Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C:2]1(C)[O:7][CH2:6][C:5]2=[CH:8][C:9]([NH:11][C:12]3[C:13](=[O:28])[N:14]([CH3:27])[CH:15]=[C:16](B4OC(C)(C)C(C)(C)O4)[CH:17]=3)=[N:10][N:4]2[CH2:3]1.[Br:30]C1C(=O)N(C)C=C(Br)C=1>>[Br:30][C:16]1[CH:17]=[C:12]([NH:11][C:9]2[CH:8]=[C:5]([CH2:6][O:7][CH3:2])[N:4]([CH3:3])[N:10]=2)[C:13](=[O:28])[N:14]([CH3:27])[CH:15]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2cc3n(n2)CC(C)(C)OC3)c1=O
Product: COCc1cc(Nc2cc(Br)cn(C)c2=O)nn1C
Yield: 71.3 %

Procedure:
Following the procedure in Example 335a, and starting with 335b (1.7 g, 12 mmol) and 3,5-dibromo-1-methylpyridin-2(1H)-one (3.2 g, 12 mmol) afforded 336c as a yellow solid (2.8 g, 71%). MS-ESI: [M+H]+ 327. 1H NMR (500 MHz, CDCl3) δ 7.86 (d, J=2.5 Hz, 1H), 7.38 (s, 1H), 6.88 (d, J=2.5 Hz, 1H), 5.86 (s, 1H), 4.41 (s, 2H), 3.82 (s, 3H), 3.58 (s, 3H), 3.36 (s, 3H).
Reaction SMILES: O=[C:2]1[CH2:11][N:10]2[C@H:12]3[CH2:17][CH2:16][N:15](C(OCC)=O)[CH2:14][C@H:13]3[C:8]3[C:9]2=[C:4]([CH:5]=[CH:6][CH:7]=3)[NH:3]1.[CH2:23](I)[CH2:24][CH2:25][CH3:26]>>[CH2:23]([N:3]1[C:4]2[CH:5]=[CH:6][CH:7]=[C:8]3[C@@H:13]4[CH2:14][NH:15][CH2:16][CH2:17][C@@H:12]4[N:10]([C:9]=23)[CH2:11][CH2:2]1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCCI
Reactant: CCOC(=O)N1CC[C@H]2[C@@H](C1)c1cccc3c1N2CC(=O)N3
Product: CCCCN1CCN2c3c(cccc31)[C@@H]1CNCC[C@@H]12

Procedure:
Utilizing the material from Example 255 Step A, the title compound was prepared in analogous fashion using n-butyl iodide as the alkyl halide and following the procedure of Step B–D of Example 255, as a viscous brown liquid. 1H NMR (CDCl3, 300 Mhz) δ 0.95 (t, 3H), 1.30–1.45 (m, 2H), 1.50–1.65 (m, 2H), 1.95–2.15 (m, 2H), 2.65–2.80 (m, 2H), 2.65–2.80 (m, 2H), 2.85–3.08 (m, 1H), 3.08–3.22 (m, 3H), 3.22–3.40 (m, 6H), 3.68–3.78 (m, 1H), 6.38 (d, J=7.1 Hz), 6.46 (d, J=7.1 Hz, 1H), 6.66 (t, J=7.7 Hz, 1H) ppm. MS (CI): 436 (M+H+).
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:13][C:14]1[CH:18]=[C:17]([Br:19])[S:16][C:15]=1[C:20]([O:22][CH3:23])=[O:21].[NH2:24][CH:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1.[Cl-].[Na+]>C1COCC1.O>[Br:19][C:17]1[S:16][C:15]([C:20]([O:22][CH3:23])=[O:21])=[C:14]([NH:13][C:2]([NH:24][CH:25]2[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:29][CH2:30]2)=[O:4])[CH:18]=1
Reactant: COC(=O)c1sc(Br)cc1N
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1sc(Br)cc1NC(=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 14 h

Procedure:
Triphosgene (8.22 g) is dissolved in dry THF (345 ml) under argon atmosphere. The solution is cooled to 0° C. and a solution of methyl 3-amino-5-bromothiophene-2-carboxylate (19.8 g) in dry THF (173 ml) is added dropwise keeping the temperature below 10° C. The mixture is stirred for 14 h at RT. The reaction mixture is cooled to 0° C. again and a solution of tert-butyl 4-aminopiperidine-1-carboxylate (17.0 g) in dry THF (173 ml) is added within 15 min keeping the temperature below 10° C. After 15 min at 0° C. and additional 3 h at RT water (495 ml) and saturated aqueous sodium chloride solution (124 ml) are added. The organic layer is separated and the aqueous layer is extracted with THF three times (124 ml each). The combined organic layers are washed with half concentrated aqueous sodium chloride solution three times (250 ml each) and with saturated aqueous sodium chloride solution (250 ml) once. After drying over sodium sulfate all volatile materials are removed in vacuo to yield the title compound as a solid which is used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:21])=[C:6]([CH:20]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]([NH2:19])=O)=[CH:13][CH:12]=1)[CH2:9][CH3:10].N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:21])=[C:6]([CH:20]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]#[N:19])=[CH:13][CH:12]=1)[CH2:9][CH3:10]
Reactant: CCN(Cc1cc(Br)ccc1O)c1ccc(C(N)=O)nn1
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: CCN(Cc1cc(Br)ccc1O)c1ccc(C#N)nn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The phenol from the previous step (1.73 g, 4.9 mmol) in THF (30 ml) was treated with pyridine (0.82 ml, 0.82 g, 10.2 mmol) followed by trifluoroacetic anhydride (1.61 ml, 2.42 g, 11.5 mmol). The mixture turned dark green and was left overnight at ambient temperature. The mixture was then evaporated to a gum, treated with an excess of an aqueous solution of sodium bicarbonate and stirred at ambient temperature for approximately 30 minutes. The resultant red solid was filtered, washed with water and sucked dry (1.8 g) and purified by MPLC to give 6-[N-(5-bromo-2-hydroxybenzyl)-N-ethylamino]-3-cyanopyridazine (as a white solid (0.87 g, 53%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][O:9][C:10]1[N:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.O.O=[CH:21][C:22]([OH:24])=[O:23]>C(#N)C>[CH3:8][O:9][C:10]1[N:15]=[CH:14][C:13]([CH:21]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:22]([OH:24])=[O:23])=[CH:12][CH:11]=1
Reactant: Nc1ccccc1
Reactant: COc1ccc(B(O)O)cn1
Reactant: O=CC(=O)O
Solvent: CC#N
Solvent: O
Product: COc1ccc(C(Nc2ccccc2)C(=O)O)cn1
Temperature: 100 °C
Yield: 23.9 %

Procedure:
A mixture of aniline (0.30 ml, 3.27 mmol), 6-methoxypyridin-3-ylboronic acid (500 mg, 3.27 mmol) and 2-oxoacetic acid hydrate (301 mg, 3.27 mmol) in acetonitrile (20 ml) was heated under microwave irradiation at 100° C. for 1 hour. The reaction mixture was evaporated to dryness, and the crude product was triturated with acetonitrile. The solid was collected by suction filtration to get 2-(6-methoxypyridin-3-yl)-2-(phenylamino)acetic acid (202 mg, 23% yield).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[CH:33]=[CH:32][C:12]([O:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([N:20](CC)[CH2:21][C:22]3C=CC(OC)=CC=3)[CH:15]=2)=[CH:11][C:10]=1[F:34].Cl.O>C(Cl)Cl>[NH2:8][C:9]1[CH:33]=[CH:32][C:12]([O:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH2:21][CH3:22])[CH:15]=2)=[CH:11][C:10]=1[F:34]
Reactant: CCN(Cc1ccc(OC)cc1)c1cc(Oc2ccc(N)c(F)c2)ccn1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCNc1cc(Oc2ccc(N)c(F)c2)ccn1
Temperature: 40 °C
Yield: 55.7 %

Procedure:
Trifluoroacetic acid (10 mL) was added to a solution of [4-(4-amino-3-fluoro-phenoxy)-pyridin-2-yl]-ethyl-(4-methoxybenzyl)amine (1.2 g, 3.27 mmol) in CH2Cl2 (50 mL) and the resulting solution was heated to 40° C. overnight. The reaction mixture was concentrated under reduced pressure and the residue was treated with HCl (5 mL, 12M, 60 mmol) and water (50 mL). The solution was washed with EtOAc (4×50 mL). The aqueous layer was treated with NaHCO3 until pH=8 and then extracted with EtOAc (3×50 mL). The combined extracts were washed with brine (3×50 mL), dried (NaSO4) and concentrated in vacuo to give 4-(4-amino-3-fluorophenoxy)-N-ethylpyridin-2-amine (0.45 g, 67% yield). 1H NMR (300 MHz, DMSO-d6) δ7.79 (d, J=5.7, 1H), 6.85 (dd, J=11.7, 2.4 Hz, 1H), 6.78 (t, J=8.7 Hz, 1H), 6.67 (dd, J=8.7, 2.4 Hz, 1H), 6.39 (m, 1H), 6.05 (dd, J=5.7, 2.1 Hz, 1H), 5.72 (d, J=2.1 Hz, 1H), 5.09 (s, 2H), 3.15 (m, 2H), 1.03 (t, J=7.2, 3H); MS (ESI) m/z: 248.2 (M+H+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][C:5]2=[C:4]([Cl:11])[CH:3]=1.[S:12]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13]1>>[Cl:11][C:4]1[CH:3]=[C:2]([C:14]2[CH:15]=[CH:16][S:12][CH:13]=2)[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][C:5]=12
Reactant: OB(O)c1ccsc1
Reactant: Clc1cc(Cl)c2c(n1)CCC2
Product: Clc1cc(-c2ccsc2)nc2c1CCC2
Yield: 70 %

Procedure:
Following general procedure F, 2,4-dichloro-6,7-dihydro-5H-cyclopenta[b]pyridine (0.150 g, 0.80 mmol) was reacted with thiophen-3-ylboronic acid (0.112 g, 0.88 mmol) to afford the title compound (0.132 g, 70%) as a white solid. MW=235.73. 1H NMR (CDCl3, 500 MHz) δ 7.88-7.82 (m, 1H), 7.61-7.56 (m, 1H), 7.40-7.34 (m, 1H), 3.11 (t, J=7.5 Hz, 2H), 3.00 (t, J=7.5 Hz, 2H), 2.16 (quin, J=7.5 Hz, 2H); APCI MS m/z 236 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:63])[C@@H:4]([NH:25][C:26](=[O:62])[C@@H:27]([NH:51]C(OCC1C=CC=CC=1)=O)[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35]CC2C=CC=CC=2)=[C:31]([O:43]CC2C=CC=CC=2)[CH:30]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13](=[O:16])[NH:14][CH3:15])=[C:8]([O:17]CC2C=CC=CC=2)[CH:7]=1.C([Cl:71])C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.CO.[Pd]>[Cl-:71].[OH:43][C:31]1[CH:30]=[C:29]([CH2:28][C@H:27]([NH3+:51])[C:26](=[O:62])[NH:25][C@H:4]([C:3]([O:2][CH3:1])=[O:63])[CH2:5][C:6]2[CH:11]=[CH:10][C:9]([O:12][C:13](=[O:16])[NH:14][CH3:15])=[C:8]([OH:17])[CH:7]=2)[CH:34]=[CH:33][C:32]=1[OH:35]
Reactant: [H][H]
Reactant: CNC(=O)Oc1ccc(C[C@H](NC(=O)[C@H](Cc2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)NC(=O)OCc2ccccc2)C(=O)OC)cc1OCc1ccccc1
Reactant: ClCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CNC(=O)Oc1ccc(C[C@H](NC(=O)[C@@H]([NH3+])Cc2ccc(O)c(O)c2)C(=O)OC)cc1O
Product: [Cl-]

Procedure:
(S)-2-[(S)-2-Benzyloxycarbonylamino-3-(3,4-bis-benzyloxy-phenyl)-propionylamino]-3-(3-benzyloxy-4-methylcarbamoyloxy-phenyl)-propionic acid methyl ester (0.40 g, 0.470 mmol) was suspended in ethyl acetate (20 ml) and methanol (20 ml). Pd/C (5%, 0.10 g) and benzyl chloride (0.065 g, 0.517 mmol) were added. The hydrogenation was carried out under 30 psi of hydrogen for 3 h. After filtration and removal of solvent, the residue was redissolved in methanol (2 ml). Diethyl ether was added and a white solid precipitated. (S)-2-(3,4-Dihydroxy-phenyl)-1-[(S)-2-(3-hydroxy-4-methylcarbam-oyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-ethyl-ammonium chloride was obtained as a white solid by filtration, 0.22 g. 1H NMR (400 MHz, d6-DMSO) 2.63 (d, 3H), 2.72 (m, 1H), 2.83-3.02 (m, 3H), 3.64 (s, 3H), 3.93 (m, 1H), 4.50 (m, 1H), 6.52 (m, 1H), 6.65 (m, 3H), 6.85 (m, 2H), 7.46 (m, 1H), 8.11 (s, 3H), 8.87 (s, 1H), 8.96 (s, 1H), 9.13 (m, 1H), 9.61 (s, 1H). m/z 448 (MH+).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][C:11]1[O:15][C:14]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][CH:17]=2)=[N:13][N:12]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:47][CH2:48][C:49]([N:51]1[CH2:56][CH2:55][CH:54]([O:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=2[Cl:64])[CH2:53][CH2:52]1)=[O:50]>CN(C=O)C.O>[Cl:64][C:59]1[CH:60]=[CH:61][CH:62]=[CH:63][C:58]=1[O:57][CH:54]1[CH2:53][CH2:52][N:51]([C:49](=[O:50])[CH2:48][NH:47][C:20](=[O:22])[C:19]2[CH:18]=[CH:17][C:16]([C:14]3[O:15][C:11]([CH3:10])=[N:12][N:13]=3)=[CH:24][CH:23]=2)[CH2:56][CH2:55]1
Reactant: NCC(=O)N1CCC(Oc2ccccc2Cl)CC1
Reactant: Cc1nnc(-c2ccc(C(=O)O)cc2)o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nnc(-c2ccc(C(=O)NCC(=O)N3CCC(Oc4ccccc4Cl)CC3)cc2)o1
Reaction time: 0.03 h
Yield: 22.9 %

Procedure:
DIPEA (180 mg, 1.47 mmol) was added to a stirred solution of 1 4-(5-methyl-[1,3,4]oxadiazol-2-yl)-benzoic acid (100 mg, 0.48 mmol) in DMF (2 mL) followed by HOBt (79 mg, 0.58 mmol) and EDCI (113 mg, 0.587 mmol). After 2 minutes of stirring, 2-amino-1-[4-(2-chloro-phenoxy)-piperidin-1-yl]-ethanone hydrochloride (179 mg, 0.587 mmol) (prepared according to Step 1 and 5 of the General Scheme) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure The residue was purified by preparative HPLC to afford 50 mg (22.52% Yield) of N-{2-[4-(2-chloro-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-4-(5-methyl-[1,3,4]oxadiazol-2-yl)-benzamide. LC/MS [M+H]+: 93.97%. 1H NMR (300 MHz, DMSO-d6): δ 8.8 (s, 1H), 8.2-7.9 (m, 4H), 7.5-7.2 (m, 3H), 7.0 (bt, 1H), 4.8 (bs, 1H), 4.2 (bs, 2H), 3.7 (bs, 2H), 3.5 (m, 2H), 2.7-2.5 (m, 3H), 2.1-1.5 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([NH2:9])[N:3]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.[N:16]([O-])=O.[Na+].C(O)(=O)C.[OH-].[Na+].[O-]S(S([O-])=O)=O.[Na+].[Na+]>O>[ClH:8].[ClH:8].[NH2:1][C:2]1[N:7]=[C:6]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[C:5]([NH2:16])=[C:4]([NH2:9])[N:3]=1
Reactant: C1COCCN1
Reactant: Nc1cc(Cl)nc(N)n1
Reactant: O=N[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Cl
Product: Nc1nc(N)c(N)c(N2CCOCC2)n1
Temperature: 21 °C
Yield: 141.3 %

Procedure:
In a 10 L 4-neck flask equipped with a mechanical stirrer, a thermometer and a heating mantle was placed 2,6-diamino-4-chloropyrimidine (870.5 g; 6.0 mol) In water (3190 ml). To the stirred resulting white suspension was added morpholine (1113 g; 12.8 moles) in one portion. The temperature raised from 14 to 28° C. and the mixture was heated until at 75° C. a clear solution was obtained and refluxed for 16 hours. After complete conversion of the starting material (controlled by HPLC analysis) the reaction mixture was cooled to room temperature and NaNO2 (465 g, 6.74 mole) was added in three portions. No heat effect was observed but the product precipitated out of the mixture. During subsequent dropwise addition of acetic acid (600 g, 9.0 moles) the mixture became so thick that faster stirring and additional water (850 mL) were necessary to achieve a well mixable suspension. A temperature raise from 15 to 28° C. was measured. After stirring for 2 hours, HPLC analysis showed complete conversion. The mixture was then allowed to cool down to room temperature and transferred to a 20 L flask. To the add (pH 4) purple slurry was added water (3500 mL) and then an aqueous NaOH solution (165 g in 825 mL) in order to neutralise to pH 7. The suspension was cooled down to 10-12° C. in an ice-water bath and Na2S2O4 (4.68 kg, 26.9 moles) was added in portions of about 500 g at 5 minutes intervals. A temperature raise to 30° C. was observed. The mixture was left stirring overnight at room temperature before being analysed (HPLC: 99.3% conversion). The suspension was filtered over filter cloth and the wet cake was washed with 2.77 L water leaving 1.5 kg of wet material which was slurried in isopropanol (10.2 L) and to the suspension was added dropwise 36% HCl/H2O (1.16 L) during which the temperature raised from 15 to 30° C. Subsequent heating of the slurry to 40° C. afforded an almost clear solution and crystallisation started suddenly showing an exotherm to 50° C. The suspension was cooled down to room temperature before the suspension was filtered over filter cloth. The wet cake was again slurried in isopropanol (5.0 L), again filtered over filter cloth and dried at 40° C. in vacuo (200 mbar) for several days. According to this procedure was obtained 1.2 kg (yield 54.1%) of 2,5,6-triamino-4-morpholino-pyrimidine dihydrochloride with a purity above 99.9% and characterised as follows: UV (MeOH, nm): 225, 254.
Reaction SMILES: [OH:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:17]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:18]=1.C(O)C.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH2:17]([O:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:18]
Reactant: CCOC(=O)c1c(O)ncc2ccccc12
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1c(OCC)ncc2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.8 %

Procedure:
To the title compound of Step A (583 mg, 2.68 mmol) in THF (13 mL) was added triphenylphosphine (1.06 g, 4.03 mmol), ethanol (0.24 mL, 4.03 mmol) and DIAD (0.79 mL, 4.03 mmol). The reaction mixture was stirred at room temperature for 16 h and then the solvent was evaporated. The crude was purified via silica gel chromatography (0-30% EtOAc in hexanes) to afford the title compound of Step B (498 mg, 76%). MS (ESI) mass calcd. for C14H15NO3, 245.1; m/z found 246.1 [M+H]+. 1H NMR (500 MHz, Chloroform-d) δ 8.97 (s, 1H), 7.91-7.82 (m, 2H), 7.65-7.60 (m, 1H), 7.42-7.36 (m, 1H), 4.59-4.48 (m, 4H), 1.48-1.39 (m, 6H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH:6](=O)[CH3:7].[CH:9]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][CH:13]=1)([CH3:11])[CH3:10]>C(O)(=O)C.S(=O)(=O)(O)O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([NH:18][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][C:12]([CH:9]([CH3:11])[CH3:10])=[CH:13][CH:14]=1)[CH3:7]
Reactant: c1ccsc1
Reactant: CC=O
Reactant: CC(C)c1ccc(C(N)=O)cc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(C)c1ccc(C(=O)NC(C)c2cccs2)cc1
Yield: 5 %

Procedure:
Thiophene (25 mmol), acetaldehyde (20 mmol) and 4-isopropylbenzamide (10 mmol) were stirred in a mixture of acetic acid/sulfuric acid (10 ml/0.2 ml) at 60° C. for one hour to obtain N-[1-(2-thienyl)ethyl]-4-isopropylbenzamide. Yield: 5%. A large part of the product was a tar-like material.
Reaction SMILES: O=[CH:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].CN(C)C=O.[NH:17]1[CH2:22][CH:21]=[CH:20][CH2:19][CH2:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(OCC)(=O)C.O1CCCC1>[N:17]1([CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH2:18][CH:19]=[CH:20][CH2:21][CH2:22]1
Reactant: C1=CCNCC1
Reactant: CC(C)(C)OC(=O)NCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCN1CC=CCC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 40.8 %

Procedure:
To 1,1-dimethylethyl N-(2-oxoethyl)carbamate (2.0 g, 13 mmol) were added N,N-dimethylformamide (50 mL), tetrahydrofuran (50 mL), 1,2,3,6-tetrahydropyridine (1.2 mL, 13 mmol) and sodium triacetoxyborohydride (5.3 g, 25 mmol), and the mixture was stirred at room temperature for 14 hours. To the reaction solution was added ethyl acetate, and the resulting mixture was washed with a 0.5 M aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate to ethyl acetate:methanol=8:2) and further purified with amino silica gel column chromatography (hexane:ethyl acetate=9:1 to ethyl acetate) to obtain the title compound (1.2 g, yield 41%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[CH:25]=O)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].NO.CC([Si](Cl)(C)C)(C)C.[NH:37]1C=CN=C1>C(O)C.CCOC(C)=O.CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[C:25]#[N:37])=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: c1c[nH]cn1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(Cl)cc2C=O)[nH]1
Agent: CC(C)(C)[Si](C)(C)Cl
Agent: NO
Solvent: CCO
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(Cl)cc2C#N)[nH]1
Temperature: 25 °C
Reaction time: 15 h
Yield: 51.2 %

Procedure:
2-[5-(4-Chloro-2-formyl-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (985 mg, 2.62 mmol) was dissolved in ethanol (20 mL) and hydroxylamine (50% w/w in H2O, 642 μl, 10.48 mmol) was added. After stirring at room temperature for 15 h, the solution was concentrated. To the crude oxime was added TBSCl (474 mg, 3.14 mmol), imidazole (357 mg, 5.24 mmol) and DMF (10 mL). The reaction mixture was stirred at 120° C. for 80 minutes at which point more TBSCl (237 mg, 1.58 mmol) and imidazole (177 mg, 2.60 mmol) were added. The reaction mixture was stirred an additional 17 hours at 120° C. then cooled to room temperature, diluted with EtOAc. The organic phase was washed with saturated aqueous NaHCO3 and brine then dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (25% to 50% EtOAc/Hexane) to afford the title compound 2-[5-(4-Chloro-2-cyano-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (500 mg, 51%).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:23])[CH2:6][C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:16][C:17]2[CH:21]=[CH:20][O:19][CH:18]=2)[C:8]=1[CH3:22]>C1COCC1.CO>[O:19]1[CH:20]=[CH:21][C:17]([CH2:16][N:9]2[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:15]3[C:7]([CH2:6][C:5]([OH:23])=[O:4])=[C:8]2[CH3:22])=[CH:18]1
Reactant: COC(=O)Cc1c(C)n(Cc2ccoc2)c2ncccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)c2cccnc2n1Cc1ccoc1
Reaction time: 18 h

Procedure:
1M Aqueous NaOH (0.25 mL) is added to a stirring solution of (1-furan-3-ylmethyl-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester (7.5 mg, 0.026 mmol) in 1:1 THF/MeOH (1 mL). After 18 hours, the reaction is evaporated and the residue dissolved in water. The aqueous solution is acidified to pH 3-4, and extracted with EtOAc. The organic layer is washed with water then brine, dried (MgSO4), then evaporated to furnish (1-furan-3-ylmethyl-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid; MH+=271.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH2:5][CH2:6][OH:7])[CH2:3][OH:4].N1C=NN=N1.C(N(CC)[P:17]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)C.ClC1C=CC=C(C(OO)=[O:44])C=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.ClCCl>[P:17]([O:7][CH2:6][CH2:5][C:2]([CH3:8])([CH3:1])[CH2:3][OH:4])([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:44]
Reactant: CCN(CC)P(OCc1ccccc1)OCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(CO)CCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: c1nnn[nH]1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(CO)CCOP(=O)(OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 68 h
Yield: 45 %

Procedure:
To a solution of the product from Example 9A (0.80 g, 6.8 mmol) and 1H-tetrazole (0.190 g) in THF (7.0 mL) at 0° C. was added dibenzyl diethylphosphoramidite (0.96 mL), and the solution was allowed to warm to room temperature and was stirred for 68 hours. To this solution was added dichloromethane (7.0 mL) and the mixture was cooled to −45° C., followed by addition of m-chloroperbenzoic acid (1.3 g). The mixture was stirred at −45° C. for 1 hour and at room temperature for 1 hour. 10% Na2CO3 was added and the reaction was extracted twice with chloroform. The combined organic layer was dried over MgSO4, filtered and evaporated. The residue was purified by chromatography on silica gel, eluting with a gradient starting with 50% ethyl acetate in chloroform and ending with ethyl acetate, to give the title compound (0.922 g, 45%).