Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].C([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[N:18][C:19]([NH:40][C@H:41]([CH2:43][CH3:44])[CH3:42])=[C:20]([N:25]3[CH2:30][CH2:29][CH:28]([O:31][C:32]4[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=4[F:39])[CH2:27][CH2:26]3)[N:21]=2)[CH2:16]1)C1C=CC=CC=1>C1COCC1.[OH-].[OH-].[Pd+2]>[C@@H:41]([NH:40][C:19]1[N:18]=[C:17]2[CH2:16][NH:15][CH2:24][CH2:23][C:22]2=[N:21][C:20]=1[N:25]1[CH2:30][CH2:29][CH:28]([O:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[F:39])[CH2:27][CH2:26]1)([CH2:43][CH3:44])[CH3:42].[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: CC[C@H](C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCN(Cc1ccccc1)C2
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCNC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of (S)-6-benzyl-N-(sec-butyl)-2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (212.2 mg, 0.341 mmol) in THF (3.4 mL) was treated with Pd(OH)2 (20 wt %, 71.9 mg, 0.102 mmol). Hydrogen gas (balloon) was bubbled through the reaction mixture for 5 min. The vent needle was removed and the reaction mixture was stirred at room temperature under hydrogen atmosphere for 3 h. The reaction mixture was opened to air and filtered through a pad of Celite™, eluting with EtOAc and MeOH. The filtrate was collected and concentrated under reduced pressure to give (S)—N-(sec-butyl)-2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine as a TFA salt (169.0 mg) as a yellow oil, which was carried forward without additional purification. ESI-MS m/z [M+H]+ 418.5.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].N1C=CC=CC=1.[C:12]1([CH2:18][CH2:19][C:20](Cl)=[O:21])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCl>[CH3:5][O:4][N:3]([CH3:2])[C:20](=[O:21])[CH2:19][CH2:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CNOC
Reactant: O=C(Cl)CCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CON(C)C(=O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of N,O-dimethylhydroxylamine hydrochloride (1.1 g) and pyridine (1.82 mL) in dichloromethane (50 mL) was added 3-phenylpropionyl chloride (1.52 mL) under ice-cooling, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure. To the residue was added 1 mol/L hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (1.89 g).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[O:3][C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][CH:27]=1)[O:7][CH:8]1[CH2:11][N:10]([C:12]2[N:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:13]=2[C:14](O)=[O:15])[CH2:9]1.Cl.[NH2:31][C:32]1([C:35]2[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][CH:36]=2)[CH2:34][CH2:33]1>>[F:29][C:2]([F:1])([F:28])[O:3][C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][CH:27]=1)[O:7][CH:8]1[CH2:11][N:10]([C:12]2[N:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][C:13]=2[C:14]([NH:31][C:32]2([C:35]3[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][CH:36]=3)[CH2:34][CH2:33]2)=[O:15])[CH2:9]1
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Reactant: O=C(O)c1cc(C(F)(F)F)cnc1N1CC(Oc2cccc(OC(F)(F)F)c2)C1
Agent: Cl
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(C(F)(F)F)cnc3N3CC(Oc4cccc(OC(F)(F)F)c4)C3)CC2)cc1
Yield: 73 %

Procedure:
The title compound (D177) (113 mg) was prepared according to the experimental procedure described in Description 144 starting from 2-(3-(3-(trifluoromethoxy)phenoxy)azetidin-1-yl)-5-(trifluoromethyl)nicotinic acid (D126) (110 mg, 0.26 mmol) and methyl 4-(1-aminocyclopropyl)benzoate (D7) (59.31 mg, 0.26 mmol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[S:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH:12]=[C:11]1[S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl.N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:19]([C:11]2[S:10][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH:12]=2)(=[O:21])=[O:20])=[C:4]([NH:9][S:19]([C:11]2[S:10][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH:12]=2)(=[O:20])=[O:21])[CH:3]=1
Reactant: O=S(=O)(Cl)c1cc2ccccc2s1
Reactant: Nc1ccc(F)cc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc(F)cc1NS(=O)(=O)c1cc2ccccc2s1)c1cc2ccccc2s1
Temperature: 25 °C
Yield: 37 %

Procedure:
To a solution of 4-fluorobenzene-1,2-diamine (1 mmol) in DCM (2 mL) and pyridine (2 mL) at 0° C., benzothiophene-2-sulfonyl chloride (2.2 mmol) was added in small portions. The reaction mixture was then stirred at rt until the reaction was complete as determined by TLC or LC-MS. The reaction mixture was then diluted with DCM (15 mL). The organic phase was washed with 10% aqueous HCl (5 mL), water (5 mL), and 5 mL of brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM/EtOAc to obtain 192 mg of N,N′-(4-fluoro-1,2-phenylene)bis(1-benzothiophene-2-sulfonamide) as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:8]=2)[N:3]=1.CC(=CC)C.Cl([O-])=[O:29].[Na+].P([O-])(O)(O)=O.[Na+]>C(O)(C)(C)C.O>[C:19]([O:18][C:16](=[O:17])[CH2:15][O:14][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([Cl:1])[C:11]([C:12]([OH:29])=[O:13])=[CH:10]2)([CH3:22])([CH3:21])[CH3:20]
Reactant: [O-][Cl+][O-]
Reactant: CC(C)(C)OC(=O)COc1ccc2nc(Cl)c(C=O)cc2c1
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C)OC(=O)COc1ccc2nc(Cl)c(C(=O)O)cc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
To a suspension of tert-butyl 2-(2-chloro-3-formylquinolin-6-yloxy)acetate (3.6 g, 11 mmol) in tert-butanol (150 mL) was added 2-methyl-2-butene (14.9 mL, 133 mmol) and a solution of sodium chlorite (8.27 g, 73.1 mmol) and sodium dihydrogenphosphate (8.10 g, 58.7 mmol) in water (50 mL). The reaction was allowed to stir at room temperature for 1 hour. The tert-butanol was removed in vacuo. The mixture was diluted with water (60 mL) and acidified to pH=4 with 1 N aqueous hydrochloric acid. The resulting precipitate was filtered, washed with water, and dried under vacuum to give the title compound (3.7 g, 100%) as a white solid. +ESI (M+H) 338.1; 1H NMR (400 MHz, CD3OD, δ): 8.69 (s, 1 H), 7.89 (d, J=9.19 Hz, 1 H), 7.56 (dd, J=9.19, 2.74 Hz, 1 H), 7.34 (d, J=2.93 Hz, 1 H), 4.76 (s, 2 H), 1.49 (s, 9 H).
Reaction SMILES: N1C(C)=CC=CC=1C.[CH2:9]([C:11]([C:30]1[CH:35]=[CH:34][C:33]([C:36]#[C:37][C:38]2([OH:43])[CH2:42][CH2:41][CH2:40][CH2:39]2)=[C:32]([CH3:44])[CH:31]=1)([C:14]1[CH:19]=[CH:18][C:17]([B:20]2[O:24][C:23]([CH3:26])([CH3:25])[C:22]([CH3:28])([CH3:27])[O:21]2)=[C:16]([CH3:29])[CH:15]=1)[CH2:12][CH3:13])[CH3:10].O([Si:53]([CH3:56])([CH3:55])[CH3:54])S(C(F)(F)F)(=O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:9]([C:11]([C:14]1[CH:19]=[CH:18][C:17]([B:20]2[O:24][C:23]([CH3:25])([CH3:26])[C:22]([CH3:27])([CH3:28])[O:21]2)=[C:16]([CH3:29])[CH:15]=1)([C:30]1[CH:35]=[CH:34][C:33]([C:36]#[C:37][C:38]2([O:43][Si:53]([CH3:56])([CH3:55])[CH3:54])[CH2:39][CH2:40][CH2:41][CH2:42]2)=[C:32]([CH3:44])[CH:31]=1)[CH2:12][CH3:13])[CH3:10]
Reactant: CCC(CC)(c1ccc(C#CC2(O)CCCC2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CCC(CC)(c1ccc(C#CC2(O[Si](C)(C)C)CCCC2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reaction time: 1 h
Yield: 87.4 %

Procedure:
2,6-Lutidine (1.24 mL, 10.6 mmol) was added to a solution of 1-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenylethynyl)-cyclopentanol (Example 32-(3); 1.04 g, 2.13 mmol) in dichloromethane (10.7 mL). Trimethylsilyl triflate (0.92 mL, 5.13 mmol) was added at 0° C., and the mixture was directly stirred for one hour. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (3% ethyl acetate/hexane) to give the title compound (1.04 g, 87%).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH:8]2[CH2:10][CH2:9]2)[S:6][CH:7]=1.CS(C)=[O:13]>CCOC(C)=O.O=[Mn]=O>[CH:8]1([C:5]2[S:6][CH:7]=[C:3]([CH:2]=[O:13])[N:4]=2)[CH2:10][CH2:9]1
Reactant: CS(C)=O
Reactant: ClCc1csc(C2CC2)n1
Agent: O=[Mn]=O
Solvent: CCOC(C)=O
Product: O=Cc1csc(C2CC2)n1
Temperature: 100 °C
Yield: 38 %

Procedure:
To a solution of 4-(chloromethyl)-2-cyclopropylthiazole (3.0 g, 17.2 mmol) in DMSO (10 mL) was charged MnO2 (1.5 g, 17.2 mmol). The mixture was heated to 100° C. overnight, cooled to room temperature and diluted with EtOAc (30 mL). The mixture was filtered through Celite and washed with EtOAc (3×30 mL). The combined organic layer was washed with brine (3×40 mL) and concentrated. The residue was purified by silica gel chromatography using 2 to 5% EtOAc in hexane to afford the title compound (1.0 g, 38%) as a light brown oil, which solidified upon standing in a refrigerator overnight. 1H NMR (400 MHz, CDCl3) δ 9.91 (s, 1H), 7.93 (s, 1H), 2.36 (m, 1H), 1.20 (m, 2H), 1.16 (m, 2H). MS (ES) m/z 154.1 (M+H+).
Reaction SMILES: Br[CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].CC[N:16]([CH:20]([CH3:22])C)[CH:17]([CH3:19])C.N1CCCC1>C(#N)C>[C:8]1([CH:2]([N:16]2[CH2:17][CH2:19][CH2:22][CH2:20]2)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)C(Br)c1ccccc1
Solvent: CC#N
Solvent: C1CCNC1
Product: CCOC(=O)C(c1ccccc1)N1CCCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 109.8 %

Procedure:
Ethyl 2-bromo-2-phenylacetate (0.22 ml, 1.23 mmol) was dissolved in acetonitrile (4.0 ml). DIPEA (0.26 ml, 1.48 mmol) and pyrrolidine (0.12 ml, 1.48 mmol) were sequentially added and the solution was stirred at room temperature for 1.5 hours. Acetonitrile was evaporated and the residue was purified by flash chromatography (petroleum ether/EtOAc=9/1) to obtain ethyl 2-phenyl-2-(pyrrolidin-1-yl)acetate (315 mg, quantitative yield) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][N:4]([CH3:7])[N:3]=1.C[O:9][C:10]([C:12]1[CH:22]=[C:21]([O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=2)[C:15]2[CH2:16][C:17]([CH3:20])([CH3:19])[O:18][C:14]=2[CH:13]=1)=O>>[CH3:7][N:4]1[CH:5]=[CH:6][C:2]([NH:1][C:10]([C:12]2[CH:22]=[C:21]([O:23][C:24]3[CH:25]=[CH:26][C:27]([C:30]#[N:31])=[CH:28][CH:29]=3)[C:15]3[CH2:16][C:17]([CH3:20])([CH3:19])[O:18][C:14]=3[CH:13]=2)=[O:9])=[N:3]1
Reactant: Cn1ccc(N)n1
Reactant: COC(=O)c1cc(Oc2ccc(C#N)cc2)c2c(c1)OC(C)(C)C2
Product: Cn1ccc(NC(=O)c2cc(Oc3ccc(C#N)cc3)c3c(c2)OC(C)(C)C3)n1

Procedure:
The title compound was prepared in a similar manner as described for Example 1, from 3-amino-1-methyl-pyrazole (366 mg, 3.96 mmol) and 4-(4-cyano-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (187a) (128 mg, 0.396 mmol) to give a white solid (121 mg, 77% yield). 1H NMR (400 MHz, CDCl3) δ 8.80 (s, 1 H) 7.56-7.69 (m, 2 H) 7.21-7.33 (m, 1 H) 6.97-7.09 (m, 4 H) 6.79 (d, J=2.02 Hz, 1 H) 3.75 (s, 3 H) 2.88 (s, 2 H) 1.49 (s, 6 H); LCMS for C22H20N4O3 m/z 389.20 (M+H+).
Reaction SMILES: [CH2:1]([OH:13])[C@H:2]([OH:12])[C@@H:3](O)[C@H:4]([OH:10])[C:5]([C:7]([OH:9])=[O:8])=[O:6]>O>[O:8]=[C:7]1[O:9][C@H:3]([C@H:2]([CH2:1][OH:13])[OH:12])[C:4]([OH:10])=[C:5]1[OH:6]
Reactant: O=C(O)C(=O)[C@@H](O)[C@H](O)[C@@H](O)CO
Solvent: O
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Yield: 7801.7 %

Procedure:
A mixture of 2-keto-L-gulonic acid (250 g, 1.15 mol, content: 89.6%, water: 8.6%) and trimethylcetylammonium chloride (0.275 g) was stirred in toluene (960 ml), and 36% conc. hydrochloric acid (30.0 g) was added. At this time, the amount of water in the reaction system was calculated as 2.0 mol per mol of 2-keto-L-gulonic acid. This mixture was stirred at 60° C. for 1 hour, a solution of hydrogen chloride gas (30.0 g) in ethylene glycol dimethyl ether (130 g) was added, and the mixture was stirred at the same temperature for 5 hours. Then, about 1200 g of the solvent was distilled away under reduced pressure while continuously introducing toluene (850 ml). The residue was filtered to give crude crystals of L-ascorbic acid. The crude crystals were dissolved in water. Quantitative analysis of the solution by high performance liquid chromatography (HPLC) showed that the solution contained L-ascorbic acid (191.1 g, yield: 94.1%) and 2-keto-L-gulonic acid (2.7 g, residual ratio: 1.2%).
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15](N(OC)C)=[O:16])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:21]1([Mg]Br)[CH2:23][CH2:22]1.C(=O)=O.CC(C)=O>C1COCC1>[CH:1]1([O:7][C:8]2[CH:9]=[CH:10][C:11]([CH2:14][C:15]([CH:21]3[CH2:23][CH2:22]3)=[O:16])=[CH:12][CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CON(C)C(=O)Cc1ccc(OC2CCCCC2)cc1
Reactant: Br[Mg]C1CC1
Agent: O=C=O
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: O=C(Cc1ccc(OC2CCCCC2)cc1)C1CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 70.9 %

Procedure:
To a stirred solution of 2-(4-cyclohexyloxy-phenyl)-N-methoxy-N-methyl-acetamide (Example 14, 1.31 mmol, 0.36 g) in anhydrous THF (1 mL) at −78° C. was added cyclopropylmagnesium bromide (2 M in diethyl ether, 2.62 mmol, 5.25 mL) dropwise over 5 minutes. The reaction was stirred for 30 minutes at −78° C. The dry ice/acetone bath was replaced with an ice bath and the reaction was stirred for an additional 30 min. The reaction mixture was quenched by addition of saturated ammonium chloride (5 mL) and extracted with ethyl acetate (2×10 mL). The combined ethyl acetate layers were washed with brine (5 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified on a 12 g SiO2 column with 6-8% ethyl acetate in hexanes to give 2-(4-cyclohexyloxy-phenyl)-1-cyclopropyl-ethanone (0.24 g).
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[CH3:17][N:18]([CH2:30][C:31]1[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=1)[C:19]1[S:20][CH:21]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:23]=1.O>O1CCCC1>[CH3:17][N:18]([CH2:30][C:31]1[CH:32]=[CH:33][C:34](/[CH:35]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:37][CH:38]=1)[C:19]1[S:20][CH:21]=[C:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:23]=1
Reactant: CN(Cc1ccc(C=O)cc1)c1nc(-c2ccccc2)cs1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)/C=C/c1ccc(CN(C)c2nc(-c3ccccc3)cs2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.6 %

Procedure:
To an ice-cooled solution of ethyl diethylphosphonoacetate (0.81 g, 3.6 mmol) in tetrahydrofuran (10 mL) was added 60% sodium hydride (0.14 g, 3.4 mmol), and the mixture was stirred for 30 min. A solution of 4-[[methyl(4-phenyl-2-thiazolyl)amino]methyl]benzaldehyde (0.80 g, 2.6 mmol) in tetrahydrofuran (10 mL) was added dropwise. The mixture was stirred at room temperature for 3 hrs, water was added, and the mixture was extracted with ethyl acetate. The extract was dried and concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=18:1) to give the title compound (0.96 g, yield 98%) as a powder.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:17]=[CH:16][O:15][N:14]=2)[CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[CH3:18]S(O)(=O)=O>CO>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:17]=[CH:16][O:15][N:14]=2)[CH2:9][C:10]([O:12][CH3:18])=[O:11])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)O
Reactant: O=C(O)CC(c1ccc(O)cc1)c1ccon1
Solvent: CO
Product: COC(=O)CC(c1ccc(O)cc1)c1ccon1
Temperature: 0 °C
Yield: 44 %

Procedure:
To a 100 mL RB flask fitted with magnetic stirrer was charged 20 mL of methanol. To the stirred solvent added 3-(4-hydroxyphenyl)-3-(1,2-oxazol-3-yl) propanoic acid (1.48 g, 6.34 mmol) and cooled to 0° C., added 1 mL of methanesulfonic acid. The resulting mixture was stirred at reflux temperature for 2 h. After completion of the reaction (reaction monitored by TLC), the solvent was removed under reduced pressure and the crude mass was dissolved in ethyl acetate (25 mL). The organic layer was washed with water (50 mL), saturated brine solution (50 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The product was obtained as pale yellow color oil (0.69 g, Yield: 44%): MS (ESI, 120 eV): m/z=248.9 (M+H)+; 1H NMR (300 MHz, CDCl3): δ 8.20 (s, 1H), 7.01-7.04 (d, 2H), 6.66-6.69 (d, 2H), 6.00 (d, 1H), 5.56 (bro s, 1H), 4.46-4.51 (t, 1H), 3.56 (s, 3H), 3.17-3.25 (q, 1H), 2.83-2.91 (q, 1H).
Reaction SMILES: [N:1]1[C:10]2[CH:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:26])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[I-].[K+].Cl[CH2:39][C:40]1[NH:44][C:43]2[C:45]([F:49])=[CH:46][CH:47]=[CH:48][C:42]=2[N:41]=1>C(#N)C>[F:49][C:45]1[C:43]2[N:44]=[C:40]([CH2:39][N:11]([CH:9]3[C:10]4[N:1]=[CH:2][CH:3]=[CH:4][C:5]=4[CH2:6][CH2:7][CH2:8]3)[CH2:12][CH2:13][CH2:14][CH2:15][N:16]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:26])[NH:41][C:42]=2[CH:48]=[CH:47][CH:46]=1
Reactant: Fc1cccc2nc(CCl)[nH]c12
Reactant: O=C1c2ccccc2C(=O)N1CCCCNC1CCCc2cccnc21
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1c2ccccc2C(=O)N1CCCCN(Cc1nc2c(F)cccc2[nH]1)C1CCCc2cccnc21
Temperature: 60 °C
Yield: 41 %

Procedure:
To a stirred solution of 2-[4-(5,6,7,8-tetrahydro-quinolin-8-ylamino)-butyl]-isoindole-1,3-dione (146 mg, 0.418 mmol), diisopropylethylamine (0.15 mL, 0.861 mmol) and potassium iodide (14 mg, 0.084 mmol) in acetonitrile (2.5 mL) was added 2-chloromethyl-7-fluoro-1H-benzimidazole (prepared according to the procedures described in Bridger et al. U.S. Provisional Application No. 60/232,891 filed Sep. 15, 2000 and from Application No. 60/234,510 filed Sep. 22, 2000) (80 mg, 0.433 mmol) and the mixture heated at 60° C. for 18 hours. The mixture was then concentrated and the residue diluted with CH2Cl2 (30 mL). The solution was washed with brine (3×15 mL). The combined aqueous phase was extracted with CH2Cl2 (1×15 mL). The combined organic phase was dried (Na2SO4), filtered and concentrated under reduced pressure to give a crude brown foam. The foam was purified by flash chromatography (1.75 cm ID, 12 g silica, 50:1:1 CH2Cl2: MeOH: NH4OH) to give pure 2-{4-[(4-fluoro-1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-butyl}-isoindole-1,3-dione (86 mg, 41%). 1H NMR (CDCl3) δ 1.33-1.76 (m, 5H), 1.85-2.10 (m, 3H), 2.14-2.25 (m, 1H), 2.54-2919 (m, 4H), 3.45-3.55 (m, 2H), 3.98-4.24 (m, 3H), 7.29-7.45 (m, 2H), 7.63-7.69 (m, 2H), 7.72-7.77 (m, 2H), 8.56-8.63 (m, 1H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:23])([F:22])[C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)=[CH:9][N:10]=2)[N:7]=1.[CH3:24][N:25]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[N:26]1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>CCOC(C)=O>[F:22][C:11]([F:23])([C:8]1[N:6]2[N:7]=[C:2]([C:28]3[CH:27]=[N:26][N:25]([CH3:24])[CH:29]=3)[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1)[C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[CH:17][CH:16]=[CH:15]2
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: FC(F)(c1ccc2ncccc2c1)c1cnc2ccc(Cl)nn12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Cn1cc(-c2ccc3ncc(C(F)(F)c4ccc5ncccc5c4)n3n2)cn1
Temperature: 150 °C

Procedure:
A microwave tube was charged with 6-[(6-chloro-imidazo[1,2-b]pyridazin-3-yl)-difluoro-methyl]-quinoline (Stage 6.1, 10 mg, 0.03 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (10 mg, 0.045 mmol), tetrakis-(triphenylphosphine)palladium (1.7 mg), 2M Na2CO3 (0.054 mL) and DME (1 mL). It was heated at 150° C. under microwave irradiation for 20 min. The RM was taken up with EtOAc (2 mL) and washed with 10% Na2CO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by HPLC to afford the title compound as a brown solid (tR 1.379 min (conditions 1), MH+=376.8, 1H-NMR in DMSO-d6: 9.00 (m, 1H); 8.65 (d, 1H); 8.52 (s, 1H); 8.30 (s, 1H); 8.21 (d, 1H); 8.14 (d, 1H); 7.99 (m, 2H); 7.87 (s, 1H); 7.66 (m, 2H); 3.86 (s, 3H)).
Reaction SMILES: [N+:1]([CH2:4][CH2:5][CH:6]1[O:10][CH2:9][CH2:8][O:7]1)([O-:3])=[O:2].[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.N1CCCCC1>C1(C)C=CC=CC=1>[F:11][C:12]1[CH:19]=[CH:18][C:15](/[CH:16]=[C:4](\[N+:1]([O-:3])=[O:2])/[CH2:5][CH:6]2[O:10][CH2:9][CH2:8][O:7]2)=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: O=[N+]([O-])CCC1OCCO1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])/C(=C\c1ccc(F)cc1)CC1OCCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a flask equipped with a Dean-Stark trap and a reflux condenser, a solution of 2-(2-nitro-ethyl)-[1,3]dioxolane (162.5 g, 1.1 mol) in toluene (1.2 L) was treated with 4-fluorobenzaldehyde (124 g, 1.0 mol) followed by piperidine (15 mL, 0.15 mol). The solution was heated at reflux under N2 for 16 h, then was cooled to rt and washed with water (2×300 mL) and satd. aq. NaCl (2×300 mL). Charcoal and MgSO4 were added, and the suspension was stirred for 1 h. Filtration and concentration of the filtrate provided the title compound, which was used in the next reaction without further purification. 1H NMR (400 MHz, CDCl3): 8.15 (s, 1H), 7.70-7.65 (m, 2H), 7.18-7.10 (m, 2H), 5.23 (t, J=4.5, 1H), 4.10-3.80 (m, 4H), 3.26 (d, J=4.5, 2H). The (Z)-olefin geometry was confirmed by nuclear Overhauser effect (NOE) studies (Stott et al. J. Magn. Reson. 1997, 125, 302-324) with a mixing time of 0.8 sec. When proton at 8.15 ppm was selectively inverted, NOE was observed at 3.25 ppm and 7.65 ppm.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7]OC1C=CC(Cl)=CC=1Br)([CH3:4])([CH3:3])[CH3:2].[Br:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([I:26])[CH:20]=1>>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:17])=[C:21]([I:26])[CH:20]=1
Reactant: Oc1ccc(Br)cc1I
Reactant: CC(C)(C)OC(=O)COc1ccc(Cl)cc1Br
Product: CC(C)(C)OC(=O)COc1ccc(Br)cc1I

Procedure:
Following the general method as outlined in Intermediate 1, starting from 4-bromo-2-iodophenol (Intermediate 189), the title compound was obtained as a brown oil after purification by flash column chromatography (silica), eluting with 2% methanol in chloroform.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[N:14]=[CH:13][O:12][N:11]=2)=[CH:4][CH:3]=1.[BH4-].[Na+].O>CO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][CH2:9][C:10]2[NH:14][CH2:13][O:12][N:11]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(SCc2ncon2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1ccc(SCC2=NOCN2)cc1

Procedure:
3-(4-Methylphenylthiomethyl)-1,2,4-oxadiazole (1.65 g, 0.008 mol) was dissolved in methanol (25 ml). AT 0° and with stirring, sodium borohydride (0.91 g, 0.024 mol) was added in portions over 30 min. The mixture was then stirred at 0° overnight and water then added to give a solid which on recrystallisation from from isopropanol gave 4.5-dihydro-3-(4-methylphenylthiomethyl)-1,2,4-oxadiazole, m.p. 85°.