Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[N:38]=[C:9]2[C:10]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=3)=[C:11]([CH3:27])[C:12]([C:14]3[N:15]([C:19]4[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=4)[N:16]=[CH:17][CH:18]=3)=[CH:13][N:8]2[N:7]=1)=[O:4].[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>>[C:25]([C:22]1[CH:23]=[CH:24][C:19]([N:15]2[C:14]([C:12]3[C:11]([CH3:27])=[C:10]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=4)[C:9]4[N:8]([N:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:39]5[CH2:44][CH2:43][O:42][CH2:41][CH2:40]5)[N:38]=4)[CH:13]=3)=[CH:18][CH:17]=[N:16]2)=[CH:20][CH:21]=1)#[N:26]
Reactant: C1COCCN1
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NC(=O)CCl)nc2c1-c1cccc(C(F)(F)F)c1
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NC(=O)CN3CCOCC3)nc2c1-c1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared from 2-chloro-N-[6-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-acetamide (Int. 17, 80 mg, 0.149 mmol) and morpholine (26 mg, 0.299 mmol) using a similar method to that employed for Example 18, Step 2 (50 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:27]2[CH:39]=[CH:38][C:30]3[N:31]=[C:32]([NH:34][C:35](=[O:37])[CH3:36])[S:33][C:29]=3[CH:28]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.[Pd]>[CH3:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([NH:8][C:4]2[CH:3]=[C:2]([C:27]3[CH:39]=[CH:38][C:30]4[N:31]=[C:32]([NH:34][C:35](=[O:37])[CH3:36])[S:33][C:29]=4[CH:28]=3)[CH:7]=[N:6][CH:5]=2)(=[O:11])=[O:10])=[CH:13][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Nc2cncc(Br)c2)cc1
Reactant: CC(=O)Nc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2s1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(=O)Nc1nc2ccc(-c3cncc(NS(=O)(=O)c4ccc(C)cc4)c3)cc2s1
Reaction time: 0.17 h

Procedure:
To a microwave vial equipped with a stir bar was charged with N-(5-bromopyridin-3-yl)-4-methylbenzenesulfonamide (0.180 g, 0.6 mmol) in 1,4-dioxane (3 ml), was added N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)acetamide (0.223 g, 0.7 mmol), Pd FibreCat® (Anchored homogeneous catalyst, Johnson Matthey, West Deptford, N.J.) (0.024 g, 20%) and 2M sodium carbonate (0.7 ml, 1 mmol). The vial was capped and then placed into a CEM Microwave for 10 minutes at 100° C., while 100 watts of energy was supplied via Powermax® (Simultaneous heating while cooling technology). The progress of the reaction was monitored by LC/MS, which showed desired product, N-deacylated material and boronic ester in the mixture. The reaction was stopped at this point, to prevent further de-acylation of product. The mixture was diluted with DCM and saturated sodium bicarbonate solution. The organic layer was collected by extracting with DCM (3×20 ml). Combined organic extracts, dried over sodium sulfate, filtered and concentrated in vacuo. The crude was purified by reverse-phase HPLC. This gave N-(6-(5-(4-methylphenylsulfonamido)pyridin-3-yl)benzo[d]thiazol-2-yl)acetamide (0.016 g, 7% yield) as a white crystalline solid. MS (ESI pos. ion) m/z: 439 (MH+). Calc'd exact mass for C21H18N4O3S2: 438. 1H NMR (400 MHz, DMSO-d6): 2.19 (s, 3H), 2.27 (s, 3H), 7.16 (d, 2H), 7.37 (s, 1H), 7.49 (s, 1H), 7.62 (d, 2H), 7.73 (d, 1H), 7.90 (s, 1H), 7.94 (s, 1H), 8.02 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:12]([CH2:13][CH2:14][N:15]3[CH2:19][CH2:18][CH2:17][C@H:16]3[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:11][CH2:10][S:9][C:8]=2[CH:27]=1)([O-])=O.CCO.I.[S:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[C:37](SC)=[NH:38].N>[Pd].CO.C(Cl)Cl>[C:23]([O:22][C:20]([C@@H:16]1[CH2:17][CH2:18][CH2:19][N:15]1[CH2:14][CH2:13][N:12]1[CH2:11][CH2:10][S:9][C:8]2[CH:27]=[C:4]([NH:1][C:37]([C:33]3[S:32][CH:36]=[CH:35][CH:34]=3)=[NH:38])[CH:5]=[CH:6][C:7]1=2)=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: CSC(=N)c1cccs1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1CCN1CCSc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Agent: I
Agent: N
Solvent: CO
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1CCN1CCSc2cc(NC(=N)c3cccs3)ccc21
Yield: 63.1 %

Procedure:
A round bottom flask containing (S)-tert-butyl 1-(2-(7-nitro-2H-benzo[b][1,4]thiazin-4(3H)-yl)ethyl)pyrrolidine-2-carboxylate (525 mg, 1.334 mmol) was purged with argon. This flask was charged with palladium on activated carbon (10% wt; 142 mg, 0.133 mmol) followed by EtOH (25 mL). The resulting suspension was evacuated using a pump, and hydrogen was let into the system via a balloon. The mixture was stirred under a balloon filled with hydrogen for 2 hours. At this time, the hydrogen balloon was removed, and methyl thiophene-2-carbimidothioate hydroiodide (761 mg, 2.67 mmol) was added to the mixture. The suspension was stirred at room temperature for 17 hours (overnight). At this time, the mixture was filtered through a pad of Celite, and the pad was rinsed with MeOH (20 mL). The filtrate was concentrated, and the residue partitioned between saturated sodium bicarbonate solution (50 mL) and CH2Cl2 (100 mL). The mixture was transferred to a separatory funnel and extracted. After extraction, the organic layer was separated, dried (Na2SO4), filtered, and concentrated to give a dark residue. This residue was subjected to flash chromatography on silica gel using 2:98 MeOH:CH2Cl2 followed by 3.5:96.5 (2M NH3 in MeOH):CH2Cl2 to give a yellow-green residue (398 mg, 63.1%). 1H-NMR (CDCl3) δ 7.39 (dd, J=1.2, 5.1 Hz, 1H), 7.37 (dd, J=1.2, 3.9 Hz, 1H), 7.05 (dd, J=3.6, 4.8 Hz, 1H), 6.73 (brd, J=5.1 Hz, 1H), 6.71 (brs, 1H), 6.65 (dd, J=2.1, 8.7 Hz, 1H), 4.86 (brs, 2H), 3.63-3.60 (m, 2H), 3.44 (t, J=7.5 Hz, 2H), 3.25-3.19 (m, 1H), 3.11 (brdd, J=5.4, 8.4 Hz, 1H), 3.04-2.94 (m, 3H), 2.71-2.59 (m, 1H), 2.45 (brdd, J=7.8, 16.2 Hz, 1H), 2.13-1.99 (m, 1H), 1.97-1.74 (m, 3H), 1.45 (s, 9H); ESI-MS (m/z, %): 473 (MH+, 90), 417 (85), 276 (100); HPLC Purity: 99.6% a/a.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[C:12](=O)[CH2:11][CH:10]3[CH3:17])=[CH:5][CH:4]=[C:3]1[C:18]#[N:19].Cl.[NH2:21][OH:22]>>[OH:22]/[N:21]=[C:12]1\[CH2:11][CH:10]([CH3:17])[C:9]2[C:13]\1=[CH:14][CH:15]=[C:7]([C:6]1[N:2]([CH3:1])[C:3]([C:18]#[N:19])=[CH:4][CH:5]=1)[CH:8]=2
Reactant: CC1CC(=O)c2ccc(-c3ccc(C#N)n3C)cc21
Reactant: NO
Agent: Cl
Product: CC1C/C(=N\O)c2ccc(-c3ccc(C#N)n3C)cc21

Procedure:
The title compound was prepared from 1-methyl-5-(3-methyl-1-oxo-2,3-dihydro-1H-inden-5-yl)-1H-pyrrole-2-carbonitrile and hydroxylamine hydrochloride according to the procedure described in example 1. MS m/z 266; HRMS: calcd for C16H15N3O+H+, 266.12879; found (ESI, [M+H]+), 266.1299; Anal. Calcd for C16H15N3O: C, 72.43; H, 5.70; N, 15.84. Found: C, 71.86; H, 6.31; N, 15.47.
Reaction SMILES: [C:1]1([CH:7](Br)[C:8]([O-:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC([CH:18]([NH2:21])[CH2:19][OH:20])=CC=1.C(N(C(C)C)CC)(C)C.CCOC(C)=O>CC#N>[C:1]1([C@H:7]2[NH:21][CH2:18][C:19](=[O:20])[O:10][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C([O-])C(Br)c1ccccc1
Reactant: NC(CO)c1ccccc1
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CN[C@H](c2ccccc2)CO1
Reaction time: 0.25 h

Procedure:
To a solution of phenylbromoacetate (18.58 g, 86 mmol) in CH3CN under nitrogen was added a solution of (R)-phenylglycinol (10.17 g, 74 mmol) and di-isopropylethylamine (34 mL, 195 mmol) in CH3CN. The volatiles were removed under reduced pressure keeping the bath temperature below 25° C. to obtain an oil that was treated with EtOAc (120 mL) and stirred for 15 min. The resulting white precipitate was removed by filtration. The filtrate was concentrated under reduced pressure and the desired product was isolated using column chromatography (SiO2) with a step gradient of 10% to 50% [v/v] EtOAc in cyclohexane to give after evaporation (R)-5-phenylmorpholin-2-one EBE 06134 (3.17 g, 24% yield) as a white solid.
Reaction SMILES: N1([CH:7]2[CH2:12][O:11][N:10]=[C:9]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[N:8]2C)CCCCC1.[C:20](O)(=O)[CH3:21].OS(O)(=O)=O.OO.[OH2:31]>>[N:8]1([CH2:7][CH:7]2[CH2:12][O:11][N:10]=[C:9]([C:13]3[CH:14]=[N+:15]([O-:31])[CH:16]=[CH:17][CH:18]=3)[NH:8]2)[CH2:21][CH2:20][CH2:18][CH2:13][CH2:9]1
Reactant: CC(=O)O
Reactant: O
Reactant: CN1C(c2cccnc2)=NOCC1N1CCCCC1
Agent: O=S(=O)(O)O
Agent: OO
Product: [O-][n+]1cccc(C2=NOCC(CN3CCCCC3)N2)c1
Temperature: 60 °C

Procedure:
6.25 g (24 mmol) of (−)-5,6-dihydro-5-(1-piperidinyl)-methyl-3-(3-pyridyl)4H-1,2,4-oxadiazine is dissolved in a mixture of 40 ml of water, 6.85 ml (120 mmol) of glacial acetic acid and 1.43 ml (24 mmol) of cc. H2SO4. The solution is heated to 60° C., and at this temperature 12 ml (75 mmol) of 21.5% hydrogen peroxide is added dropwise, and the reaction mixture is kept on stirring at this temperature. After 10 hours to the reaction mixture further 6 ml of 21.5% hydrogen peroxide is added dropwise. After another 20 hours the reaction mixture is cooled to 0° C., and it is introduced dropwise into 60 ml of 0° C. 20% NaOH, then extracted 5 times with 50 ml of dichloromethane. The combined organic phases are washed with water, dried over magnesium-sulfate and evaporated. The evaporation residue is purified by column chromatography. The suitable fractions are triturated with 20 ml of acetone and kept in refrigerator overnight. Next day the product is filtered, washed with cold acetone and dried, then recrystallized from ethanol-ethylacetate.
Reaction SMILES: C[O-].[Na+].[C:4](OC)(=O)[CH2:5][C:6]([O:8][CH3:9])=[O:7].[CH2:13]([C:18]1C(=O)[CH2:20][CH2:21][C:22]=1[O:23]C)[CH2:14][CH2:15][CH2:16][CH3:17].Cl>CO>[CH3:9][O:8][C:6](=[O:7])[CH2:5][C:4]1[CH2:20][CH2:21][C:22](=[O:23])[C:18]=1[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: COC(=O)CC(=O)OC
Reactant: CCCCCC1=C(OC)CCC1=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCCCC1=C(CC(=O)OC)CCC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The air in a reactor (a volume of 0.3 L) was preliminarily replaced with nitrogen at ordinary pressure. The reactor was charged with 13.5 g (70 mmol) of a 28% methanol solution of sodium methoxide and 140 ml of absolute methanol. Thereto was added 6.6 g (50 mmol) of dimethyl malonate, and the mixture was stirred for 30 minutes at 25° C. Thereto was added 6.6 g (36 mmol) of 2-pentyl-3-methoxy-2-cyclopentenone, and the mixture was heated under reflux for 24 hours in a nitrogen atmosphere. The resulting mixture was ice-cooled and neutralized by gradually adding 6.1 ml of concentrated hydrochloric acid, and methanol was distilled off. Thereto were added 50 ml of water and 100 ml of toluene, and then the mixture was stirred sufficiently and allowed to stand to separate the organic phase. The toluene in the organic phase was distilled off in vacuo followed by vacuum distillation, yielding methyl(2-pentyl-3-keto-1-cyclopentenyl-)acetate (a compound in which R22 represents an n-pentyl group, and R23 represents a methyl group in the above formula (15)). Gas chromatographic analysis showed that the yield of methyl(2-pentyl-3-keto-1-cyclopentenyl-)acetate relative to 2-pentyl-3-methoxy-2-cyclopentenone was 90%.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)[O:14][C:12](=[O:13])[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]1=2)=O.C(OCC)(=[O:25])C>ClCCl>[OH:25][C:8]1[CH:9]=[CH:10][C:11]([C:12]([OH:14])=[O:13])=[CH:6][CH:7]=1
Reactant: CCOC(C)=O
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=C(O)c1ccc(O)cc1
Yield: 56 %

Procedure:
To prepare 22, a solution of 3 (Srinivasan et al., PLoS Biol. 10:e1001237 (2012), which is hereby incorporated by reference in its entirety) (181.5, 413 μmol) in dry tetrahydrofuran (0.5 mL) was added to a mixture of LiOH (8.9 mg, 371 μmol) and water (0.2 mL) in 1,4-dioxane (1 mL). After stirring at 67° C. for 40 minutes the solution was acidified with few drops of glacial acetic acid and concentrated in vacuo. Flash column chromatography on silica using a gradient of 10-40% ethyl acetate in hexanes afforded 20 (48.5 mg, 145 μmol, 35%) as a colorless oil. A solution of 20 (48.5 mg, 145 μmol) in dry dichloromethane (2 mL) was treated with Dess-Martin periodinane (88 mg, 208 μmol). After 5 hours the solution was diluted with 10 mL dichloromethane and washed three times with a solution of 5% Na2S2O3 in H2O. The organic layer was dried over Na2SO4 and concentrated in vacuo. Flash column chromatography on silica using a gradient of 0-30% ethyl acetate in hexanes afforded 21 (26.8 mg, 81 μmol, 56%) as a colorless oil. A solution of 21 (24.5 mg, 74 μmol) in 1:1 dichloromethane:methanol (0.7 mL) was treated with NaBH4 (12 mg, 317 μmol). After 10 minutes the solution was acidified with glacial acetic acid and diluted with dichloromethane and concentrated in vacuo. Flash column chromatography on silica using a gradient of 0-40% ethyl acetate in hexanes afforded (2S,3R,5S,6R)-6-((R)-hex-5-en-2-yloxy)-5-hydroxy-2-methyltetrahydro-2H-pyran-3-yl benzoate (22) (18.2 mg, 54 μmol, 74%) as a colorless oil. 1H NMR (600 MHz, acetone-d6): δ (ppm) 8.04-8.01 (m, 2H), 7.67-7.63 (m, 1H), 7.55-7.50 (m, 2H), 5.89 (ddt, J=17.1 Hz, J=10.3 Hz, J=6.6 Hz, 1H), 5.09-5.04 (m, 1H), 4.99-4.95 (m, 1H), 4.84 (d, J=3.7, 1H), 4.69 (ddd, J=11.4 Hz, J=9.8 Hz, J=4.6 Hz, 1H), 4.04-3.98 (m, 1H), 3.89-3.82 (m, 1H), 3.78-3.71 (m, 1H), 2.29-2.16 (m, 3H), 1.93-1.86 (m, 1H), 1.79-1.72 (m, 1H), 1.65-1.58 (m, 1H), 1.19 (d, J=6.1 Hz, 3H), 1.16 (d, J=6.3 Hz, 3H). 13C NMR (151 MHz, acetone-d6): δ (ppm) 165.9, 139.6, 134.1, 131.1, 130.2, 129.5, 114.9, 96.4, 73.7, 72.9, 67.8, 66.8, 37.3, 34.3, 30.7, 19.5, 17.9. See FIGS. 94A-B.
Reaction SMILES: O.Cl.Cl.[NH:4]1[CH2:8][CH2:7][N:6]=[C:5]1[CH:9]([O:11][C:12]1[C:13]([CH3:19])=[C:14]([NH2:18])[CH:15]=[CH:16][CH:17]=1)[CH3:10].C(#N)C.[C:23](OC(=O)C)(=[O:25])[CH3:24]>>[OH2:11].[NH:6]1[CH2:7][CH2:8][N:4]=[C:5]1[CH:9]([O:11][C:12]1[C:13]([CH3:19])=[C:14]([NH:18][C:23](=[O:25])[CH3:24])[CH:15]=[CH:16][CH:17]=1)[CH3:10].[NH:6]1[CH2:7][CH2:8][N:4]=[C:5]1[CH:9]([O:11][C:12]1[C:13]([CH3:19])=[C:14]([NH:18][C:23](=[O:25])[CH3:24])[CH:15]=[CH:16][CH:17]=1)[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(N)cccc1OC(C)C1=NCCN1
Agent: Cl
Solvent: O
Solvent: CC#N
Product: CC(=O)Nc1cccc(OC(C)C2=NCCN2)c1C

Procedure:
The title compound of Example 4 (1.5 g, 4.8 mmole) was stirred in 60 ml of acetonitrile containing 2.3 ml (ca. 24 mmole) of acetic anhydride. After 18 hours the reaction mixture was concentrated to dryness in vacuo and the residue was dissolved in water. The solution was then made alkaline with aqueous sodium bicarbonate and extracted with dichloromethane. After the organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo, the residue was recrystallized from diethyl ether to give 398 mg of the title compound. Structure assignment was supported by nmr spectrum and by elemental analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4](O)[C:5]([CH3:16])([CH3:15])[CH:6]2[O:11][C:12](=[O:14])[CH3:13].[NH:18]1[CH:22]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[N:20]=[CH:19]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.Cl.O1CCOCC1>C1COCC1>[CH3:26][O:25][C:23]([C:21]1[N:20]([CH:4]2[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[Cl:1])[CH:6]([O:11][C:12](=[O:14])[CH3:13])[C:5]2([CH3:16])[CH3:15])[CH:19]=[N:18][CH:22]=1)=[O:24]
Reactant: COC(=O)c1c[nH]cn1
Reactant: CC(=O)OC1c2cccc(Cl)c2C(O)C1(C)C
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: COC(=O)c1cncn1C1c2c(Cl)cccc2C(OC(C)=O)C1(C)C
Temperature: 0 °C
Reaction time: 12 h

Procedure:
To a solution of acetic acid 4-chloro-3-hydroxy-2,2-dimethyl-indan-1-yl ester (1.55 g, 6.1 mmol) in THF (30 mL) is added methyl 4-imidazolecarboxylate (CAS#17325-26-7, 1.53 g, 12.2 mmol), and triphenylphosphine (3.2 g, 12.2 mmol). The reaction is cooled to 0° C. and di-t-butyl azodicarboxylate (2.81 g, 12.2 mmol) is added. The reaction is placed at room temperature and permitted to stir for ca. 12 hours and then is heated to 40° C. for 1.5 hours. The reaction mixture is cooled to 0° C., quenched with 4 N HCl in dioxane (20 mL, 80 mmol), and stirred for 30 minutes. The reaction is concentrated to near dryness and diluted with ethyl acetate. The organic layer is extracted three times with 1 N aqueous HCl. The aqueous extracts are combined, neutralized with Na2CO3, and extracted three times with ethyl acetate. The combined organic layers are dried with Na2SO4, filtered, and concentrated. The resulting residue is purified by silica gel flash chromatography (ethyl acetate-dichloromethane, 0:1 to 1:3) to furnish 3-(3-acetoxy-7-chloro-2,2-dimethyl-indan-1-yl)-3H-imidazole-4-carboxylic acid methyl ester; MS: (ESI) m/z 332.04 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[CH3:18][N:19]1[C:23]2[CH:24]=[C:25]([CH3:30])[C:26]([CH3:29])=[C:27]([NH2:28])[C:22]=2[N:21]=[CH:20]1>>[CH3:18][N:19]1[C:23]2[CH:24]=[C:25]([CH3:30])[C:26]([CH3:29])=[C:27]([NH:28][C:2]3[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]4[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=4)[N:3]=3)[C:22]=2[N:21]=[CH:20]1
Reactant: Cc1cc2c(ncn2C)c(N)c1C
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Product: Cc1cc2c(ncn2C)c(Nc2cc(C(F)(F)F)nc(-c3cccnc3)n2)c1C

Procedure:
The title compound was prepared from 4-chloro-2-(3-pyridinyl)-6-trifluoromethylpyrimidine (50 mg, 0.192 mmol) and 1,5,6-trimethyl-4-aminobenzimidazole (50 mg, 0.288 mmol) similar to Example 185 and was isolated as a solid (5 mg, 6%). 1H NMR (CDCl3): 9.36 (ddd, J=7.8, 3.0, 1,2 Hz, 1H), 9.68 (s, 1H), 9.01 (ddd, J=5.7, 2.7, 1.2 Hz, 1H), 8.87 (s, 1H), 8.46 (dd, J=8.4, 6.0 Hz, 1H), 8.04 (s, 1H), 7.71 (s, 1H), 7.48 (s, 1H), 6.93 (s, 1H), 2.62 (s, 3H), 2.24 (s, 3H), 2.21 (s, 3H).
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[CH2:5]([O:12][C:13]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(C)[C:14](O)=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CN(C)C=O.C1(C)C=CC=CC=1>[CH2:5]([O:12][CH:13]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:14][C:1]([Cl:4])=[O:2])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC(OCc1ccccc1)(Oc1ccccc1)C(=O)O
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)CC(OCc1ccccc1)Oc1ccccc1
Temperature: 80 °C

Procedure:
A three-liter, round-bottom flask was obtained and fitted with an overhead stirrer, a thermocouple, a temperature controller, an addition funnel with a cold trap overhead, and a line leading to a phosgene cyclinder. Also it was fitted with an exit line to a nitrogen/vacuum source, a heating mantle, and a catch basin. The exit line went to a condenser and a caustic scrubber. Into this flask was placed 183.2 g (0.67 mole) benzyloxyphenoxypropionic acid, 900 ml of toluene, and 2.9 g (0.04 mole) dimethylformamide. The phosgene cyclinder was turned on and 75 ml (1.05 moles) phosgene was allowed to accumulate in the funnel. The reactants were heated to 80° C. with stirring while the phosgene was added thereto. During the course of the phosgene addition, solids formed in the flask; however, ultimately they went into solution. After the phosgene addition, nitrogen was slowly added to the flask. The reaction was stopped, and a vacuum pulled on the flask to boil off the excess phosgene. The flask was then placed under a nitrogen atmosphere. The solvent was stripped off, leaving 233.2 g of yellow solids, which were identified by suitable analytical techniques as being the subject compound.
Reaction SMILES: [C:1]([C@@H:5]1[CH2:10][O:9][CH2:8][O:7][C@@H:6]1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].[N+:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O-:24])=[O:23])([O-])=O.CO.N>[Pd].C1COCC1>[C:1]([C@@H:5]1[CH2:10][O:9][CH2:8][O:7][C@@H:6]1[O:11][CH3:12])([CH3:4])([CH3:2])[CH3:3].[NH2:13][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O-:24])=[O:23]
Reactant: O=C([O-])CCCCCC[N+](=O)[O-]
Agent: [Pd]
Agent: CO[C@H]1OCOC[C@H]1C(C)(C)C
Agent: N
Solvent: CO
Solvent: C1CCOC1
Product: NCCCCCCC(=O)[O-]

Procedure:
5 g (18.2 mmol) of the cis-t-butyl-2-methoxy-3,5-dioxane-7-nitro-heptanoate obtained in Example 1 was added to a mixture solvent of 50 mL of MeOH and 50 mL of THF saturated with ammonia. Hydrogenation was performed for 6 hours at room temperature in the presence of 10% Pd/C catalyst. 4.43 g (88.6%) of the target compound was obtained as colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH2:5][NH2:6].[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1([C:29](Cl)=[O:30])[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH2:5][NH:6][C:29]([C:16]1([CH2:15][CH2:14][CH2:13][CH2:12][Br:11])[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:30]
Reactant: NCc1ccc(F)c(F)c1
Reactant: O=C(Cl)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: O=C(NCc1ccc(F)c(F)c1)C1(CCCCBr)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from 3,4-difluorobenzylamine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH2:6][C:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH:8]=1.[C:19](Cl)(=O)[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1.[Sn].C(=O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:16]2[C:5](=[CH:6][C:7]3[S:11][C:10]4[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=4[C:8]=3[C:19]=2[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH:4]=1
Reactant: COc1cccc(Cc2cc3ccccc3s2)c1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: O=C=O
Agent: [Sn]
Solvent: ClCCl
Product: COc1ccc(-c2c3ccc(OC)cc3cc3sc4ccccc4c23)cc1
Yield: 62.7 %

Procedure:
To a cold (-78° C.) solution of 2-(3-methoxybenzyl)-benzo[b]thiophene (2.10 g, 8.26 mmol) and p-anisoyl chloride (1.48 g, 8.67 mmol) in anhydrous methylene chloride (31 mL) was added tin IV chloride (2.90 mL, 24.8 mmol, 3 eq) dropwise over a period of 24 minutes. After stirring overnight in the warming dry ice bath and at ambient temperature for 7 hours the reaction mixture was poured onto water (175 mL) and the organics were extracted with diethyl ether (2×300 mL). The extracts were combined, and washed with brine. Silica gel was added and the solvent was removed. The adsorbate was flash chromatographed (97/3 petroleum ehter/ethyl acetate) to give the title compound as a white solid (1.92 g, 63%): mp 158-159° C.; MS (+FAB): [M+] 370; Anal. Calc. for C24H18O2S: C, 77.81, H, 4.90, N, 0.00. Found: C, 78.00, H, 4.76, N, 0.03.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[CH2:10](C([Sn])=C(CCCC)CCCC)[CH2:11]CC>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:8][N:6]1[CH:7]=[C:2]([CH:10]=[CH2:11])[CH:3]=[CH:4][C:5]1=[O:9]
Reactant: Cn1cc(Br)ccc1=O
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: C=Cc1ccc(=O)n(C)c1
Reaction time: 0.08 h
Yield: 746.1 %

Procedure:
The title compound was prepared by following general procedure 2. To a solution of 5-bromo-1-methylpyridin-2(1H)-one (2 g, 10.63 mmol) in 20 mL of 1,4-dioxane, dichlorobis(triphenylphosphine)palladium(II) (0.834 g, 1.19 mmol) was added at RT and stirred at the same temperature for 5 min. Tributylvinyltin (3.46 mL, 1.19 mmol) was added slowly at RT and stirred at 100-105° C. for 2 h. The reaction was monitored by TLC and LCMS. After completion of the starting material, the solvent was evaporated and the residue purified by column chromatography using 60% ethyl acetate-hexane to afford 1.2 g of 1-methyl-5-vinylpyridin-2(1H)-one.