Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[NH4+].CC[N:5]=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.[C:34]([O:38][C:39]([NH:41][C@H:42]1[CH2:47][CH2:46][CH2:45][CH2:44][C@H:43]1[NH:48][C:49]1[C:57]([F:58])=[CH:56][C:52]([C:53]([OH:55])=O)=[C:51]([NH:59][C:60]2[C:69]3[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=3)[CH:63]=[N:62][CH:61]=2)[N:50]=1)=[O:40])([CH3:37])([CH3:36])[CH3:35]>C(OCC)(=O)C.CN(C=O)C.O>[NH2:5][C:53]([C:52]1[CH:56]=[C:57]([F:58])[C:49]([NH:48][C@H:43]2[CH2:44][CH2:45][CH2:46][CH2:47][C@H:42]2[NH:41][C:39](=[O:40])[O:38][C:34]([CH3:36])([CH3:37])[CH3:35])=[N:50][C:51]=1[NH:59][C:60]1[C:69]2[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=2)[CH:63]=[N:62][CH:61]=1)=[O:55]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(Nc2cncc3ccccc23)c(C(=O)O)cc1F
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1Nc1nc(Nc2cncc3ccccc23)c(C(N)=O)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.5 %

Procedure:
Ammonium chloride (28 mg), WSC.HCl (75 mg), HOBt.H2O (60 mg), and diisopropylethylamine (180 μl) were added to a DMF (1.3 ml) suspension containing 6-(cis-2-(tert-butoxycarbonylamino)cyclohexylamino)-5-fluoro-2-(isoquinoline 4-ylamino)nicotinic acid (65 mg), followed by stirring at room temperature for 3 hours. A saturated aqueous ammonium chloride solution and ethyl acetate were added to the reaction mixture. Solid matter was collected by filtration and washed with water and ethyl acetate, and a light yellow solid of tert-butyl cis-2-(5-aminocarbonyl-3-fluoro-6-(isoquinolin-4-ylamino)pyridin-2-ylamino)cyclohexylcarbamate (47 mg) was thus obtained.
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:13]=[CH:12][C:11]([O:14]C)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([S-])C.[Na+].O.Cl>CN(C=O)C.C(OCC)(=O)C>[CH:1]1([O:7][C:8]2[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1ccc(OC2CCCCC2)cc1
Agent: CC[S-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Oc1ccc(OC2CCCCC2)cc1
Temperature: 25 °C
Yield: 45.8 %

Procedure:
To 1-cyclohexyloxy-4-methoxy-benzene (2.06 g, 10 mmol), prepared in accordance with the procedure of He, et. al., J. Am. Chem. Soc., 2005, 127, 6966, in DMF (20 mL) was added sodium ethanethiolate (1.15 g, 11 mmol). The reaction mixture was stirred at reflux for two hours. The reaction mixture was then cooled to room temperature. Water (5 mL) was added after which the mixture was neutralized with hydrochloric acid (2N). Ethyl acetate (200 mL) was then added and the organic phase washed with water three times, brine twice, and dried (Na2SO4). Silica gel chromatography (EtOAc/heptane) provided 0.88 g of the title compound.
Reaction SMILES: [CH2:1](OC(=O)C=CC1C=C(C)C=CC=1)C.CO[C:17]1[C:18](Cl)=[CH:19][C:20]2[CH:21]([CH3:29])[CH:22]3[CH2:26][NH:25][CH2:24][CH:23]3[C:27]=2[CH:28]=1.C(OC(=O)CP(OCC(F)(F)F)(OCC(F)(F)F)=O)C.C1OCCOCCOCCOCCOCCOC1.C1(C)C=CC=C(C=O)C=1>C1COCC1>[CH3:1][C:17]1[CH:18]=[CH:19][C:20]2[CH:21]([CH3:29])[CH:22]3[CH2:26][NH:25][CH2:24][CH:23]3[C:27]=2[CH:28]=1
Reactant: CCOC(=O)C=Cc1cccc(C)c1
Reactant: COc1cc2c(cc1Cl)C(C)C1CNCC21
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CCOC(=O)CP(=O)(OCC(F)(F)F)OCC(F)(F)F
Agent: Cc1cccc(C=O)c1
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)C1CNCC1C2C
Reaction time: 0.5 h

Procedure:
3-m-Tolyl-acrylic acid ethyl ester. (Scheme 3) KHMDS (4.0 g, 20.0 mmol) was added to a solution of ethyl[bis(2,2,2-trifluoro-ethoxy)phosphinyl]acetate (4.7 mL, 20.0 mmol) and 18-crown-6 (10.6 g, 40.0 mmol) in THF (200 mL) at −78° C., and stirred for 30 minutes. m-Tolualdehyde (2.1 mL, 18 mmol) was added and the reaction mixture was stirred for 3 hours from −78° C. to room temperature. The reaction was quenched with aqueous hydrochloric acid (1M solution, 100 mL), and the product was extracted with EtOAc (3×100 mL). The organic extracts were washed with brine (100 mL), dried over MgSO4, and concentrated to afford the subtitle compound, which was used without further purification. MS calculated for C12H14O2+H: 191, observed: 191.
Reaction SMILES: C([N:3]([CH2:13][CH3:14])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:11])C.[OH:15][CH:16]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22]CC#N)[CH2:17]1>>[OH:15][CH:16]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:14][C:13]2[NH:3][C:4](=[O:12])[C:5]3[C:6]([CH:11]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:17]1
Reactant: CCN(CC)C(=O)c1ccccc1C
Reactant: N#CCCCN1CCC(O)C1
Product: O=c1[nH]c(CCCN2CCC(O)C2)cc2ccccc12
Yield: 20.2 %

Procedure:
By the reaction in the same manner as in Example 1a, using N,N-diethyl-2-methylbenzamide (3.45 g) and 4-(3-hydroxypyrrolidin-1-yl)butyronitrile (1.5 g), 3-[3-(3-hydroxypyrrolidin-1-yl)propyl]-2H-isoquinolin-1-one (536.3 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Cl.[CH3:18][N:19]([CH3:24])[CH2:20][CH2:21][CH2:22]Cl.C([O-])([O-])=O.[K+].[K+].[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C.O.C(O)C>[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35].[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35].[CH3:18][N:19]([CH3:24])[CH2:20][CH2:21][CH2:22][N:12]1[CH2:11][CH2:10][CH:9]([C:6]2[C:5]3[CH:15]=[CH:16][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)[CH2:14][CH2:13]1
Reactant: CN(C)CCCCl
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C(O)/C=C/C(=O)O
Solvent: O
Solvent: CC#N
Solvent: CCO
Product: CN(C)CCCN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 60 °C
Yield: 56.9 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.05 g, 13.8 mmol), 3-dimethylaminopropyl chloride hydrochloride (3.4 g, 21 mmol), K2CO3 (6.2 g, 45 mmol), tetrabutylammonium hydrogen sulfate (phase transfer catalyst, 1.5 g) in acetonitrile (100 ml) and water (50 ml) was heated at 60° C. overnight. The aqueous phase was separated, and acetonitrile was removed at reduced pressure. The residue was extracted into DCM. The organic solution was washed with H2O and brine, then dried with MgSO4. The solvent was removed and the crude product (4.3 g) was treated with fumaric acid (1.58 g, 1.0 eq) in dilute ethanol. The crystals were collected (2.53 g), m.p.=192°-194° C. Recrystallization from ethanol yielded 2.08 g of white crystals, mp=194°-195° C.
Reaction SMILES: C(O[C:4](=[O:21])[CH2:5][CH2:6][CH:7]([NH2:20])[C:8]1[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)[N:9]=1)C.[C:22]([O:26][C:27](=[O:43])[N:28]([CH2:32][C:33]1[CH:42]=[CH:41][C:36]2[O:37][CH2:38][CH2:39][O:40][C:35]=2[CH:34]=1)[CH2:29][CH:30]=O)([CH3:25])([CH3:24])[CH3:23]>>[C:22]([O:26][C:27](=[O:43])[N:28]([CH2:32][C:33]1[CH:42]=[CH:41][C:36]2[O:37][CH2:38][CH2:39][O:40][C:35]=2[CH:34]=1)[CH2:29][CH2:30][N:20]1[C:4](=[O:21])[CH2:5][CH2:6][CH:7]1[C:8]1[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)[N:9]=1)([CH3:23])([CH3:24])[CH3:25]
Reactant: CCOC(=O)CCC(N)c1cc(C)nc(-n2ccnc2)n1
Reactant: CC(C)(C)OC(=O)N(CC=O)Cc1ccc2c(c1)OCCO2
Product: Cc1cc(C2CCC(=O)N2CCN(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)nc(-n2ccnc2)n1

Procedure:
(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-{2-[2-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-5-oxo-pyrrolidin-1-yl]-ethyl}-carbamic acid tert-butyl ester was prepared following the procedures described in the preparation of Example 77c using 4-amino-4-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-butyric acid ethyl ester and (2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-(2-oxo-ethyl)-carbamic acid tert-butyl ester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[OH:41][C:42]1[C:51]([C:52](O)=[O:53])=[C:50]([CH3:55])[C:49]2[C:44](=[CH:45][C:46]([C:56]([F:59])([F:58])[F:57])=[CH:47][CH:48]=2)[N:43]=1>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH:6][C:52]([C:51]1[C:42]([OH:41])=[N:43][C:44]2[C:49]([C:50]=1[CH3:55])=[CH:48][CH:47]=[C:46]([C:56]([F:58])([F:59])[F:57])[CH:45]=2)=[O:53]
Reactant: Cc1c(C(=O)O)c(O)nc2cc(C(F)(F)F)ccc12
Reactant: NCc1cccc(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)NCc2cccc(F)c2)c(O)nc2cc(C(F)(F)F)ccc12
Temperature: 50 °C
Reaction time: 16 h
Yield: 70.3 %

Procedure:
508 mg (4.1 mmol) 3-fluorobenzylamine, 1.4 g (3.7 mmol) HATU and 1.5 ml (10.7 mmol) NEt3 were added consecutively to a solution of 1.0 g (3.7 mmol) 2-hydroxy-4-methyl-7-(trifluoromethyl)quinoline-3-carboxylic acid (synthesis see Example 4 Section a)) in THF (28 ml) and the solution was then stirred for 16 h at 50° C. The solution was subsequently diluted with EtOAc (30 ml). The resultant precipitate was filtered off and suspended in a EtOAc/MeOH/DCM mixture. Concentration in a vacuum was subsequently carried out. 1.0 g (2.6 mmol, 71%) N-(3-fluorobenzyl)-2-hydroxy-4-methyl-7-(trifluoromethyl)quinoline-3-carboxylic acid amide was obtained as a residue. The raw product was further converted without additional purification.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]=[CH2:20])=[CH:15][C:14]=2[F:21])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:34][O:35][CH2:36][CH2:37][OH:38]>>[F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]=[CH2:20])=[CH:15][C:14]=2[F:21])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([NH:34][O:35][CH2:36][CH2:37][OH:38])=[O:7]
Reactant: C=Cc1ccc(Nc2c(C(=O)O)ccc(F)c2F)c(F)c1
Reactant: NOCCO
Agent: O=C(n1ccnc1)n1ccnc1
Product: C=Cc1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(F)c1
Yield: 78 %

Procedure:
The title compound was prepared from reaction of the product of Example 4, Step A, 3,4-difluoro-2-[(2-fluoro-4-vinylphenyl)amino]benzoic acid with CDI and 2-(aminooxy)ethanol by the general procedure of Example 1, Step E, then purified by flash column chromatography on silica gel (10% EtOAc/hexanes) to give 3,4-difluoro-2-[(2-fluoro-4-vinylphenyl)amino]-N-(2-hydroxyethoxy)benzamide as a crystalline white solid (78%); m.p. (EtOAc/hexanes) 134–138° C. 1H NMR [400 MHz, (CD3)2SO] δ 11.85 (br s, 1 H), 8.82 (br s, 1 H), 7.45–7.38 (m, 1 H), 7.37 (dd, J=12.9, 1.8 Hz, 1 H), 7.21–7.15 (m, 1 H), 7.14 (dd, J=8.4, 1.7 Hz, 1 H), 6.83 (td, J=8.7, 4.8 Hz, 1 H), 6.65 (dd, J=17.6, 10.8 Hz, 1 H), 5.73 (d, J=17.9 Hz, 1 H), 5.18 (d, J=11.1 Hz, 1 H), 4.70 (br s, 1 H), 3.85 (t, J=4.8 Hz, 1 H), 3.56 (t, J=4.8 Hz, 2 H). Anal. Calcd for C17H15F3N2O3: C, 58.0; H, 4.3; N, 8.0. Found C, 57.6; H, 4.6; N, 8.1.
Reaction SMILES: [CH:1]1([Si:4]([CH:10]2[CH2:12][CH2:11]2)([C:6](O)(C)[CH3:7])C)[CH2:3][CH2:2]1.C1([Si](C2CC2)(CC)C(O)(C)C)CC1.[Cl:26][SiH2]CC(C1CC1)C1CC1.C([SiH2]CC(C1CC1)C1CC1)(=O)C.Cl[Si](Cl)(Cl)CC.C1([Li])CC1>>[CH:1]1([Si:4]([CH:10]2[CH2:12][CH2:11]2)([CH2:6][CH3:7])[Cl:26])[CH2:3][CH2:2]1
Reactant: CC(C)(O)[Si](C)(C1CC1)C1CC1
Reactant: Cl[SiH2]CC(C1CC1)C1CC1
Agent: CC(=O)[SiH2]CC(C1CC1)C1CC1
Agent: CC[Si](C1CC1)(C1CC1)C(C)(C)O
Agent: CC[Si](Cl)(Cl)Cl
Product: CC[Si](Cl)(C1CC1)C1CC1
Yield: 50 %

Procedure:
Following the procedure for the preparation of dicyclopropyl(1-hydroxy-1-methylethyl)methylsilane (see Example 1), dicyclopropyl(ethyl)(1-hydroxy-1-methylethyl)silane was prepared from the precursors chloro(dicyclopropyl)ethylsilane and acetyl(dicyclopropyl)ethylsilane. Reaction of trichloro(ethyl)silane (10.2 g, 62.4 mmol) with cyclopropyl lithium (prepared from bromocyclopropane (15.2 g, 126 mmol) and Li (1.80 g, 259 mmol) in Et2O (80 ml)) followed by distillation (79° C., 20 mbar) afforded 5.43 g (50%) of dicyclopropyl(ethyl)chlorosilane. Reaction of dicyclopropyl(ethyl)chlorosilane (5.00 g, 28.6 mmol) with ethoxyvinyl lithium (prepared from ethyl vinyl ether (2.52 g, 35.0 mmol) and tert-butyl lithium (1.9 M in pentane, 16.5 ml, 31.4 mmol) in THF (45 ml)) followed by hydrolysis with acetone/1 N HCl (2:1, 64 ml) and purification by silica-gel chromatography (silica gel 40-63 μm, hexane/EtOAc, 9:1) afforded 2.00 g (38% over 2 steps) of acetyl(dicyclopropyl)ethylsilane, of which 1.10 g (6.03 mmol) was reacted with methyl lithium (1.6 M in Et2O, 33.9 ml, 54.2 mmol) to provide after purification by silica-gel flash chromatography (silica gel 15-40 μm, hexane/EtOAc, 9:1) 720 mg (60%) of the odoriferous title compound.
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[CH:5][NH:6][CH:7]=1.O=S(Cl)Cl.[N-:12]=[N+:13]=[N-:14].[Na+].C([O-])(O)=O.[Na+]>CC#N.CN(C=O)C.CCOC(C)=O.O>[N:12]([CH2:2][C:3]1[N:4]=[CH:5][NH:6][CH:7]=1)=[N+:13]=[N-:14]
Reactant: [N-]=[N+]=[N-]
Reactant: OCc1c[nH]cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1c[nH]cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 4-hydroxymethylimidazole II-1 (1.09 g, 11.1 mmol) in CH3CN (12 mL), SOCl2 (5 mL) was added. After being stirred at room temperature for 30 min, the suspension became clear. After stirring for additional 2 h, the solution was concentrated in vacuo to give a solid, which was then dissolved in DMF (15 mL). To the solution, NaN3 (2.16 g, 33.2 mmol) was added. After the mixture was stirred at room temperature overnight, water and EtOAc were added, then 5% aq. NaHCO3 was also added. The organic layer was separated, dried over Na2SO4, concentrated in vacuo to give 4-azidomethylimidazole as a solid (0.759 g). MS 124.1 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]([OH:10])[C:7]([OH:9])=O)=[CH:4][C:3]=1[O:13][CH3:14].[CH2:15]([NH2:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].CCCC(NC(=O)C(O)C1C=CC(O)=C(OC)C=1)CCC>>[CH2:15]([NH:22][C:7](=[O:9])[CH:6]([OH:10])[C:5]1[CH:11]=[CH:12][C:2]([OH:1])=[C:3]([O:13][CH3:14])[CH:4]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCN
Reactant: COc1cc(C(O)C(=O)O)ccc1O
Agent: CCCC(CCC)NC(=O)C(O)c1ccc(O)c(OC)c1
Product: CCCCCCCNC(=O)C(O)c1ccc(O)c(OC)c1
Yield: 89 %

Procedure:
N-heptyl-2-hydroxy-2-(4-hydroxy-3-methoxyphenyl)acetamide was prepared from 4-hydroxy-3-methoxymandelic acid and n-heptylamine by the same procedure described for the preparation of N-(heptan-4-yl)-2-hydroxy-2-(4-hydroxy-3-methoxyphenyl)acetamide. White crystals of the title compound (6.7 g, 89% yield) were obtained.
Reaction SMILES: [C:1]([NH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:17]1([F:28])[CH:22]=[CH:21][C:20]([C:23](=[O:27])[CH2:24][CH2:25][CH3:26])=[CH:19][CH2:18]1.[I-].[Na+]>CN(C)C=O>[F:28][C:17]1[CH:18]=[CH:19][C:20]([C:23](=[O:27])[CH2:24][CH2:25][CH2:26][N:13]2[CH2:14][CH2:15][CH:10]([NH:9][C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:11][CH2:12]2)=[CH:21][CH:22]=1
Reactant: O=C(NC1CCNCC1)c1ccccc1
Reactant: CCCC(=O)C1=CCC(F)(Cl)C=C1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(CCCN1CCC(NC(=O)c2ccccc2)CC1)c1ccc(F)cc1
Yield: 28.6 %

Procedure:
4-Benzamidopiperidine (2.0 g.), 4'-chloro-p-fluorobutyrophenone (1.0 g.) and a trace of sodium iodide in dimethylformamide (5 ml.) were maintained at 70° C for 18 hours. On cooling, the solid which separated was collected, suspended in water, and refiltered. Recrystallisation from ethanol-water gave the title compound (0.52 g.), m.p. 161°-2° C. (Found: C, 71.9; H, 6.85; N, 7.5. C22H25FN2O2 requires C, 71.7; H, 6.8; N, 7.6%).
Reaction SMILES: C[O:2][C:3](=[O:29])/[C:4](=[N:25]\[N:26]([CH3:28])[CH3:27])/[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:7][CH:6]=1.[OH-].[Na+]>CO.O1CCCC1.O>[CH3:27][N:26]([CH3:28])/[N:25]=[C:4](/[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:7][CH:6]=1)\[C:3]([OH:29])=[O:2]
Reactant: COC(=O)/C(=N\N(C)C)c1ccc(OCCOc2ccc3ccccc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CN(C)/N=C(\C(=O)O)c1ccc(OCCOc2ccc3ccccc3c2)cc1
Yield: 69.1 %

Procedure:
A mix of (Z)-alpha-(dimethylhydrazono)-4-[2-(2-naphthalenyloxy)ethoxy]benzeneacetic acid methyl ester (0.45 g) in warm methanol (3 mL) and tetrahydrofuran (10 mL) was treated with 1N sodium hydroxide (2 mL), heated on the steam bath for 2 hours, and the mixture was diluted with water and concentrated to remove the organic solvents. The residue was acidified with excess hydrochloric acid and extracted with dichloromethane containing a little tetrahydrofuran. The organic layer was washed with water, dried (Na2SO4), filtered and evaporated to give crude product. Crystallization from dichloromethane-hexane provided 0.3 g of pure (Z)-alpha-(dimethylhydrazono)-4-[2-(2-naphthalenyloxy)ethoxy]benzeneacetic acid as a colorless solid, mp 136° C. with decomposition.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:25]([O:26][CH3:27])=[CH:24][C:6]2[N:7]([C:10]3[S:11][C:12]([C:21]([OH:23])=O)=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:14]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1.C(N(CC)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1>CN(C)C=O.C(OCC)(=O)C>[C:61]1([NH:60][C:21]([C:12]2[S:11][C:10]([N:7]3[C:6]4[CH:24]=[C:25]([O:26][CH3:27])[C:3]([O:2][CH3:1])=[CH:4][C:5]=4[N:9]=[CH:8]3)=[N:14][C:13]=2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:23])[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1
Reactant: Nc1ccccc1
Reactant: COc1cc2ncn(-c3nc(-c4ccccc4)c(C(=O)O)s3)c2cc1OC
Agent: CCN(CC)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc2ncn(-c3nc(-c4ccccc4)c(C(=O)Nc4ccccc4)s3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 87.6 %

Procedure:
To a solution of 2-(5,6-Dimethoxy-benzoimidazol-1-yl)-4-phenyl-thiazole-5-carboxylic acid (30 mg, 0.075 mmol) in dimethylformamide (1 ml) was added diethylisopropylamine (15.6 μL, 0.09 mmol) and HATU (28.5 mg, 0.075 mmol). The mixture was stirred under ambient temperature for 5 min. Aniline (6.8 μL, 0.075 mmol) was added. The mixture was stirred for 1 hr. Ethyl acetate (5 ml) was added. The mixture was washed with water (2×3 ml), brine, dried with magnesium sulfate and concentrated in vacuo. The crude was purified with flash chromatography (0 to 2% methanol dichloromethane) to afford 2-(5,6-Dimethoxy-benzoimidazol-1-yl)-4-phenyl-thiazole-5-carboxylic acid phenylamide (30 mg, 86.4%) as a yellow solid. MS m/z 457 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:7]=[C:6]([CH2:8][C:9]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:11])[CH3:10])[N:5]([CH2:20][CH2:21][CH3:22])[N:4]=1)#[N:2].[Br:23]Br>C(Cl)(Cl)Cl>[Br:23][C:7]1[C:3]([C:1]#[N:2])=[N:4][N:5]([CH2:20][CH2:21][CH3:22])[C:6]=1[CH2:8][C:9]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:11])[CH3:10]
Reactant: BrBr
Reactant: CCCn1nc(C#N)cc1CC(C)(C)NC(=O)OC(C)(C)C
Solvent: ClC(Cl)Cl
Product: CCCn1nc(C#N)c(Br)c1CC(C)(C)NC(=O)OC(C)(C)C

Procedure:
tert-Butyl 2-(3-cyano-1-propyl-1H-pyrazol-5-yl)-1,1-dimethylethylcarbamate (5.15 g, 16.8 mmol) was brominated using a modified version of the method described in Part F of Examples 1-4. In the reaction, 1.4 equivalents of bromine were used instead of 1.1 equivalents, chloroform was used instead of dichloromethane in the work-up, and no chromatographic purification was performed. The product, tert-butyl 2-(4-bromo-3-cyano-1-propyl-1H-pyrazol-5-yl)-1,1-dimethylethylcarbamate (6.97 g), was isolated as a clear, colorless oil that may have contained some chloroform.
Reaction SMILES: [OH2:1].NN.[C:4]1(=O)[N:8]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][CH2:10]2)[C:7](=O)C2=CC=CC=C12>C(O)C>[NH2:8][CH2:9][CH2:10][CH2:11][O:1][C:16]1[CH:17]=[C:18]2[C:13]([CH2:12][CH2:11][CH2:10][CH:9]2[N:8]([CH3:7])[CH3:4])=[CH:14][CH:15]=1
Reactant: O
Reactant: O=C1c2ccccc2C(=O)N1C1CCCc2ccccc21
Agent: NN
Solvent: CCO
Product: CN(C)C1CCCc2ccc(OCCCN)cc21

Procedure:
85% hydrazine hydrate solution (3.2 ml) is added to a solution of the phthalimido tetrahydronaphthalene (about 15 g) obtained in the preceding step dissolved in absolute ethanol (160 ml). The stirred reaction mixture is refluxed for 3 hours, after which it is allowed to cool and the resulting precipitate removed by filtration. The clear yellow filtrate is evaporated in vacuo leaving a moist yellow solid, which is triturated in 5% aqueous HCl solution. The resulting thick slurry is filtered and the clear filtrate made strongly alkaline with 50% sodium hydroxide solution, resulting in the formation of an oily precipitate. The precipitate is extracted with diethyl ether and the ether layers washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and the filtrate evaporated in vacuo, yielding 7.8 g of a light amber oil. NMR and IR analysis indicate that this oil is the desired amino product, which is used without further treatment for the next reaction step.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:50][CH3:51])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([C:30]([NH:32][CH2:33][C:34]4[CH:35]=[C:36]([C:42]5[CH:47]=[CH:46][CH:45]=[C:44]([CH:48]=O)[CH:43]=5)[C:37]([O:40][CH3:41])=[CH:38][CH:39]=4)=[O:31])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[NH:52]1[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1.C(O)(=O)C>CS(C)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:50][CH3:51])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([C:30]([NH:32][CH2:33][C:34]4[CH:35]=[C:36]([C:42]5[CH:47]=[CH:46][CH:45]=[C:44]([CH2:48][N:52]6[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]6)[CH:43]=5)[C:37]([O:40][CH3:41])=[CH:38][CH:39]=4)=[O:31])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cc(C)cc(C(=O)NCc2ccc(OC)c(-c3cccc(C=O)c3)c2)c1
Reactant: C1CNCCN1
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cc(C)cc(C(=O)NCc2ccc(OC)c(-c3cccc(CN4CCNCC4)c3)c2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 65.4 %

Procedure:
N-{[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-{[3′-formyl-6-(methyloxy)-3-biphenylyl]methyl}-5-methyl-1,3-benzenedicarboxamide (40.1 mg. 0.06 mmol) was diluted in DMSO (1.5 mL) and dispensed into a 1 dram vial, with fitted magnetic stir bar, containing piperazine (0.18 mmol), and acetic acid (3.6 mg, 0.6 mmol). The resulting solution was stirred at room temperature for 4 h. MP-B(OAc)3H (0.6 mmol, 140 mg) was added and the solution was stirred for another 12 h. The polymer reagent was filtered and purification was completed via Gilson HPLC (with 0.1% TFA in the solvents). The product was dissolved in 3 mL of MeOH and passed through 0.5 g amine columns (washed with 8 mL MeOH) to afford 29.8 mg (65.3%) of the title compound. LC-MS m/z 760 (M+H)+, 1.224 min (ret time).
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][CH2:2]1.[CH3:5][C:6]1([CH3:20])[C:10]([CH3:12])([CH3:11])[O:9][B:8]([C:13]2[CH:14]=[C:15]([CH:18]=O)[S:16][CH:17]=2)[O:7]1.C([BH3-])#N.[Na+].[N-]=C=O>C1COCC1>[CH3:5][C:6]1([CH3:20])[C:10]([CH3:11])([CH3:12])[O:9][B:8]([C:13]2[CH:14]=[C:15]([CH2:18][N:1]3[CH2:4][CH2:3][CH2:2]3)[S:16][CH:17]=2)[O:7]1
Reactant: C1CNC1
Reactant: CC1(C)OB(c2csc(C=O)c2)OC1(C)C
Agent: [BH3-]C#N
Agent: [N-]=C=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)OB(c2csc(CN3CCC3)c2)OC1(C)C
Reaction time: 0.5 h
Yield: 59.7 %

Procedure:
A solution of azetidine (0.014 g, 0.252 mmol) in THF (1 mL) was added to a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-thiophenecarbaldehyde (0.05 g, 0.210 mmol) in THF (1 mL) in 1-Dram vial and let stir for 30 minutes. Sodium Cyanoborohydride Resin (0.128 g, 0.583 mol, 2.33 mmol/g)) was then added to the mixture and let stir 3 days. The mixture was then agitated for 3 hrs with MP-Isocyanate Resin (0.135 g, 0.230 mmol, 1.7 mmol/g) and THF (2 mL). The reaction was resubjected to the same amounts of Sodium Cyanoborohydride Resin and amine as above and stirred for 2 days. The resins were then filtered and solvent concentrated to give 0.035 g of the title compound.