Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9]/[CH:10]=[N:11]/[S:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(Cl)Cl.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[Li].CO>[NH4+].[Cl-]>[CH3:5][C:4]([CH3:7])([Si:1]([CH3:3])([CH3:2])[O:8][CH2:9][C@H:10]([C:22]1[S:21][CH:25]=[CH:24][CH:23]=1)[NH:11][S+:12]([O-:13])[C:14]([CH3:17])([CH3:16])[CH3:15])[CH3:6]
Reactant: [Li]c1cccs1
Reactant: CC(C)(C)S(=O)/N=C/CO[Si](C)(C)C(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)[S+]([O-])N[C@H](CO[Si](C)(C)C(C)(C)C)c1cccs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A three necked round bottom flask fitted with a temperature probe, nitrogen inlet, mechanical stirrer and slow addition funnel was charged with N-[(1E)-2-{[tert-butyl(dimethyl)silyl]oxy}ethylidene]-2-methylpropane-2-sulfinamide (176 g, 0.530 mol) and DCM (2 L). At an internal temperature of −65° C., 2-thienyl lithium (1.0 M in THF) (0.794 L, 0.794 mol) was added dropwise such that the internal temperature was maintained <−65° C. The reaction mixture was stirred for 60 minutes, quenched at −65° C. with methanol (0.214 L, 5.30 mol), diluted with NH4Cl (2 L) and warmed to room temperature. The layers were then separated and the aqueous layer was back extracted with DCM (2 L). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude concentrate was pre-loaded onto silica, divided into 4 batches, and purified by automated flash chromatography (4×1.5 kg SiO2 columns, hexanes:EtOAc; 5% to 50% gradient over to provide the title compound as an amber oil. 1H NMR ((CD3)2CO) δ 7.42 (1H, d, J=4.0 Hz), 7.14 (1H, s), 7.01 (1H, J=4.0, 3.5 Hz), 4.78-4.75 (1H, m), 4.48 (1H, s), 3.95-3.92 (1H, m), 3.86-3.82 (1H, m), 1.23 (9H, s), 0.94 (9H, s), 0.12 (6H, s).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1>CO.CN(C=O)C.[Pd]>[NH2:1][C@H:2]([C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)NCc1ccccc1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CN(C)C=O
Product: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)NCc1ccccc1

Procedure:
Same procedure as above with Z-Trp-NHCH2Ph (616 mg, 1.44 mmol), 10% Pd/C (153 mg) in MeOH/DMF (14.5 mL, 1/1). After purification by flash chromatography on silica gel (3-12% MeOH/CH2Cl2), Trp-NHCH2Ph was isolated as a pale yellow oil (351 mg, 83%). 1H NMR (300 MHz, CDCl3) δ 2.98 (dd, J=14.4 Hz, J=8.7 Hz, 1H, CH2), 3.44 (dd, J=14.4 Hz, J=4.1 Hz, 1H, CH2), 3.80 (dd, J=8.7 Hz, J=4.2 Hz, 1H, CHα), 4.46 (m, 2H, CH2 (Bn)), 7.06 (d, J=2.1 Hz, 1 aromatic H), 7.13-7.36 (m, 7 aromatic H), 7.41 (d, J=8 Hz, 1 aromatic H), 7.61 (m, 1H, NH amide), 7.72 (d, J=7.8 Hz, 1 aromatic H), 8.3 (broad s, 1H, NH indole). 13C NMR (75 MHz, MeOD) δ 30.5 (CH2 Trp), 42.7 (CH2 Ph), 55.4 (CHα), 109.3, 111, 118.1, 118.5, 121.2, 123.5, 126.8, 127, 127.1, 127.4, 128, 128.1, 136.8, 138 (14 aromatic C), 174.6 (CO amide).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:11][C:12]1([C:19](Cl)=[O:20])[CH2:17][CH2:16][CH2:15][CH:14]([CH3:18])[CH2:13]1>>[Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:19]([C:12]3([CH3:11])[CH2:17][CH2:16][CH2:15][CH:14]([CH3:18])[CH2:13]3)=[O:20])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC1CCCC(C)(C(=O)Cl)C1
Reactant: Brc1cnc2[nH]ccc2n1
Product: CC1CCCC(C)(C(=O)c2c[nH]c3ncc(Br)nc23)C1

Procedure:
(2-Bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-(1,3-dimethyl-cyclohexyl)-methanone was prepared starting from 2-bromo-5H-pyrrolo[2,3-b]pyrazine and 1,3-dimethyl cyclohexanecarbonyl chloride (Journal of Organic Chemistry (1951), 16 920-9) following general procedures as described in these Examples. M+H=336.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.[C:17]([Zn]C#N)#[N:18]>CN(C=O)C.O.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>[F:14][C:13]([F:16])([F:15])[C:10]1[CH:11]=[CH:12][C:7]([C:6]2[O:5][CH:4]=[N:3][C:2]=2[C:17]#[N:18])=[CH:8][CH:9]=1
Reactant: N#C[Zn]C#N
Reactant: FC(F)(F)c1ccc(-c2ocnc2Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ncoc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 240.6 %

Procedure:
A mixture of Example 56B (500 mg, 1.71 mmol), dicyanozinc (221 mg, 1.88 mmol), and Pd(Ph3P)4 (101 mg, 0.087 mmol) in DMF (3 mL) was heated in a microwave reactor to 160° C. for 6 min. The reaction mixture was cooled to ambient temperature, diluted with water (50 mL) and extracted with EtOAc. The combined organic extracts were filtered through celite, and the filtrate was washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. An identical reaction was then performed using Example 56B (1.0 g, 3.4 mmol), dicyanozinc (442 mg, 3.77 mmol), and Pd(Ph3P)4 (198 mg, 0.171 mmol) in DMF (6 mL). The crude product from both reactions was combined and purified by chromatography on silica gel (25% EtOAc/hexanes) to afford 980 mg (80%) of the title compound as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.10 (dd, J=8.9, 0.7, 2H), 8.00 (s, 1H), 7.81 (dd, J=8.7, 0.5, 2H). MS (DCI+) m/z 256 (M+NH4).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-])=O.[CH:11](=O)[CH2:12][CH3:13]>>[CH2:12]([CH:11]1[NH:6][C:5]2[C:4](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:1]2[CH:10]=[CH:4][CH:5]=[C:7]12)[CH3:13]
Reactant: CCC=O
Reactant: Nc1ccccc1[N+](=O)[O-]
Product: CCC1Nc2ccccc2-n2cccc21

Procedure:
The title compound was prepared from 2-nitro aniline according to the sequence of Example 1 and 2, and the resulting oil treated with proprionaldehyde according to the procedure of Example 3 to yield a light orange oil, which was used in the next step without further characterization.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH3:7])[CH3:6])=[O:4].C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>ClCCl>[CH3:6][N:5]([CH3:7])[C:3](=[O:4])[CH2:2][NH:1][S:16]([CH3:15])(=[O:18])=[O:17]
Reactant: CN(C)C(=O)CN
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)CNS(C)(=O)=O

Procedure:
To a cold (0° C.) solution of 2-amino-N,N-dimethylacetamide (1.62 g, 10 mmol) and triethylamine (3.4 mL, 25 mmol) in dichloromethane (50 mL), methanesulfonyl chloride (0.85 mL, 11 mmol) was added over a period of 5 minutes. The resultant mixture was stirred at room temperature for overnight. The product mixture was diluted with dichloromethane and washed with sat. aq. sodium bicarbonate. The organic extract was dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide the title acetamide as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8]C)[CH:5]=[CH:4][C:3]=1[C:10]1[N:14](C)[N:13]=[C:12]([C:16]23[CH2:23][CH2:22][C:19]([CH2:24][CH2:25][CH2:26][CH:27]([OH:29])[CH3:28])([CH2:20][CH2:21]2)[CH2:18][CH2:17]3)[N:11]=1.[CH2:30]([S-])C.[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:10]1[N:11]=[C:12]([C:16]23[CH2:23][CH2:22][C:19]([CH2:24][CH2:25][CH2:26][CH:27]([OH:29])[CH3:28])([CH2:18][CH2:17]2)[CH2:20][CH2:21]3)[N:13]([CH3:30])[N:14]=1
Reactant: CC[S-]
Reactant: COc1ccc(-c2nc(C34CCC(CCCC(C)O)(CC3)CC4)nn2C)c(Cl)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(O)CCCC12CCC(c3nc(-c4ccc(O)cc4Cl)nn3C)(CC1)CC2
Temperature: 100 °C

Procedure:
5-{4-[5-(2-Chloro-4-methoxyphenyl)-1-methyl-1-H-1,2,4-triazol-3-yl]bicyclo[2.2.2]oct-1-yl}pentan-2-ol (5-J) (0.036 g, 0.086 mmol) was placed in a small vial with 0.5 mL of DMF. Sodium ethanethiolate (0.0218 g, 0.260 mmol) was added to the solution. The vial was sealed and heated to 100° C. for 1.5 h. The incomplete reaction required another 1.5 equivalents of sodium ethanethiolate (0.011 g). The vial was resealed and heated at 100° C. for 1 h. The product, 3-chloro-4-{5-[4-(4-hydroxypentyl)bicyclo[2.2.2]oct-1-yl]-1-methyl-1-H-1,2,4-triazol-3-yl}phenol (5-K) was purified by preparative reverse phase HPLC on a C-18 silica gel column using a gradient of acetonitrile-water buffered with 0.1% trifluoroacetic acid. The effluent containing the pure triazole was made basic with 10% NaHCO3, evaporated in vacuo to remove most of the acetonitrile, and extracted with methylene chloride. The organic extract was dried (MgSO4) and evaporated, and the residue dried under vacuum to provide the desired compound. MS (ESI+)=404.4 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:13](=[O:22])[C:14]3[CH:19]=[CH:18][C:17]([CH2:20][NH2:21])=[CH:16][CH:15]=3)[S:11][C:7]=2[C:6]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:5][CH:4]=1.[CH3:29][O:30][CH2:31][CH2:32][C:33](Cl)=[O:34]>>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:13](=[O:22])[C:14]3[CH:19]=[CH:18][C:17]([CH2:20][NH:21][C:33](=[O:34])[CH2:32][CH2:31][O:30][CH3:29])=[CH:16][CH:15]=3)[S:11][C:7]=2[C:6]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(CN)cc3)nc12
Reactant: COCCC(=O)Cl
Product: COCCC(=O)NCc1ccc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)cc1

Procedure:
Using N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4-aminomethyl-benzamide and 3-methoxy-propionyl chloride, the title compound was prepared as white crystals (44% yield). MS: m/e=485(M+H+).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][C:12]1[C:13](=[O:18])[NH:14][CH:15]=[CH:16][CH:17]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].N[C@@H]1CCCC[C@H]1N>CCOC(C)=O.[Cu]I.O1CCOCC1>[CH3:11][C:12]1[C:13](=[O:18])[N:14]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: Cc1ccc[nH]c1=O
Reactant: O=[N+]([O-])c1ccc(I)cc1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cccn(-c2ccc([N+](=O)[O-])cc2)c1=O
Yield: 35.6 %

Procedure:
1-Iodo-4-nitrobenzene (1.61 g, 6.45 mmol) was combined with 3-methyl-2-pyridone (0.845 g, 7.74 mmol), CuI (0.246 g, 1.29 mmol), and K3PO4 (2.74 g, 12.9 mmol). 1,4-Dioxane (6 mL) was added followed by trans-1,2-diaminocyclohexane (0.194 mL, 1.61 mmol). The mixture was heated to reflux for 19 h before cooling and diluting with EtOAc. The mixture was filtered through a plug of silica, eluting with EtOAc, and the filtrate concentrated under reduced pressure. Purification of the crude product by flash chromatography provided 159-a (0.528 g, 36%) as a brown solid. MS: APCI (AP+): 231.1 (M)+.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[H-].[Na+].[OH:15][CH:16]([CH2:20][N:21]1[CH:25]=[C:24]([I:26])[CH:23]=[N:22]1)[C:17]([NH2:19])=[O:18]>C(=O)(OCC)OCC.[Cl-].[NH4+]>[I:26][C:24]1[CH:23]=[N:22][N:21]([CH2:20][CH:16]2[O:15][C:1](=[O:2])[NH:19][C:17]2=[O:18])[CH:25]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NC(=O)C(O)Cn1cc(I)cn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOC(=O)OCC
Product: O=C1NC(=O)C(Cn2cc(I)cn2)O1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
1,1′-Carbonyldiimidazole (3.5 g, 21 mmol) and sodium hydride (0.85 g, 21 mmol, 60 wt %) were added to a mixture of 2-hydroxy-3-(4-iodo-1H-pyrazol-1-yl)propanamide (2 g, 7 mmol) in diethyl carbonate (50 mL). The mixture was stirred at 50° C. for 5 hours. After cooling to room temperature, the mixture was diluted with aqueous ammonium chloride solution and extracted with DCM. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/EtOAc) to afford 5-((4-iodo-1H-pyrazol-1-yl)methyl)oxazolidine-2,4-dione. MS ESI calc'd. for C7H7IN3O3 [M+H]+ 308. found 308. 1H NMR (400 MHz, CDCl3) δ 7.55 (s, 1H), 7.50 (s, 1H), 5.16 (s, 1H), 4.68 (d, J=4 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[C:34]([F:35])=[CH:33][C:5]2[NH:6][C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]4[C:22]([C:23]5[CH:28]=[CH:27][N:26]=[C:25](S(C)(=O)=O)[N:24]=5)=[CH:21][CH:20]=[CH:19][N:18]=4)=[CH:12][CH:11]=3)=[N:8][C:4]=2[CH:3]=1.[CH3:36][N:37]1[CH2:42][CH2:41][N:40]([CH2:43][CH2:44][CH2:45][NH2:46])[CH2:39][CH2:38]1.CC(O)C>C(Cl)Cl>[F:1][C:2]1[C:34]([F:35])=[CH:33][C:5]2[NH:6][C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]4[C:22]([C:23]5[CH:28]=[CH:27][N:26]=[C:25]([NH:46][CH2:45][CH2:44][CH2:43][N:40]6[CH2:39][CH2:38][N:37]([CH3:36])[CH2:42][CH2:41]6)[N:24]=5)=[CH:21][CH:20]=[CH:19][N:18]=4)=[CH:12][CH:11]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: CN1CCN(CCCN)CC1
Reactant: CS(=O)(=O)c1nccc(-c2cccnc2Oc2ccc(Nc3nc4cc(F)c(F)cc4[nH]3)cc2)n1
Solvent: CC(C)O
Solvent: ClCCl
Product: CN1CCN(CCCNc2nccc(-c3cccnc3Oc3ccc(Nc4nc5cc(F)c(F)cc5[nH]4)cc3)n2)CC1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
A resealable pressure vial was charged with 5,6-difluoro-N-(4-(3-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amine (0.14 g, 0.28 mmol), 3-(4-methylpiperazin-1-yl)propan-1-amine (0.18 g, 1.13 mmol), and 2-propanol (1.89 ml, 0.15 M). The reaction vessel was sealed and the mixture stirred at 70° C. for 16 h. The reaction mixture was cooled to RT, diluted with DCM, and washed with Aq. NaHCO3. The organic layer was collected, dried over Na2SO4, and concentrated to afford brown residue, which was purified by Gilson reverse phase chromatography (10% to 90% CH3CN/H2O/0.1% TFA). The product-containing fractions were combined, basified by addition of aq. NaHCO3 and extracted with ethyl acetate. The organic portion was dried with Na2SO4, filtered, and concentrated to afford pure 5,6-difluoro-N-(4-(3-(2-(3-(4-methylpiperazin-1-yl)propylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amine as a yellow solid. MS m/z=572.2 [M+H]+. Calc'd for C30H31F2N9O: 571.62.
Reaction SMILES: [NH2:1][CH:2]([C:6]([NH2:8])=[O:7])[C:3]([NH2:5])=[O:4].[CH3:9]C([OH:12])C.C(OCC)(OCC)OCC.[ClH:23]>O>[OH2:4].[OH2:12].[ClH:23].[OH:4][C:3]1[NH:5][CH:9]=[N:1][C:2]=1[C:6]([NH2:8])=[O:7]
Reactant: NC(=O)C(N)C(N)=O
Reactant: CC(C)O
Agent: Cl
Solvent: CCOC(OCC)OCC
Solvent: O
Product: NC(=O)c1nc[nH]c1O
Temperature: 80 °C
Reaction time: 0.83 h

Procedure:
Under the nitrogen atmosphere, 5.00 g of 2-aminomalonamide was added to 100 mL of 2-propanol. After heating to 80° C., 17.7 mL of triethyl orthoformate was added dropwise to the mixture over 30 minutes. Subsequently, the reaction mixture was stirred for 7 hours and 50 minutes at 83 to 84° C. Subsequently, after cooling to 50 to 60° C., the reaction mixture was added with an aqueous solution prepared with 4 mL of conc. hydrochloric acid and 5 mL of water. After cooling the mixture to 20 to 30° C., the crystal was collected by filtration and then washed with 25 mL of acetone to give 8.04 g of 5-hydroxy-1H-imidazole-4-carboxamide hydrochloric acid salt dihydrate as a pale yellow crystal.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][S:11][CH2:12][CH2:13][CH:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH2:24][C:25]([O:27]C)=[O:26])[C:17]=2[O:16][CH2:15]1.[OH-].[Na+].O>CO>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][S:11][CH2:12][CH2:13][CH:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH2:24][C:25]([OH:27])=[O:26])[C:17]=2[O:16][CH2:15]1
Reactant: COC(=O)COc1cccc2c1OCC2CCSCCCc1ccccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)COc1cccc2c1OCC2CCSCCCc1ccccc1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93.9 %

Procedure:
Methyl (+)-3-(2-(3-(2-hydroxyphenyl)propylthio)ethyl)-2,3-dihydrobenzofuran-7-yloxyacetate (160 mg) was dissolved in methanol (4 ml), and a 2N sodium hydroxide aqueous solution (0.4 ml) was added to the resultant solution, and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was poured into water and then extracted with ethyl acetate twice. The combined organic layers were washed with saturated brine, and dried over sodium sulfate. Sodium sulfate was filtered off, and the filtrate was concentrated. The residue was purified by Lober® column DIOL (elution solvent: hexane/ethyl acetate=1/2) to obtain (+)-3-(2-(3-(2-hydroxyphenyl)propylthio)ethyl)-2,3-dihydrobenzofuran-7-yloxyacetic acid (145 mg). This product was dissolved in chloroform, and diethanolamine was added to the resultant solution. The solvent was distilled off under reduced pressure, and the residue was recrystallized from hexane/ethanol to obtain the object compound (140 mg, yield 76%).
Reaction SMILES: [F:1][C:2]1[S:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12](=[O:17])[CH2:13][N:14]=[N+]=[N-])[CH3:10]>C(O)C>[CH2:9]([O:11][C:12]([C:13]1[NH:14][C:4]2[CH:3]=[C:2]([F:1])[S:6][C:5]=2[CH:7]=1)=[O:17])[CH3:10]
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: O=Cc1ccc(F)s1
Solvent: CCO
Product: CCOC(=O)c1cc2sc(F)cc2[nH]1

Procedure:
5-Fluoro-thiophene-2-carbaldehyde (see, for example, Schuetz, R. D. and Nilles, G. P., J. Org. Chem., 36: 2188-90 (1971)) was annulated according to Procedure H (aldehyde and azido-acetic acid ethyl ester added as ethanol solution (0.6 M of ester); acrylate organic phase washed with saturated aqueous NaCl prior to drying; acrylate not purified).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.C([N-]C(C)C)(C)C.[Li+].[C:16]1([C:22](=[O:34])[C:23]([O:25][C@@H:26]2[CH:31]3[CH2:32][CH2:33][N:28]([CH2:29][CH2:30]3)[CH2:27]2)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1>[OH:34][C:22]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH2:1][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1)[C:23]([O:25][C@@H:26]1[CH:31]2[CH2:30][CH2:29][N:28]([CH2:33][CH2:32]2)[CH2:27]1)=[O:24]
Reactant: Cc1cnccn1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C(=O)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)C(O)(Cc1cnccn1)c1ccccc1
Reaction time: 1 h

Procedure:
2-Methylpyrazine (0.94 g) in tetrahydrofuran (THF) (5 ml) was added dropwise to lithium diisopropylamide (LDA) (7.51 ml of a 1.5 molar solution in THF) in THF (20 ml) at -78° C. After 0.75 hour a solution of (R)-3-quinuclidinyl 2-phenylglyoxalate (see Preparation 2) (2.59 g) in THF (20 ml) was added, the reaction mixture was allowed to reach room temperature, stirred for 1 hour and partitioned between ethyl acetate and 10% aqueous potassium carbonate. The organic layer was then dried over magnesium sulphate and evaporated to leave a residue which was purified by chromatography on silica gel performing a gradient elution using chloroform plus methanol (0→15%). Appropriate fractions were combined and evaporated to give the title compound, as a yellow oil (1.4 g, 39%).
Reaction SMILES: C[O:2][C:3](=[O:31])[C@@H:4]([O:28][CH2:29][CH3:30])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:17][C:18]=2[CH3:19])=[CH:8][C:7]=1[CH2:26][CH3:27].[Li+].[OH-]>>[CH2:29]([O:28][C@@H:4]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:17][C:18]=2[CH3:19])=[CH:8][C:7]=1[CH2:26][CH3:27])[C:3]([OH:31])=[O:2])[CH3:30]
Reactant: CCO[C@@H](Cc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1CC)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Product: CCO[C@@H](Cc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1CC)C(=O)O

Procedure:
In analogy to the procedure described in example 1 g], (S)-2-ethoxy-3-[2-ethyl-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propionic acid methyl ester was treated with LiOH to obtain (S)-2-ethoxy-3-[2-ethyl-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propionic acid as colorless foam.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([OH:17])=[O:16])=[CH:11][CH:10]=1.C([O-])([O-])=O.[Na+].[Na+].[C:24](Cl)([O:26][CH2:27][CH:28]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]2[C:29]1=[CH:30][CH:31]=[CH:32][CH:33]=2)=[O:25].Cl>O.O1CCOCC1.CCOC(C)=O>[C:24]([CH:2]([NH2:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([OH:17])=[O:16])=[CH:11][CH:10]=1)([O:26][CH2:27][CH:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:35]2[C:40]1=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:25]
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: NCc1ccccc1-c1ccc(C(=O)O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: NC(C(=O)OCC1c2ccccc2-c2ccccc21)c1ccccc1-c1ccc(C(=O)O)cc1
Temperature: 5 °C

Procedure:
Cool to 5° C. a mixture of 2′-aminomethylbiphenyl-4-carboxylic acid (Preparation D, Step 5) (1.14 g, 5.0 mmol) and Na2CO3 (1.33 g, 12.5 mmol) in water:dioxane (2:1, 70 mL). Add Fmoc-Cl (1.3 g, 5.0 mmol) and stir at ice-bath temperature for 4 hours, then overnight at room temperature. Pour into a mixture of warm EtOAc (1 L) and 1N aqueous HCl (100 mL) and stir vigorously. Separate organic layer, dry (MgSO4), and concentrate in vacuo until solids appear. Collect the title compound, m.p. 215-218° C. MS (Cl+/CH4) m/z 450 [M+H]+.
Reaction SMILES: I(O)(=O)(=O)=O.[F:6][C:7]1[N:11]([CH3:12])[N:10]=[C:9]([CH:13]([F:15])[F:14])[C:8]=1[CH:16]=[O:17].C(OCC)(=[O:20])C>C(#N)C.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>[F:15][CH:13]([F:14])[C:9]1[C:8]([C:16]([OH:20])=[O:17])=[C:7]([F:6])[N:11]([CH3:12])[N:10]=1
Reactant: CCOC(C)=O
Reactant: Cn1nc(C(F)F)c(C=O)c1F
Agent: O=[Cr](=O)([O-])Cl
Agent: [O-][I+3]([O-])([O-])O
Agent: c1cc[nH+]cc1
Solvent: CC#N
Product: Cn1nc(C(F)F)c(C(=O)O)c1F
Reaction time: 0.5 h
Yield: 83 %

Procedure:
A suspension of 79.7 g (350 mmol) of periodic acid in 640 ml of absolute acetonitrile was stirred for 30 min. At 0° C., 56.6 g (318 mmol) of 5-fluoro-1-methyl-3-difluoromethyl-1H-pyrazole-4-carbaldehyde (IV-1) and 1.4 g (6 mmol) of PCC dissolved in 130 ml of dry acetonitrile were added. The reaction mixture was subsequently stirred at room temperature for 2.5 hours. After 1600 ml of ethyl acetate had been added, the reaction mixture was washed in succession with saturated sodium chloride solution/water (1:1), saturated sodium metabisulphite solution and saturated sodium chloride solution. The organic phase was dried over sodium sulphate and concentrated to obtain 51.4 g (83% of theory) of 3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carboxylic acid (V-1) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:11]2[S:12][C:13]([CH3:16])=[C:14]([CH3:15])[C:10]=2[C:9]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([N+:24]([O-])=O)[CH:18]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.NN.C(O)C>O>[NH2:24][C:19]1[CH:18]=[C:17]([C:9]2[C:10]3[C:14]([CH3:15])=[C:13]([CH3:16])[S:12][C:11]=3[C:2]([Br:1])=[C:3]3[C:8]=2[CH:7]=[CH:6][CH:5]=[CH:4]3)[CH:22]=[CH:21][C:20]=1[OH:23]
Reactant: Cc1sc2c(Br)c3ccccc3c(-c3ccc(O)c([N+](=O)[O-])c3)c2c1C
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1sc2c(Br)c3ccccc3c(-c3ccc(O)c(N)c3)c2c1C
Temperature: 85 °C
Yield: 101.8 %

Procedure:
Using a procedure similar to Tet. Lett. 1990, 1181-1182, Montmorillinite K10 clay (425 mg) was added to a solution of 4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-nitro-phenol (0.608 g, 1.42 mmol), anhydrous hydrazine (0.276 μL, 8.95 mmol) and ethanol (4.2 mL) and the suspension was heated at 85° C. for 30 min. The reaction mixture was cooled to room temperature, added to water and extracted with ether. The ether was dried and concentrated to provide the title compound as a white solid (0.576 g, 100%): mp 173-175° C.: NMR (DMSO-d6); δ 9.26 (s, 1H), 8.14 (dd, J=8, 1 Hz, 1H), 7.63-7.58 (m, 2 H), 7.42 (ddd, J=8, 6, 1 Hz, 1H), 6.78 (d, J=8 Hz, 1H), 6.54 (d, J=2 Hz, 1H), 6.35 (dd, J=8, 2 Hz, 1H), 4.67 (broad s, 2H), 2.42 (s, 3H), 1.69 (s, 3H); MS (+FAB): 1 bromine isotope pattern 398 (30%, M+H), 400 (30%, M+H); Anal. Calc. for C20H16BrNOS: C, 60.31, H, 4.05, N, 3.52; Found: C, 61.36, H, 4.08, N, 3.25.