Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH:3]1[CH2:12][CH2:13][C:14]([OH:16])=O.[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>ClCCl>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH:3]1[CH2:12][CH2:13][C:14]([N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:16]
Reactant: O=C(O)CCC1CCc2ccccc2C1=O
Reactant: C1CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2CCC1CCC(=O)N1CCCCC1
Yield: 86.2 %

Procedure:
To a solution of 1,2,3,4-tetrahydro-1-oxo-2-naphthalenepropanoic acid (6.3 g), piperidine (3.7 g) and BOP Reagent (15.4 g) in dichloromethane (150 ml) was added dropwise triethylamine (3.5 g) at 25° C., and the mixture was refluxed for three hours. The reaction mixture was washed successively with water and 10% hydrochloric acid, and dried over anhydrous magnesium sulfate. The resultant was concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography (eluent; toluene:ethyl acetate=10:1), and the fractions containing the desired compound were combined, and concentrated under reduced pressure to give the desired compound (7.1 g) as an oily product.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH2:10]([CH:17]([CH2:21][C:22]([NH:24][C:25]1[CH:30]=[C:29]([CH2:31][C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:35](=[O:42])[NH:34][N:33]=2)[CH:28]=[CH:27][C:26]=1[F:43])=[O:23])[C:18]([OH:20])=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CN(C)C=O>[CH2:10]([CH:17]1[CH2:21][C:22](=[O:23])[N:24]([C:25]2[CH:30]=[C:29]([CH2:31][C:32]3[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:35](=[O:42])[NH:34][N:33]=3)[CH:28]=[CH:27][C:26]=2[F:43])[C:18]1=[O:20])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(CC(Cc1ccccc1)C(=O)O)Nc1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1CC(Cc2ccccc2)C(=O)N1c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.9 %

Procedure:
O-Benzotriazol-1-yl-N,N,N′N′-tetramethyluronium tetrafluoroborate (0.14 g, 0.44 mmol) and diisopropylethylamine (0.097 g, 0.44 mmol) were added sequentially at ambient temperature to a stirred solution of 2-benzyl-N-[2-fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)phenyl]succinamic acid (0.156 g, 0.34 mmol) in dimethylformamide (2 ml), the mixture was stirred at ambient temperature for 3 hours, then it was added dropwise to ice-cold water (10 ml). The mixture was stirred for 30 minutes, then the resulting solid was collected by filtration, washed with water (5 ml) and dried in vacuo to give 3-benzyl-1-[2-fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)phenyl]pyrrolidine-2,5-dione (0.120 g) as a white solid, 250 MHz 1H-nmr (d6-DMSO) δ (ppm): 2.6–3.4 (m 5H) (—CH2CH(CO2H)CH2Ph), 4.5 (s, 2H) (ArCH2—), 7.3–7.6 (m, 7H) (7×ArH), 7.6–7.7 (m, 1H) (ArH), 7.9–8.2 (m, 3H) (3×ArH), 8.4 (m, 1H) (ArH), 12.8 (br s, 1H) (CONH); m/z (M+H)+ 442, 96.8% purity.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:10][C@@H:9]1[CH2:24][CH2:25][OH:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:28].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl.[Cl-].[Na+].O>[CH2:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C@@H:9]([CH2:24][C:25]([OH:28])=[O:26])[CH2:10]1)=[O:15])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C[C@@H]1CCO
Agent: [Cl-]
Agent: [Na+]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C[C@@H]1CC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.9 %

Procedure:
(S)-2-(2-Hydroxy-ethyl)-piperazine-1,4-dicarboxylic acid 4-benzyl ester 1-tert-butyl ester (cf. WO 96/31501; S. Fustero et al., Org. Lett. 9 (2007), 5283; 2.862 g, 7.85 mmol) was dissolved in 78.5 ml of DCM and pyridinium dichromate (14.772 g, 39.27 mmol) was added. The mixture was stirred at room temperature overnight, then diluted into brine (330 ml) and extracted three times with EA (70 ml). The combined organic phases were washed with water (300 ml), filtered over diatomaceous earth, dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure. The product was dissolved in EA and extracted three times with a 1 N solution of sodium hydroxide. The combined aqueous phases were acidified to pH 1 with 6 N hydrochloric acid, extracted with EA and the combined extracts were washed with water and brine, dried over sodium sulfate, filtered and evaporated to dryness. 2.226 g of the title compound were obtained as a thick colorless oil.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:19]=[CH:18][C:10]([C:11]([C:13]2[CH:17]=[CH:16][O:15][N:14]=2)=[O:12])=[CH:9][CH:8]=1.CO>ClCCl>[OH:6][C:7]1[CH:19]=[CH:18][C:10]([C:11]([C:13]2[CH:17]=[CH:16][O:15][N:14]=2)=[O:12])=[CH:9][CH:8]=1
Reactant: COc1ccc(C(=O)c2ccon2)cc1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: O=C(c1ccc(O)cc1)c1ccon1
Reaction time: 72 h

Procedure:
9.2 ml of boron tribromide in 40 ml of dichloromethane are slowly added at −70° C. to 13 g of 3-(4-methoxybenzoyl)isoxazole in 200 ml of dichloromethane and stirring is then carried out at room temperature for 3 days. Then, at 0° C., 50 ml of methanol are added dropwise thereto; concentration is carried out and the residue is stirred with 100 ml of 1N hydrochloric acid and 300 ml of ethyl acetate. After concentration of the organic phase and purification over silica gel, 3-(4-hydroxybenzoyl)isoxazole is obtained in the form of beige crystals, m.p: 125-127° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[C:12]([OH:19])[C:11]=1[CH2:20][CH2:21][CH3:22].[S:24]([O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33]OS(=O)(=O)C)(=[O:27])(=[O:26])[CH3:25].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C)C=O>[CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[C:12]([O:19][CH2:33][CH2:32][O:31][CH2:30][CH2:29][O:28][S:24]([CH3:25])(=[O:27])=[O:26])[C:11]=1[CH2:20][CH2:21][CH3:22]
Reactant: CCCc1c(OCCCCCC(=O)OC)ccc(C(C)=O)c1O
Reactant: CS(=O)(=O)OCCOCCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(OCCCCCC(=O)OC)ccc(C(C)=O)c1OCCOCCOS(C)(=O)=O
Yield: 81.9 %

Procedure:
A mixture of 4.0 g (0.012 mole) of 6-(4-acetyl-3-hydroxy-2-propylphenoxy)hexanoic acid methyl ester, 16.3 g (0.062 mole) of diethyleneglycol dimesylate and 3.4 g (0.024 mole) of anhydrous potassium carbonate in 90 ml of anhydrous acetone and 4 ml of anhydrous dimethylformamide was stirred at reflux for 22 hours. The solvents were removed in vacuo and the residue was treated with 100 ml of 50% ethyl acetate-hexane. Some of the residual starting dimesylate was insoluble and was removed by filtration. The filtrate was concentrated in vacuo and the residual oil was purified by HPLC to give 4.8 g (80% yield) of 6-[4-acetyl-3-[2-[2-[(methylsulfonyl)oxy]ethoxy]ethoxy]-2-propylphenoxy]hexanoic acid methyl ester as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14]([OH:16])=[O:15])[CH2:12][C@:11]2([CH2:17]OS(C)(=O)=O)[C@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Na+].[I-].CO[CH2:27][CH2:28]OC>[Zn]>[CH2:27]([O:16][C:14]([C@@H:13]1[CH2:12][C@:11]2([CH3:17])[C@@H:9]([CH2:10]2)[N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:15])[CH3:28]
Reactant: COCCOC
Reactant: CC(C)(C)OC(=O)N1[C@H](C(=O)O)C[C@@]2(COS(C)(=O)=O)C[C@@H]12
Agent: [I-]
Agent: [Na+]
Agent: [Zn]
Product: CCOC(=O)[C@@H]1C[C@@]2(C)C[C@H]2N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (1R,3S,5S)-5-methanesulfonyloxymethyl-2-aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-tert-butyl ester (100 mg, 0.24 mmol) in DME (2.6 mL) were successively added NaI (355 mg, 2.37 mmol) and zinc powder (155 mg, 2.37 mmol). The reaction mixture was refluxed 30 min under argon atmosphere, cooled to RT and quenched by addition of a saturated aqueous solution of NH4Cl (1.6 mL). CH2Cl2 (1.6 mL) and few Na2S crystals were added and the biphasic mixture was stirred at RT for 1 h. The layers were separated, the organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude residue was purified by flash column chromatography on silica gel (eluent: c-hexane to c-hexane/EtOAc). TLC, Rf (c-hexane/EtOAc 2:1)=0.60; MS (UPLC/MS): 270.3 [M+H]+, 214.2 [MH−tBu]+, 170.2 [MH−Boc]+; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 4.11 (m, 2H), 3.95 (m, 1H), 3.10 (m, 1H), 2.42 (m, 1H), 1.84 (m, 1H), 1.38 (m, 9H), 1.20 (t, 3H), 1.18 (s, 3H) 0.69 (dd, 1H), 0.64 (m, 1H).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([N:10]1[C@@H:15]2[C@H:16]([C:18]3[N:19]=[N:20][N:21]([CH2:23][C:24](=[O:26])[CH3:25])[N:22]=3)[CH2:17][C@@:11]1([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C@H:12]([O:27][CH2:28][C:29]1[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[C:31]([C:39]([F:42])([F:41])[F:40])[CH:30]=1)[CH2:13][CH2:14]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO.C1COCC1>[CH2:3]([N:10]1[C@@H:15]2[C@H:16]([C:18]3[N:19]=[N:20][N:21]([CH2:23][CH:24]([OH:26])[CH3:25])[N:22]=3)[CH2:17][C@@:11]1([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C@H:12]([O:27][CH2:28][C:29]1[CH:34]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:32]=[C:31]([C:39]([F:41])([F:42])[F:40])[CH:30]=1)[CH2:13][CH2:14]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)Cn1nnc([C@@H]2C[C@@]3(c4ccccc4)[C@H](OCc4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC[C@@H]2N3Cc2ccccc2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(O)Cn1nnc([C@@H]2C[C@@]3(c4ccccc4)[C@H](OCc4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC[C@@H]2N3Cc2ccccc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.4 %

Procedure:
Sodium borohydride (13 mg, 0.34 mmol) was added to a solution of (1R*,2R*,5S*,6R*)-8-benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-[2-(2-oxopropyl)-2H-tetrazol-5-yl]-1-phenyl-8-azabicyclo[3.2.1]octane (Compound 3i in Table 3; 0.2 g, 0.31 mmol) in methanol (10 ml) and THF (2 ml). The mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the residue partitioned between saturated sodium hydrogen carbonate and ethyl acetate. The organic layer was separated, dried (MgSO4), filtered and concentrated. The residue was chromatographed on silica gel eluting with 25 and 35% ethyl acetate/iso-hexanes to yield the title compound (189 mg, 95%).
Reaction SMILES: [NH2:1][C@H:2]([C:13]1[N:18]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=2)[C:17](=[O:27])[C:16]2=[C:28]([C:31]#[N:32])[CH:29]=[CH:30][N:15]2[N:14]=1)[CH2:3][CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:33][C:34]1[C:39]([C:40]#[N:41])=[C:38](Cl)[N:37]=[CH:36][N:35]=1.C(N(CC)C(C)C)(C)C>C(O)CCC>[NH2:33][C:34]1[N:35]=[CH:36][N:37]=[C:38]([NH:1][C@H:2]([C:13]2[N:18]([C:19]3[CH:20]=[C:21]([F:26])[CH:22]=[C:23]([F:25])[CH:24]=3)[C:17](=[O:27])[C:16]3=[C:28]([C:31]#[N:32])[CH:29]=[CH:30][N:15]3[N:14]=2)[CH2:3][CH2:4][O:5][CH2:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:39]=1[C:40]#[N:41]
Reactant: N#Cc1ccn2nc([C@@H](N)CCOCc3ccccc3)n(-c3cc(F)cc(F)c3)c(=O)c12
Reactant: N#Cc1c(N)ncnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: N#Cc1c(N)ncnc1N[C@@H](CCOCc1ccccc1)c1nn2ccc(C#N)c2c(=O)n1-c1cc(F)cc(F)c1
Temperature: 120 °C
Reaction time: 8 h
Yield: 61.4 %

Procedure:
In a reactor vessel (S)-2-(1-amino-3-(benzyloxy)propyl)-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-5-carbonitrile (42 mg, 0.1 mmol) and 4-amino-6-chloropyrimidine-5-carbonitrile (16 mg, 0.1 mmol) were dissolved in 1-butanol (840 μl) under argon atmosphere. N,N-Diisopropylethylamine (76 μl, 0.87 mmol) was added and the reaction mixture was heated at 120° C. overnight. Further N,N-diisopropylethylamine (76 μl, 0.87 mmol) was added afterwards and the reaction mixture was stirred at 120° C. overnight. The crude was evaporated and purified using SP1® Purification System (0% to 100%, hexane-ethyl acetate) to obtain 34 mg (64% yield) of the title compound as a yellow solid. Purity 97%.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]2[C:12]3([CH2:28][O:29][C:8]=2[CH:7]=1)[C:20]1[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=1)[N:14]([CH2:21][C@H:22]1[CH2:26][CH2:25][CH2:24][O:23]1)[C:13]3=[O:27].[OH-].[Li+].Cl>O1CCCC1.O>[O:27]=[C:13]1[C:12]2([C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:30])=[O:2])=[CH:7][C:8]=3[O:29][CH2:28]2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]1[CH2:21][C@H:22]1[CH2:26][CH2:25][CH2:24][O:23]1
Reactant: COC(=O)COc1ccc2c(c1)OCC21C(=O)N(C[C@H]2CCCO2)c2ccccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)COc1ccc2c(c1)OCC21C(=O)N(C[C@H]2CCCO2)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
To a solution of methyl({2′-oxo-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-1,2′-dihydrospiro[1-benzofuran-3,3′-indol]-6-yl}oxy)acetate (0.51 g, 1.25 mmol) in tetrahydrofuran (4 mL) and water (1 mL) was added lithium hydroxide (0.05 g, 1.62 mmol). The reaction mixture was stirred at ambient temperature for 16 h. To the reaction mixture was added 1 N HCl to adjust pH<2, then extracted with ethyl acetate (2×50 mL). The combined organic solution was washed with water and brine, then dried over sodium sulfate, filtered and concentrated to afford ({2′-oxo-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-1′,2′-dihydrospiro[1-benzofuran-3,3′-indol]-6-yl}oxy)acetic acid (0.42 g, 85%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 7.33-7.26 (m, 1H), 7.15-7.00 (m, 3H), 6.64 (d, J=8.4 Hz, 1H), 6.54 (d, J=2.4 Hz, 1H), 6.40-6.34 (m, 1H), 4.96 (d, J=9.0 Hz, 1H), 4.70 (d, J=9.0 Hz, 1H), 4.59 (s, 2H), 4.35-4.24 (m, 1H), 3.99-3.68 (m, 4H), 2.10-1.86 (m, 3H), 1.79-1.65 (m, 1H); MS (ES+) m/z 396.0 (M+1), 417.9 (M+23).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[NH2:8].[CH3:17][C:18]1[CH:19]=[C:20]([CH:26]=[CH:27][C:28]=1[CH3:29])[CH:21]=[CH:22][C:23](O)=O>>[CH3:17][C:18]1[CH:19]=[C:20]([CH:26]=[CH:27][C:28]=1[CH3:29])/[CH:21]=[CH:22]/[C:23]1[NH:1][C:2]2[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=2[N:8]=1
Reactant: Cc1ccc(C=CC(=O)O)cc1C
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Product: CCCn1c(=O)c2[nH]c(/C=C/c3ccc(C)c(C)c3)nc2n(CCC)c1=O

Procedure:
Substantially the same procedure as in Reference Example 1 was repeated using 5.90 g (26.0 mmol) of 5,6-diamino-1,3-dipropyluracil and 5.5 g (31.3 mmol) of 3,4-dimethylcinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 7.70 g (yield of Compound 30 as a white powder.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=O)=[CH:4][C:3]=1[CH2:12][O:13]C.[Cl:15][C:16]1[CH:17]=[C:18]([C:23](=[N:25]O)[NH2:24])[CH:19]=[N:20][C:21]=1[Cl:22]>>[Cl:22][C:21]1[C:16]([Cl:15])=[CH:17][C:18]([C:23]2[N:25]=[C:12]([C:3]3[CH:2]=[CH:11][C:10]([C:2]4[CH:11]=[CH:10][CH:5]=[CH:4][C:3]=4[CH3:12])=[C:5]([CH2:6][O:8][CH3:9])[CH:4]=3)[O:13][N:24]=2)=[CH:19][N:20]=1
Reactant: NC(=NO)c1cnc(Cl)c(Cl)c1
Reactant: COCc1cc(C(=O)OC)ccc1Br
Product: COCc1cc(-c2nc(-c3cnc(Cl)c(Cl)c3)no2)ccc1-c1ccccc1C

Procedure:
The title compound was prepared following procedure described in Method B starting from Intermediate A1 and 5,6-dichloro-N′-hydroxypyridine-3-carboximidamide (WO2000015637). The title compound was obtained as a white powder. HPLC (Method A), Rt: 6.7 min (purity: 95.0%). UPLC/MS, M+(ESI): 426.1. 1H NMR (DMSO-d6, 300 MHz) δ 9.08 (d, J=2.1 Hz, 1H), 8.72 (d, J=2.1 Hz, 1H), 8.34 (d, J=1.8 Hz, 1H), 8.19 (dd, J=7.9, 1.8 Hz, 1H), 7.44 (d, J=7.9 Hz, 1H), 7.36 (m, 2H), 7.30 (m, 1H), 7.15 (d, J=7.1 Hz, 1H), 4.23 (d, J=12.7 Hz, 1H), 4.16 (d, J=12.7 Hz, 1H), 3.25 (s, 3H), 2.03 (s, 3H).
Reaction SMILES: FC(F)(F)C([O-])=O.[C:8]([C:11]1[C:12]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:13][N:14]([C:16]2([CH2:22][C:23]#[N:24])[CH2:21][CH2:20][NH2+:19][CH2:18][CH2:17]2)[CH:15]=1)(=[O:10])[NH2:9].C1CCN2C(=NCCC2)CC1.[C:43]([CH2:45][C:46](OC)=[O:47])#[N:44].C([O-])(O)=O.[Na+]>>[C:43]([CH2:45][C:46]([N:19]1[CH2:20][CH2:21][C:16]([N:14]2[CH:15]=[C:11]([C:8]([NH2:9])=[O:10])[C:12]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:13]2)([CH2:22][C:23]#[N:24])[CH2:17][CH2:18]1)=[O:47])#[N:44]
Reactant: COC(=O)CC#N
Reactant: N#CCC1(n2cc(C(N)=O)c(Nc3ccccc3)n2)CC[NH2+]CC1
Agent: O=C([O-])C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Product: N#CCC(=O)N1CCC(CC#N)(n2cc(C(N)=O)c(Nc3ccccc3)n2)CC1

Procedure:
To a suspension of 4-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl) piperidinium trifluoroacetate (60 mg, 0.14 mmol) in Me-THF (2.0 mL) was added DBU (0.065 mL, 0.43 mmol), followed by methyl cyanoacetate (28 mg, 0.29 mmol). The resulting mixture was allowed to stir for 1 hour before saturated aqueous NaHCO3 solution was added and the resulting mixture was extracted with EtOAc (3×). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 50-100%, EtOAc/hexanes followed by elution with 10% MeOH/EtOAc) to afford the title compound, Example #36-1.
Reaction SMILES: C[Mg]Br.[F:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[N:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][C:19]3=[O:21])[CH2:14][C:13](=[O:22])[CH2:12]2)=[CH:7][CH:6]=1.[Cl-].[NH4+].[C:25](OCC)(=O)C>C1COCC1>[F:4][C:5]1[CH:6]=[CH:7][C:8]([C@@H:11]2[CH2:12][C@@:13]([OH:22])([CH3:25])[CH2:14][C@@H:15]3[N:20]2[C:19](=[O:21])[CH2:18][CH2:17][CH2:16]3)=[CH:9][CH:10]=1
Reactant: CCOC(C)=O
Reactant: O=C1C[C@H]2CCCC(=O)N2[C@H](c2ccc(F)cc2)C1
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C[C@@]1(O)C[C@H]2CCCC(=O)N2[C@H](c2ccc(F)cc2)C1
Reaction time: 0.83 h

Procedure:
Methylmagnesium bromide (0.96 M solution in THF, 5.98 mL) was added to a solution of (4S*,9aR*)-4-(4-fluorophenyl)hexahydroquinolizine-2,6-dione (1.0 g) in THF (15 mL) under ice-cooling, and the reaction solution was stirred for 50 minutes. Because the starting material did not disappear, methylmagnesium bromide (0.96 M solution in THF, 5.98 mL) was further added to the reaction solution, which was then stirred for 30 minutes. A saturated ammonium chloride solution and ethyl acetate were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system->ethyl acetate-methanol system) to obtain a mixture of the starting material with the title compound. Methylmagnesium bromide (0.96 M solution in THF, 5.98 mL) was added to a solution of the resulting mixture in THF (15 mL) again under ice-cooling, and the reaction solution was stirred for one hour. A saturated ammonium chloride solution and ethyl acetate were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system->ethyl acetate-methanol system) to obtain a mixture of the starting material with the title compound. Methylmagnesium bromide (0.96 M solution in THF, 5.98 mL) was added to a solution of the mixture obtained again in THF (15 mL) again under ice-cooling, and the reaction solution was stirred for 1.5 hours. A saturated ammonium chloride solution and ethyl acetate were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system->ethyl acetate-methanol system) to obtain 760 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[CH3:21])(=[O:12])=[O:11])([O-])=O.O.O.Cl[Sn]Cl.[OH-].[K+]>CCOC(C)=O>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[CH3:21])(=[O:12])=[O:11]
Reactant: Cc1ccc(C)c(NS(=O)(=O)c2ccccc2[N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(C)c(NS(=O)(=O)c2ccccc2N)c1
Temperature: 25 °C

Procedure:
2-nitro-N-(2,5-dimethyl-phenyl)-benzenesulfonamide (6.1 g, 20 mmol) in EtOAc (60 mL) is treated with SnCl2.2H2O (22.5 g, 100 mmol). The reaction mixture is heated to reflux for 30 minutes and then allowed to cool to room temperature. 2 N KOH (250 mL, 500 mmol) is added and the resulting mixture stirred vigorously until all solids dissolve. The aqueous layer is separated and extracted 2×100 mL EtOAc. The combined organic layers are washed with sat. brine, dried over MgSO4, filtered, and concentrated to a solid, which is recrystallized from hot EtOAc/hexanes to provide 2-amino-N-(2,5-dimethyl-phenyl)-benzenesulfonamide.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:9]1[C@@:13]2([CH3:28])[CH2:14][CH2:15][CH2:16]/[C:17](=[CH:18]\[CH:19]=[C:20]3\[CH2:21][C@@H:22]([OH:27])[CH2:23][CH2:24][C:25]\3=[CH2:26])/[C@@H:12]2[CH2:11][CH2:10]1)[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].C(N(CC)C(C)C)(C)C.Cl[CH2:39][O:40][CH3:41].[Cl-].[NH4+]>ClCCl>[CH3:39][O:40][CH2:41][O:27][CH:22]1[CH2:23][CH2:24][C@@:25]2([CH3:26])[C:20](=[CH:19][CH:18]=[C:17]3[C@@H:16]2[CH2:15][CH2:14][C@@:13]2([CH3:28])[C@H:12]3[CH2:11][CH2:10][C@@H:9]2[C@@H:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH:6]([CH3:7])[CH3:8])[CH2:21]1
Reactant: COCCl
Reactant: C=C1CC[C@H](O)C/C1=C/C=C1\CCC[C@]2(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@@H]12
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOC1CC[C@@]2(C)C(=CC=C3[C@@H]4CC[C@H]([C@@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]32)C1
Reaction time: 8 h
Yield: 88.7 %

Procedure:
Commercially available 7-dehydrocholesterol (18.3 g, 47.6 mmol) was dissolved in dichloromethane (150 mL), and N,N-diisopropylethylamine (24.9 mL, 143 mmol) and chloromethylmethyl ether (7.23 mL, 95.2 mmol) were added thereto at room temperature, followed by stirring overnight. A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with chloroform twice. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to yield a residue. The residue was purified by silica gel column chromatography to obtain (S)-3-methoxymethoxy-5,7-cholestadiene (18.1 g, 89%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[CH2:19]([O:21][CH2:22][CH2:23][CH2:24][NH2:25])[CH3:20]>>[Cl:1][C:2]1[N:3]=[C:4]([NH:25][CH2:24][CH2:23][CH2:22][O:21][CH2:19][CH3:20])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: Fc1ccc(C2CCc3c(Cl)nc(Cl)nc32)cc1
Reactant: CCOCCCN
Product: CCOCCCNc1nc(Cl)nc2c1CCC2c1ccc(F)cc1

Procedure:
2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Preparation H) was reacted as described in Preparation Hr with 3-ethoxypropan-1-amine to afford 2-chloro-N-(3-ethoxypropyl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (Preparation Hu). LC-MS (M+H)+=350.1.