Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([CH3:12])([CH3:11])[C:3]1[O:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1.C([N-]C(C)C)(C)C.[Li+].[CH:21]([S:24]C(C)C)([CH3:23])[CH3:22].O>O1CCCC1>[CH:21]([S:24][C:5]1[CH:4]=[C:3]([Si:2]([CH3:12])([CH3:11])[CH3:1])[O:7][C:6]=1[C:8]([OH:10])=[O:9])([CH3:23])[CH3:22]
Reactant: CC(C)SC(C)C
Reactant: C[Si](C)(C)c1ccc(C(=O)O)o1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Sc1cc([Si](C)(C)C)oc1C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 25.01 g (136.0 mmol) of 5-trimethylsilyl-2-furancarboxylic acid (Carpenter, A. J. and Chadwick, D. J., Tetrahedron Lett., 26, 1777 (1985)) in 50 mL of dry tetrahydrofuran is added over 10 minutes to a -76° C. solution of freshly generated lithium diisopropylamide (328.0 mmol, 2.41 equiv) in dry tetrahydrofuran (175 mL) under nitrogen atmosphere and the resulting mixture is stirred at -76° to 65° C. for 1.5 hours. The reaction is recooled to -76° C. and treated with 23.58 g (151.0 mmol, 1.11 equiv) of diisopropyl sulfide in 25 mL of tetrahydrofuran and the resulting mixture is stirred for 4 hours while slowly warming to room temperature. The reaction is poured onto 1.5 L of water and the aqueous mixture is extracted with diethyl ether (200 mL, 3x), treated with 400 g of ice, and acidified with concentrated hydrochloric acid. The resulting precipitate is collected by vacuum filtration and recrystallized from diethyl ether/cyclohexane to give 18.22 g (35.14 g theo., 52%) of analytically pure 3-isopropylthio-5-trimethylsilyl-2-furancarboxylic acid as a tan solid; mp 181°-183° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[C:10](#[N:12])[CH3:11].CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1>[NH2:7][C:6]([C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=1)=[CH:11][C:10]#[N:12]
Reactant: CC#N
Reactant: N#Cc1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: N#CC=C(N)c1ccc(F)cc1
Reaction time: 24 h
Yield: 92.6 %

Procedure:
To a solution of 4-fluorobenzonitrile (5.00 g, 41.3 mmol) and acetonitrile (4.35 mL, 82.5 mmol) in toluene (100 mL) was added potassium tert-butoxide (13.9 g, 124 mmol). The mixture was stirred for 24 h, and then quenched by slow addition of aqueous sodium bicarbonate. The resulting suspension was extracted with dichloromethane (3×50 mL). The organic solution was washed with water, dried (Na2SO4), and concentrated under reduced pressure. The residue was triturated with EtOH/Et2O to afford 3-amino-3-(4-fluorophenyl)acrylonitrile (6.20 g, 93%) as a white solid. 1H NMR (300 MHz, acetone-d6) δ 4.23 (s, 1H), 6.20 (s, 2H), 7.22 (ddd, 2H), 7.71 (m, 2H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CCN(CC)CC>C(Cl)Cl>[CH2:6]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][S:2]([CH3:1])(=[O:4])=[O:3])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: OCCCCOCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
MsCl (2.48 mL, 32.1 mmol) was added slowly to a solution of 4-benzyloxy-butan-1-ol (5.26 g, 29.2 mmol) and Et3N (6.1 mL, 43 mmol) in CH2Cl2 (100 mL) at 0° C. (bath temp). The reaction mixture was stirred at rt for 2 h and then quenched with H2O (100 mL). The aqueous layer was extracted with CH2Cl2, dried (MgSO4), and concentrated in vacuo to give the title compound as a colorless liquid: yield 7.5 g (99%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9]O.P(Br)(Br)[Br:12].C(=O)(O)[O-].[Na+]>ClCCl>[Br:12][CH2:9][C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: OCc1cc(F)ccc1F
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Fc1ccc(F)c(CBr)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.3 %

Procedure:
To a solution of (2,5-difluoro-phenyl)-methanol (4.8 g, 33.6 mmol) in dichloromethane (40 mL) was added drop wise phosphorus tribromide (94 g, 33.6 mmol). The mixture was stirred at room temperature for 16 h. The reaction was poured onto ice/water. The aqueous phase was made basic with sodium bicarbonate. The aqueous phase was extracted with dichloromethane. The organic phase was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with (hexanes/ethyl acetate 90:10) to give the title compound (3.5 g, 50%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([CH2:16][C:17]([N:19]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:20][CH2:21][C:22]([CH3:27])([CH3:26])[CH2:23][C:24]#[CH:25])=[O:18])[CH:9]2[CH2:12][O:13]CC)=[CH:4][C:3]=1[O:32][CH3:33].[OH-].[K+].[O:36]1CCOCC1.Cl>O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([CH2:16][C:17]([N:19]([C:28]([CH3:30])([CH3:31])[CH3:29])[CH2:20][CH2:21][C:22]([CH3:27])([CH3:26])[CH2:23][C:24]#[CH:25])=[O:18])[CH:9]2[C:12]([OH:36])=[O:13])=[CH:4][C:3]=1[O:32][CH3:33]
Reactant: C1COCCO1
Reactant: C#CCC(C)(C)CCN(C(=O)CN1CCc2cc(OC)c(Br)cc2C1COCC)C(C)(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: C#CCC(C)(C)CCN(C(=O)CN1CCc2cc(OC)c(Br)cc2C1C(=O)O)C(C)(C)C
Temperature: 60 °C

Procedure:
A mixture of 430 mg of 24f, 300 mg of KOH, 10 ml of dioxane and 1.5 ml of water was warmed at 60° C. for 1 hr. Reaction was cooled and diluted with 30 ml of water and acidified to pH3 with 0.5 N HCl. The product was extracted into ethyl acetate. The organic extract was washed twice with water, dried and concentrated, to leave 390 mg of 24g, as a colorless oil. Rf (toluene/acetone 1/1) 0.55. NMR (CDCl3) δ 7.70 and 6.65 (2×s, 2, Ar—H), 5.79 (s, 1, CH), 3.90 (s, 3, OCH3), 1.97 (t, 1, acetylene), 0.90 (s, 6, 2×CH3), 1.55 (s, 9, tertC4H9).
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)=[CH:16][N:17]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH-].[K+].C(O)CCC.C1(C)C=CC(S(O[CH2:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])(=O)=O)=CC=1>O>[CH2:1]([C:7]1[CH:8]=[CH:9][C:10]([C:13]2[S:14][C:15]([C:18]3[CH:19]=[CH:20][C:21]([O:24][CH2:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])=[CH:22][CH:23]=3)=[CH:16][N:17]=2)=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: Cc1ccc(S(=O)(=O)OCCC[Si](C)(C)C)cc1
Reactant: CCCCCCc1ccc(-c2ncc(-c3ccc(O)cc3)s2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Solvent: O
Product: CCCCCCc1ccc(-c2ncc(-c3ccc(OCCC[Si](C)(C)C)cc3)s2)cc1
Temperature: 100 °C
Yield: 70.3 %

Procedure:
0.34 g (1.0 mM) of 2-(4-hexylphenyl)-5-(4-hydroxyphenyl)-1,3-thiazole, 0.07 g of 85%-KOH and 12 ml of n-butanol were mixed. To the mixture, 0.29 g (1.0 mM) of 3-(trimethylsilyl)propyl p-toluenesulfonate was added dropwise under stirring at 100° C., followed by further stirring for 9 hours at 100° C. After the reaction, the reaction mixture was poured into water and extracted with ethyl acetate, followed by washing with water and drying with anhydrous magnesium sulfate. The magnesium sulfate in the resultant mixture was filtered off and the filtrate was condensed into a solid, followed by purification by silica gel column chromatography (eluent: toluene) and recrystallization from a mixture solvent (ethanol/ethyl acetate) to obtain 0.32 g of 2-(4-hexylphenyl)-5-[4-(3-trimethylsilylpropoxy)phenyl]-1,3-thiazole (Yield: 70.8%). ##STR81##
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=1.[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[O:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[O:1][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=1
Reactant: COC(=O)c1ccc(CO)nc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(COC2CCCCO2)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.5 %

Procedure:
Methyl 6-(hydroxymethyl)nicotinate (1.0 g, 6.0 mmol), 2,3-dihydropyran (1.5 mL, 16.5 mmol), and p-TsOH (1.14 g, 6.0 mmol) were combined in CH2Cl2 (100 mL) and stirred at room temperature for 18 hours. An additional 1 mL of 2,3-dihyropyran was added and the reaction was continued at room temperature for 24 hours. The reaction mixture was washed with water (200 mL), dried (MgSO4), filtered, and concentrated, to afford methyl 6-((tetrahydro-2H-pyran-2-yloxy)methyl)nicotinate (1.5 g, quantitative).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:29][CH2:30][N:31]([C:37](=[O:38])[CH2:36][O:35][CH3:34])[CH2:32][CH2:33]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1
Reactant: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c1
Reactant: COCC(=O)Cl
Agent: Cl
Product: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCN(C(=O)COC)CC4)c(C)[nH]c23)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-ethylphenyl]-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f48) and commercially available methoxyacetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11](=[O:13])[CH3:12])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[OH2:14]>C(O)(=O)C.C(OC(=O)C)(=O)C.[O-2].[O-2].[O-2].[Cr+6]>[O:14]=[C:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11](=[O:13])[CH3:12])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O
Reactant: CC(=O)Nc1ccc2c(c1)CCC2
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc2c(c1)CCC2=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of N-(2,3-dihydro-1H-inden-5-yl)acetamide (50 g, 0.29 mol) in 150 mL of acetic acid and 40 mL of acetic anhydride was added dropwise to a solution of chromium trioxide in a mixed solution (30 mL of water and 140 mL of acetic acid) at a temperature of 10° C. (achieved by external cooling). After stirring overnight, the solution was poured into 2 L of ice water with vigorous stirring. The resulting solid was filtered and washed with cooled EtOH to give the title compound.
Reaction SMILES: [C:1]([C@H:5]1[C@@H:11]([C:12]2[CH:17]=[CH:16][C:15]([Si](C)(C)C)=[CH:14][CH:13]=2)[CH2:10][C@H:9]2[N:22]([CH3:23])[C@@H:6]1[CH2:7][CH2:8]2)([O:3][CH3:4])=[O:2].[I:24]Cl.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)(Cl)Cl>[C:1]([C@H:5]1[C@@H:11]([C:12]2[CH:17]=[CH:16][C:15]([I:24])=[CH:14][CH:13]=2)[CH2:10][C@H:9]2[N:22]([CH3:23])[C@@H:6]1[CH2:7][CH2:8]2)([O:3][CH3:4])=[O:2]
Reactant: ClI
Reactant: COC(=O)[C@H]1[C@@H](c2ccc([Si](C)(C)C)cc2)C[C@@H]2CC[C@H]1N2C
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)[C@H]1[C@@H](c2ccc(I)cc2)C[C@@H]2CC[C@H]1N2C
Reaction time: 2 h

Procedure:
50 mg of 2β-carbomethoxy-3β-(4-trimethylsilylphenyl)tropane was dissolved in 5 ml of CCl4 at ambient temperature. To this was added 40 mg of iodine monochloride after which the solution was stirred for 2 h, then poured into 20 mL of 10% sodium thiosulfate (Reaction 7). The two phase solution was shaken until the dark color disappeared, made basic with saturated sodium bicarbonate, and the organic layer separated. The aqueous layer was extracted three times with 10 mL portions of CHCl3 and the combined organic layers were then washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was dissolved in a small portion of ether and chromatographed using a flash SiO2 column (10"×1/2", ether/hexane 1/2) and the eluents concentrated to yield 53 mg of (91%) CIT. No isomerization of the ester moiety was detected by TLC or NMR.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Li]CCCC.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]2[C:22]([CH:32]=[O:33])=[CH:23][C:24]3[N:28]([CH3:29])[CH:27]=[N:26][C:25]=3[C:30]=2[F:31])=[C:16]([Cl:34])[CH:15]=1>C1COCC1>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]2[C:22]([CH:32]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[OH:33])=[CH:23][C:24]3[N:28]([CH3:29])[CH:27]=[N:26][C:25]=3[C:30]=2[F:31])=[C:16]([Cl:34])[CH:15]=1
Reactant: Cn1cnc2c(F)c(Nc3ccc(Br)cc3Cl)c(C=O)cc21
Reactant: Brc1ccccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1cnc2c(F)c(Nc3ccc(Br)cc3Cl)c(C(O)c3ccccn3)cc21
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 62 %

Procedure:
To a solution of 2-bromopyridine (0.10 mL, 1.04 mmol) in THF (3 mL) at −78° C. is added n-BuLi (0.39 mL, 0.98 mmol, 2.5 M solution in hexane). After stirring for 10 minutes at −78° C., a solution of 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carbaldehyde 10 h (25 mg, 0.064 mmol) in THF (1 mL) is added. The resulting reaction mixture is stirred for 1.5 hours at −78° C., quenched with saturated aqueous NH4Cl, and extracted with EtOAc. The organic layer is dried over MgSO4, filtered, concentrated in vacuo, and purified by flash chromatography (2.5% MeOH in CH2Cl2) to afford the desired product (18 mg, 62%): MS APCI (+) m/z 461, 463 (M+, Br pattern) detected; 1H NMR (400 MHz, CD3OD) δ 8.31 (d, 1H), 8.16 (s, 1H), 7.65 (m, 3H), 7.38 (d, 1H), 7.10 (m, 1H), 7.00 (dd, 1H), 6.11 (dd, 1H), 6.05 (s, 1H), 3.94 (s, 3H); 19F NMR (376 MHz, CD3OD) −135.79 (s).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[O:9][CH2:8][CH2:7][C:6]=2[CH:14]=1.[F:15][C:16]1[C:17]([NH:26][C:27]2[C:32]([Cl:33])=[CH:31][N:30]=[C:29](Cl)[N:28]=2)=[C:18]([CH:23]=[CH:24][CH:25]=1)[C:19]([NH:21][CH3:22])=[O:20]>CC(O)C.Cl.O1CCOCC1>[F:15][C:16]1[C:17]([NH:26][C:27]2[C:32]([Cl:33])=[CH:31][N:30]=[C:29]([NH:1][C:2]3[CH:3]=[CH:4][C:5]4[N:11]([CH3:12])[C:10](=[O:13])[O:9][CH2:8][CH2:7][C:6]=4[CH:14]=3)[N:28]=2)=[C:18]([CH:23]=[CH:24][CH:25]=1)[C:19]([NH:21][CH3:22])=[O:20]
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: CN1C(=O)OCCc2cc(N)ccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)CCOC(=O)N3C)ncc1Cl
Temperature: 120 °C

Procedure:
A mixture of 2-amino-5-methyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one and 3-fluoro-2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide in IPA (3 mL) was treated with 4 drops of 4N HCl/dioxane and microwave-heated at 120° C. for 90 minutes. The mixture was concentrated and purified by semipreparative HPLC to afford 3-fluoro-2-[5-chloro-2-(5-methyl-6-oxo-5,6,8,9-tetrahydro-7-oxa-5-aza-benzocyclohepten-2-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide: 1H NMR (300 MHz, CDCl3) δ 8.87 (s, 1H), 8.08 (s, 1H), 7.30 (m, 5H), 6.91 (d, 2H), 6.10 (bq, 1H), 4.41 (t, 2H), 3.35 (s, 3H), 2.92 (d, 3H), 2.81 (t, 2H); MS (m/e) 471 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([O:8][CH:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)=[CH:4][CH:3]=1.[NH:17]1[C:25]2[C:20](=[CH:21][C:22](B(O)O)=[CH:23][CH:24]=2)[CH:19]=[CH:18]1.N>>[N:11]12[CH2:16][CH2:15][CH:14]([CH2:13][CH2:12]1)[CH:9]([O:8][C:5]1[N:6]=[N:7][C:2]([C:22]3[CH:21]=[C:20]4[C:25](=[CH:24][CH:23]=3)[NH:17][CH:18]=[CH:19]4)=[CH:3][CH:4]=1)[CH2:10]2
Reactant: Clc1ccc(OC2CN3CCC2CC3)nn1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Agent: N
Product: c1cc2cc(-c3ccc(OC4CN5CCC4CC5)nn3)ccc2[nH]1

Procedure:
The product of Example 7A (200 mg, 0.8 mmol) was coupled with 5-indolylboronic acid (161 mg, 1 mmol) according to the procedure of Example 3A. The title product was purified by preparative HPLC (Gilson, column, Symmetry® C-8 7 μm, 40×100 mm. Eluting Solvent, MeCN/H2O (with 0.2% v. TFA) (v. 90/10 to 10/90 over 20 min.) Flow rate, 75 mL/min., uv, 250 nm) as solid (35 mg, yield, 14%). 1H NMR (300 MHz, CD3OD) δ 1.50–1.65 (m, 1H), 1.70–1.93 (m, 2H), 2.00–2.16 (m, 1H), 2.29–2.37 (m, 1H), 2.78–3.05 (m, 5H), 3.44–3.55 (m, 1H), 5.26–5.35 (m, 1H), 6.56 (dd, J=3.3, 1.1 Hz, 1H)), 7.25 (d, J=9.2 Hz, 1H), 7.31 (d, J=3.4 Hz, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.73 (dd, J=8.5, 1.7 Hz, 1H), 8.08 (d, J=9.5 Hz, 1H), 8.14 (d, J=1.7 Hz, 1H) ppm. MS (DCl/NH3): m/z 321 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][C:11](=O)[CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.[NH2:23][CH2:24][CH2:25][C@H:26]1[O:31][C:30]2([CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[O:29][C@@H:28]([CH2:37][C:38]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:39])[CH2:27]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:23]([CH2:24][CH2:25][C@H:26]3[O:31][C:30]4([CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)[O:29][C@@H:28]([CH2:37][C:38]([O:40][CH2:41][C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=4)=[O:39])[CH2:27]3)[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][C:9]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: NCC[C@@H]1C[C@H](CC(=O)OCc2ccccc2)OC2(CCCCC2)O1
Reactant: CC(C)C(=O)CC(C(=O)c1ccc(F)cc1)c1ccccc1
Product: CC(C)c1cc(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H]1C[C@H](CC(=O)OCc2ccccc2)OC2(CCCCC2)O1

Procedure:
According to the same method as in Example 4-1, the title compound was synthesized using 1-(4-fluorophenyl)-5-methyl-2-phenyl-1,4-hexanedione and benzyl 2-((2R,4R)-4-(2-aminoethyl)-1,5-dioxaspiro[5.5]undecan-2-yl)acetate.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[C:7]([NH:9][C:10](=[N:13][CH2:14][CH2:15][S:16][CH2:17][C:18]1[NH:22][CH:21]=[N:20][C:19]=1[CH3:23])SC)#[N:8]>C(O)C>[C:7]([NH:9][C:10]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6])=[N:13][CH2:14][CH2:15][S:16][CH2:17][C:18]1[NH:22][CH:21]=[N:20][C:19]=1[CH3:23])#[N:8]
Reactant: CSC(=NCCSCc1[nH]cnc1C)NC#N
Reactant: NCCCCO
Solvent: CCO
Product: Cc1nc[nH]c1CSCCN=C(NC#N)NCCCCO
Yield: 38.6 %

Procedure:
4-Aminobutanol (2.7 g) and N-cyano-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-S-methylisothiourea (4.05 g) were refluxed in ethanol (30 ml) for 4 hours. The reaction mixture was evaporated to yield an oil which was chromatographed on a silica gel column and eluted with chloroform and chloroform/methanol (20:1) to give the title compound as a colourless oil (1.8 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[C:18]([N:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]([CH:30]3[CH2:32][CH2:31]3)[CH2:22][CH2:21]2)=[O:19])[C:8]([Cl:33])=[CH:7][C:3]=1[C:4](O)=[O:5].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.[CH3:68][O:69][C:70](=[O:73])[CH2:71][NH2:72]>CN(C)C=O>[CH3:68][O:69][C:70](=[O:73])[CH2:71][NH:72][C:4](=[O:5])[C:3]1[CH:7]=[C:8]([Cl:33])[C:9]([O:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[C:18]([N:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]([CH:30]3[CH2:31][CH2:32]3)[CH2:22][CH2:21]2)=[O:19])=[CH:10][C:2]=1[Cl:1]
Reactant: COC(=O)CN
Reactant: O=C(O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)CNC(=O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 82 %

Procedure:
To a solution of 0.18 g (0.37 mmol) 2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoic acid in 2 mL N,N-dimethylformamide were added 0.148 g (0.39 mmol) 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, commercially available, CAS RN 148893-10-1) and 0.25 mL (1.49 mmol) N,N-diisopropylethylamine. To the light brown solution 0.049 g (0.39 mmol) glycine methyl ester hydrochloride (commercially available, CAS RN 5680-79-5) was added and the solution was stirred at room temperature for 2.5 hours. The solution was poured on water and extracted three times with ethyl acetate. The combined organic layers were washed twice with water and brine, dried over magnesium sulfate, filtered, treated with silica gel and evaporated. The resulting powder was purified by silica gel chromatography using a MPLC system (10 g silica gel column, CombiFlash Companion, Isco Inc.) with a gradient of n-heptane:ethyl acetate (100:0 to 0:100) to yield 0.169 g (82%) of the desired compound as a light brown solid. MS (ESI): m/z=555.12 [M+H]+.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10](=[S:13])SC)([OH:3])=[O:2].[N-:14]=[N+:15]=[N-:16].[Na+].[OH-].[Na+]>>[C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:10]([SH:13])=[N:16][N:15]=[N:14]1)([OH:3])=[O:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CSC(=S)NCCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCCCn1nnnc1S

Procedure:
Reaction of methyl 5-carboxypentyldithiocarbamate with sodium azide and sodium hyroxide as described in Example 7 gave 1-(5-carboxypentyl)tetrazole-5-thiol, m.p. 100°-100.5°.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH2:24]O)[CH:19]=[CH:20][C:21]=1[CH2:22][CH3:23]>>[Cl:15][C:16]1[CH:17]=[C:18]([CH2:24][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)[CH:19]=[CH:20][C:21]=1[CH2:22][CH3:23]
Reactant: CCc1ccc(CO)cc1Cl
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: CCc1ccc(COc2ccnn2-c2cc(C#N)ccn2)cc1Cl

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (3-chloro-4-ethylphenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 1.23 (3H, t, J=8.0 Hz), 2.76 (2H, t, J=8.0 Hz), 5.18 (2H, s), 5.74 (1H, d, J=0.8 Hz), 7.26 (2H, s), 7.40-7.44 (2H, m), 7.57 (1H, s), 8.03 (1H, s), 8.72 (1H, d, J=4.8 Hz). [M+H] Calc'd for C18H15ClN4O, 339; Found, 339.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[Br:9]C1C(=O)C(Br)=CC(Br)(Br)C=1.[OH-].[Na+]>C(Cl)Cl>[Br:9][C:8]1[CH:7]=[CH:6][C:4]([NH2:5])=[CH:3][C:2]=1[I:1]
Reactant: Nc1cccc(I)c1
Reactant: O=C1C(Br)=CC(Br)(Br)C=C1Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Nc1ccc(Br)c(I)c1
Temperature: -10 °C
Reaction time: 4 h

Procedure:
To a solution of 3-iodoaniline (12 mL, 100 mmol) in 400 mL CH2Cl2 at −10° C. was added in portions 2,4,4,6-tetrabromo-2,5-cyclohexadienone (45.1 g, 110 mmol) while maintaining an internal temperature of −10° C. After stirring for 4 hours, 150 mL of 1N NaOH was added, and the product was extracted with CH2Cl2. The combined extracts were washed with water and then brine and dried over Na2SO4. After concentration in vacuo the crude product was recrystallized with 2:1 hexanes:toluene to yield the desired product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C[O:16][C:17](=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24]Br>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:24][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[C:17]([OH:26])=[O:16])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccccc1CBr
Reactant: Cc1ccc(-c2ccc(O)cc2)cc1
Product: Cc1ccc(-c2ccc(OCc3ccccc3C(=O)O)cc2)cc1

Procedure:
2-(4′-Methyl-biphenyl-4-yloxymethyl)-benzoic acid was prepared using general procedure A from 4′-methyl-biphenyl-4-ol (purchased from Maybridge plc, Tintagel, Cornwall, UK or from Intermediate 5) and 2-bromomethyl-benzoic acid methyl ester (Intermediate 1). Yield: 54 mg. Mass spectrum (ES) MH+=319.