Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.O.[Sn](Cl)Cl.[N+:6]([C:9]1[CH:10]=[C:11]([NH:16][C:17](=[O:26])[C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=2)[CH:12]=[CH:13][C:14]=1[CH3:15])([O-])=O.[OH-].[Na+]>Cl.C(O)(=O)C>[NH2:6][C:9]1[CH:10]=[C:11]([NH:16][C:17](=[O:26])[C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=2)[CH:12]=[CH:13][C:14]=1[CH3:15]
Reactant: Cc1ccc(NC(=O)c2ccc(C#N)cc2)cc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(NC(=O)c2ccc(C#N)cc2)cc1N
Temperature: 25 °C
Yield: 98.4 %

Procedure:
A solution of tin(II) chloride dihydrate (15.4 g) in concentrated hydrochloric acid (80 ml) was added to a suspension of N-(3-nitro-4-methylphenyl)-4-cyanobenzamide (6.39 g) in acetic acid (120 ml). The mixture was stirred and heated to reflux for 2 hours. The mixture was allowed to cool to ambient temperature and was basified by the addition of 2N sodium hydroxide solution. The precipitated solid was isolated and dried under vacuum at 55° C. to give N-(3-amino-4-methylphenyl)-4-cyanobenzamide (5.62 g); NMR Spectrum: (DMSOd6) 2.01 (s, 3H), 4.85 (s, 2H), 6.8 (d, 1H), 6.86 (d, 1H), 7.11 (s, 1H), 7.96 (d, 2H), 8.06 (d, 2H), 10.11 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH2:6][N:7]2[CH:11]=[C:10]([N+:12]([O-])=O)[N:9]=[CH:8]2)[CH2:5][O:4][CH2:3]1.[F:15][C:16]1[CH:17]=[C:18]2[C:23](=[C:24]([F:26])[CH:25]=1)[CH2:22][CH:21]([NH:27][CH:28]([CH2:32][CH2:33][CH3:34])[C:29](O)=[O:30])[CH2:20][CH2:19]2>>[CH3:1][C:2]1([CH2:6][N:7]2[CH:11]=[C:10]([NH:12][C:29](=[O:30])[C@@H:28]([NH:27][CH:21]3[CH2:20][CH2:19][C:18]4[C:23](=[C:24]([F:26])[CH:25]=[C:16]([F:15])[CH:17]=4)[CH2:22]3)[CH2:32][CH2:33][CH3:34])[N:9]=[CH:8]2)[CH2:5][O:4][CH2:3]1
Reactant: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)O
Reactant: CC1(Cn2cnc([N+](=O)[O-])c2)COC1
Product: CCC[C@H](NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1cn(CC2(C)COC2)cn1

Procedure:
1-(3-Methyl-oxetan-3-ylmethyl)-4-nitro-1H-imidazole was reduced and then coupled with 2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid (U.S. Ser. No. 11/078,898 filed Mar. 11, 2005) to afford the title compound: MS 433.3 m/z (M+1).
Reaction SMILES: [CH:1]([N:3]1[C:7](=[O:8])[C:6]2=[CH:9][CH:10]=[CH:11][CH:12]=[C:5]2[C:4]1=[O:13])=[CH2:2].C(N(CC)CC)C.Br[C:22]1[CH:31]=[CH:30][C:29]2[N:28]=[CH:27][C:26]3[N:32]=[C:33]([CH2:44][CH2:45][O:46][CH3:47])[N:34]([CH2:35][CH2:36][CH2:37][N:38]4[CH2:42][CH2:41][CH2:40][C:39]4=[O:43])[C:25]=3[C:24]=2[CH:23]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(#N)C>[CH3:47][O:46][CH2:45][CH2:44][C:33]1[N:34]([CH2:35][CH2:36][CH2:37][N:38]2[CH2:42][CH2:41][CH2:40][C:39]2=[O:43])[C:25]2[C:24]3[CH:23]=[C:22]([CH:2]=[CH:1][N:3]4[C:7](=[O:8])[C:6]5[C:5](=[CH:12][CH:11]=[CH:10][CH:9]=5)[C:4]4=[O:13])[CH:31]=[CH:30][C:29]=3[N:28]=[CH:27][C:26]=2[N:32]=1
Reactant: C=CN1C(=O)c2ccccc2C1=O
Reactant: COCCc1nc2cnc3ccc(Br)cc3c2n1CCCN1CCCC1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COCCc1nc2cnc3ccc(C=CN4C(=O)c5ccccc5C4=O)cc3c2n1CCCN1CCCC1=O
Temperature: 120 °C
Yield: 101.6 %

Procedure:
A thick walled glass tube, equipped with a stir bar, was charged with palladium (II) acetate (17 mg, 0.08 mmol), acetonitrile (50 mL), N-vinylphthalimide (716 mg, 4.13 mmol), triethylamine (1.6 mL, 11 mmol), tri-o-tolylphosphine (69 mg, 0.22 mmol) and 1-{3-[8-bromo-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}pyrrolidin-2-one (1.62 g, 3.76 mmol). The reaction mixture was purged with nitrogen and the tube was sealed and heated at 120° C. in an oil bath for 15 hours. The reaction was cooled to ambient temperature and methanol (50 mL) and chloroform (50 ml) were added. After filtering through a 0.2 micron PTFE membrane, the solution was concentrated under reduced pressure and then purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with a 0-8% gradient of methanol in dichloromethane) to provide 2.0 g of 2-(2-{2-(2-methoxyethyl)-1-[3-(2-oxopyrrolidin-1-yl)propyl]-1H-imidazo[4,5-c]quinolin-8-yl}ethenyl)-1H-isoindole-1,3(2H)-dione as a bright yellow solid.
Reaction SMILES: C(O[C:4]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=O)C.BrC[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:16]1([CH2:15][CH2:14][CH2:4][N:6]2[CH2:7][CH2:8][NH:9][CH2:10][CH2:11]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCCCc1ccccc1
Reactant: CCOC(=O)N1CCNCC1
Product: c1ccc(CCCN2CCNCC2)cc1

Procedure:
1-Ethoxycarbonylpiperazine and 1-bromo-3-phenylpropane were used as the starting materials and treated in the same manner as in Reference Example 9 to give 1-(3phenylpropyl)piperazine.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:10]=[C:11](Cl)[C:12]2[S:17][C:16]([NH2:18])=[N:15][C:13]=2[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[NH2:29][C@H:30]([CH2:33][CH2:34][CH3:35])[CH2:31][OH:32].O>CN1C(=O)CCC1>[NH2:18][C:16]1[S:17][C:12]2[C:11]([NH:29][C@H:30]([CH2:33][CH2:34][CH3:35])[CH2:31][OH:32])=[N:10][C:9]([S:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:14][C:13]=2[N:15]=1
Reactant: CCC[C@@H](N)CO
Reactant: Nc1nc2nc(SCc3ccccc3)nc(Cl)c2s1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCC[C@H](CO)Nc1nc(SCc2ccccc2)nc2nc(N)sc12
Temperature: 110 °C
Yield: 97 %

Procedure:
5-(Benzylthio)-7-chloro[1,3]thiazolo[4,5-d]pyrimidin-2-amine (6.0 g, 19.4 mmol) was dissolved in NMP (30 mL). DIPEA (8.4 mL, 48.5 mmol) and 2-amino-(2R)-1-pentanol (3.5 g, 33.9 mmol) were added and the mixture was heated to 110° C. for 4 days. After cooling to room temperature, the mixture was poured into water (200 mL). The precipitated product was collected by filtration, washed with water and used in the next step without further purification (7.0 g, 97% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[CH3:11][O:12][CH:13]([O:16][CH3:17])[CH2:14]Br.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.O.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:14][CH:13]([O:16][CH3:17])[O:12][CH3:11])[N:6]=[CH:5]2
Reactant: Brc1ccc2[nH]ncc2c1
Reactant: COC(CBr)OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: COC(Cn1ncc2cc(Br)ccc21)OC
Temperature: 40 °C
Reaction time: 18 h
Yield: 58.4 %

Procedure:
To a solution of 5-bromo-1H-indazole (10.0 g, 51.2 mmol) in DMSO (120 mL) was added 2-bromoacetaldehyde dimethyl acetal (12.1 mL, 103 mmol) and Cs2CO3 (66.8 g, 205 mmol). The reaction mixture was stirred at 40° C. for 18 h; then the reaction mixture was diluted with H2O (100 mL) and EtOAc (175 mL). The aqueous layer was extracted with EtOAc (4×175 mL). The combined organics were washed with brine (2×100 mL), dried (Na2SO4), filtered, and concentrated. Purification by flash chromatography (ISCO 330 g column, 95:5 hexanes/EtOAc to hexanes/EtOAc 50:50, 60 min, 40 mL/min) gave the title compound (8.52 g, 46%) as a light orange solid: 1H NMR (300 MHz, CDCl3) 7.94 (s, 1H), 7.85 (d, J=1.2, 1H), 7.48-7.42 (dd, J=8.9, 1.7 Hz, 1H), 7.37 (d, J=8.9 Hz, 1H), 4.71 (t, J=5.4 Hz, 1H), 4.44 (d, J=5.5 Hz, 2H), 3.33 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]=[S:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])([CH3:13])=[O:12])=[O:9])=[CH:4][C:3]=1[C:22]#[C:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[CH:25]=1.[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][C:41]=1[O:42][CH3:43])[C:36](O)=[O:37]>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]=[S:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])([CH3:13])=[O:12])=[O:9])=[CH:4][C:3]=1[C:22]#[C:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:36](=[O:37])[C:35]2[CH:39]=[CH:40][C:41]([O:42][CH3:43])=[C:33]([O:32][CH3:31])[CH:34]=2)[CH:25]=1
Reactant: COC(=O)CCCCS(C)(=O)=NC(=O)c1cnc(N)c(C#Cc2cccc(N)c2)c1
Reactant: COc1ccc(C(=O)O)cc1OC
Product: COC(=O)CCCCS(C)(=O)=NC(=O)c1cnc(N)c(C#Cc2cccc(NC(=O)c3ccc(OC)c(OC)c3)c2)c1

Procedure:
In a manner similar to that described in Example 25, methyl 5-[N-({6-amino-5-[(3-aminophenyl)ethynyl]pyridin-3-yl}carbonyl)-S-methylsulfonimidoyl]pentanoate and 3,4-dimethoxybenzoic acid were coupled to give the title compound as a white foam (102 mg).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.Br[CH2:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[C:25]#[N:26]>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:22][C:23]4[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=4[C:25]#[N:26])[C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Reactant: N#Cc1ccccc1CBr
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(Cc3ccccc3C#N)C2=O)cn1
Yield: 27 %

Procedure:
Prepared as in example 10-5 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) and 2-(bromomethyl)benzonitrile. Yield: 27%. MS M+H calculated 391.1; found 391.1. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.5 μM.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH:7]=[C:8]1[CH2:15][C@@H:14]2[C@@H:10]([CH2:11][C:12]3([O:19][CH2:18][CH2:17][O:16]3)[CH2:13]2)[CH2:9]1)(O)=[O:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O1CCCC1>[OH:2][CH2:1][CH2:4][CH2:5][CH2:6][CH:7]=[C:8]1[CH2:15][C@@H:14]2[C@@H:10]([CH2:11][C:12]3([O:16][CH2:17][CH2:18][O:19]3)[CH2:13]2)[CH2:9]1
Reactant: O=C(O)CCCC=C1C[C@@H]2CC3(C[C@@H]2C1)OCCO3
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCCCC=C1C[C@@H]2CC3(C[C@@H]2C1)OCCO3
Temperature: 25 °C
Yield: 100.8 %

Procedure:
49.10 g of 3-(4-carboxybutylidene)-7,7-ethylenedioxy-cis-bicyclo[3,3,0]octane (prepared as described in Preparation 1) in 150 ml of tetrahydrofuran were added dropwise to a suspension of 10.50 g of lithium aluminum hydride in 675 ml of tetrahyarofuran, whilst cooling with ice. The mixture was then heated under reflux for 80 minutes. Upon completion of the reaction, 42 ml of a 4% w/v aqueous solution of sodium hydroxide were added, and the mixture was stirred at room temperature. The resulting precipitate was removed by filtration, and the filtrate was condensed by evaporation under reduced pressure, giving 46.90 g of a residue. On purifying the residue by silica gel column chromatography, 40.10 g of the title compound were obtained as an oil, from the fractions eluted with hexane containing 20-30% by volume of ethyl acetate.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:21])[C:4](=[O:20])[C@H:5]([CH3:19])[C@H:6]([OH:18])[C@@H:7]([CH3:17])[CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].[CH2:22](OC(=N)C(Cl)(Cl)Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH3:1][O:2][N:3]([CH3:21])[C:4](=[O:20])[C@H:5]([CH3:19])[C@H:6]([O:18][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C@@H:7]([CH3:17])[CH2:8][O:9][Si:10]([C:13]([CH3:15])([CH3:16])[CH3:14])([CH3:12])[CH3:11]
Reactant: N=C(OCc1ccccc1)C(Cl)(Cl)Cl
Reactant: CON(C)C(=O)[C@H](C)[C@H](O)[C@@H](C)CO[Si](C)(C)C(C)(C)C
Product: CON(C)C(=O)[C@H](C)[C@H](OCc1ccccc1)[C@@H](C)CO[Si](C)(C)C(C)(C)C

Procedure:
This material is prepared from N-methoxy-N-methyl-2-(R)-methyl-3-(R)-hydroxy-4-(S)-methyl-5-t-butyldimethylsiloxypentanamide using the reagent benzyltrichloroacetimidate and following the procedure described by Bundle et al. in J. C. S. Chem. Comm. 1981, 1240.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:19]([N:26]1[C:30]2=[N:31][CH:32]=[N:33][C:34]([O:35][C@@H:36]([CH2:47][O:48][CH2:49][CH2:50][O:51][Si](C(C)(C)C)(C3C=CC=CC=3)C3C=CC=CC=3)[C:37]([NH:39][C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][N:41]=3)=[O:38])=[C:29]2[CH:28]=[N:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[CH2:19]([N:26]1[C:30]2=[N:31][CH:32]=[N:33][C:34]([O:35][C@@H:36]([CH2:47][O:48][CH2:49][CH2:50][OH:51])[C:37]([NH:39][C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][N:41]=3)=[O:38])=[C:29]2[CH:28]=[N:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1ccc(NC(=O)[C@H](COCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)Oc2ncnc3c2cnn3Cc2ccccc2)nc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)[C@H](COCCO)Oc2ncnc3c2cnn3Cc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.8 %

Procedure:
A solution of tetrabutylammonium fluoride (1M in THF) (0.896 mL, 0.90 mmol) was added to a stirred solution of (S)-2-(1-benzyl-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-N-(5-methylpyridin-2-yl)propanamide (Intermediate AL1) (342 mg, 0.50 mmol) in tetrahydrofuran (20 mL). The resulting solution was stirred at ambient temperature for 30 minutes. The reaction mixture was quenched with saturated NH4Cl (10 mL), and diluted with water (20 mL) and EtOAc (70 mL). The organic layer was separated and the aqueous layer extracted with EtOAc (70 mL), The combined organics were dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 80 to 100% EtOAc in isohexane to afford the product (170 mg, 76%). 1H NMR (400 MHz, CDCl3) 2.28 (3H, s), 2.91 (1H, s), 3.68-3.74 (4H, m), 4.09-4.20 (2H, m), 5.65 (2H, s), 6.05 (1H, t), 7.25-7.36 (5H, m), 7.50-7.53 (1H, m), 8.05-8.07 (2H, m), 8.21 (1H, s), 8.57 (1H, s), 8.88 (1H, s); m/z (ES+) (M+H)+=449; HPLC tR=1.90 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.O.C(=O)([O-])O.[Na+].[F:15][C:16]([F:27])([F:26])[C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20](Cl)=[O:21]>O1CCCC1>[OH:8][C:4]1[CH:3]=[C:2]([NH:1][C:20](=[O:21])[C:19]2[CH:23]=[CH:24][CH:25]=[C:17]([C:16]([F:15])([F:26])[F:27])[CH:18]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccc(O)c1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1cccc(O)c1)c1cccc(C(F)(F)F)c1
Yield: 108.4 %

Procedure:
To a solution of 3-aminophenol (11.3 g, 104 mmol) in tetrahydrofuran (250 mL) were added water (250 mL) in which sodium hydrogen carbonate (10.6 g, 126.4 mmol) has been dissolved and 3-(trifluoromethyl)benzoyl chloride (22.4 g, 107 mmol), and the mixture was vigorously stirred at room temperature for 2 hr. The aqueous layer was separated, and the organic layer was diluted with ethyl acetate (150 mL) and washed with saturated brine (150 mL). The combined aqueous layer was extracted with ethyl acetate (150 mL). The combined organic layer was dried over anhydrous magnesium sulfate, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The crude product was recrystallized from ethyl acetate and hexane to give title compound (31.7 g) as pale-brown crystals.
Reaction SMILES: O1CCCC1.[NH2:6][C:7]1[C:12]([C:13]2[O:17][N:16]=[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:11][CH:10]=[C:9]([NH2:26])[N:8]=1.[OH-].[Na+].Cl[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][N:32]=1>CN(C)C=O>[F:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][O:25][C:22]2[CH:23]=[CH:24][C:19]([CH2:18][C:15]3[CH:14]=[C:13]([C:12]4[C:7]([NH2:6])=[N:8][C:9]([NH2:26])=[CH:10][CH:11]=4)[O:17][N:16]=3)=[CH:20][CH:21]=2)=[N:32][CH:33]=1
Reactant: Nc1ccc(-c2cc(Cc3ccc(O)cc3)no2)c(N)n1
Reactant: Fc1ccc(CCl)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Nc1ccc(-c2cc(Cc3ccc(OCc4ccc(F)cn4)cc3)no2)c(N)n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
To a tetrahydrofuran (3 mL) solution of 4-(5-(2,6-diamino-pyridin-3-yl)-isoxazol-3-ylmethyl)-phenol (25.5 mg, 0.09 mmol) described in Manufacturing Example 18-1-1 was added a 5 N sodium hydroxide aqueous solution (18.1 μL, 0.09 mmol), which was dissolved by irradiating ultrasonic wave for 1 minute. The reaction solution was concentrated under a reduced pressure, which gave a white solid. An N,N-dimethylformamide (1 mL) solution of 2-chloromethyl-5-fluoro-pyridine (13.2 mg, 0.09 mmol) described in manufacturing Example 41-1-2 was added to a suspension of this solid in N,N-dimethylformamide (1 mL), which was stirred for 1 hour at 60° C. The reaction mixture was cooled to room temperature and then partitioned into water and ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure. The residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid) to obtain the title compound (23.6 mg, 67%) as a ditrifluoroacetic acid salt.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:10]=[CH:11][C:12]([Cl:16])=[C:13]([CH:15]=2)[NH2:14])[CH2:3]1.[Br:17][C:18]1[S:22][C:21]([S:23](Cl)(=[O:25])=[O:24])=[CH:20][CH:19]=1>N1C=CC=CC=1.ClCCl>[Br:17][C:18]1[S:22][C:21]([S:23]([NH:14][C:13]2[CH:15]=[C:9]([N:4]3[CH2:5][C@H:6]([CH3:8])[NH:7][C@H:2]([CH3:1])[CH2:3]3)[CH:10]=[CH:11][C:12]=2[Cl:16])(=[O:25])=[O:24])=[CH:20][CH:19]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Reactant: C[C@@H]1CN(c2ccc(Cl)c(N)c2)C[C@H](C)N1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[C@@H]1CN(c2ccc(Cl)c(NS(=O)(=O)c3ccc(Br)s3)c2)C[C@H](C)N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 5-(cis-3,5-Dimethyl-1-piperazinyl)-2-chloroaniline (D34) (100 mg, 0.42 mmol) in pyridine:dichloromethane (1:1, 4 ml) was treated with 5-bromo-2-thiophenesulfonyl chloride (132 mg, 0.51 mmol). The solution was stirred at room temperature for 2 hours, quenched with methanol and concentrated in vacuo. The residue was applied to a SCX cartridge (Varian bond-elute, 5 g) and washed with methanol and 2M ammonia in methanol. The combined basic fractions were concentrated in vacuo and the resulting residue was purified by column chromatography (FlashMaster) (gradient of dichloromethane to 4% metlianol:dichloromethane) to afford the title product (D36). MS (ES+) m/e 464/466/468 [M+H]+.
Reaction SMILES: F[C:2](F)(F)[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[N:15][C:16]=3[NH:20]C3C=CC=CC=3)[NH:11][CH:10]=2)=[CH:5][CH:4]=1.Cl[C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37](OCC)=O)=[CH:32][CH:31]=1.FC(F)(F)C1C=CC(CC(OCC)=O)=CC=1.C(N)CC1C=CC=CC=1.NC1C=CC=CC=1>>[C:3]1([CH3:2])[CH:8]=[CH:7][C:6]([C:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[N:15][C:16]=3[NH:20][CH2:37][CH2:36][C:33]3[CH:34]=[CH:35][CH:30]=[CH:31][CH:32]=3)[NH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)Cc1ccc(Cl)cc1
Reactant: O=c1c(-c2ccc(C(F)(F)F)cc2)c[nH]c2ccnc(Nc3ccccc3)c12
Agent: CCOC(=O)Cc1ccc(C(F)(F)F)cc1
Agent: NCCc1ccccc1
Solvent: Nc1ccccc1
Product: Cc1ccc(-c2c[nH]c3ccnc(NCCc4ccccc4)c3c2=O)cc1

Procedure:
3-(4-Trifluoromethylphenyl)-1,4-dihydro-4-oxo-5-phenylamino-1,6-naphthyridine The title compound was prepared as described in Example 1 above except that ethyl (4-chlorophenyl)acetate was replaced with ethyl (4-trifluoromethyl-phenyl)acetate and phenethylamine was replaced with aniline. MS 382 (M+1)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[CH2:4][CH2:5][N:6]1[C:15]2[C:10](=[CH:11][C:12]([N+:16]([O-:18])=[O:17])=[CH:13][CH:14]=2)[CH2:9][CH2:8][C:7]1=O)[CH3:2].C1COCC1>CO>[CH2:20]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]1[C:15]2[C:10](=[CH:11][C:12]([N+:16]([O-:18])=[O:17])=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1)[CH3:21]
Reactant: CCN(CC)CCN1C(=O)CCc2cc([N+](=O)[O-])ccc21
Solvent: CO
Solvent: C1CCOC1
Product: CCN(CC)CCN1CCCc2cc([N+](=O)[O-])ccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 91.4 %

Procedure:
A solution of 1-(2-(diethylamino)ethyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (1 g, 3.43 mmol) and 1M BH3 in THF (17.16 ml, 17.16 mmol) was stirred at room temperature overnight. After this time, the reaction was cooled to 0° C. then treated with methanol (25 mL) dropwise with caution. The mixture was stirred at 0° C. for 10 minutes then concentrated on the rotovap to give a yellow solid. This compound was dissolved in 40 mL methanol and heated at reflux for 3 hours. After cooling, the solvent was evaporated and the resulting yellow brown residue was subjected to flash chromatography on silica gel using 5% 2M NH3 in methanol/95% CH2Cl2 to give a bright yellow residue (0.87 g, 91%). 1H-NMR (CDCl3) δ 7.96 (dd, J=2.7, 9.0 Hz, 1H), 7.85-7.84 (m, 1H), 6.51 (d, J=9.0 Hz, 1H), 3.47 (t, J=5.4 Hz, 4H), 2.74 (t, J=6.3 Hz, 2H), 2.68-2.59 (m, 6H), 1.99-1.91 (m, 2H), 1.05 (t, J=6.9 Hz, 6H). MS (ESI): 278.2 (M+1).
Reaction SMILES: [CH:1]1([C:4]([C@H:6]2[C@H:11]([CH3:12])[CH2:10][C@H:9]3[C@H:13]4[C:22]([C@@H:23]([C:25]5[CH:30]=[CH:29][C:28]([C:31]6[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=6)=[CH:27][CH:26]=5)[CH2:24][C@:7]23[CH3:8])=[C:21]2[C:16](=[CH:17][C:18](=[O:37])[CH2:19][CH2:20]2)[CH2:15][CH2:14]4)=[O:5])[CH2:3][CH2:2]1.[ClH:38].O>C(#N)C>[ClH:38].[CH:1]1([C:4]([CH:6]2[CH:11]([CH3:12])[CH2:10][C@H:9]3[C@H:13]4[C:22]([CH:23]([C:25]5[CH:26]=[CH:27][C:28]([C:31]6[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=6)=[CH:29][CH:30]=5)[CH2:24][C@:7]23[CH3:8])=[C:21]2[C:16](=[CH:17][C:18](=[O:37])[CH2:19][CH2:20]2)[CH2:15][CH2:14]4)=[O:5])[CH2:3][CH2:2]1
Reactant: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(-c4cccnc4)cc3)C[C@]2(C)[C@H]1C(=O)C1CC1
Agent: Cl
Solvent: O
Solvent: CC#N
Product: CC1C[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3C(c3ccc(-c4cccnc4)cc3)C[C@]2(C)C1C(=O)C1CC1

Procedure:
To a solution of (11β,16α,17β)-17-cyclopropylcarbonyl-16-methyl-11-[4-(3-pyridinyl)phenyl]estra-4,9-dien-3-one (40 mg, 0.081 mmol) in acetonitrile (1 mL) were added 2 N hydrochloric acid (40 μL) and water (5 mL). Lyophilisation of this mixture gave 11β,16α,17β)-17-cyclopropylcarbonyl-16-methyl-11-[4-(3-pyridinyl)phenyl]estra-4,9-dien-3-one hydrochloride in quantitative yield (40 mg, 0.08 mmol). 1H NMR (400 MHz, CDCl3): δ 0.34 (s, 3H), 0.80-2.85 (m, 24H), 4.47 (d, J=7 Hz, 1H), 5.81 (s, 1H), 7.31-7.35 (m, 2H), 7.51-7.55 (m, 2H), 7.64 (dd, J=8 and 5 Hz, 1H), 8.18 (dt, J=8 and 1 Hz, 1H), 8.62 (d, J=5 Hz, 1H), 8.90 (d, J=1 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]3[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]3)[N:9]=[C:10]([I:11])[C:3]=12.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[I:11][C:10]1[C:3]2[C:4](=[N:5][CH:6]=[N:7][C:2]=2[NH2:1])[N:8]([C@H:12]2[CH2:17][CH2:16][C@@H:15]([N:23]3[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]3)[CH2:14][CH2:13]2)[N:9]=1
Reactant: CN1CCNCC1
Reactant: Nc1ncnc2c1c(I)nn2C1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Temperature: 40 °C
Reaction time: 0.17 h
Yield: 56.8 %

Procedure:
A mixture of 4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-cyclohexanone (Intermediate AK) (1.32 g, 0.0037 mol), N-methylpiperazine (1.11 g, 0.011 mol) and acetic acid (0.66 g, 0.011 mol) in 1,2-dichloroethane (50 mL) was stirred for 10 min at 40° C. and sodium triacetoxyborohydride (1.09 g, 0.0052 mol) was added at once. The mixture was stirred at ambient temperature under an atmosphere of nitrogen for 24 hours and sodium triacetoxyborohydride (0.25 g, 0.0012 mol) was added. The mixture was stirred for another 48 hours , the solvent removed under reduced pressure and the residue partitioned between saturated aqueous sodium bicarbonate solution (80 mL) and chloroform (50 mL). The organic layer was separated and the aqueous layer further extracted with chloroform (3×50 mL). The combined organic extracts were dried over magnesium sulfate and the solvent removed under reduced pressure to yield a yellow oil. The compound was further purified by flash chromatography on silica gel using dichloromethane/triethylamine/methanol (88:11:1) as a mobile phase to yield cis-3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a white solid (0.93 g, 0.0021 mol): 1H NMR (DMSO-d6, 400 MHz) 8.18 (s, 1H), 4.71 (m, 1H), 2.38-1.9 (m, 13H), 2.17 (s, 3H), 1.63-1.5 (m, 4H); TLC (dichloromethane/triethylamine=9:1) Rf 0.24 and trans-3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a white solid (0.38 g, 0.00086 mol): 1H NMR (DMSO-d6, 400 MHz) 8.18 (s, 1H), 4.55 (m, 1H), 2.38-1.9 (m, 15H), 2.15 (s, 3H), 1.42 (m, 2H); TLC (dichloromethane/triethylamine=9:1) Rf 0.11.