Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:32]=[CH:31][C:5]([CH2:6][C:7]2([C:19]([NH:21][CH2:22][CH:23]([OH:30])[CH2:24][C:25]([CH3:29])([CH3:28])[CH2:26][CH3:27])=[O:20])[CH2:11][CH2:10][CH2:9][N:8]2[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:4][CH:3]=1.Br[C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][N:35]=1.C[Sn](C)C.C[Sn](C)C.[F-].[K+]>O1CCOCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[F:40][C:37]1[CH:38]=[CH:39][C:34]([C:2]2[CH:32]=[CH:31][C:5]([CH2:6][C:7]3([C:19]([NH:21][CH2:22][CH:23]([OH:30])[CH2:24][C:25]([CH3:28])([CH3:29])[CH2:26][CH3:27])=[O:20])[CH2:11][CH2:10][CH2:9][N:8]3[C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])=[CH:4][CH:3]=2)=[N:35][CH:36]=1
Reactant: CCC(C)(C)CC(O)CNC(=O)C1(Cc2ccc(Br)cc2)CCCN1C(=O)OC(C)(C)C
Reactant: Fc1ccc(Br)nc1
Agent: [Pd]
Agent: C[Sn](C)C
Agent: [F-]
Solvent: C1COCCO1
Product: CCC(C)(C)CC(O)CNC(=O)C1(Cc2ccc(-c3ccc(F)cn3)cc2)CCCN1C(=O)OC(C)(C)C
Temperature: 110 °C
Reaction time: 8 h

Procedure:
Palladium tetrakis(triphenylphosphine) (1.38 g, 1.20 mmol) was added to a degassed, ambient temperature solution of tert-butyl 2-(4-bromobenzyl)-2-{[(2-hydroxy-4,4-dimethylhexyl)amino]carbonyl}pyrrolidine-1-carboxylate (6.11 g, 12 mmol), 2-bromo-5-fluoropyridine (2.1 g, 12 mmol), and hexamethylditin (3.9 g, 12 mmol) in 1,4-dioxane (120 mL). After stirring at 110° C. overnight, potassium fluoride (50% on celite) was added and the solution was vigorously stirred for 1 h at ambient temperature. The mixture was filtered and the filtrate was washed with water, dried (magnesium sulfate), filtered and concentrated in vacuo. Chromatography over silica eluting with 0-50% ethyl acetate/hexane afforded tert-butyl 2-[4-(5-fluoropyridin-2-yl)benzyl]-2-{[(2-hydroxy-4,4-dimethylhexyl)amino]carbonyl}pyrrolidine-1-carboxylate.
Reaction SMILES: C[O:2][C:3](=[O:28])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][C:9]2[O:25][C:12]3([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:11](=[O:26])[C:10]=2[CH:27]=1.[OH-].[Na+]>>[C:21]([O:20][C:18]([N:15]1[CH2:16][CH2:17][C:12]2([C:11](=[O:26])[C:10]3[CH:27]=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:28])=[O:2])[CH:7]=[CH:8][C:9]=3[O:25]2)[CH2:13][CH2:14]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)C1(CCN(C(=O)OC(C)(C)C)CC1)O2
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)N1CCC2(CC1)Oc1ccc(/C=C/C(=O)O)cc1C2=O
Yield: 98.6 %

Procedure:
(E)-3-{1′-Tert-butoxycarbonyl-3-oxo-spiro[benzofuran-2(3H), 4′-piperidin]-5-yl}-acrylic acid methyl ester (100 mg, 0.258 mmol, Intermediate 4, Step E) was hydrolyzed with NaOH following the procedure described in Example 1, Step A, giving (E)-3-{1′-tert-butoxycarbonyl-3-oxo-spiro[benzofuran-2(3H), 4′-piperidin]-5-yl}-acrylic acid as a white solid (95 mg, 98%). The product was treated with NH2OTHP according to the procedure described in Example 1, Step B, giving (E)-3-{1′-tert-butoxycarbonyl-3-oxo-spiro[benzofuran-2(3H), 4′-piperidin]-5-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide as a yellow solid (89 mg, 74%). Finally, removal of the protecting groups following the procedure described in Example 1, Step C gave (E)-3-{3-oxo-spiro[benzofuran-2(3H), 4′-piperidin]-5-yl}-N-hydroxy-acrylamide (14 mg, 23%) as its hydrochloride salt.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]3[O:17][N:16]=[C:15]([C:18]([O:20]CC)=O)[N:14]=3)[N:10]=[C:9]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[CH:8]=2)=[CH:4][CH:3]=1.[CH3:31][NH:32][CH3:33].C(O)(=O)/C=C\C(O)=O>CCO.CCOC(C)=O>[F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]3[O:17][N:16]=[C:15]([C:18]([N:32]([CH3:33])[CH3:31])=[O:20])[N:14]=3)[N:10]=[C:9]([C:23]3[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=3)[CH:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1noc(Cn2nc(-c3ccncc3)cc2Cc2ccc(F)cc2)n1
Reactant: CNC
Agent: O=C(O)/C=C\C(=O)O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN(C)C(=O)c1noc(Cn2nc(-c3ccncc3)cc2Cc2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To a suspension of ethyl 5-{[5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]methyl}-1,2,4-oxadiazole-3-carboxylate (73 mg, 0.18 mmol) in EtOH (3 ml) was added dimethylamine (2 M in MeOH, 4 mL) and the mixture was stirred overnight at room temperature. The solvent was removed and the residue was purified by flash chromatography (2:98 MeOH/CH2Cl2) to give a clear oil. This was taken up in EtOAc (5 ml) and a solution of maleic acid (15 mg, 0.13 mmol) in EtOAc (2 mL) was added to the solution. The resulting salt suspension was stirred for 30 min , filtered and dried overnight to give the title compound (57 mg, 89 %) as an off white solid. 1H NMR (400 MHz, DMSO-D6) δ ppm 8.62 (d, 2 H), 7.82 (d, 2 H), 7.26-7.35 (m, 2 H), 7.12 (t, 2 H,) 6.82 (s, 1 H), 6.00 (s, 2 H), 4.18 (s, 2 H), 3.03 (s, 3 H), 2.95 (s, 3 H); m/z (APCI+) for C21H19N6O2F 407.1 (M+H)+.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[C:15]([F:28])[CH:14]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[NH2:29][C:30]1[N:35]=[C:34]([C:36]#[N:37])[C:33](Br)=[CH:32][CH:31]=1>>[NH2:29][C:30]1[N:35]=[C:34]([C:36]#[N:37])[C:33]([C:16]2[CH:17]=[CH:18][C:13]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[S:4]([CH:1]3[CH2:3][CH2:2]3)(=[O:6])=[O:5])=[CH:14][C:15]=2[F:28])=[CH:32][CH:31]=1
Reactant: CC1(C)OB(c2ccc(-c3ccccc3S(=O)(=O)C3CC3)cc2F)OC1(C)C
Reactant: N#Cc1nc(N)ccc1Br
Product: N#Cc1nc(N)ccc1-c1ccc(-c2ccccc2S(=O)(=O)C2CC2)cc1F

Procedure:
The title compound was prepared using analogous conditions to those described in Example 6 2-(2′-(cyclopropylsulfonyl)-3-fluoro-[1,1′-biphenyl]-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and 6-amino-3-bromo-2-cyanopyridine. MS (ESI): mass calcd. for C21H16FN3O2S, 393.09; m/z found, 393.9 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 8.07 (d, J=7.9, 1H), 7.71-7.64 (m, 1H), 7.64-7.58 (m, 2H), 7.54-7.48 (m, 1H), 7.40 (dd, J=19.2, 9.2, 2H), 7.33 (dd, J=7.9, 1.6, 1H), 6.86 (d, J=8.7, 1H), 6.79 (d, J=10.0, 3H), 1.03 (s, 9H).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([N:10]3[C:14]4=[N:15][CH:16]=[CH:17][CH:18]=[C:13]4[NH:12][C:11]3=[O:19])=[CH:4][C:3]=2[O:2]1.[CH2:20]=[O:21]>>[OH:21][CH2:20][N:12]1[C:13]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[N:10]([C:5]2[CH:6]=[CH:7][C:8]3[O:9][CH2:1][O:2][C:3]=3[CH:4]=2)[C:11]1=[O:19]
Reactant: C=O
Reactant: O=c1[nH]c2cccnc2n1-c1ccc2c(c1)OCO2
Product: O=c1n(CO)c2cccnc2n1-c1ccc2c(c1)OCO2

Procedure:
A mixture of 500 mg. of 1,3-dihydro-3-(3,4-methylenedioxyphenyl)imidazo[4,5-b]pyridin-2-one and 30 ml. of 37% formaldehyde was heated on the steam bath for 1.5 hours. The hot solution was treated with decolorizing carbon, filtered, and the filtrate was treated with 2 ml. of 2.5 N sodium hydroxide and 30 ml. of water. The precipitate was collected: 400 mg. of 1,3-dihydro-1-hydroxymethyl-3-(3,4-methylenedioxyphenyl)imidazo[4,5-b]pyridin-2-one, m.p. 268° C.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:18][OH:19])[CH:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[CH2:7][CH2:6][NH:5]1.C1C=CC=CC=1.[C:26]1([N:32]=[C:33]=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[OH:1][CH2:2][CH:3]([CH2:18][OH:19])[CH:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[CH2:7][CH2:6][N:5]1[C:33](=[O:34])[NH:32][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1cc2c(cc1OC)C(C(CO)CO)NCC2
Reactant: O=C=Nc1ccccc1
Solvent: c1ccccc1
Product: COc1cc2c(cc1OC)C(C(CO)CO)N(C(=O)Nc1ccccc1)CC2
Temperature: 25 °C
Yield: 91 %

Procedure:
To a solution of 0.01 mole (2.7 g) of 1-[bis-(hydroxymethyl)-methyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline in 30 ml of absolute benzene 0.01 mole (0.3 g) of phenyl isocyanate is added, and the mixture is refluxed for 30 to 60 minutes. The reaction mixture is allowed to cool to room temperature, the precipitated crystals are filtered off, washed with ether and crystallized. The aimed compound is obtained with a melting point of 191° to 192° C. (ethyl acetate).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14](=[O:16])[CH3:15])=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH:14]([OH:16])[CH3:15])=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(-c2ccc(F)cc2)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(O)c1ccc(-c2ccc(F)cc2)cn1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 59.5 %

Procedure:
To a solution of 1-(5-(4-fluorophenyl)pyridin-2-yl)ethanone (0.75 g, 3.48 mmol) in MeOH (20 mL) was added NaBH4 (0.264 g, 6.97 mmol) and the contents stirred at 0-5° C. for 2 h. The mixture was diluted with ethyl acetate (150 mL) and then washed with ammonium chloride solution (2×50 mL) and brine solution (2×100 mL). The organic layer was dried over sodium sulphate and distilled off to obtain the crude compound. The crude product was purified by flash chromatography (230-400; 35% ethyl acetate in hexane) to afford 1-(5-(4-fluorophenyl)pyridin-2-yl)ethanol (0.45 g, 60% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.74 (s, 1H), 8.03 (dd, 1H), 7.74 (t, 2H), 7.56 (d, 1H), 7.30 (t, 2H), 5.35 (d, 1H), 4.74 (q, 1H), 1.38 (d, 3H); LC-MS m/z calcd for [M+H]+ 218.25. found 218.0.
Reaction SMILES: [CH2:1]([N:8]([C:10]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[CH:20])=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([O:23][C:24](=[O:32])[C:25]1[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=1)[CH3:22]>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([N:8]([CH3:9])[C:10]1([C:13]2[CH:14]=[CH:15][C:16]([C:19]#[C:20][C:28]3[CH:29]=[CH:30][C:25]([C:24]([O:23][CH2:21][CH3:22])=[O:32])=[CH:26][CH:27]=3)=[CH:17][CH:18]=2)[CH2:12][CH2:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: C#Cc1ccc(C2(N(C)Cc3ccccc3)CC2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc(C3(N(C)Cc4ccccc4)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
Using General Procedure F; benzyl-[1-(4-ethynylphenyl)-cyclopropyl]-methylamine (Intermediate 132, 70.0 mg, 0.28 mmol) and ethyl-4-iodo benzoate (Reagent A, 77.0 mg, 0.28 mmol) in triethylamine (5 mL) was treated with copper(I)iodide (18.0 mg, 0.10 mmol) and sparged with argon for 5 minutes. Dichlorobis (triphenylphosphine)palladium(II) (65 mg, 0.10 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-5% EtOAc-hexanes) afforded 86 mg (75%) of the title compound as an oil.
Reaction SMILES: C[O:2][C:3](=[O:29])[C@@H:4]([NH2:28])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:18][C:19]=2[CH3:20])=[C:8]([Br:27])[CH:7]=1.[F:30][C:31](=[CH:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:32](O)=[O:33]>>[Br:27][C:8]1[CH:7]=[C:6]([CH2:5][C@H:4]([NH:28][C:32](=[O:33])[C:31]([F:30])=[CH:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:3]([OH:2])=[O:29])[CH:11]=[CH:10][C:9]=1[O:12][CH2:13][CH2:14][C:15]1[N:16]=[C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:18][C:19]=1[CH3:20]
Reactant: O=C(O)C(F)=Cc1ccccc1
Reactant: COC(=O)[C@@H](N)Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c(Br)c1
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C[C@H](NC(=O)C(F)=Cc2ccccc2)C(=O)O)cc1Br
Yield: 28 %

Procedure:
Following the procedures described in Example 1, Intermediate 3B was used in place of Intermediate 3A, and α-fluorocinnamic acid was used in place of cinnamic acid to give (2S)-3-{3-bromo-4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)-ethoxy]-phenyl}-2-(2-fluoro-3-phenyl-acryloylamino)-propionic acid as a white solid with the yield of 28% and mp: 243˜245° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][N:6]=1.[C-:14]#[N:15].[Na+]>CN(C)C=O>[C:14]([CH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][N:6]=1)#[N:15]
Reactant: [C-]#N
Reactant: ClCCCc1n[nH]c2ccccc12
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCCCc1n[nH]c2ccccc12
Temperature: 90 °C
Yield: 449.8 %

Procedure:
A solution of (3-chloropropyl)indazole (Sasakura et al, Synth. Comm., 18, pg 259 (1988))(750 mg, 3.75 mM) in dimethylformamide (25 ml) was stirred at room temperature and sodium cyanide (370 mg, 7.5 mM) added in one portion. The resulting mixture was heated at 90° C. for 4 hr. The dimethylformamide was removed in vacuo and the residue partitioned between water and ethyl acetate. The combined organics were dried over magnesium sulfate. Column chromatography (ethyl acetate/cyclohexane, 1:1) provided 3-(3-cyanopropyl)indazole as a clear oil (3.21 g, 83%).
Reaction SMILES: [Br:1][C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7](S(C)=O)[N:8]=[CH:9][C:4]=2[C:3]=1[CH3:21].[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[N:8]=[CH:9][C:4]=2[C:3]=1[CH3:21]
Reactant: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(S(C)=O)ncc12
Reactant: Nc1ccccn1
Solvent: Cc1ccccc1
Product: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(Nc3ccccn3)ncc12
Temperature: 110 °C
Yield: 30 %

Procedure:
A mixture of 6-bromo-8-cyclopentyl-2-methanesulfinyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (370 mg, 1 mmol, prepared as in Example 6 of WO 01/707041 which is incorporated here by reference) and 2-aminopyridine(140 mg, 1.5 mmol) in toluene (5 mL) was heated at 110° C. for 18 hours then cooled to room temperature. The solid formed was collected by filtration and washed with toluene, then acetone, and dried in vacuo to give 6-bromo-8-cyclopentyl-5-methyl-2-(pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one as a beige solid (22 mg, 30%). mp 267˜268° C. Anal. Calc'd. for C18H18BrN5O.0.33H2O: C, 53.22; H, 4.63; N, 17.24. Found: C, 52.88; H, 4.38; N, 17.04.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][N:14]3[C:23]=2[NH2:24])=[C:7]([CH3:25])[CH:6]=1)(=O)C.Cl>>[NH2:24][C:23]1[N:14]2[CH:15]=[CH:16][C:17]3[C:22]([C:13]2=[N:12][C:11]=1[C:8]1[CH:9]=[CH:10][C:5]([OH:4])=[CH:6][C:7]=1[CH3:25])=[CH:21][CH:20]=[CH:19][CH:18]=3
Reactant: CC(=O)Oc1ccc(-c2nc3c4ccccc4ccn3c2N)c(C)c1
Agent: Cl
Product: Cc1cc(O)ccc1-c1nc2c3ccccc3ccn2c1N

Procedure:
2-(4-Acetoxy-2-methylphenyl)-3-aminoimidazo[2,1-a]isoquinoline (Compound 70) hydrochloride
Reaction SMILES: CC1CCCC(CC(Cl)=O)CC1.C1(C(Cl)=O)CCCCC1.[C:22]([NH:26][CH2:27][C:28]([C:30]1[CH:35]=[CH:34][C:33]([O:36][C:37](=[O:47])[CH2:38][CH:39]2[CH2:45][CH2:44][CH2:43][CH:42]([CH3:46])[CH2:41][CH2:40]2)=[C:32]([O:48][C:49](=[O:59])[CH2:50][CH:51]2[CH2:57][CH2:56][CH2:55][CH:54]([CH3:58])[CH2:53][CH2:52]2)[CH:31]=1)=[O:29])([CH3:25])([CH3:24])[CH3:23]>>[CH3:58][CH:54]1[CH2:55][CH2:56][CH2:57][CH:51]([CH2:50][C:49]([O:48][C:32]2[CH:31]=[C:30]([CH:35]=[CH:34][C:33]=2[O:36][C:37](=[O:47])[CH2:38][CH:39]2[CH2:45][CH2:44][CH2:43][CH:42]([CH3:46])[CH2:41][CH2:40]2)[CH:28]([OH:29])[CH2:27][NH:26][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:59])[CH2:52][CH2:53]1
Reactant: CC1CCCC(CC(=O)Oc2ccc(C(=O)CNC(C)(C)C)cc2OC(=O)CC2CCCC(C)CC2)CC1
Agent: CC1CCCC(CC(=O)Cl)CC1
Agent: O=C(Cl)C1CCCCC1
Product: CC1CCCC(CC(=O)Oc2ccc(C(O)CNC(C)(C)C)cc2OC(=O)CC2CCCC(C)CC2)CC1

Procedure:
When 4-methylcycloheptaneacetyl chloride is substituted for the cyclohexanecarbonyl chloride in the procedure described in Example 15A above, the acylation product obtained is 3,4-bis(4-methylcycloheptaneacetoxy)phenyl tert-butylaminomethyl ketone; and when this product is catalytically hydrogenated using the procedure described in Example 15B above, there is obtained 3,4-bis(4-methylcycloheptaneacetoxy)-alpha-(tert-butylaminomethyl)benzyl alcohol.
Reaction SMILES: [N:1]1[N:5]2[CH:6]=[CH:7][N:8]=[CH:9][C:4]2=[C:3]([C:10]2[N:15]=[C:14](O)[CH:13]=[CH:12][N:11]=2)[CH:2]=1.P(Cl)(Cl)([Cl:19])=O.[OH-].[Na+]>C(OCC)(=O)C>[Cl:19][C:14]1[CH:13]=[CH:12][N:11]=[C:10]([C:3]2[CH:2]=[N:1][N:5]3[CH:6]=[CH:7][N:8]=[CH:9][C:4]=23)[N:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ccnc(-c2cnn3ccncc23)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Clc1ccnc(-c2cnn3ccncc23)n1
Temperature: 25 °C
Yield: 104.8 %

Procedure:
A solution of 2-(pyrazolo[1,5-a]pyrazin-3-yl)pyrimidin-4-ol (Preparation 10b, 150 mg, 0.7 mmol) in phosphorous oxychloride (1.42 mL, 15.51 mmol) was heated overnight at 110° C. After cooling to ambient temperature, the reaction mixture was poured with caution onto water and basified by addition of a 2N aqueous sodium hydroxide solution. Ethyl acetate was then added and the organic phase was separated, washed with water and brine, dried (MgSO4), filtered and evaporated under reduced pressure to yield the title compound (170 mg, 87%) as a solid which was used in the next synthetic step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:12][O:13][C:14]=2[CH3:15])[N:5]=[N:4][C:3]=1[C:22]([OH:24])=O.[CH:25]([NH2:28])([CH3:27])[CH3:26]>>[CH:25]([NH:28][C:22]([C:3]1[N:4]=[N:5][C:6]([O:8][CH2:9][C:10]2[C:11]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[N:12][O:13][C:14]=2[CH3:15])=[CH:7][C:2]=1[CH3:1])=[O:24])([CH3:27])[CH3:26]
Reactant: CC(C)N
Reactant: Cc1cc(OCc2c(-c3ccccc3)noc2C)nnc1C(=O)O
Product: Cc1cc(OCc2c(-c3ccccc3)noc2C)nnc1C(=O)NC(C)C
Yield: 40 %

Procedure:
As described for example 44, 4-methyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid (200 mg, 0.61 mmol) was converted, using isopropylamine instead of 4-amino-tetrahydropyran, to the title compound (SiO2, heptane:ethyl acetate=100:0 to 60:40, 90 mg, 40%) which was obtained as a white solid. MS: m/e=367.2 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:12]=[C:11]([S:13][C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=2)[C:17]([OH:19])=O)[NH:10][N:9]=1.[C:23]1([S:29]([N:32]2[CH2:35][CH:34]([NH:36]C(=O)OC(C)(C)C)[CH2:33]2)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:23]1([S:29]([N:32]2[CH2:33][CH:34]([NH:36][C:17](=[O:19])[C:16]3[CH:20]=[CH:21][CH:22]=[C:14]([S:13][C:11]4[NH:10][N:9]=[C:8]([NH:7][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=5)[CH:12]=4)[CH:15]=3)[CH2:35]2)(=[O:30])=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)NC1CN(S(=O)(=O)c2ccccc2)C1
Reactant: O=C(O)c1cccc(Sc2cc(Nc3ccccn3)n[nH]2)c1
Product: O=C(NC1CN(S(=O)(=O)c2ccccc2)C1)c1cccc(Sc2cc(Nc3ccccn3)n[nH]2)c1
Yield: 50.4 %

Procedure:
3-(3-(Pyridine-2-ylamino)-1H-pyrazol-5-ylthio)benzoic acid (0.060 g, 0.192 mmol) and tert-butyl 1-(phenylsulfonyl)azetidin-3-ylcarbamate (0.060 g, 0.192 mmol) were treated as described in Example 3, except that the purification was done on Prep HPLC (MeCN/H2O/0.1% TFA). This afforded the title material (0.049 g, 41%, trifluoroacetic acid salt) as a solid. 1H NMR 400 MHz DMSO-d6 δ (ppm): 3.73 (2H, dd, J=8.72, 6.44 Hz), 3.99 (2H, t, J=8.21 Hz), 4.32-4.46 (1H, m), 6.43 (1H, s), 6.99 (1H, t, J=6.19 Hz), 7.20 (1H, d, J=8.59 Hz), 7.32-7.50 (2H, m), 7.59-7.74 (4H, m), 7.75-7.82 (1H, m), 7.82-7.95 (3H, m), 8.21 (1H, d, J=4.55 Hz), 8.98 (1H, d, J=6.06 Hz), 10.76 (1H, s). HPLC ret. time (Condition B): 3.950 min.; 85%. LCMS (+ESI, M+H+) m/z 507, (−ESI M−H+) m/z 505, HRMS: calc. 507.1273, found 507.1264.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]([F:14])([F:13])[F:12])[CH:7]=[CH:6][C:5]=1Br)([O-:3])=[O:2].[Cu][C:17]#[N:18]>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]([F:14])([F:13])[F:12])[CH:7]=[CH:6][C:5]=1[C:17]#[N:18])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc(OC(F)(F)F)ccc1Br
Reactant: N#C[Cu]
Solvent: Cc1ccccc1
Product: N#Cc1ccc(OC(F)(F)F)cc1[N+](=O)[O-]
Temperature: 150 °C
Yield: 68.5 %

Procedure:
A solution of 2-nitro-4-trifluoromethoxy-bromobenzene (2.0 g) in N,N-dimetbylformamide (2 ml) was treated with copper (I) cyanide (0.62 g) and the mixture heated at 150° C. for 1 hour. Toluene (10 ml) was added and the mixture was maintained at reflux for 1 hour. The mixture was filtered and the filtrate evaporated to give a dark oil which was purified by chromatography eluting with ethyl acetate/hexane (1:9) to give 2-nitro-4-trifluoromethoxybenzonitrile (1.1 g) as a yellow liquid, NMR (CDCl3) 7.65(m,1H), 8.0(d,1H), 8.15(m,1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)[N:11]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=3)[CH:13]=[C:12]([NH:22][C:23]3[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=3)[N:11]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Product: COc1ccc2c(Oc3ccc(Cl)cc3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 10 was used, starting from 4-chloro-phenol and (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [1-(4-Chloro-phenoxy)-6-methoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 382(MH+).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:23])[NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=1)=O)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:13]([CH:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)=[O:23])=[CH:16][CH:17]=1)#[N:22]
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)Nc1ccc(C#N)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(NC(=O)C2CCCN2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(4-Cyano-phenylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (3 g, 8 mmol) was dissolved in 90 mL of a 1:2 mixture of trifluoroacetic acid and dichloromethane. The reaction was stirred at ambient temperature for one hour then concentrated to yield title compound as an amber oil which was carried onto next step as is. APCI (AP−): 214.1 (M−H)−.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1.C1N2CN3CN(C2)CN1C3.[C:20](O)(=[O:22])C>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[C:2]1[CH:20]=[O:22]
Reactant: CC(=O)O
Reactant: c1cnc2[nH]ccc2c1
Agent: C1N2CN3CN1CN(C2)C3
Product: O=Cc1cc2cccnc2[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 58 %

Procedure:
To a solution of 7-Azaindole (Aldrich Chemical Co. Cat No. A9,550-2, 4.12 g, 34.9 mmol) in 33% acetic acid (43 ml) was added Hexamethylenetetramine (7.3 g, 5.2 mmol) and the reaction was heated at reflux for 6 hours. The reaction mixture was cooled to room temperature and diluted with ice water (100 ml). The mixture was then left at 0° C. for 18 h. to crystallize product. The beige powder was filtered and washed with water to provide 7-azaindole-2-carboxaldehyde (2.95 g, 58%). 1H NMR (DMSO-d6) δ:7.28 (1H, dd, J=4.8 Hz, 7.9 Hz), 8.37 (1H, dd, J=1.6 Hz, 4.8 Hz), 8.42 (1H, dd, J=1.6 Hz, 7.9 Hz), 8.47 (1H, s), 9.94 (s, 1H).