Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([P:3]([CH2:9][OH:10])(=[O:8])[O:4][CH:5]([CH3:7])[CH3:6])[CH3:2].[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18](Cl)(=[O:20])=[O:19].[P].ClC1C=C(C=CC=1)C(OO)=O.S([O-])([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+]>CN(C1C=CN=CC=1)C.O.C(Cl)Cl.ClCCCl.C(N(CC)CC)C>[CH2:1]([P:3]([CH2:9][O:10][S:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[Cl:11])(=[O:20])=[O:19])(=[O:8])[O:4][CH:5]([CH3:7])[CH3:6])[CH3:2]
Reactant: CCP(=O)(CO)OC(C)C
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Agent: CN(C)c1ccncc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: O
Product: CCP(=O)(COS(=O)(=O)c1ccccc1Cl)OC(C)C
Temperature: 25 °C
Reaction time: 192 h
Yield: 29.7 %

Procedure:
A solution of 4.10 g of O-isopropyl P-ethyl-(hydroxymethyl)-phosphinate, prepared in Example 22, Method A, 4.4 ml of triethylamine and 20 ml of methylene chloride was added dropwise over 40 minutes to a mixture of 25 ml of methylene chloride, 5.75 g of 2-chlorobenzenesulfonyl chloride, and 0.1 g of DMAP. The reaction temperature was kept between 15° C. and 28° C. during the addition. The reaction was allowed to stir at room temperature for eight days and was then diluted with 100 ml of water and 100 ml of methylene chloride. The organic phase was separated, dried with magnesium sulfate, filtered and concentrated to yield the crude product. Phosphorus NMR indicated two products in a 5:1 ratio. The crude product was dissolved in 30 ml of 1,2-dichloroethane and then 1.8 g of 3-chloroperoxybenzoic acid (MCPBA) was added. The reaction mixture was refluxed for three hours, allowed to cool to room temperature and stand overnight. The reaction mixture was diluted with 100 ml of methylene chloride. Then 100 ml of 10% of sodium sulfite solution was added, followed by the careful addition of 100 ml of saturated sodium bicarbonate solution in small portions. Once the foaming ceased small portions of solid sodium bicarbonate were added until all foaming ceased. The phases were separated, the organic phase washed with 100 ml of water, dried with magnesium sulfate, filtered and concentrated to yield 3.3 g of the crude product as an oil. The oil was dissolved in 4 ml of methylene chloride and flash chromatographed on Merck silica gel (230-400 mesh) using blends of hexanes and ethyl acetate ranging from 1/1 to 0/100 hexanes/ethyl acetate, respectively. Similar fractions were combined and concentrated to yield 2.5 g of the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[S-:11][C:12]#[N:13].[K+].BrBr>CC(O)=O>[NH2:13][C:12]1[S:11][C:3]2[CH:4]=[C:5]([CH2:8][C:9]#[N:10])[CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: N#C[S-]
Reactant: N#CCc1ccc(N)cc1
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: N#CCc1ccc2nc(N)sc2c1
Temperature: 25 °C
Yield: 86 %

Procedure:
To a solution of 2-(4-aminophenyl)acetonitrile (6.00 g, 45.4 mmol) in AcOH (70 mL) was added potassium thiocyanate (17.6 g, 181 mmol) at rt in one portion. The mixture was stirred at rt until it became a clear solution. To this solution was then added a solution of bromine (2.3 mL, 44.9 mmol) in AcOH (30 mL) at rt over 1 hr. The resulting mixture was stirred at rt for 4 hr. The precipitate that formed during the reaction was collected by suction filtration, and then suspended into water (100 mL). The pH value of the aqueous suspension was adjusted to 8 with concentrated ammonium hydroxide. The insoluble product (7.39 g, 86% yield) was collected as a pale yellow solid by suction filtration and dried over Drierite® under vacuum at 65° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([CH3:27])([CH3:26])[C:22]([O:24]C)=[O:23])=[CH:17][CH:16]=3)[CH:11]=[C:10]([CH2:28][CH3:29])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.O1CCOCC1.O.[OH-].[Li+].Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([CH3:26])([CH3:27])[C:22]([OH:24])=[O:23])=[CH:17][CH:16]=3)[CH:11]=[C:10]([CH2:28][CH3:29])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCc1cc(Cc2ccc(C(C)(C)C(=O)OC)cc2)nc(-c2cccc(Cl)c2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCc1cc(Cc2ccc(C(C)(C)C(=O)O)cc2)nc(-c2cccc(Cl)c2)n1
Temperature: 50 °C
Reaction time: 7 h
Yield: 154.1 %

Procedure:
An 250-mL round bottom flask was charged with methyl 2-(4-((2-(3-chlorophenyl)-6-ethylpyrimidin-4-yl)methyl)phenyl)-2-methylpropanoate (0.472 g, 1.15 mmol), dioxane (24 ml) and water (12 ml). To this solution was then added lithium hydroxide monohydrate (0.242 g, 5.77 mmol). The resulting mixture was stirred at 50° C. for 7 h. After this time the reaction mixture was cooled and treated with 2M aqueous HCl until pH˜5. The volatile materials were removed under reduced pressure to afford the title compound (0.70 g, >100%) as a white solid. MW=394.89. 1H NMR (DMSO-d6, 500 MHz) δ 12.26 (br s, 1H), 8.38-8.34 (m, 2H), 7.61-7.53 (m, 2H), 7.35-7.27 (m, 5H), 4.09 (s, 2H), 2.78 (q, J=8.0 Hz, 2H), 1.44 (s, 6H), 1.27 (t, J=7.5 Hz, 3H). ESI MS m/z 395 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:40])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([NH:15][C@@H:16]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]([F:39])([F:38])[F:37])[CH2:17][N:18]2C(=O)C3C(=CC=CC=3)C2=O)=[O:14])[O:10][C:11]=1[CH3:12].NN>O1CCCC1.CO>[NH2:18][CH2:17][C@@H:16]([NH:15][C:13]([C:9]1[O:10][C:11]([CH3:12])=[C:7]([C:6]2[N:5]([CH3:40])[N:4]=[CH:3][C:2]=2[Cl:1])[CH:8]=1)=[O:14])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36]([F:39])([F:38])[F:37]
Reactant: Cc1oc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Cl)cnn1C
Agent: NN
Solvent: C1CCOC1
Solvent: CO
Product: Cc1oc(C(=O)N[C@H](CN)Cc2ccccc2C(F)(F)F)cc1-c1c(Cl)cnn1C
Yield: 55.8 %

Procedure:
To a solution of 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-2-furancarboxamide (246 mg, 0.43 mmol) in tetrahydrofuran (2.1 ml) and methanol (2.1 ml) at 25° C. was added hydrazine (135 μl, 4.31 mmol) dropwise. After 12 h the solution was concentrated, dry loaded onto silica and purified by column chromatography (5% MeOH in DCM (1% NH4OH)). The free base was converted to the HCl salt by addition of excess 4M HCl in dioxane (1 ml) to the residue in MeOH (2 ml) affording the HCl salt of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxamide (125 mg, 0.24 mmol, 56% yield) as a yellow solid: LCMS (ES) m/z=441, 443 (M, M+2)+, 1H NMR (400 MHz, DMSO-d6) δ ppm 8.63 (d, J=9.09 Hz, 1H) 8.04 (br. s., 3H) 7.65-7.72 (m, 2H) 7.59 (d, J=7.33 Hz, 1H) 7.57 (br. s., 1H) 7.39-7.47 (m, 1H) 7.29-7.37 (m, 1H) 4.54 (br. s., 1H) 3.73 (s, 3H) 2.98-3.09 (m, 4H) 2.33 (s, 3H).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1)[CH2:4][CH3:5])[CH3:2].O[CH:15]=[C:16]1[C:24]2[C:19](=[CH:20][C:21]([C:25]([C:27]3[CH:28]=[C:29]([NH:33][C:34]([C:36]4[N:40]([CH3:41])[N:39]=[C:38]([CH3:42])[CH:37]=4)=[O:35])[CH:30]=[CH:31][CH:32]=3)=[O:26])=[CH:22][CH:23]=2)[NH:18][C:17]1=[O:43]>C1COCC1>[CH2:1]([N:3]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH:11]/[CH:15]=[C:16]2\[C:17](=[O:43])[NH:18][C:19]3[C:24]\2=[CH:23][CH:22]=[C:21]([C:25]([C:27]2[CH:28]=[C:29]([NH:33][C:34]([C:36]4[N:40]([CH3:41])[N:39]=[C:38]([CH3:42])[CH:37]=4)=[O:35])[CH:30]=[CH:31][CH:32]=2)=[O:26])[CH:20]=3)=[CH:12][CH:13]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)n(C)n1
Reactant: CCN(CC)Cc1ccc(N)cc1
Solvent: C1CCOC1
Product: CCN(CC)Cc1ccc(N/C=C2\C(=O)Nc3cc(C(=O)c4cccc(NC(=O)c5cc(C)nn5C)c4)ccc32)cc1
Temperature: 70 °C
Yield: 55.5 %

Procedure:
A mixture of 4-((diethylamino)methyl)aniline (A-04; 100 mg, 0.25 mmol, 1 equivalent) and N-(3-(3-(hydroxymethylene)-2-oxoindoline-6-carbonyl)phenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide (Scaffold S1; 50 mg, 0.25 mmol, 1 equivalent) was taken in anhydrous THF (2 mL, 0.125 M) and heated at 70° C. for 16 h. Solvent was evaporated under vacuum and the crude product was purified by preparative RP-HPLC. 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid (3-{3-[1-(4-diethylaminomethyl-phenylamino)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-1H-indole-6-carbonyl}-phenyl)-amide (78 mg, 55%) was obtained as a brown powder.
Reaction SMILES: [Br:1]/[C:2](/[CH:10]([OH:19])[C:11]#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]#[CH:18])=[CH:3]\[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[K+].[CH3:22]I>CS(C)=O>[Br:1]/[C:2](/[CH:10]([O:19][CH3:22])[C:11]#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]#[CH:18])=[CH:3]\[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CI
Reactant: C#CCCCCC#CC(O)/C(Br)=C/c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: C#CCCCCC#CC(OC)/C(Br)=C/c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 67.4 %

Procedure:
To a solution of Compound 7 (303.0 mg, 0.96 mmol) and KOH (214.1 mg, 3.82 mmol) in DMSO (20 mL) was added MeI (271.3 mg, 1.91 mmol) followed by stirring at room temperature for 5 hours. The reaction was then quenched with saturated aqueous NH4Cl (20 mL) and extracted with EtOAc (50 mL×2). The combined organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 20 percent EtOAc in hexane) to give 214.3 mg (68 percent) of Compound 8: pale yellow oil; Rf=0.56 (20 percent EtOAc in hexane); IR (neat) 3296, 2940, 2232, 2116, 1446, 1078 cm−1; 1H NMR (300 MHz, CDCl3) δ7.68-7.65 (m, 2H), 7.38-7.25 (m, 3H), 7.29 (s, 1H), 4.76 (s, 1H), 3.42 (s, 3H), 2.36-2.31 (m, 2H), 2.26-2.21 (m, 2H), 1.95 (t, J=2.67 Hz, 1H), 1.74-1.65 (m, 4H); 13C NMR (75 MHz, CDCl3) δ135.4, 131.4, 129.8, 129.1, 128.8, 123.9, 89.2, 84.6, 77.5, 76.8, 69.3, 56.0, 28.1, 27.9, 19.0, 18.5; MS (+CI) m/z (relative intensity) 333 (M+H+, 81Br, 10), 331 (M+H+, 79Br, 12), 251 (100); HRMS (+EI) calcd for C18H19BrO 330.0619 (M+), found 330.0606.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][CH:24]=[N:25][CH:26]=3)=[CH:17][CH:16]=2)[CH:7]=1.Cl.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[S:35](Cl)(=[O:37])=[O:36]>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([S:35]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=2)(=[O:37])=[O:36])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][CH:24]=[N:25][CH:26]=3)=[CH:17][CH:16]=2)[CH:7]=1
Reactant: O=S(=O)(Cl)c1ccccn1
Reactant: COC(=O)CCc1cccc(CNCc2ccc(-c3cncnc3)cc2)c1
Agent: Cl
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc(-c3cncnc3)cc2)S(=O)(=O)c2ccccn2)c1

Procedure:
The title compound of Step A was prepared from 3-{3-[(4-pyrimidin-5-yl-benzylamino)-methyl]-phenyl}-propionic acid methyl ester, of Step A of Example 11t, and pyridine-2-sulfonyl chloride hydrochloride, of Preparation 47, following the method described in Example 1, Step B using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 9.20 (s, 1H), 8.90 (s, 2H), 8.70 (d, 1H), 7.99 (m, 1H), 7.89 (m, 1H), 7.49 (m, 1H), 7.42 (d, 2H), 7.29 (d, 2H), 7.10 (m, 1H), 7.01 (d, 1H), 6.93 (d, 1H), 6.89 (s, 1H), 4.56 (s, 2H), 4.48 (s, 2H), 3.66 (s, 3H), 2.79 (t, 2H), 2.48 (t, 2H); MS 503 (M+1).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:28]([O:30]C)=[O:29])=[C:5]2[C:9]=1[N:8]=[CH:7][N:6]2[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]2[NH:27][N:26]=[N:25][N:24]=2)=[CH:13][CH:12]=1>[OH-].[Na+].CO>[CH3:1][C:2]1[S:3][C:4]([C:28]([OH:30])=[O:29])=[C:5]2[C:9]=1[N:8]=[CH:7][N:6]2[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]2[NH:24][N:25]=[N:26][N:27]=2)=[CH:13][CH:12]=1
Reactant: COC(=O)c1sc(C)c2ncn(Cc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1sc(C(=O)O)c2c1ncn2Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
A solution of methyl 4-methyl-1-[[2'-(1H-tetrazol-5-yl) biphenyl-4-yl]methyl]thieno[3,4-d]imidazole-6-carboxylate (0.1 g) in a mixture of 1N NaOH (1.5 ml) and methanol (5 ml) was heated for two days under reflux. The reaction mixture was neutralized with 1N HC1 to give crystals. Recrystallization from methanol--ethyl acetate afforded colorless crystals (0.1 g, quantitatively), m p 187°-189° C. (dec.).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[O:14][C:15](=[O:17])[CH3:16])(=[O:3])[CH3:2].CC(OC(C)=O)=O.[N+:25]([O-])([OH:27])=[O:26]>O1CCOCC1>[C:15]([O:14][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([N+:25]([O-:27])=[O:26])[C:5]=1[NH:4][C:1](=[O:3])[CH3:2])[C:9]([OH:11])=[O:10])(=[O:17])[CH3:16]
Reactant: CC(=O)Nc1ccc(C(=O)O)cc1OC(C)=O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: C1COCCO1
Product: CC(=O)Nc1c(OC(C)=O)cc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 89.9 %

Procedure:
Compound 102 (1.00 g, 4.21 mmol) was suspended with stirring in a mixture of Ac2O (8.33 mL, 8.99 g, 88.2 mmol) and dioxane (6.6 mL). This was cooled to 0° C., and a cold solution of the nitrating mixture made from Ac2O (3.33 mL, 3.59 g, 35.2 mmol) and concentrated HNO3 (3.33 mL) was slowly added to the mixture containing 102. The reaction mixture was then warmed to 30-35° C. until the reaction was complete as evidenced by TLC. The reaction mixture was poured onto ice/water (100 mL), extracted with EtOAc (4×50 mL), dried (NaSO4), and concentrated to dryness on a rotary evaporator to give crude 104 (1.05 g, 89.9%) as an oil. Trituration with CHCl3 gave a solid: mp 196-201° C. (dioxane/hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([NH:13][C@@H:14]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:15]([OH:17])=O)=[O:12])[NH:8][C:5]2=[CH:6][N:7]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[CH2:18]([C@H:14]([NH:13][C:11]([C:9]1[NH:8][C:5]2=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]2[CH:10]=1)=[O:12])[C:15](=[O:17])[N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: C1CCNC1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)c1cc2cc(Cl)ncc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)N1CCCC1)c1cc2cc(Cl)ncc2[nH]1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-phenylpropionic acid (EXAMPLE 42, 50 mg, 0.15 mmol) in DMF (3 mL) was added pyrrolidine (13 μL, 0.16 mmol), HOBt (20 mg, 0.15 mmol) and DIPEA (51 μL, 0.29 mmol). After 5 min, EDCI (36 mg, 0.19 mmol) was added and the reaction was stirred at rt for 16 h. The solvent was removed in vacuo and the solid was triturated with water, filtered and dried to give the title compound as a beige solid. m/z (ES+)=397 [M+H]+; RT=3.38 min.
Reaction SMILES: C(OC(N1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]3[N:23]=[C:24]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[O:25][C:26]=3[C:27]([F:30])([F:29])[F:28])=[O:21])=[CH:15][N:14]=2)[CH2:9]C1)=O)(C)C.[C:37]([O:40][C:41](=[O:74])[N:42]([CH3:73])[CH:43]1[CH2:48]CCCN1C1C=CC(NC(C2N=C(C3C=CC=CC=3)OC=2C(F)(F)F)=O)=CN=1)([CH3:39])=[CH2:38].FC(F)(F)C(O)=O.CNC1CCN(C2C=CC(NC(C3N=C(C4C=CC=CC=4)OC=3C(F)(F)F)=O)=CN=2)CC1.ClC(OC(C)=C)=O>>[C:37]([O:40][C:41](=[O:74])[N:42]([CH3:73])[CH:43]1[CH2:48][CH2:9][N:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]3[N:23]=[C:24]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[O:25][C:26]=3[C:27]([F:28])([F:30])[F:29])=[O:21])=[CH:15][N:14]=2)[CH2:11][CH2:12]1)([CH3:39])=[CH2:38]
Reactant: C=C(C)OC(=O)N(C)C1CCCCN1c1ccc(NC(=O)c2nc(-c3ccccc3)oc2C(F)(F)F)cn1
Reactant: CC(C)OC(=O)N1CCN(c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cn2)CC1
Agent: C=C(C)OC(=O)Cl
Agent: CNC1CCN(c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cn2)CC1
Solvent: O=C(O)C(F)(F)F
Product: C=C(C)OC(=O)N(C)C1CCN(c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cn2)CC1

Procedure:
With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid isopropyl ester above, methyl-{5′-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-yl}-carbamic acid isopropenyl ester was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-methylamino-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-amide trifluoroacetate and isopropenyl chloroformate. LCMS calcd for C26H26F3N5O4 (m/e) 529, obsd 530 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[C:16](S(C2C=CC(C)=CC=2)(=O)=O)[C:17]#[N:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCN2C(=NCCC2)CC1.[N+:40]([CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])#[C-:41].O>C1COCC1.CCOC(C)=O>[CH2:46]([O:45][C:43]([C:42]1[NH:40][CH:41]=[C:16]([C:17]#[N:18])[C:15]=1[C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)=[O:44])[CH3:47]
Reactant: Cc1ccc(S(=O)(=O)C(C#N)=Cc2ccc(OCc3ccccc3)cc2)cc1
Reactant: [C-]#[N+]CC(=O)OCC
Solvent: O
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1[nH]cc(C#N)c1-c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
A solution of 3-(4-benzyloxy-phenyl)-2-(toluene-4-sulfonyl)-acrylonitrile (250.43 g, 0.643 mol, prepared directly above) in anhydrous THF (2,500 mL) is treated with DBU (385.00 mL, 2.574 mol), followed by ethyl isocyanoacetate (150.00 g, 1.286 mol). The resulting reaction mixture is allowed to stir at room temperature for 2 hours. The reaction mixture is poured into water (4,000 mL) and the resulting solution is separated into 2 equal parts. Each part is extracted with EtOAc (3×800 mL each), then the combined organics are washed with 1N HCl (1,000 mL), water (1,000 mL), and brine (1,000 mL), dried over anhydrous MgSO4, filtered, then concentrated in vacuo to afford an off-white solid. The solid is slurried in EtOAc (200 mL), then treated with excess hexanes, causing a solid to precipitate. The solid is recovered by vacuum filtration, washing with hexanes, and drying under vacuum filtration to afford the title compound (204.21 g, 91% yield) as an off-white solid: 1H NMR (500 MHz; CDCl3) δ 9.44 (bs, 1H), 7.48-7.45 (m, 4H), 7.42-7.38 (m, 3H), 7.36-7.32 (m, 1H), 7.03 (d, 2H), 5.11 (s, 2H), 4.25 (q, 2H), 1.22 (t, 3H); MS(ES) m/z 347.1 (M++H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])=[N:15][C:14]3[C:9]2=[N:10][CH:11]=[N:12][C:13]=3[C:25]#[N:26])=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])=[N:15][C:14]3[C:9]2=[N:10][CH:11]=[N:12][C:13]=3[CH2:25][NH2:26])=[CH:6][CH:7]=1
Reactant: N#Cc1ncnc2c1nc(-c1ccc(Cl)cc1Cl)n2-c1ccc(Cl)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: NCc1ncnc2c1nc(-c1ccc(Cl)cc1Cl)n2-c1ccc(Cl)cc1
Temperature: -78 °C

Procedure:
9-(4-Chlorophenyl)-8-(2,4-dichlorophenyl)-9H-purine-6-carbonitrile I-(16A-1)a (110 mg, 0.27 mmol) was dissolved in methylene chloride (0.9 ml) and the solution cooled to −78° C. Diisobutyl aluminum hydride (1 M in methylene chloride; 590 μl, 0.59 mmol) was added dropwise to the reaction mixture and stirring continued at −78° C. until TLC indicated the starting material had been consumed. Methanol (100 μl) was added to the mixture to quench the reaction and the cooling bath was removed. The reaction mixture was extracted with ethyl acetate from 1 M HCl. The organic layer was back-extracted with 1M HCl and the aqueous layers combined. The aqueous layers were then brought to a basic pH with sodium hydroxide and extracted with ethyl acetate. The organic layers were combined, dried (Na2SO4), filtered, and evaporated to dryness to afford the desired compound I-(16A-1)b: +ESI MS (M+1) 404.4; 1H NMR (400 MHz, CD3OD) δ 8.92 (s, 1H), 7.69 (d, J=8.3 Hz, 1H), 7.57 (d, J=1.7 Hz, 1H), 7.53–7.43 (m, 3H), 7.36 (d, J=8.3 Hz, 2H), 4.40 (s, 2H).
Reaction SMILES: [CH2:1]([NH:3][CH:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:14][CH3:15])[CH:10]=2)[CH2:5]1)[CH3:2].C(N(CC)CC)C.[CH3:23][O:24][C:25]([CH2:27][CH2:28][C:29](Cl)=[O:30])=[O:26]>C1C=CC=CC=1>[CH2:1]([N:3]([CH:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:14][CH3:15])[CH:10]=2)[CH2:5]1)[C:29](=[O:30])[CH2:28][CH2:27][C:25]([O:24][CH3:23])=[O:26])[CH3:2]
Reactant: COC(=O)CCC(=O)Cl
Reactant: CCNC1CCc2cc(OC)ccc2C1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCN(C(=O)CCC(=O)OC)C1CCc2cc(OC)ccc2C1
Reaction time: 8 h
Yield: 91.3 %

Procedure:
To a mixture of 8.8 g of N-ethyl-6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine, 6.1 g of triethylamine and 80 ml of anhydrous benzene, 7.1 g of 3-(methoxycarbonyl)-propionyl chloride dissolved in 10 ml of anhydrous benzene was added dropwise. After the resulting solution was heated for 2.5 hours at reflux, the solution was allowed to stand overnight at room temperature (about 25° C.). The reaction solution was washed with a 2N-HCl aqueous solution, water, a 2 N-NaOH aqueous solution and water in order, and dried over anhydrous sodium sulfate. Then, the solution was concentrated under reduced pressure to obtain 12.5 g of N-ethyl-N-[3-(methoxycarbonyl)propionyl]-6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine as a pale-yellow oily product.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([O-])(=O)C.[K+].Br[C:18]1[C:19]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=2)=[N:20][N:21]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=12.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.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.ClCCl>[F:37][C:33]1[CH:32]=[C:31]([C:19]2[C:18]([C:2]3[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=3)=[C:22]3[CH:23]=[CH:24][C:25]([C:27]([F:29])([F:30])[F:28])=[CH:26][N:21]3[N:20]=2)[CH:36]=[CH:35][CH:34]=1
Reactant: Fc1cccc(-c2nn3cc(C(F)(F)F)ccc3c2Br)c1
Reactant: NS(=O)(=O)c1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: NS(=O)(=O)c1ccc(-c2c(-c3cccc(F)c3)nn3cc(C(F)(F)F)ccc23)cc1
Yield: 34.7 %

Procedure:
A mixture of 4-iodobenzenesulphonamide (651 mg); dipinacoldiborane (495 mg)2; potassium acetate (860 mg); and [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride complex:dichloromethane (1:1) (50 mg); in DMF (5 ml) was heated under nitrogen at 80° for 1.5 h. To the cooled reaction mixture was added 3-bromo-2-(3-fluoro-phenyl)-6-trifluoromethyl-pyrazolo[1,5-a]pyridine (330 mg, 0.919 mmol), 2N Na2CO3 (4 ml) and tetrakis(triphenylphosphine)palladium(0) (40 mg) and the mixture heated at reflux under nitrogen for 18 hours. The cooled reaction mixture was poured into water (30 ml) and the suspension extracted with ethyl acetate (3×20 ml). The organic extracts were combined, dried (Na2SO4) and concentrated in vacuo. The residue was purified by SPE chromatography eluting with a gradient of cyclohexane:ethyl acetate (100:0 to 0:100, 10% step). Trituration of the concentrated fractions containing product with diethyl ether gave the title compound as a white solid (139 mg, 35%). MH+ 436