Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N.C[N:3](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[O:34][C:35]3[CH:44]=[C:43]([NH:45][S:46]([CH3:49])(=[O:48])=[O:47])[C:42]([O:50][CH:51]([CH3:53])[CH3:52])=[CH:41][C:36]=3[C:37]=2[C:38](O)=[O:39])=[CH:29][CH:28]=1>CN(C=O)C.CCOC(C)=O>[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[O:34][C:35]3[CH:44]=[C:43]([NH:45][S:46]([CH3:49])(=[O:48])=[O:47])[C:42]([O:50][CH:51]([CH3:53])[CH3:52])=[CH:41][C:36]=3[C:37]=2[C:38]([NH2:3])=[O:39])=[CH:29][CH:28]=1
Reactant: CC(C)Oc1cc2c(C(=O)O)c(-c3ccc(F)cc3)oc2cc1NS(C)(=O)=O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)Oc1cc2c(C(N)=O)c(-c3ccc(F)cc3)oc2cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
Ammonia (6.1 ml, 12.2 mmol, 2M in MeOH) was added to a stirring solution of HATU (1.1 g, 2.95 mmol) and 2-(4-fluorophenyl)-5-isopropoxy-6-(methylsulfonamido)benzofuran-3-carboxylic acid (1.0 g, 2.46 mmol) in DMF (20 ml) at 0° C. It was allowed to warm to rt and stir for 1 hr. The mixture was diluted with EtOAc and washed with sat NaHCO3, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated to give the title compound (925 mg, 93%). 1H NMR (300 MHz, DMSO-D6) δ ppm 1.30-1.37 (m, 6H) 2.98 (s, 3H) 4.64-4.77 (m, 1H) 7.19 (s, 1H) 7.30-7.41 (m, 2H) 7.54 (s, 1H) 7.63-7.71 (m, 1H) 7.89 (s, 1H) 7.93-8.02 (m, 2H) 8.85 (s, 1H). LC-MS retention time: 1.26 min; m/z (MH+) 407. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([C:23](=[O:31])[C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=3)[C@@H:15]([CH3:32])[CH2:14]2)[C:9](=[O:12])[CH2:10][CH3:11])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:36][CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40].C(O)C>CN(C=O)C>[CH2:42]([O:41][C:39](=[O:40])[CH2:38][CH2:37][CH2:36][O:30][C:27]1[CH:26]=[CH:25][C:24]([C:23]([N:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@H:13]([N:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:9](=[O:12])[CH2:10][CH3:11])[CH2:14][C@@H:15]2[CH3:32])=[O:31])=[CH:29][CH:28]=1)[CH3:43]
Reactant: CCC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(O)cc2)c2ccccc21
Reactant: CCOC(=O)CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CCOC(=O)CCCOc1ccc(C(=O)N2c3ccccc3[C@H](N(C(=O)CC)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Reaction time: 0.5 h

Procedure:
(±)-Cis-4-(4-{4-[(4-chloro-phenyl)-propionyl-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxy)-butyric acid ethyl ester was prepared from (±)-cis-N-(4-chloro-phenyl)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-propionamide. (±)-Cis-N-(4-chloro-phenyl)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]-propionamide (140 mg, 0.31 mmol) was dissolved in DMF (5 mL) at room temperature. Sodium hydride (60% in oil, 32 mg, 0.81 mmol) was added and the mixture allowed to stir 30 min. Ethyl 4-bromobutyrate (207 mg, 1.06 mmol) was added and the reaction was allowed to stir over night. Ethanol was added and the reaction was concentrated in vacuo. The crude residue was purified by silica gel chromatography (80/20 hexanes/ethyl acetate-50/50 hexanes ethyl acetate gradient) to afford the product (171 mg, 0.304 mmol, 98%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=3)[N:11]=[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=3)[N:9]=2)=[CH:4][CH:3]=1.C(OB([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)O)=C.C(=O)([O-])[O-].[Na+].[Na+].[CH2:51]1COC[CH2:52]1>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>[C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:12]2[N:11]=[C:10]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:28][CH:29]=3)[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:42]4[CH:41]=[CH:40][C:39]([CH:51]=[CH2:52])=[CH:44][CH:43]=4)=[CH:3][CH:4]=3)[N:13]=2)=[CH:15][CH:16]=1)([CH3:22])([CH3:23])[CH3:21]
Reactant: C1CCOC1
Reactant: CC(C)(C)c1ccc(-c2nc(-c3ccc(Br)cc3)nc(-c3ccc(C(C)(C)C)cc3)n2)cc1
Reactant: C=COB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: C=Cc1ccc(-c2ccc(-c3nc(-c4ccc(C(C)(C)C)cc4)nc(-c4ccc(C(C)(C)C)cc4)n3)cc2)cc1

Procedure:
2.0 g (0.0040 mol) of 2-(4-bromophenyl)-4,6-bis-(4-tert-butylphenyl)-1,3,5-triazine and 0.8878 g (0.006 mol) of vinylphenylboronic acid and 0.050 g (0.0432 mmol) of Pd(PPh3)4 are initially introduced. After addition of 26 ml of sodium carbonate solution and 54 ml of THF, the mixture is brought to reaction under reflux for 24 h. For work-up, the mixture is filtered through Celite and taken up in ethyl acetate. The organic phase is extracted a number of times with water. The solvent of the combined organic phases is removed completely. A recrystallisation is carried out from chloroform/ethanol, and subsequent column chromatography is carried out with hexane:ethyl acetate. After the column chromatography, 1.6 g (76%) of clean substance are isolated.
Reaction SMILES: [C:1]1([S:7]([N:10]=[C:11]=[O:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][C:14]1[CH:15]=[C:16]([C:22]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH2:35][CH3:36])[CH:27]=2)=[CH:23][C:24]#[N:25])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]>C1COCC1>[C:1]1([S:7]([NH:10][C:11]([NH:13][C:14]2[CH:15]=[C:16]([C:22]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH2:35][CH3:36])[CH:27]=3)=[CH:23][C:24]#[N:25])[CH:17]=[CH:18][C:19]=2[O:20][CH3:21])=[O:12])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOc1cc(C(=CC#N)c2ccc(OC)c(N)c2)ccc1OC
Reactant: O=C=NS(=O)(=O)c1ccccc1
Solvent: C1CCOC1
Product: CCOc1cc(C(=CC#N)c2ccc(OC)c(NC(=O)NS(=O)(=O)c3ccccc3)c2)ccc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.1 %

Procedure:
Benzenesulfonyl isocyanate (0.4 mL, 2.6 mmol) was added to a stirred solution of (E/Z) 3-(3-amino-4-methoxy-phenyl)-3-(3-ethoxy-4-methoxy-phenyl)-acrylonitrile (0.70 g, 2.2 mmol) in anhydrous THF (25 mL). The reaction mixture was stirred at room temperature for 2 h. Removal of solvent and chromatography (Silica Gel) gave a mixture of (E/Z) 1-benzenesulfonyl-3-{5-[2-cyano-1-(3-ethoxy-4-methoxy-phenyl)-vinyl]-2-methoxy-phenyl}-urea as a solid (0.66 g, 61% yield): mp, 168-170° C.; 1H NMR (CDCl3) δ 1.38-1.46 (m, 6H, 2CH3), 3.87-4.14 (m, 16H, 4OCH3+2CH2), 5.55-5.58 (2s, 2H, 2CH), 6.78-7.98 (m, 22H, Ar), 8.03-9.06 (m, 4H, 4NH); 13C NMR (CDCl3) δ 14.67, 55.92, 55.97, 56.06, 56.24, 64.53, 92.07, 92.54, 109.82, 109.88, 110.99, 111.07, 112.65, 114.13, 118.58, 118.78, 119.77, 121.04, 122.25, 123.07, 125.52, 125.98, 126.56, 126.80, 127.02, 127.11, 129.35, 129.45, 129.50, 129.87, 131.16, 132.15, 133.96, 134.05, 139.46, 147.88, 148.19, 149.75, 150.25, 150.85, 151.59, 162.14, 162.83; Anal. Calcd for C26H25N3O6S+0.12H2O: C, 61.27; H, 4.99; N, 8.24; S, 6.29. Found: C, 60.90; H, 5.04; N, 8.05; S, 6.28.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[CH3:19][C:20]([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)([CH3:23])[CH2:21][NH2:22]>>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][NH:22][CH2:21][C:20]([CH3:23])([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH3:19])=[CH:8][C:6]=2[N:7]=1
Reactant: CC(C)(CN)N1CCOCC1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: CC(C)(CNCc1cc2nc(Cl)nc(N3CCOCC3)c2s1)N1CCOCC1

Procedure:
Following the procedures for 172, 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde and 2-methyl-2-morpholinopropan-1-amine were reacted by reductive amination to give N-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-2-methyl-2-morpholinopropan-1-amine, which was converted to the 2-tributylstannyl intermediate and reacted with 2-methyl-1H-benzo[d]imidazole to give 203. LCMS m/z: 522.2 (MH+)
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH2:4][CH2:3]1.[Br:6][C:7]1[C:8]([Cl:17])=[N:9][CH:10]=[C:11]([S:13](Cl)(=[O:15])=[O:14])[CH:12]=1>C(Cl)Cl.N1C=CC=CC=1>[N:2]1([S:13]([C:11]2[CH:12]=[C:7]([Br:6])[C:8]([Cl:17])=[N:9][CH:10]=2)(=[O:15])=[O:14])[CH2:5][CH2:4][CH2:3]1
Reactant: C1CNC1
Reactant: O=S(=O)(Cl)c1cnc(Cl)c(Br)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(c1cnc(Cl)c(Br)c1)N1CCC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 37.3 %

Procedure:
Azetidine hydrochloride (0.32 g, 3.44 mmol) was added to a solution of 3-bromo-2-chloropyridine-5-sulfonyl chloride (1 g, 3.44 mmol) in DCM (4 mL) and pyridine (10 mL) and stirred at RT for 22 hours. The solvent was removed in vacuo and ethyl acetate (30 mL) added. The organic phase was washed with 1M hydrochloric acid (20 mL), water (20 mL), brine (20 mL), dried (MgSO4), filtered and the solvent removed in vacuo to give the desired compound (0.4 g).
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:10][C:9](=[S:18])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][Cl:24]>CCO>[ClH:24].[Br:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][S:18][C:9]1[NH:8][C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C@H:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=1
Reactant: ClCc1cccc(Br)c1
Reactant: S=C1N[C@H](c2ccccc2)[C@H](c2ccccc2)N1
Solvent: CCO
Product: Brc1cccc(CSC2=N[C@@H](c3ccccc3)[C@@H](c3ccccc3)N2)c1
Product: Cl
Temperature: 25 °C
Yield: 82.5 %

Procedure:
A mixture of intermediate 25 (200 mg, 0.786 mmol) and 3-bromobenzyl chloride (0.201 mL, 1.57 mmol) in abs. EtOH (2 mL) is heated at 95° C. for 24 h. The reaction mixture is cooled to RT, evaporated to dryness, and the residue suspended in Et2O. The insoluble material is filtered to give 298 mg of the product 220. 1H NMR (DMSO-d6) δ 11.30 (s, 2H), 7.95-7.80 (m, 1H), 7.75-7.50 (m, 2H), 7.50-7.35 (m, 1H), 7.15-6.90 (m, 6H), 6.90-6.60 (m, 4H), 5.78 (s, 2H), 4.80 (s, 2H); MS: m/z 423 (M++1).
Reaction SMILES: [C:1](O)([C:3](F)(F)F)=[O:2].N1C2C(=NC=CC=2)N(N2C(/C=[C:23]3\[C:24](=[O:33])[NH:25][C:26]4[C:31]\3=CC(F)=CC=4)=C(C)C(C([O-])=O)=C2C)N=1.CC[N:41](C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[NH2:41][C@H:23]1[CH2:31][CH2:26][N:25]([CH2:3][CH2:1][OH:2])[C:24]1=[O:33]
Reactant: O=C(O)C(F)(F)F
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1c(C(=O)[O-])c(C)n(-n2nnc3cccnc32)c1/C=C1\C(=O)Nc2ccc(F)cc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N[C@H]1CCN(CCO)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 233.2 %

Procedure:
NaBH4 (85 mg, 2.24 mmol) was added to a solution of 40b (160 mg, 0.56 mmol) in ter-butyl alcohol (5 mL). The temperature was brought to 80° C., and MeOH (0.6 mL) was added slowly. The resulting mixture was kept under reflux for 2 h. After cooling under an ice bath, H2O (20 mL) was added and the alcohols were evaporated under vacuum. The aqueous phase was extracted with EA for several times. The organic layer was dried over anhydrous MgSO4 and concentrated. The residue was purified by Prep TLC to provide 41a (38 mg). To a solution of compound 41a (38 mg, 0.156 mmol) in 5 mL of DCM, was added TFA (0.18 mL, 2.34 mmol). The resulting mixture was stirred at r.t. for about 1 h and evaporated. The residue was added to a solution of A4 (36 mg, 0.086=101) and DIEA (0.08 mL, 0.43 mmol) in 20mL of DMF. The reaction Mixture was stirred at room temperature for several hours. LC/MS detection was applied to determine completion of the reaction. DMF was evaporated under reduced pressure and the residue was precipitated with 5% diethylamine/methanol (5 mL) The precipitate was collected by filtration, washed with ethanol and dried in vacuo to give an orange solid (29 mg, 79.2% yield): 1H NMR (300 MHz, DMSO-d6): δ=13.69 (s, 1H), 10.91 (s, 1H), 7.72-7.85 (m, 3H), 6.82-6.96 (m, 2H), 4.58-4.74 (m, 2H), 3.37-3.54 (m, 4H), 3.12-3.20 (m, 1H), 1.87-2.45 (m, 8H), 1.23-1.97 (m, 1H). LC/MS: 427.0 [M+H]+.
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]#[C:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH3:15])=[CH:8][CH:7]=1.[N:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[CH:17]=1>C(#N)C>[Br-:1].[CH2:12]([C:9]1[CH:10]=[CH:11][C:6]([C:5]#[C:4][CH2:3][CH2:2][N+:16]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[CH:17]=2)=[CH:7][CH:8]=1)[CH2:13][CH2:14][CH3:15]
Reactant: Cc1cncc(C)c1
Reactant: CCCCc1ccc(C#CCCBr)cc1
Solvent: CC#N
Product: CCCCc1ccc(C#CCC[n+]2cc(C)cc(C)c2)cc1
Product: [Br-]
Yield: 80 %

Procedure:
1-(4-Bromo-but-1-ynyl)-4-butyl-benzene (1 mmol) was added to a solution of 3,5-lutidine (2 mmol) in acetonitrile, and the solution was refluxed for 24 hours. The acetonitrile was removed in a vacuum, and the resulting residue was partitioned between ether and water. The aqueous layer was washed extensively with ether until no lutidine was left in the aqueous layer. The resulting aqueous solution of the product was extracted with chloroform. The chloroform was removed to afford the product (80%). 1HNMR (300 MHz, CDCl3, ppm), 9.39 (s, 1H), 9.13 (d, J=6.3, 1H), 7.70 (d, J=6.3, 1H), 7.17 (d, J=8.1, 2H), 7.07 (d, J=8.1, 2H), 5.13 (t, J=6.0, 2H), 3.23 (t, J=6.0, 2H), 2.57 (t, J=7.8, 2H), 2.53 (s, 3H), 2.48 (s, 3H), 1.50-1.58 (m, 2H), 1.28-1.37 (m, 2H), 0.90 (t, J=7.2, 3H); 13CNMR, 158.19, 143.98, 138.11, 131.53, 128.69, 128.05, 119.45, 83.11, 59.60, 35.84, 33.64, 23.12, 22.62, 20.77, 17.35, 14.23.
Reaction SMILES: [I-].[Na+].Br[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[C:14](=[O:20])[N:13]([CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)[C:12]1[C:30]3[CH:31]=[C:32]4[O:40][CH2:39][O:38][C:33]4=[CH:34][C:35]=3[C:36](=[O:37])[C:11]2=1.[CH3:41][NH:42][CH3:43]>O1CCOCC1.C(Cl)(Cl)Cl>[CH3:41][N:42]([CH3:43])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[C:14](=[O:20])[N:13]([CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)[C:12]1[C:30]3[CH:31]=[C:32]4[O:40][CH2:39][O:38][C:33]4=[CH:34][C:35]=3[C:36](=[O:37])[C:11]2=1
Reactant: CNC
Reactant: COc1cc2c(=O)n(CCCN3CCOCC3)c3c(c2cc1OCCCBr)C(=O)c1cc2c(cc1-3)OCO2
Agent: [I-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: COc1cc2c(=O)n(CCCN3CCOCC3)c3c(c2cc1OCCCN(C)C)C(=O)c1cc2c(cc1-3)OCO2
Yield: 48.2 %

Procedure:
Sodium iodide (0.061 g, 0.408 mmol) and compound 19 (0.020 g, 0.034 mmol) were diluted with dioxane (10 mL), and dimethylamine (0.023 mL, 0.408 mmol) was added dropwise. The mixture was stirred at reflux for 52 h. The mixture was diluted to a volume of 250 mL with CHCl3, washed with H2O (2×50 mL) and saturated aq NaCl (50 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography (SiO2, ˜40 g), eluting first with a gradient of 0.5% MeOH in CHCl3, and then with 1% MeOH in CHCl3, to yield the product 23 as a solid (0.009 g, 47%): mp 176-178° C. (dec). IR (film) 2922, 1698, 1650, 1483, 1306, 1032, 786 cm−1: 1H NMR (CDCl3) δ 8.02 (s, 1H), 7.63 (s, 1H), 7.43 (s, 1H), 7.08 (s, 1H), 6.09 (s, 2H), 4.54-4.48 (t, 8.4 Hz, 2H), 4.29-4.25 (t, J=6.3 Hz, 2H), 3.95 (s, 3H), 3.78-3.74 (t, J=4.8 Hz, 2H), 2.57-2.53 (m, 14H), 2.27 (s, 2H), 2.03-2.02 (m, 2H); ESIMS m/550 (MH+); HRESIMS m/z 550.2558 (MH+), calcd for C30H36N3O7 550.2553; HPLC purity: 97.57% (C-18 reverse phase. MeOH—H2O, 85:15).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[F:11][C:12]1[C:13]([O:19][CH3:20])=[N:14][C:15](F)=[CH:16][CH:17]=1>C1COCC1.O>[CH2:1]([O:8][C:15]1[N:14]=[C:13]([O:19][CH3:20])[C:12]([F:11])=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1nc(F)ccc1F
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1nc(OCc2ccccc2)ccc1F
Reaction time: 0.5 h
Yield: 41.6 %

Procedure:
step 2—To a solution of benzyl alcohol (1.12 g, 10.3 mmol) in THF was added NaH (0.413 g, 10.3 mmol, 60% mineral oil dispersion) and stirred for 30 min. To this solution was added 140 (1.5 g, 10.3 mmol) and the resulting solution was irradiated in the microwave synthesizer at 100° C. for 1 h. The reaction was cooled, diluted with H2O, extracted with EtOAc (2×50 mL). The combined extracts were washed with brine, dried (Na2SO4), filtered and concentrated. The crude product was purified by SiO2 chromatography to afford 1 g (41%) of 6-benzyloxy-3-fluoro-2-methoxy-pyridine (142).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1)[CH3:2].[CH3:10][I:11]>CC(C)=O>[I-:11].[CH2:1]([N+:3]1([CH3:10])[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCC(=O)CC1
Reactant: CI
Solvent: CC(C)=O
Product: CC[N+]1(C)CCC(=O)CC1
Product: [I-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 100 g (0.789 mol) of 1-ethyl-4-oxopiperidine in 1000 mL of acetone was stirred at rt in a water bath. To this was added 62.2 mL (142 g, 1 mol) of methyl iodide, dropwise at such a rate to keep the temperature below 30 degrees. A precipitate developed within minutes and the mixture was stirred at rt for 4 h. The mixture was filtered and the precipitate washed with acetone and dried to afford the title compound as a white solid. Mass spectrum (ESI) 142 (M+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:11]([OH:27])=[CH:12][C:13]([O:16][Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])=[CH:14][CH:15]=1.C(N(CC)C(C)C)(C)C.[CH3:37][O:38][CH2:39]Cl.[Cl-].[NH4+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][Si:17]([CH:21]([CH3:23])[CH3:22])([CH:24]([CH3:26])[CH3:25])[CH:18]([CH3:20])[CH3:19])=[CH:12][C:11]=1[O:27][CH2:37][O:38][CH3:39]
Reactant: COc1ccc(F)c(-c2ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc2O)c1
Reactant: COCCl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCOc1cc(O[Si](C(C)C)(C(C)C)C(C)C)ccc1-c1cc(OC)ccc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2′-fluoro-5′-methoxy-4-((triisopropylsilyl)oxy)biphenyl-2-ol (4.01 g) and N,N-diisopropylethylamine (5.4 mL) in DMF (30 mL) was added chloromethyl methyl ether (1.5 mL), and the mixture was stirred at room temperature for 3 hr. The mixture was further stirred at 50° C. for 1 hr, and saturated aqueous ammonium chloride solution was added to the reaction mixture. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the residue was dissolved in DMF (30 mL), and N,N-diisopropylethylamine (2.7 mL) and chloromethyl methyl ether (1.0 mL) were added. The reaction mixture was stirred at room temperature for 2 hr, and saturated aqueous ammonium chloride solution was added. The reaction mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (3.50 g) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[F:11].O.C(O)(=O)C>[Fe].C(O)C>[Br:1][C:2]1[C:3]([F:11])=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cccc(Br)c1F
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: Nc1cccc(Br)c1F

Procedure:
1-Bromo-2-fluoro-3-nitro-benzene (3 g, 13.64 mmol), iron (2.28 g, 40.91 mmol), water (34.39 ml, 1909 mmol) and acetic acid (11.7 ml, 204.55 mmol) were added to ethanol (60 ml) and heated to reflux for 2 h. The reaction mixture was then filtered through Celite and evaporated. Water was added and the solution was made basic by the addition of 2 N NaOH, followed by extraction with DCM. The organic layers were washed with water and brine, dried with Na2SO4 evaporated to dryness and the crude product was obtained and used without further purification. Yield: 1.46 g, 56%
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[CH:5]=[O:6].[C:12](#[N:14])[CH3:13]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]([OH:6])[CH2:13][C:12]#[N:14])[CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1
Reactant: COc1cc(Br)cc(C=O)c1
Reactant: CC#N
Product: COc1cc(Br)cc(C(O)CC#N)c1

Procedure:
Alkylation of 3-bromo-5-methoxybenzaldehyde with acetonitrile following the method used in Example 115 gave 3-(3-bromo-5-methoxyphenyl)-3-hydroxypropanenitrile as a pale yellow oil. Yield (4.1 g, 70%): 1H NMR (400 MHz, DMSO-d6) δ 7.16-7.15 (m, 1H), 7.04-7.03 (m, 1H), 6.97-6.96 (m, 1H), 6.04 (d, J=4.8 Hz, 1H), 4.87-4.83 (m, 1H), 3.74 (s, 3H), 2.89 (ABd, J=16.4, 5.2 Hz, 1H), 2.81 (ABd, J=16.8, 6.8 Hz, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=O)=[CH:5][CH:4]=1)#[N:2].[CH2:19]([N:21]1[C:33]2[CH:32]=[CH:31][C:30]([NH2:34])=[CH:29][C:28]=2[C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH3:20]>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([NH:34][C:30]2[CH:31]=[CH:32][C:33]3[N:21]([CH2:19][CH3:20])[C:22]4[C:27]([C:28]=3[CH:29]=2)=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:17])=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(NC(=O)CCCCC(=O)O)cc1
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Product: CCn1c2ccccc2c2cc(NC(=O)CCCCC(=O)Nc3ccc(C#N)cc3)ccc21

Procedure:
Using the compound obtained in Step 1 and 9-ethyl-9H-carbazol-3-amine, and by the reaction and purification in the same manner as in the method described in Step 2 of Example 3, the title compound was obtained.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:24][N:25]1[C:29]([C:30](=O)[C:31]([O:33][CH3:34])=[O:32])=[C:28]([O:36][CH2:37][C:38]2[N:39]=[C:40]([CH3:43])[S:41][CH:42]=2)[C:27]([CH3:44])=[N:26]1.O>C1COCC1.CCCCCC>[CH3:24][N:25]1[C:29](/[C:30](=[CH:2]\[O:3][CH3:4])/[C:31]([O:33][CH3:34])=[O:32])=[C:28]([O:36][CH2:37][C:38]2[N:39]=[C:40]([CH3:43])[S:41][CH:42]=2)[C:27]([CH3:44])=[N:26]1
Reactant: COC(=O)C(=O)c1c(OCc2csc(C)n2)c(C)nn1C
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CO/C=C(/C(=O)OC)c1c(OCc2csc(C)n2)c(C)nn1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38 %

Procedure:
To a suspension of methoxymethyltriphenylphosphonium chloride (2 g, 5.84 mmol) in anhyrous THF was added 3.5 ml solution of lithium n-butylate (1.6 mol) in hexane. After stirring at room temperature for 30 minutes, methyl {1,3-dimethyl-4-[1-(2-methylthiazol-4-yl)methyloxy]pyrazol-5-yl}glyoxalate (0.6 g, 1.95 mmol) in anhydrous THF (6 ml) was added thereto and the mixture was allowed to stand for two hours. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over magnesium sulfate and concentrated in vacuo. The residue was chromatographed over silica gel to obtain (E)-methyl 2-{1,3-dimethyl-4-[1-(2-methylthiazol-4-yl)methyloxy]pyrazol-5-yl}-3-methoxyacrylate (compound No. 9 in Table 1) as an oil (0.25 g, 38.1%).