassium carbonate (4.15 g, 0.03 mol) provided (±)-(5-chloro-7-hydroxy-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a brown oil. Treatment of the phenyl with sodium hydride (3.2 g, 0.053 mol) and allyl bromide (6.4 g, 0.053 mol) generally according to the procedure described for Intermediate 37 afforded (±)-[7-(allyloxy)-5-chloro-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate. Treatment of the allyl ether in refluxing mesitylene (250 mL) generally according to the procedure described for Intermediate 1 afforded 4.5 g (19%) of (±)-(6-allyl-5-chloro-7-hydroxy-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a pale yellow solid. mp 128-131° C.; Anal. calcd. for C19H19ClO5S: C, 57.79; H, 4.85. Found: C, 58.28; H, 4.68.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3=[N:11][C:12]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]([O:26]CC)=[O:25])[CH:17]=4)=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:29][CH3:30])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O.[OH-].[K+]>C(O)C>[CH:1]1([N:6]2[C:10]3=[N:11][C:12]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]([OH:26])=[O:25])[CH:17]=4)=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:29][CH3:30])[NH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)COc1cccc(-c2nc3n(C4CCCC4)[nH]c(CC)c-3c(=O)n2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCc1[nH]n(C2CCCC2)c2nc(-c3cccc(OCC(=O)O)c3)nc(=O)c1-2
Temperature: 25 °C
Yield: 85.4 %

Procedure:
To a slurry of 1-cyclopentyl-3-ethyl-6-[3-(ethoxycarbonylmethoxy)phenyl]pyrazolo[3,4-d]pyrimidin-4-one (1.23 g, 3.0 mmol) in ethanol (10 ml) was added water (100 ml), followed by 85% KOH (0.4 g). The reaction mixture was heated on a steam bath for 3 hours, cooled to room temperature and filtered. The filtrate was chilled and acidified with acetic acid to afford a white precipitate, which was collected by filtration and washed with water, then ethanol, and finally ether. The product was combined with the product from another experimental run and then was recrystallized from DMF/CH3CN to afford 0.98 g of 1-cyclopentyl-3-ethyl-6-[3-(carboxymethoxy)phenyl]pyrazolo[3,4-d]pyrimidin-4-one, m.p. 299-300° C.