Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN1C=CN=C1.[CH:7]1([CH2:12][C@H:13]([CH2:30][N:31]([CH:39]=[O:40])[O:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[C:14]([N:16]2[CH:20]([C:21]([OH:23])=O)[CH2:19][CH2:18][N:17]2[C:24]([O:26][CH2:27][CH:28]=[CH2:29])=[O:25])=[O:15])[CH2:11][CH2:10][CH2:9][CH2:8]1.S(Cl)(C)(=O)=O.[CH3:46][O:47][C:48]1[CH:49]=[N:50][C:51]([NH2:54])=[N:52][CH:53]=1>ClCCl>[CH:7]1([CH2:12][C@H:13]([CH2:30][N:31]([CH:39]=[O:40])[O:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[C:14]([N:16]2[C@H:20]([C:21]([NH:54][C:51]3[N:52]=[CH:53][C:48]([O:47][CH3:46])=[CH:49][N:50]=3)=[O:23])[CH2:19][CH2:18][N:17]2[C:24]([O:26][CH2:27][CH:28]=[CH2:29])=[O:25])=[O:15])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: COc1cnc(N)nc1
Reactant: C=CCOC(=O)N1CCC(C(=O)O)N1C(=O)[C@H](CC1CCCC1)CN(C=O)OC1CCCCO1
Agent: CS(=O)(=O)Cl
Agent: Cn1ccnc1
Solvent: ClCCl
Product: C=CCOC(=O)N1CC[C@@H](C(=O)Nc2ncc(OC)cn2)N1C(=O)[C@H](CC1CCCC1)CN(C=O)OC1CCCCO1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 44.4 %

Procedure:
1-Methylimidazole (158 μl, 1.987 mmol) was added into the solution of 2-((2R)-3-cyclopentyl-2-{[formyl(tetrahydro-2H-pyran-2-yloxy)amino]methyl}propanoyl)-1-[(2-propen-1-yloxy)carbonyl]-3-pyrazolidinecarboxylic acid (319 mg, 0.662 mmol) in dichloromethane (DCM) (4.5 ml). The resulting solution was cooled to 0° C., and then mesyl chloride (53.8 μl, 0.696 mmol) was added dropwise at 0° C. To the reaction mixture was added 5-(methyloxy)-2-pyrimidinamine (87 mg, 0.696 mmol). After stirring for 30 min at ambient temperature, the solvent was removed under reduced pressure to give a residue which was purified by RP-HPLC to yield 2-propen-1-yl (3S)-2-((2R)-3-cyclopentyl-2-{[formyl(tetrahydro-2H-pyran-2-yloxy)amino]methyl}propanoyl)-3-({[5-(methyloxy)-2-pyrimidinyl]amino}carbonyl)-1-pyrazolidinecarboxylate (173 mg, 0.294 mmol, 44% yield). MS (ES+) m/z 589.1 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[C:8]([C:15]([C:20]1[N:21]=[CH:22][NH:23][CH:24]=1)([OH:19])[CH:16]([CH3:18])[CH3:17])[CH:7]=[CH:6]2.CC1(C)COP(=O)(O)OC1C1C=CC=CC=1.C(OC(C)C)(C)C>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[C:8]([C@@:15]([C:20]1[N:21]=[CH:22][NH:23][CH:24]=1)([OH:19])[CH:16]([CH3:18])[CH3:17])[CH:7]=[CH:6]2
Reactant: COc1cc2ccc(C(O)(c3c[nH]cn3)C(C)C)cc2cc1OC
Agent: CC1(C)COP(=O)(O)OC1c1ccccc1
Solvent: CO
Solvent: CC(C)OC(C)C
Product: COc1cc2ccc([C@](O)(c3c[nH]cn3)C(C)C)cc2cc1OC
Reaction time: 5 h
Yield: 74.6 %

Procedure:
1-(6,7-dimethoxy-2-naphthyl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol(485 mg) and (−)-5,5-dimethyl-2-hydroxy-4-phenyl-1,3,2-dioxaphosphorinane 2-oxide (653 mg) were dissolved in methanol (4 mL). Diisopropyl ether (3 mL) was added and the resulting clear solution was left at room temperature for 5 h to give needles. The needles were washed with a mixed solution of methanol-diisopropyl ether (1:3, 4 mL) and diisopropyl ether (1 mL) and then dried to give the titled compound (362 mg) as colorless needles. Optical purity; >99% ee (Chiralcel OJ-R, manufactured by Daicel Chemical Industries, Ltd.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH2:13][C:14]([N:16]2[CH2:21][C@H:20]([CH3:22])[N:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:18][C@H:17]2[CH3:31])=[O:15])=[C:6]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:7]=1.[CH:32]([N:35]=[C:36]=[O:37])([CH3:34])[CH3:33].CCCCCCC=CCCC>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH2:13][C:14]([N:16]2[CH2:21][C@H:20]([CH3:22])[N:19]([CH2:23][C:24]3[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=3)[CH2:18][C@H:17]2[CH3:31])=[O:15])=[C:6]([S:8]([NH:11][C:36]([NH:35][CH:32]([CH3:34])[CH3:33])=[O:37])(=[O:9])=[O:10])[CH:7]=1
Reactant: CC(C)N=C=O
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1S(N)(=O)=O
Agent: CCCC=CCCCCCC
Solvent: C1CCOC1
Product: CC(C)NC(=O)NS(=O)(=O)c1cc(Cl)ccc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Temperature: 60 °C
Reaction time: 8 h
Yield: 72.1 %

Procedure:
To a solution of 5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-benzenesulfonamide (0.07 g, 0.150 mmol) in tetrahydrofuran (1.5 mL) was added isopropyl isocyanate (0.022 mL, 0.23 mmol) and 1,8-diazabycyclo[5.4.0 ]undec-7-ene (0.034 mL, 0.23 mmol). The reaction was stirred at 60° C. overnight. The reaction was concentrated and purified by chromatography on silica gel to give the title compound (0.06 g, LRMS: 555.2)
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C@H:5]([C@H:7]2[NH:10][C:9](=[O:11])[CH2:8]2)[CH2:4][O:3]1.[C:13]([Si:17]([CH3:20])([CH3:19])Cl)([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C>CN(C)C=O.CCOCC>[Si:17]([N:10]1[C@H:7]([C@@H:5]2[CH2:4][O:3][C:2]([CH3:12])([CH3:1])[O:6]2)[CH2:8][C:9]1=[O:11])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC1(C)OC[C@@H]([C@@H]2CC(=O)N2)O1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC1(C)OC[C@@H]([C@@H]2CC(=O)N2[Si](C)(C)C(C)(C)C)O1
Reaction time: 2 h

Procedure:
A solution, cooled to 0°, of 17.1 g (0.1 mmol) of (S)-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-azetidinone and 15.1 g (0.1 mol of t-butyldimethylchlorosilane in 100 ml of dimethylformamide is treated while stirring with 10.6 g (0.105 mol) of triethylamine, whereby a precipitate results immediately. The mixture is stirred at 0° for 2 hours, then diluted with 200 ml of ether and the reaction mixture is washed five times with 80 ml of water each time. The aqueous phases are then extracted with 100 ml of ether. The organic phases are dried over sodium sulphate and evaporated, whereupon the residual oil is distilled. There is obtained (S)-1-(t-butyldimethylsilyl)-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-azetidinone of boiling point 84°-87° (0.5 Torr); [α]D20 =-22.7° (c=1, ethyl acetate).
Reaction SMILES: [CH2:1]([C:3]1([N:9]2[CH2:18][C:17]3=[CH:19][NH:20][C:15]4[C:16]3=[C:11]([CH:12]=[CH:13][N:14]=4)[C:10]2=[O:21])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].[C:22](O)(=[O:25])[CH2:23][CH3:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C1C=CN=CC=1.CN(C=O)C>[CH2:1]([C:3]1([N:9]2[CH2:18][C:17]3=[CH:19][NH:20][C:15]4[C:16]3=[C:11]([CH:12]=[CH:13][N:14]=4)[C:10]2=[O:21])[CH2:8][CH2:7][N:6]([C:22](=[O:25])[CH2:23][CH3:24])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCC(=O)O
Reactant: CCC1(N2Cc3c[nH]c4nccc(c34)C2=O)CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCC(=O)N1CCC(CC)(N2Cc3c[nH]c4nccc(c34)C2=O)CC1
Reaction time: 3 h
Yield: 32.2 %

Procedure:
4-(4-Ethylpiperidin-4-yl)-3,4-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-5(1H)-one (12 mg, 0.042 mmol), propionic acid (4 mg, 0.055 mmol), 4-dimethylaminopyridine (10 mg, 0.084 mmol), and HATU (32 mg, 0.084 mmol) were dissolved in DMF (3 mL) at room temperature and allowed to stir for 3 h. The solution was concentrated in vacuo and purified via preparative HPLC 10% to 40% B in A and gave 4.6 mg of the title compound as its TFA salt. 1H NMR (400 MHz, CD3OD) δ 7.58 (m, 1H), 7.41 (m, 1H), 5.12 (s, 2H), 3.70-3.74 (m, 1H), 3.59-3.63 (m, 3H), 2.58-2.61 (m, 1H), 2.41-2.43 (m, 3H), 2.21-2.30 (m, 4H), 1.11 (t, 3H, J=7.6 Hz), 0.94 (t, 3H, J=7.6 Hz). [M+H] found 341.
Reaction SMILES: N([O-])=O.[Na+].[CH3:5][O:6][C:7]1[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[C:10]([NH2:17])=[CH:9][C:8]=1[O:18][CH3:19].Cl.[N-:21]=[N+:22]=[N-].[Na+].C([O-])(=O)C.[Na+]>O>[N:17]([C:10]1[CH:9]=[C:8]([O:18][CH3:19])[C:7]([O:6][CH3:5])=[CH:12][C:11]=1[C:13]([O:15][CH3:16])=[O:14])=[N+:21]=[N-:22]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1cc(OC)c(OC)cc1N
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=N[O-]
Solvent: O
Product: COC(=O)c1cc(OC)c(OC)cc1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81.5 %

Procedure:
A solution of sodium nitrite (486 mg, 7.1 mmol) in H2O (6 mL) was added to a solution of methyl 2-amino-4,5-dimethoxy benzoate (1.0 g, 4.7 mmol) in 6N—HCl (20 mL) at 0° C. under N2 atmosphere. After stirring for 15 min, the mixture was then added dropwise to a stirred solution of sodium azide (611 mg, 9.4 mmol) and sodium acetate (3.86 g, 47 mmol) in H2O (30 mL) at 0° C. under N2 atmosphere. After the addition was completed, the reaction mixture was warmed to room temperature and stirred for 2 hrs. The resulting precipitate was collected by vacuum filtration, wash with cold water and dried under reduced pressure to yield methyl 2-azido-4,5-dimethoxybenzoate (909 mg, 82%). 1H NMR (CDCl3, 600 MHz) δ 7.42 (s, 1H), 6.66 (s, 1H), 3.95 (s, 3H), 3.90 (s, 6H); MS (ES+) m/z 238.2 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[N+:22]([O-])=O)[C:5]([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:10][CH:9]=1)=[O:6]>C(OCC)(=O)C.[Pd]>[NH2:22][C:21]1[CH:20]=[CH:19][C:4]([C:5]([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:10][CH:9]=2)=[O:6])=[CH:3][C:2]=1[CH3:1]
Reactant: CCCCCc1ccc(OC(=O)c2ccc([N+](=O)[O-])c(C)c2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCc1ccc(OC(=O)c2ccc(N)c(C)c2)cc1
Yield: 98.5 %

Procedure:
16.2 g of 4-pentylphenyl 3-methyl-4-nitrobenzoate (49.5 mM) were dissolved in 250 ml of ethyl acetate and 1.5 g of Pd/C (10%) were added. This mixture was hydrogenated at normal pressure. When the theoretical amount of hydrogen was consumed, it was filtered through a pad of celite filter aid and evaporated to dryness to give 14.5 g (49.0 mM, 98%) of 4-pentylphenyl 4-amino-3-methylbenzoate as beige crystals.
Reaction SMILES: Cl.[C@@H:2]12[N:10]([CH2:11][CH:12]([C:14]3[CH:21]=[C:20]([O:22][CH3:23])[C:17]([C:18]#[N:19])=[CH:16][N:15]=3)[OH:13])[C@@H:6]([CH2:7][NH:8][CH2:9]1)[CH2:5][O:4][CH2:3]2.[CH3:24][C:25]1[C:33]2[CH2:32][O:31][C:30](=[O:34])[C:29]=2[CH:28]=[CH:27][C:26]=1[C@@H:35]1[CH2:37][O:36]1>>[OH:13][C@@H:12]([C:14]1[CH:21]=[C:20]([O:22][CH3:23])[C:17]([C:18]#[N:19])=[CH:16][N:15]=1)[CH2:11][N:10]1[CH:6]2[CH2:7][N:8]([CH2:37][CH:35]([OH:36])[C:26]3[C:25]([CH3:24])=[C:33]4[C:29](=[CH:28][CH:27]=3)[C:30](=[O:34])[O:31][CH2:32]4)[CH2:9][CH:2]1[CH2:3][O:4][CH2:5]2
Reactant: COc1cc(C(O)CN2[C@@H]3CNC[C@H]2COC3)ncc1C#N
Reactant: Cc1c([C@@H]2CO2)ccc2c1COC2=O
Agent: Cl
Product: COc1cc([C@H](O)CN2C3COCC2CN(CC(O)c2ccc4c(c2C)COC4=O)C3)ncc1C#N

Procedure:
(R)-6-(1-Hydroxy-2-(7-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl)ethyl)-4-methoxynicotinonitrile was prepared in a similar fashion to that described for the synthesis of EXAMPLE 1 starting from 6-(2-((1R,5S)-3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl)-1-hydroxyethyl)-4-methoxynicotinonitrile hydrochloride (INTERMEDIATE 25) and 4-methyl-5-[(2R)-oxiran-2-yl]-2-benzofuran-1 (3H)-one [INTERMEDIATE 2].
Reaction SMILES: I[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.C([Mg]Cl)(C)C.[CH2:12]([O:19][CH:20]1[CH2:25][CH2:24][C:23]([N:28]([CH3:30])[CH3:29])(C#N)[CH2:22][CH2:21]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:12]([O:19][CH:20]1[CH2:25][CH2:24][C:23]([N:28]([CH3:30])[CH3:29])([C:2]2[S:3][CH:4]=[CH:5][CH:6]=2)[CH2:22][CH2:21]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CN(C)C1(C#N)CCC(OCc2ccccc2)CC1
Reactant: Ic1cccs1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN(C)C1(c2cccs2)CCC(OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4.67 g of 2-iodothiophene were dissolved in 20 ml of tetrahydrofuran, and 7.26 ml of two molar isopropylmagnesium chloride solution in tetrahydrofuran were added dropwise under a nitrogen atmosphere, while cooling with an ice bath. After one hour, 2.50 g of 4-benzyloxy-1-dimethylaminocyclohexanecarbonitrile were added dropwise, dissolved in 10 ml of tetrahydrofuran. After stirring overnight at room temperature, the mixture was again cooled in an ice bath and 25 ml of cold ammonium chloride solution (20 wt. %) were added. The phases were separated and extracted three times using 40 ml of diethyl ether each time, and the combined organic phases were dried over sodium sulfate, filtered and concentrated. The resulting crude product (3.82 g) was separated on silica gel with diethyl ether. 1.59 g of the non-polar and 260 mg of the polar diastereoisomer of (4-benzyloxy-1-thiophen-2-yl-cyclohexyl)dimethylamine were obtained and, as described for Example 1, were converted into 1.11 g (Example 11) and 210 mg (Example 12) of the corresponding hydrochlorides using chlorotrimethylsilane and water in 2-butanone.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[C:10](=[O:21])[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([NH2:19])=[C:14]([Cl:20])[CH:13]=2)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].CO[CH:24]1[CH2:28][CH2:27][CH:26](OC)O1.C(O)(=O)C.ClCCCl>O.C(Cl)Cl.CO>[CH2:1]([O:3][P:4]([C:9]1[C:10](=[O:21])[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([N:19]1[CH:24]=[CH:28][CH:27]=[CH:26]1)=[C:14]([Cl:20])[CH:13]=2)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(OCC)c1cc2cc(N)c(Cl)cc2[nH]c1=O
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O
Product: CCOP(=O)(OCC)c1cc2cc(-n3cccc3)c(Cl)cc2[nH]c1=O
Temperature: 75 °C
Reaction time: 1 h

Procedure:
A biphasic suspension of 2.43 g (7.35 mmol) of the compound obtained in Step D of Example 1 and 1.33 ml (10.29 mmol) of 2,5-dimethoxytetrahydrofuran in a mixture of 24 ml of distilled water, 12 ml of acetic acid and 36 ml of 1,2-dichloroethane is stirred vigorously at 75° C. for 60 minutes. In TLC (CH2Cl2/MeOH 9:1), a small amount of starting material is still observed. 0.2 eq. of 2,5-dimethoxytetrahydrofuran (2.06 mmol, 0.26 ml) is added, and heating is maintained for 30 minutes. The mixture is left to return to room temperature and extraction is carried out with CH2Cl2. The organic phase is washed 4 times with water and then with a saturated NaCl solution. Drying is carried out over MgSO4, followed by evaporation and chromatography of the resulting oil over 200 g of Merck 7734 silica whilst eluting with a mixture of CH2Cl2/MeOH 95:5. An oil corresponding to the title product is obtained, which is crystallised from isopropyl ether.
Reaction SMILES: [CH:1]1([C@H:7]([O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)/[CH:8]=[CH:9]/[C@@H:10]2[C@@H:17]3[C@@H:13]([O:14][C:15](=[O:18])[CH2:16]3)[CH2:12][C@H:11]2[O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>C1COCC1>[CH:1]1([C@H:7]([O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)/[CH:8]=[CH:9]/[C@@H:10]2[C@@H:17]3[C@@H:13]([O:14][CH:15]([OH:18])[CH2:16]3)[CH2:12][C@H:11]2[O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1C[C@@H]2[C@@H](/C=C/[C@@H](OC3CCCCO3)C3CCCCC3)[C@H](OC3CCCCO3)C[C@@H]2O1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OC1C[C@@H]2[C@@H](/C=C/[C@@H](OC3CCCCO3)C3CCCCC3)[C@H](OC3CCCCO3)C[C@@H]2O1
Reaction time: 2 h
Yield: 82.1 %

Procedure:
To a solution of lactone 24 (5.7 g, 12.7 mmol) in 40 mL of THF at -78° C. was added dropwise a 1.5M solution of DIBAL-H in toluene (11.5 mL, 17.2 mmol). After 2 h, the reaction was poured into 70 mL of a saturated solution of sodium potassium tartrate and was stirred for 30 min. The mixture was extracted with ethyl acetate (3×50 mL), the combined organic layers were dried over MgSO4, filtered and concentrated, and the residue was chromatographed on silica gel (1/1 hexane/ethyl acetate) to afford 4.7 g (82%) of lactol 35.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH2:18][CH2:17][CH:16]([NH:19][OH:20])[CH:15]=3)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[Si]([N:25]=[C:26]=[O:27])(C)(C)C.CCO>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH2:18][CH2:17][CH:16]([N:19]([OH:20])[C:26]([NH2:25])=[O:27])[CH:15]=3)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: ONC1C=C(c2ccc(Sc3ccc(F)cc3)o2)CC1
Reactant: C[Si](C)(C)N=C=O
Solvent: C1CCOC1
Solvent: CCO
Product: NC(=O)N(O)C1C=C(c2ccc(Sc3ccc(F)cc3)o2)CC1
Reaction time: 1 h
Yield: 32.3 %

Procedure:
To a stirred solution of N-[3-[5-(4-fluorophenylthio)-2-furyl]-2-cyclopenten-1-yl]-N-hydroxylamine (1.35 g; 4.64 mM) in THF (13 ml) was added TMSNCO (0.755 g; 5.56 mM) at room temperature under N2. After stirring for 1 hr, EtOH (20 ml) was added. Volatiles were removed, and the resulting residue was recrystallized from ethyl acetate-EtOH (20 ml-120 ml) to provide 0.5 g of the title compound as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)[N:5]=[C:4]([C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][CH:24]=2)[CH:3]=1.[Cl-].[NH4+].C1COCC1>[Zn].CO>[NH2:29][C:26]1[CH:25]=[CH:24][C:23]([C:4]2[CH:3]=[C:2]([Cl:1])[C:7]([C:8]#[N:9])=[C:6]([C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)=[CH:12][CH:11]=3)[N:5]=2)=[CH:28][CH:27]=1
Reactant: N#Cc1c(Cl)cc(-c2ccc([N+](=O)[O-])cc2)nc1-c1ccc(Oc2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1c(Cl)cc(-c2ccc(N)cc2)nc1-c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 40.2 %

Procedure:
A mixture of 4-chloro-6-(4-nitrophenyl)-2-(4-phenoxyphenyl)nicotinonitrile (136.3 mg, 0.319 mmol), zinc dust (312 mg, 4.78 mmol), ammonium chloride (256 mg, 4.78 mmol), THF (3 mL) and methanol (3 mL) was stirred at room temperature for 15 min, and filtered. The filtrate was concentrated and partitioned with dichloromethane and saturated sodium bicarbonate. The organic layer was separated and concentrated. Silica gel chromatography, eluting with 0-40% ethyl acetate in hexanes, gave pure 6-(4-aminophenyl)-4-chloro-2-(4-phenoxyphenyl)nicotinonitrile as yellow solid (51 mg). 1H NMR (400 MHz, CDCl3) δ ppm 7.96-8.04 (4H, m), 7.70 (1H, s), 7.40 (2H, t, J=8.03 Hz), 7.18 (1H, t, J=7.40 Hz), 7.08-7.14 (4H, m), 6.76 (2H, δ, J=8.78 Hz), 4.04 (2H, s); MS (ES+) m/z: 398 (M+H); LC retention time: 4.551 min (analytical HPLC Method A). Additional impure product was also obtained from the chromatography (48.1 mg).
Reaction SMILES: CN1C=C(CN(C)C(C2N(C3C=CC(F)=CC=3)C(S)=NC=2)=O)C(C)=N1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:37]([C:38]([O:40]CC)=[O:39])=[CH:36][N:35]=[CH:34]2)=[CH:29][CH:28]=1.[OH-].[Li+].C1COCC1>O.CO>[F:26][C:27]1[CH:28]=[CH:29][C:30]([N:33]2[C:37]([C:38]([OH:40])=[O:39])=[CH:36][N:35]=[CH:34]2)=[CH:31][CH:32]=1
Reactant: CCOC(=O)c1cncn1-c1ccc(F)cc1
Agent: Cc1nn(C)cc1CN(C)C(=O)c1cnc(S)n1-c1ccc(F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cncn1-c1ccc(F)cc1

Procedure:
1-(4-Fluorophenyl)-1H-imidazole-5-carboxylic acid (14b) was prepared in a similar manner as that described for the synthesis of compound 7 using ethyl 1-(4-fluorophenyl)-1H-imidazole-5-carboxylate (14a) (143 mg, 0.61 mmol), lithium hydroxide (59 mg, 2.44 mmol), THF (0.2 mL), methanol (0.4 mL), and water (0.8 mL).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].C(=O)=O.CC(O)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].F[C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][N:36]=1)[C:31]([OH:33])=[O:32]>C1COCC1>[F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:34]1[CH:35]=[N:36][CH:28]=[CH:29][C:30]=1[C:31]([OH:33])=[O:32]
Reactant: O=C(O)c1ccnc(F)c1
Reactant: Nc1ccc(I)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C=O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-fluoro-4-iodoaniline (20.0 g, 84.38 mmol) in dry THF (80 mL) was cooled to −67° C. (dry ice/IPA bath) under nitrogen, prior to slow addition of 1.0 M lithium bis(trimethylsilyl)amide (255 mL, 255 mmol) via addition funnel, at a rate that kept the internal temp below −59° C. (˜2 h). After final addition, the yellow-green slurry was stirred for 30 min and then treated with 2-fluoroisonicotinic acid (8.0 g, 56.69 mmol). The bath was not removed, but the contents were allowed to slowly warm to room temp. After 4 days, the dark slurry was poured into a biphasic mixture of aqueous 2.0 N sodium hydroxide (1000 mL) and ethyl acetate (150 mL). The aqueous layer was separated and the organics were again extracted with base (1000 mL). The pH of the two aqueous layers was adjusted to ˜2 with concentrated hydrochloric acid. A yellow solid precipitated, which was filtered. The resultant yellow cake was washed with water (2×400 mL) and dried under high vacuum at 40° C. (17-19 g). LC/MS [(5.2 min; 359 (M+1)].
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][N+:19]([O-])=[CH:18][CH:17]=3)[CH:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.C[Si]([C:29]#[N:30])(C)C.CN(C)C(Cl)=O>C(#N)C>[F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:29]#[N:30])[CH:17]=3)[CH:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: [O-][n+]1ccc(-c2ccnc(Nc3cccc(C(F)(F)F)c3)n2)cc1
Reactant: C[Si](C)(C)C#N
Agent: CN(C)C(=O)Cl
Solvent: CC#N
Product: N#Cc1cc(-c2ccnc(Nc3cccc(C(F)(F)F)c3)n2)ccn1
Reaction time: 12 h

Procedure:
0.8 g (2.41 mmol) of N-(3-trifluoromethyl-phenyl)-4-(N-oxido4-pyridyl)-2-pyrimidineamine is suspended in 40 ml of acetonitrile. 0.834 ml (6.65 mmol) of tri-methylsilyl cyanide and 0.611 ml (6.665 mmol) of dimethylcarbamoyl chloride are added and the reaction mixture is stirred for 12 hours at 60°. After concentration under reduced pressure, crystallisation is effected from tetrahydrofuran/diethyl ether. N-(3-trifluoromethyl-phenyl)-4-(2-cyano-4-pyridyl)-2-pyrimidineamine is obtained; m.p. 164°-166°, Rf =0.40 (n-hexane:ethyl acetate=1:1).
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH2:18][C:19]([O:21]C)=[O:20])=[C:8]2[CH3:23])=[CH:4][CH:3]=1.[OH-].[K+].CO.Cl>C1COCC1.O>[Br:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH2:18][C:19]([OH:21])=[O:20])=[C:8]2[CH3:23])=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1c(C)n(Cc2ccc(Br)cc2)c2ccc(OC)cc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2c(c1)c(CC(=O)O)c(C)n2Cc1ccc(Br)cc1
Yield: 98.3 %

Procedure:
A solution of methyl 1-(4-bromobenzyl)-5-methoxy-2-methylindole-3-acetate (10 g, 24.9 mmol) and KOH (1.7 g, 30 mmol) in 45 mL of THF, 5 mL of H2O, and 2 mL of methanol was heated at reflux for 1 h. The reaction mixture was cooled to 0° C. and neutralized with concentrated HCl. The solvent volume was reduced by rotary evaporation. The precipitate was collected and washed with H2O. The white solid was dried in a vacuum oven to give 9.5 g (98%) of the carboxylic acid.