Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]([CH2:10][O:11][CH3:12])=[N:8][CH:9]=1)=[O:4].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:20][C:21]1[CH:25]=[C:24]([C:26]2[S:27][C:28]([Cl:31])=[CH:29][CH:30]=2)[O:23][N:22]=1.O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:20][C:21]2[CH:25]=[C:24]([C:26]3[S:27][C:28]([Cl:31])=[CH:29][CH:30]=3)[O:23][N:22]=2)[C:7]([CH2:10][O:11][CH3:12])=[N:8][CH:9]=1)=[O:4]
Reactant: COCc1ncc(C(=O)OC)[nH]1
Reactant: Clc1ccc(-c2cc(CBr)no2)s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COCc1ncc(C(=O)OC)n1Cc1cc(-c2ccc(Cl)s2)on1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 50 mg 2-Methoxymethyl-3H-imidazole-4-carboxylic acid methyl ester in 1 ml DMF, 95 mg caesium carbonate and 82 mg 3-Bromomethyl-5-(5-chloro-thiophen-2-yl)-isoxazole [prepared by adopting a procedure described by Ewing, William R.; Becker, Michael R.; Choi-Sledeski, Yong Mi; Pauls, Heinz W.; He, Wei; Condon, Stephen M.; Davis, Roderick S.; Hanney, Barbara A.; Spada, Alfred P.; Burns, Christopher J.; Jiang, John Z.; Li, Aiwen; Myers, Michael R.; Lau, Wan F.; Poli, Gregory B; PCT Int. Appl. (2001), 460 pp. WO 0107436 A2] were added and the mixture was stirred for 2 h at RT. After addition of 5 ml water the mixture was filtered through a chem elut® cartridge by elution with ethyl acetate and then concentrated under reduced pressure. The residue was directly subjected to the subsequent saponification reaction without further purification. Yield: 72 mg.
Reaction SMILES: FC(F)(F)C(N1CCC([N:11]2[CH:15]=[C:14]([C:16]3[CH:17]=[N:18][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]5[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=5)[CH:23]=4)=[N:20][CH:21]=3)[CH:13]=[N:12]2)CC1)=O.IC1C=NN([C@H:42]2[CH2:47][CH2:46][C@H:45]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][C:49]3=[O:54])[CH2:44][CH2:43]2)C=1>>[CH3:33][N:31]1[CH:32]=[C:28]([C:24]2[CH:23]=[C:22]([C:19]3[N:20]=[CH:21][C:16]([C:14]4[CH:13]=[N:12][N:11]([CH:42]5[CH2:43][CH2:44][CH:45]([N:48]6[CH2:53][CH2:52][O:51][CH2:50][C:49]6=[O:54])[CH2:46][CH2:47]5)[CH:15]=4)=[CH:17][N:18]=3)[CH:27]=[CH:26][CH:25]=2)[CH:29]=[N:30]1
Reactant: Cn1cc(-c2cccc(-c3ncc(-c4cnn(C5CCN(C(=O)C(F)(F)F)CC5)c4)cn3)c2)cn1
Reactant: O=C1COCCN1[C@H]1CC[C@H](n2cc(I)cn2)CC1
Product: Cn1cc(-c2cccc(-c3ncc(-c4cnn(C5CCC(N6CCOCC6=O)CC5)c4)cn3)c2)cn1

Procedure:
The title compound was obtained following procedure described for example 182 but starting from 5-Bromo-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidine (intermediate 2; 230 mg; 0.73 mmol; 1.0 eq.) and trans-4-[4-(4-Iodo-pyrazol-1-yl)-cyclohexyl]-morpholin-3-one (intermediate 26; 274 mg; 0.73 mmol; 1.0 eq.). The crude was purified by recrystallisation in methylisobutylketone. The title compound was obtained as a beige solid (16 mg, 5%). 1H NMR (300 MHz, DMSO) δ 9.16 (s, 2H), 8.54 (s, 2H), 8.40-8.06 (m, 3H), 7.93 (s, 1H), 7.71 (d, J=7.9 Hz, 1H), 7.52 (t, J=7.9 Hz, 1H), 4.31 (d, J=39.6 Hz, 2H), 4.05 (s, 2H), 3.95-3.71 (m, 5H), 2.20 (d, J=11.5 Hz, 2H), 2.03-1.49 (m, 6H), 1.23 (s, 1H), 0.84 (t, J=7.3 Hz, 1H). HPLC (Condition A): Rt 3.31 min (purity 99.2%). MS (ESI+): 484.4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:20][C@H:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)[CH3:22]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[C:6]([CH:10]=1)[C:7]([NH:20][C@H:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)[CH3:22])=[O:9]
Reactant: O=C(O)c1cc(Cl)ccc1Oc1cccc(F)c1
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)ccc2Oc2cccc(F)c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 5-chloro-2-(3-fluorophenoxy)benzoic acid (step 2) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 3 of Example 5): 1H-NMR (CDCl3) δ 8.17 (1H, d, J=2.8 Hz), 7.93 (2H, d, J=8.4 Hz), 7.65 (1H, d, J=7.4 Hz), 7.42–7.26 (4H, m), 6.94–6.88 (2H, m), 6.74–6.65 (2H, m), 5.28 (1H, dq, J=7.4, 7.3 Hz), 3.90 (3H, s), 1.48 (3H, d, J=7.3 Hz).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[CH:2].Br[C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[CH2:18][CH2:19][OH:20]>>[OH:20][CH2:19][CH2:18][C:17]1[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=1[C:2]#[C:1][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1
Reactant: OCCc1ccccc1Br
Reactant: C#Cc1ccc(CCC(=O)OC)cc1
Product: COC(=O)CCc1ccc(C#Cc2ccccc2CCO)cc1

Procedure:
The title compound was prepared from methyl 3-(4-ethynylphenyl)propanoate (107 mg, 0.57 mmol) and 2-bromophenethyl alcohol (100 μL, 0.74 mmol) according to the general procedure IF to give 83 mg (47%) of a dark orange oil after purification by flash chromatography (SiO2, EtOAc:PE, 1:1). Rf=0.19 (EtOAc:PE, 1:1); 1HNMR (CDCl3): δ 7.46-7.44 (m, 1H), 7.38-7.36 (m, 2H), 7.21-7.20 (m, 2H), 7.18-7.14 (m, 1H), 7.13-7.10 (m, 2H), 3.91-3.87 (m, 2H), 3.60 (s, 3H), 3.06 (t, J=5.1 Hz, 2H), 2.89 (t, J=5.7 Hz, 2H), 2.56 (t, J=5.4 Hz, 2H); 13CNMR (CDCl3): δ 173.1, 141.1, 140.4, 132.4, 131.7, 131.7, 129.7, 128.5, 126.6, 123.2, 121.2, 93.2, 87.6, 62.9, 51.7, 38.1, 35.4, 30.9.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]([CH3:15])([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1)[CH3:5].C(O)(=O)C>C1COCC1.[Zn]>[CH3:1][O:2][C:3](=[O:16])[C:4]([C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[CH:10][CH:11]=1)([CH3:15])[CH3:5]
Reactant: COC(=O)C(C)(C)c1ccc([N+](=O)[O-])cc1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)c1ccc(N)cc1
Reaction time: 1 h

Procedure:
2-Methyl-2-(4-nitro-phenyl)-propionic acid methyl ester (2.1 g) was dissolved in THF (70 ml) and acetic acid (5 ml) and Zn (10 g) were added. The mixture was stirred for 1 h and filtered through Celite®. The filtrate was rinsed with EtOAc and the organics were evaporated to a residue which was purified on silica gel chromatography (40%EtOAc/hexanes) to provide the desired compound as a yellow oil. M+H 194.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2Cl)=[CH:4][CH:3]=1.[CH2:13]([Mg]Cl)[CH2:14][CH2:15][CH3:16]>C(OCC)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[CH2:13][CH2:14][CH2:15][CH3:16])=[CH:4][CH:3]=1
Reactant: Clc1nccc2ccc(Br)cc12
Reactant: CCCC[Mg]Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCCCc1nccc2ccc(Br)cc12
Temperature: 25 °C
Yield: 24.4 %

Procedure:
To a refluxing solution of 7-bromo-1-chloroisoquinoline (4.85 g, 23.28 mmol) in diethyl ether (75 mL) was added butylmagnesium chloride (17.8 mL, 2.0 M ether, 35.6 mmol) and the reaction maintained at reflux for 2 h. The reaction mixture was cooled to room temperature, carefully diluted with an equal volume of ethyl acetate, washed with saturated sodium bicarbonate, water, and saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure to give an brown oil. Purification by flash column chromatography (silica, 1-10% ether/hexanes) gave the desired 7-bromo-1-butylisoquinoline (1.50 g): ESI MS m/z 264 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:14]=[C:13]2[OH:24].[C:25]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([C:20]([F:22])([F:21])[F:23])[CH:14]=[C:13]2[O:24][CH3:25]
Reactant: O=C([O-])[O-]
Reactant: Oc1cc(C(F)(F)F)nc2ccc(-c3cc4ccccc4o3)cc12
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc(C(F)(F)F)nc2ccc(-c3cc4ccccc4o3)cc12
Reaction time: 4 h
Yield: 67.1 %

Procedure:
To a stirring solution of 6-(1-benzofuran-2-yl)-4-hydroxy-2-(trifluoromethyl)-quinoline (1.33 g, 4.04 mmol) in DMF (40 mL) at room temperature was added K2CO3 (0.670 g, 4.85 mmol) followed by methyl iodide (0.276 mL, 4.44 mmol) drop-wise. The reaction mixture was stirred for 4 hours then concentrated and the residue was diluted with EtOAc (200 mL). The organic layer was washed with H2O (20 mL), sat. aq. NaHCO3 (20 mL), and brine (20 mL) and then dried (Na2SO4). After concentration, the residue was purified on a Biotage Flash 40 apparatus (5-15% EtOAc:petroleum ether) to afford the product (0.930 g) as a solid. Mass spectrum (+ESI, [M+H]+) m/z 344. 1H NMR (500 MHz, DMSO-d6): δ 8.67 (s, 1H), 8.46 (d, 1H, J=9.1 Hz), 8.19 (d, 1H, J=9.1 Hz), 7.68-7.79 (m, 3H), 7.48 (s, 1H), 7.40 (t, 1H, J=7.8 Hz), 7.32 (t, 1H, J=7.8 Hz), and 4.26 ppm (s, 3H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]([CH3:14])[C:8]=1[Si](C)(C)C)(=O)=O.[F-].[Cs+].[C:23]1([P:29]([O:33]CC)[O:30][CH2:31][CH3:32])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(#N)C>CCOC(C)=O>[CH3:14][C:9]1[CH:10]=[CH:11][C:12]([CH3:13])=[CH:7][C:8]=1[P:29]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:33])[O:30][CH2:31][CH3:32]
Reactant: CCOP(OCC)c1ccccc1
Reactant: Cc1ccc(C)c([Si](C)(C)C)c1OS(=O)(=O)C(F)(F)F
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOP(=O)(c1ccccc1)c1cc(C)ccc1C

Procedure:
3,6-dimethyl-2-(trimethylsilyl)phenyl trifluoromethanesulfonate (25 mg, 0.077 mmol), Cesium Fluoride (64 mg, 0.421 mmol), Diethyl phenylphosphonite (60 mg, 0.306 mmol), Acetonitrile (1 ml): Reaction Time: 32 h; Rf: 0.4 (1:1 EtOAc:Pet Ether); Thick oil; 13.0 mg, 62%; 1H NMR (400 MHz, CDCl3, TMS) δ 7.81-7.70 (m, 3H), 7.52-7.40 (m, 3H), 7.23 (d, J=7.8 Hz, 1H), 7.12-7.05 (m, 1H), 4.11 (apparent quint, J=7.0 Hz, 2H), 2.36 (s, 3H), 2.33 (s, 3H), 1.38 (t, J=7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3, TMS) δ 138.6 (d, J=10.8 Hz), 135.0 (d, J=12.3 Hz), 133.9 (d, J=9.3 Hz), 132.5 (d, J=124.1 Hz), 128.4 (d, J=13.4 Hz), 131.7, 131.5 (d, J=7.7 Hz), 131.4, 131.3, 129.0 (d, J=133.3 Hz), 128.4 (d, J=13.1 Hz), 60.7 (d, J=5.4 Hz), 20.9, 20.7 (d, J=3.9 Hz), 16.4 (d, J=6.9 Hz); 31P NMR (162 MHz, CDCl3,) δ 32.2; HRMS-ESI (m/z) calcd (C16H19O2P+H)+: 275.1195. found: 275.1193.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]2([NH:18][C:17](=[O:19])[C:16]3[CH:20]=[C:21](Br)[CH:22]=[CH:23][C:15]=3[O:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25]([O:29][CH3:30])(=[O:28])[CH:26]=[CH2:27].COC(=O)/C=C/C1C=C2C(=CC=1)OC1(CNC1)CC2=O>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:30][O:29][C:25](=[O:28])/[CH:26]=[CH:27]/[C:21]1[CH:22]=[CH:23][C:15]2[O:14][C:10]3([CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]3)[NH:18][C:17](=[O:19])[C:16]=2[CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCCC2(C1)NC(=O)c1cc(Br)ccc1O2
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CNC1)O2
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)NC1(CCCN(C(=O)OC(C)(C)C)C1)O2
Yield: 90.7 %

Procedure:
A solution of (±)-6-bromo-3,4-dihydro-4-oxo-spiro-[2H-(1,3)-benzoxazine-2,3′-piperidine]-1′-carboxylic acid tert-butyl ester (2.50 g, 6.30 mmol) in dry DMF (5 ml) was treated with Pd(OAc)2 (26.0 mg, 0.130 mmol), P(o-tol)3 (76.6 mg, 0.252 mmol), TEA (2.6 ml, 19 mmol) and methyl acrylate (1.7 ml, 19 mmol) following the procedure described for Intermediate 4, Step B, to give (±)-(E)-3-{1′-tert-butoxycarbonyl-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl}-acrylic acid methyl ester (2.30 g) as a light orange solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:14]=[N:15][C:16]([N:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[N:17][CH:18]=2)[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[Li+].[CH3:33]C([N-]C(C)C)C.CI>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:13]2[CH:14]=[N:15][C:16]([N:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[N:17][CH:18]=2)([CH3:33])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)C(c1ccc(F)cc1)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C(C)(c1ccc(F)cc1)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 77.2 %

Procedure:
To a mixture of tert-butyl 4-(5-(1-(4-fluorophenyl)-2-methoxy-2-oxoethyl)pyrimidin-2-yl)piperazine-1-carboxylate (1.0 g, 2.33 mmol) in THF (20 mL) at −78° C. was added LDA (2 M, 2.33 mL, 4.65 mmol) dropwise, After stirred at −78° C. for 30 min, CH3I (0.66 g, 4.65 mmol) was added. After stirred at RT for another 1 h, the reaction was quenched by water and extracted with EA. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered and concentrated. The residue was passed a column (silica gel, PE:EA=6:1) to afford the title compound (0.8 g, 77%) as a yellow solid. MS (ES+) C23H29FN4O4 requires: 444. found: 445 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]([F:19])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18].C(OC([NH:28][C@H:29]1[C@@H:33]([CH3:34])[CH2:32][NH:31][CH2:30]1)=O)(C)(C)C.C1CCN2C(=NCCC2)CC1>C(#N)C>[NH2:28][C@H:29]1[C@@H:33]([CH3:34])[CH2:32][N:31]([C:3]2[C:2]([Br:1])=[C:11]3[C:6]([C:7](=[O:18])[C:8]([C:15]([OH:17])=[O:16])=[CH:9][N:10]3[CH:12]3[CH2:14][CH2:13]3)=[CH:5][C:4]=2[F:19])[CH2:30]1
Reactant: O=C(O)c1cn(C2CC2)c2c(Br)c(F)c(F)cc2c1=O
Reactant: C[C@H]1CNC[C@H]1NC(=O)OC(C)(C)C
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C[C@H]1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2Br)C[C@H]1N
Reaction time: 2.5 h
Yield: 25.6 %

Procedure:
A mixture of 8-bromo-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.19 g), cis-3-t-butoxycarbonylamino-4-methylpyrrolidine (0.14 g), DBU (0.095 g) and anhydrous acetonitrile (5 ml) was refluxed for 2 hours and then concentrated. The resulting residue was dissolved in chloroform (70 ml), washed with 10% aqueous citric acid solution, water successively, dried over anhydrous sodium sulfate and then concentrated. To the resulting oily residue was added hot methanol to crystallize and cooled. The resulting precipitate was collected by filtration, added to the mixture of concentrated hydrochloric acid-methanol (1:1, 3 ml) and stirred for 2.5 hours under elevated temperature. The reaction mixture was neutralized with concentrated aqueous ammonia, the resulting precipitate was collected by filtration, washed with ice-water and recrystallized from dichloromethane-methanol-concentrated aqueous ammonia (10:10:1) to give the title compound (0.06 g) as yellow prisms, mp 225°-226.5° C. (decompd.).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][CH2:21][O:22][CH3:23])[N:14]([CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([OH:24])=[CH:5][C:4]=2[N:3]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31]O)[CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.C(#N)C>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][CH2:21][O:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:18])([OH:19])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([O:24][CH2:31][C:27]3[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=3)=[CH:5][C:4]=2[N:3]=1
Reactant: OCc1cccnc1
Reactant: COCCc1nc2c(N)nc3cc(O)ccc3c2n1CC(C)(C)O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CC#N
Product: COCCc1nc2c(N)nc3cc(OCc4cccnc4)ccc3c2n1CC(C)(C)O
Reaction time: 0.75 h
Yield: 41 %

Procedure:
4-Amino-1-(2-hydroxy-2-methylpropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-7-ol, (2.5 g, 7.5 mmol) was slurried in 75 mL of THF to which 3-pyridylcarbinol (350 mg, 3.18 mmol) and triphenylphosphine (1.59 g, 6.06 mmol) were added. To this was added 1.2 g (5.93 mmol) of diisopropyl azodicarboxylate (DIAD) and the reaction mixture was stirred for 45 minutes. Approximately 3 additional equivalents of each reagent were added to complete the reaction. The reaction mixture was then concentrated and partitioned between chloroform and aqueous sodium carbonate. The organic fraction was dried and passed through an ion exchange resin with methanol, followed by 1M ammonia in methanol as the eluents. The solvent was concentrated and the residue was purified by flash column chromatography on silica gel using a gradient of 0-40% CMA in chloroform. The desired fractions were concentrated to produce an oil which was taken up in 20 mL of refluxing acetonitrile. Upon cooling, white crystals formed which were filtered and dried to provide 0.55 g of 1-[4-amino-2-(2-methoxyethyl)-7-(pyridin-3-ylmethoxy)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol, mp 200.0-202.0° C.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[O-]CC.[Na+].[Na].Cl[CH2:18][CH2:19][O:20][CH2:21][CH2:22]Cl>C(O)C>[CH2:10]([O:9][C:1]([C:2]1([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:8])[CH3:11]
Reactant: ClCCOCCCl
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C1(C(=O)OCC)CCOCC1
Reaction time: 0.17 h
Yield: 44 %

Procedure:
A solution of diethyl malonate (15.2 mL, 99.8 mmol) in ethanol (10 mL) was added dropwise to a solution of sodium ethoxide in ethanol [freshly prepared from sodium (2.3 g, 100 mmol) and ethanol (30 mL)] at ambient temperature and stirred for 10 min. Bis(2-chloroethyl)ether (12 mL, 102 mmol) was added dropwise and the whole mixture heated at reflux overnight. It was then cooled to 10° C. before another portion of freshly-prepared sodium ethoxide in ethanol [prepared from sodium (2.3 g, 100 mmol) and ethanol (30 mL)] was added. The mixture was heated at reflux for 48 h then cooled, filtered to remove the precipitated sodium chloride then the filtrate was concentrated to dryness. Water was added to the residue which was then extracted with ether (3×25 mL). The combined ether layers were washed with water, brine and dried over anhydrous sodium sulfate. Concentration under reduced pressure yielded tetrahydropyran-4,4-dicarboxylic acid diethyl ester (10.1 g, 44%) as a mobile oil.
Reaction SMILES: ClCCl.[Cl:4][C:5]1[CH:6]=[C:7]([N:11]([O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[C:12]([C:14]2[O:15][C:16]3[C:23]([NH2:24])=[CH:22][CH:21]=[CH:20][C:17]=3[C:18]=2O)=[NH:13])[CH:8]=[CH:9][CH:10]=1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>N1C=CC=CC=1>[Cl:4][C:5]1[CH:6]=[C:7]([N:11]([O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[C:12]([C:14]2[O:15][C:16]3[C:23]([NH:24][C:32](=[O:34])[CH3:33])=[CH:22][CH:21]=[CH:20][C:17]=3[CH:18]=2)=[NH:13])[CH:8]=[CH:9][CH:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: N=C(c1oc2c(N)cccc2c1O)N(OC1CCCCO1)c1cccc(Cl)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1cccc2cc(C(=N)N(OC3CCCCO3)c3cccc(Cl)c3)oc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 99 %

Procedure:
To a dichloromethane solution of 42 mg of N-(3-chloro-phenyl)-hydroxy-7-amino-N-(tetrahydro-pyran-2-yloxy)- benzofuran-2-carboxamidine was 200 μl of pyridine and 200 μl of acetic anhydride. The resulted solution was stirred at room temperature for 20 min. The reaction mixture was concentrated under vacuum. The crude product was purified by flash chromatography on silica gel eluted with 5–10% methanol/dichloromethane to give 43 mg of N-{2-[N-(3-chloro-phenyl)-N-(tetrahydro-pyran-2-yloxy)-carbamimidoyl]-benzofuran-7-yl}-acetamide in 99% yield.
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]2[CH:10]=[CH:11][N:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:7]2=[CH:6][CH:5]=1)(=O)[CH3:2].[CH3:20][C:21]([S@:24]([NH2:26])=[O:25])([CH3:23])[CH3:22]>C1COCC1.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[C:21]([S@:24]([N:26]=[C:1]([C:4]1[N:9]=[C:8]2[CH:10]=[CH:11][N:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:7]2=[CH:6][CH:5]=1)[CH3:2])=[O:25])([CH3:23])([CH3:22])[CH3:20]
Reactant: CC(=O)c1ccc2c(ccn2C(=O)OC(C)(C)C)n1
Reactant: CC(C)(C)[S@](N)=O
Agent: [Ti+4]
Agent: CC[O-]
Solvent: C1CCOC1
Product: CC(=N[S@](=O)C(C)(C)C)c1ccc2c(ccn2C(=O)OC(C)(C)C)n1
Temperature: 75 °C
Reaction time: 16 h
Yield: 53.7 %

Procedure:
To a solution of tert-butyl 5-acetylpyrrolo[3,2-b]pyridine-1-carboxylate (2.0 g, 7.68 mmol) and (R)-2-methylpropane-2-sulfinamide (1.04 g, 8.45 mmol) dissolved in anhydrous THF (50 mL) was added titanium (IV) ethoxide (3.2 mL, 15.37 mmol) at RT under a N2 atmosphere. The reaction mixture was stirred at 75° C. under N2 for 16 h. The solvent was removed in vacuo and the crude residue was diluted with EtOAc (ca. 100 mL). The reaction mixture was vigorously stirred while a saturated solution of brine (−20 mL) was added slowly. The reaction mixture was stirred for 15 min and filtered through a pad of Celite®. The organic layer from the filtrate was washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with EtOAc/heptane to afford 1.50 g (53.7%) of (R)-tert-butyl 5-(1-(tert-butylsulfinylimino)-ethyl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate as yellow solid: 1H NMR (400 MHz, CDCl3) δ 8.38 (d, J=8.6 Hz, 1H), 8.16 (d, J=8.8 Hz, 1H), 7.88 (d, J=3.8 Hz, 1H), 6.83 (d, J=3.8 Hz, 1H), 2.94 (s, 3H), 1.69 (s, 9H), 1.35 (s, 9H); MS (ESI) m/z: 364.3 [M+1]+.
Reaction SMILES: CO[C:3]1[CH:13]=[C:12]([C@@H:14]2[CH2:16][C@H:15]2[C:17](=[O:28])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][CH2:26][NH2:27])[CH:19]=2)[CH:11]=[CH:10][C:4]=1[O:5][CH2:6][C:7]([OH:9])=[O:8].F[C:30](F)(F)C(O)=O>>[NH2:27][CH2:26][CH2:25][O:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[C:17]([C:15]1[CH:14]=[C:12]2[C:13](=[CH:30][CH:16]=1)[CH:3]=[C:4]([O:5][CH2:6][C:7]([OH:9])=[O:8])[CH:10]=[CH:11]2)=[O:28]
Reactant: COc1cc([C@@H]2C[C@H]2C(=O)c2cccc(OCCN)c2)ccc1OCC(=O)O
Reactant: O=C(O)C(F)(F)F
Product: NCCOc1cccc(C(=O)c2ccc3cc(OCC(=O)O)ccc3c2)c1

Procedure:
Ex. 315. (+/-)-trans-[[2-methoxy-4-[2-((3-(2-aminoethoxy)benzoyl))cyclopropyl]phenoxy]]acetic acid.trifluoroacetic acid. MS(NH3): 404 (5%, M+NH4), 386 (base, M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]=O.Cl.[F:11][C:12]1([F:17])[CH2:16][CH2:15][NH:14][CH2:13]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CO>[F:11][C:12]1([F:17])[CH2:16][CH2:15][N:14]([CH2:8][C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[NH2:1])[CH2:13]1
Reactant: FC1(F)CCNC1
Reactant: Nc1cnccc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Nc1cnccc1CN1CCC(F)(F)C1
Reaction time: 18 h
Yield: 56.3 %

Procedure:
3-Amino-pyridine-4-carbaldehyde (250 mg, 2.05 mmol) was dissolved in DCM (4 mL) and MeOH (4 mL), and 3,3-difluoropyrrolidine hydrochloride (353 mg, 2.46 mmol) and NaBH(OAc)3 (521 mg, 2.46 mmol) were added. The reaction mixture was stirred for 18 h, quenched with water (5 mL) and the solvents were removed in vacuo. The residue was dissolved in DCM (20 mL) and washed with sat aq Na2CO3 (5 mL). The aqueous phase was extracted with DCM (3×20 mL) and the combined organic fractions were dried (MgSO4) and concentrated in vacuo to give the crude title compound as a yellow gum (246 mg, 56%). LCMS (ES+): 214.0 (M+H)+.