Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:20]([O:24][C:25](=[O:65])[CH2:26][N:27]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH:37]([C:49]3[S:53][C:52]([C:54]4[CH:59]=[CH:58][C:57]([C:60]([F:63])([F:62])[F:61])=[CH:56][CH:55]=4)=[N:51][C:50]=3[CH3:64])[CH2:38][CH2:39][CH2:40][O:41][Si](C(C)(C)C)(C)C)[CH:34]=2)[CH:29]=[CH:28]1)([CH3:23])([CH3:22])[CH3:21]>O1CCCC1>[C:20]([O:24][C:25](=[O:65])[CH2:26][N:27]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH:37]([C:49]3[S:53][C:52]([C:54]4[CH:59]=[CH:58][C:57]([C:60]([F:62])([F:63])[F:61])=[CH:56][CH:55]=4)=[N:51][C:50]=3[CH3:64])[CH2:38][CH2:39][CH2:40][OH:41])[CH:34]=2)[CH:29]=[CH:28]1)([CH3:22])([CH3:23])[CH3:21]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(CCCO[Si](C)(C)C(C)(C)C)Oc1ccc2ccn(CC(=O)OC(C)(C)C)c2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(CCCO)Oc1ccc2ccn(CC(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 1 M solution of tetrabutylammonium fluoride hydrate (30 μl, 30 μmol) was added to an ice-cooled solution of [rac]-(6-[4-(tert-butyl-dimethyl-silanyloxy)-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-butoxy}-indol-1-yl)-acetic acid tert-butyl ester (17 mg, 25 μmol) in tetrahydrofuran (0.5 ml). The ice bath was removed and the solution stirred for 30 min at ambient temperature. Ethyl acetate was added and the solution was washed with 1 N HCl. The aqueous layer was extracted with ethyl acetate and the combined extracts were washed two times with brine and dried over sodium sulfate. Evaporation of the solvent gave 14 mg (25 μmol, quant.) of the title compound as yellow oil.
Reaction SMILES: [C:1]([N:8]1[CH2:15][C@@H:14]([N:16]([CH:24]2[CH2:29][CH2:28][C:27]([CH3:31])([CH3:30])[CH2:26][CH2:25]2)[C:17]([C@@H:19]2[CH2:23][CH2:22][CH2:21][O:20]2)=[O:18])[CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:32][NH:33][CH2:34][CH3:35]>>[C:1]([N:8]1[CH2:15][C@@H:14]([N:16]([CH:24]2[CH2:29][CH2:28][C:27]([CH3:31])([CH3:30])[CH2:26][CH2:25]2)[C:17]([C@@H:19]2[CH2:23][CH2:22][CH2:21][O:20]2)=[O:18])[CH2:13][C@H:9]1[C:10]([N:33]([CH2:34][CH3:35])[CH3:32])=[O:12])([O:3][C:4]([CH3:7])([CH3:5])[CH3:6])=[O:2]
Reactant: CC1(C)CCC(N(C(=O)[C@@H]2CCCO2)[C@H]2C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C2)CC1
Reactant: CCNC
Product: CCN(C)C(=O)[C@@H]1C[C@H](N(C(=O)[C@@H]2CCCO2)C2CCC(C)(C)CC2)CN1C(=O)OC(C)(C)C

Procedure:
The title compound was prepared according to the procedure described in Step D of Example A1, using (4S)-1-BOC-4-{(4,4-dimethylcyclohexyl)[(2S)-tetrahydrofuran-2-ylcarbonyl]amino}-L-proline (0.96 g, 2.2 mmol) prepared in Step B and commercially available N-methylethylamine (0.92 g, 93%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=O)[S:5][CH:6]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:23][NH:24][CH3:25].C(O)(=O)C>ClCCCl.ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:7][N:24]([CH3:25])[CH3:23])[S:5][CH:6]=1
Reactant: O=Cc1cc(Br)cs1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN(C)Cc1cc(Br)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.7 %

Procedure:
To a solution of 4-bromo-2-thiophene carboxaldehyde (5 g, 26.2 mmol) in 1,2-dichloroethane (50 mL) is added sodium triacetoxyborohydride (8.3 g, 39.3 mmol) and dimethylamine (14.5 mL, 28.8 mmol) followed by acetic acid (1.55 mL, 39.3 mmol). The mixture is stirred at room temperature for 2 hours. The insoluble is filtered and washed with diethyl ether. The mother liquor is concentrated. The resulting thick oil that is chromatographed through silica gel (dichloromethane-1.0M ammonia in methanol, 95:05 to 90:10 as eluant) to afford an orange oil. It is dissolved in dichloromethane and was washed with a saturated aqueous sodium bicarbonate solution. The organic layer is dried over magnesium sulfate and concentrated to produce (4-bromo-thiophen-2-ylmethyl)-dimethyl-amine [4.08 g, 71%, intermediate (1)] as an orange oil. LC/MS: RT=0.63 minutes, 219.99 m/e (M+H).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH3:9])[CH:4]=1.[C-:10]#[N:11].[K+].C1OCCOCCOCCOCCOCCOC1.C(P(CCCC)CCCC)CCC>C(#N)C.O>[C:10]([CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH3:9])[CH:4]=1)#[N:11]
Reactant: Cc1cc(CO)ccn1
Reactant: [C-]#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CCCCP(CCCC)CCCC
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1cc(CC#N)ccn1
Temperature: 25 °C
Reaction time: 25 h
Yield: 62 %

Procedure:
To a stirred mixture of 4-hydroxymethyl-2-methyl-pyridine [CAS No. 105250-16-6] (3.37 g, 27.4 mmol), potassium cyanide (3.56 g, 54.7 mmol) and 18-crown-6 (0.72 g, 2.74 mmol) in acetonitrile (75 ml) was added dropwise at 15-20° C. a solution of tributylphosphine (7.16 g, 30.1 mmol) in acetonitrile (25 ml). The reaction mixture was stirred at room temperature for 25 h, poured into water (100 ml) and extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with water (3×100 ml), brine (100 ml) dried (MgSO4) and evaporated. The crude product was further purified by column chromatography on silica gel (ethyl acetate) to yield 4-cyanomethyl-2-methyl-pyridine (2.26 g, 62%) as a brown oil.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:39])[C@H:15]([CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C@@H:16]([OH:30])[C@@H:17]([O:19][Si](C(C)C)(C(C)C)C(C)C)[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CCO>[OH:30][C@H:16]1[C@H:17]([CH3:18])[O:19][C:14](=[O:39])[C@@H:15]1[CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[Si](O[C@@H](C)[C@H](O)[C@@H](CCc1ccccc1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1)(C(C)C)C(C)C
Agent: Cl
Solvent: CCO
Product: C[C@@H]1OC(=O)[C@H](CCc2ccccc2)[C@H]1O
Product: O=C1N[C@H](Cc2ccccc2)CO1
Temperature: 80 °C
Yield: 88 %
Yield: 84 %

Procedure:
To a solution of (R)-4-benzyl-3-((2R,3R,4S)-3-hydroxy-2-phenethyl-4-((triisopropylsilyl)oxy)pentanoyl)-oxazolidin-2-one (2.52 g, 4.55 mmol) in EtOH (18 mL) was added 1 N HCl (2 mL, 2 mmol) and the mixture heated to 80° C. for a 3 h. The solution was concentrated in vacuo, and the residue was dissolved in CH2Cl2, loaded onto a pre-packed Celite® cartridge, and purified by flash chromatography (SiO2, 0→100% EtOAc/hexanes) gave (3R,4R,5S)-4-hydroxy-5-methyl-3-phenethyldihydrofuran-2(3H)-one (840 mg, 3.81 mmol, 84% yield) and (R)-4-benzyloxazolidin-2-one (710 mg, 4.01 mmol, 88% yield). The title product was obtained as a colorless, amorphous solid: 1H NMR (600 MHz, CDCl3) δ 7.33-7.28 (m, 2H), 7.25-7.19 (m, 3H), 4.20-4.13 (m, 1H), 3.80 (dd, J=8.9, 7.3 Hz, 1H), 2.96-2.88 (m, 1H), 2.86-2.79 (m, 1H), 2.59-2.52 (m, 1H), 2.28-2.17 (m, 2H), 1.97-1.88 (m, 1H), 1.43 (d, J=6.3 Hz, 3H); 13C NMR (151 MHz, CDCl3) δ 175.91, 140.94, 128.64, 128.51, 126.34, 79.89, 79.36, 47.98, 32.81, 30.25, 18.19; ESIMS m/z 221 ([M+H]+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@H:9]1[CH2:21][N:22]1C(=O)C2C(=CC=CC=2)C1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCl.O.NN>C(O)C>[NH2:22][CH2:21][C@H:9]1[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)[C@H](CN2C(=O)c3ccccc3C2=O)C1
Agent: NN
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)[C@H](CN)C1
Yield: 70 %

Procedure:
Into a 200 mL round bottom flask was added 15R (6.66 g, 15.3 mmol) and 110 mL of 10:1 dichloromethane:ethanol. Hydrazine hydrate (7.66 g, 10 equiv.) was added and the reaction was heated to reflux for three hours. The precipitate which had formed was removed by filtration through Celite. The filtrate was concentrated under high vacuum and temperature (to remove hydrazine). The residue was resuspended in dichloromethane and the resultant precipitate was removed by filtration through a Buchner funnel. The filtrate was concentrated to leave a clear oil 15S (3.27 g, 73%) which was analytically pure.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][OH:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:18][C:19]([F:28])([F:27])[C:20]1[CH:21]=[C:22](O)[CH:23]=[CH:24][CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O.O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][O:17][C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([C:19]([F:28])([F:27])[F:18])[CH:25]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCO)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CCCOc2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Yield: 85.9 %

Procedure:
4-(3-Hydroxypropyl)piperidine-1-carboxylic acid tert-butyl ester (15.0 g, 61.6 mmol), 3-trifluoromethylphenol (19.4 g, 64.7 mmol), triphenylphosphine (1.40 g, 73.9 mmol) and tetrahydrofuran (200 ml) were mixed. While stirring the mixture at room temperature, DEAD (21.1 ml, 80.0 mmol) was added thereto dropwise and heated at reflux for 2 days. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. After filtering, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=87:13) to afford the title compound as a pale yellow oil (20.5 g, yield 86%).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[CH:7]=[CH:6]2)#[N:2].[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[O:31][C:32]([F:35])([F:34])[F:33])[C:25](O)=O>>[Cl:21][C:22]1[CH:23]=[C:24]([C:25]2[O:15][N:14]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:17]([F:19])([F:20])[F:18])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)[N:16]=2)[CH:28]=[CH:29][C:30]=1[O:31][C:32]([F:33])([F:34])[F:35]
Reactant: O=C(O)c1ccc(OC(F)(F)F)c(Cl)c1
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3ccc(OC(F)(F)F)c(Cl)c3)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 241 from 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide and 3-chloro-4-[(trifluoromethyl)oxy]benzoic acid: MS (APCl) m/z 488 (M+1).
Reaction SMILES: Cl[C:2](Cl)(Cl)C(O)=O.C([Zn]CC)C.ICI.[N+:16]([C:19]1[C:28]([O:29][CH:30]=[CH2:31])=[CH:27][CH:26]=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22])([O-:18])=[O:17]>ClCCl>[CH:30]1([O:29][C:28]2[C:19]([N+:16]([O-:18])=[O:17])=[C:20]([CH:25]=[CH:26][CH:27]=2)[C:21]([O:23][CH3:24])=[O:22])[CH2:2][CH2:31]1
Reactant: C=COc1cccc(C(=O)OC)c1[N+](=O)[O-]
Reactant: O=C(O)C(Cl)(Cl)Cl
Agent: CC[Zn]CC
Solvent: ICI
Solvent: ClCCl
Product: COC(=O)c1cccc(OC2CC2)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59.7 %

Procedure:
In a 3 necked, 500 mL flask, a solution of 2,2,2-trichloroacetic acid (16.30 g, 100 mmol) in dichloromethane (100 mL) was slowly added via an addition funnel to a −10° C. solution of diethylzinc (1M hexanes, 100 mL, 100 mmol) under a nitrogen atmosphere. The reaction mixture was stirred for 10 min. Next, diiodomethane (8 mL, 100 mmol) was dropwise added by syringe, and the reaction solution was stirred for 10 min. A solution of methyl 2-nitro-3-(vinyloxy)benzoate (7.42 g, 33.2 mmol) in dichloromethane (20 mL) was added slowly via an addition funnel. The solution was allowed to warm to room temperature overnight. The reaction mixture was cooled to 0° C. and quenched with 1M HCl. The reaction solution was transferred to a separatory funnel, and the aqueous layer extracted with dichloromethane (3×). The combined extracts were washed with saturated sodium bicarbonate, water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product mixture was purified by ISCO (0% of EtOAc/heptane in 15 minutes, 220 g column) to provide methyl 3-cyclopropoxy-2-nitrobenzoate (4.7 g, 19.81 mmol, 60.0% yield). HPLC: RT=2.66 min (H2O/MeOH with TFA, SunFire C18 3.5 μm, 2.1×30 mm, gradient=4 min, wavelength=220 nm); MS(ES):m/z=260 [M+Na]+; 1H NMR (400 MHz, chloroform-d) δ 7.68-7.57 (m, 2H), 7.57-7.41 (m, 1H), 4.03-3.82 (m, 4H), 0.94-0.78 (m, 4H).
Reaction SMILES: Br[C:2]1[C:3]([F:22])=[C:4]([CH:19]=[CH:20][CH:21]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].[N:23]1[CH:28]=[C:27](B(O)O)[CH:26]=[N:25][CH:24]=1>>[F:22][C:3]1[C:2]([C:27]2[CH:28]=[N:23][CH:24]=[N:25][CH:26]=2)=[CH:21][CH:20]=[CH:19][C:4]=1[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6]
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cccc(Br)c1F
Reactant: OB(O)c1cncnc1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cccc(-c2cncnc2)c1F

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 57 using 3-bromo-2-fluoro-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 60.1) and pyrimidin-5-ylboronic acid to afford the title compound as a white powder. UPLC-MS (Condition 2) tR=1.04 min, m/z=378.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 7.39 (d, J=8.99 Hz, 2H) 7.51 (t, J=7.62 Hz, 1H) 7.74-7.91 (m, 4H) 9.09 (s, 2H) 9.27 (d, J=1.17 Hz, 1H) 10.72 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]([OH:9])=O)[CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH2:16][C:17]1[CH:18]=[C:19]([CH:36]=[CH:37][CH:38]=1)[O:20][C:21]1[CH:22]=[CH:23][C:24]2[N:25]([CH:27]=[C:28]([NH:30][C:31]([CH:33]3[CH2:35][CH2:34]3)=[O:32])[N:29]=2)[N:26]=1.C(N(CC)CC)C>CN(C)C=O.O1CCCC1>[CH:33]1([C:31]([NH:30][C:28]2[N:29]=[C:24]3[CH:23]=[CH:22][C:21]([O:20][C:19]4[CH:18]=[C:17]([NH:16][C:7]([C:4]5[CH:3]=[C:2]([CH3:1])[O:6][N:5]=5)=[O:9])[CH:38]=[CH:37][CH:36]=4)=[N:26][N:25]3[CH:27]=2)=[O:32])[CH2:34][CH2:35]1
Reactant: Cc1cc(C(=O)O)no1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)c2)no1
Yield: 57.5 %

Procedure:
Using 5-methylisoxazole-3-carboxylic acid (87 mg, 0.679 mmol), N,N-dimethylformamide (1 drop), oxalyl chloride (75.8 μL, 0.88 mmol), N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (140 mg, 0.453 mmol), triethylamine (138 mg, 1.36 mmol) and tetrahydrofuran (15 mL) as starting materials and in the same manner as in Example 109, the title compound (109 mg, 58%) was obtained as a white powder.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([CH3:10])[N:3]=1.Cl.Cl.[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][C@H:15]1[CH3:20].C(N(CC)CC)C.CO>C1COCC1>[Cl:9][C:6]1[C:7]([F:8])=[C:2]([N:17]2[CH2:18][CH2:19][N:14]([CH3:13])[C@H:15]([CH3:20])[CH2:16]2)[N:3]=[C:4]([CH3:10])[N:5]=1
Reactant: Cc1nc(Cl)c(F)c(Cl)n1
Reactant: C[C@@H]1CNCCN1C
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1nc(Cl)c(F)c(N2CCN(C)[C@H](C)C2)n1
Reaction time: 8 h
Yield: 93.5 %

Procedure:
To a solution of 4,6-dichloro-5-fluoro-2-methylpyrimidine (0.181 g, 1.0 mmol) and (2R)-1,2-dimethylpiperazine dihydrochloride (0.189 g, 1.0 mmol) in THF (10 mL) was added triethylamine (0.42 mL, 3.0 mmol). MeOH (1 mL) was added to improve solubility. Reaction left to stir overnight. The solvent was removed in vacuo, and THF and ether were added to the resulting residue, which was washed with water. The organics were dried (Na2SO4) and concentrated in vacuo to provide 4-chloro-6-[(3R)-3,4-dimethyl-1-piperazinyl]-5-fluoro-2-methylpyrimidine as a yellow oil (0.242 g, 94%). LCMS: (M+H)+=259.3.
Reaction SMILES: [Na].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12](SC)[N:13]=[N:14][C:15]=2[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[CH:6][CH:5]=1.[CH3:26][OH:27]>C(OCC)C>[CH3:26][O:27][C:12]1[N:13]=[N:14][C:15]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=2)[N:11]=1
Reactant: COc1ccc(-c2nnc(SC)nc2-c2ccc(OC)cc2)cc1
Reactant: CO
Agent: [Na]
Solvent: CCOCC
Product: COc1ccc(-c2nnc(OC)nc2-c2ccc(OC)cc2)cc1

Procedure:
Sodium, 3.0 g. (0.13 mole), was added piecewise under a nitrogen atmosphere to 100 ml. of dry methanol, followed by the addition of a slurry of 31.6 g. (0.1 mole) of 5,6-bis(4-methoxyphenyl)-3-methylthio-1,2,4-triazine in methanol. The reaction mixture was heated at reflux overnight. The reaction mixture was cooled and filtered. The filter cake and the filtrate were extracted with diethyl ether. The diethyl ether was concentrated, giving a solid, m.p. >220° C. The solid was taken up in diethyl ether and the insoluble material was removed by filtration. The filtrate was dried over anhydrous sodium sulfate and concentrated to give a solid residue which was recrystallized from petroleum ether to give 3-methoxy-5,6-bis(4-methoxyphenyl)-1,2,4-triazine, m.p. about 105°-108° C.
Reaction SMILES: C([O:8][C:9]1[CH:33]=[CH:32][C:12]([O:13][C:14]2[CH:15]=[CH:16][C:17]([N+:29]([O-])=O)=[C:18]([N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:19]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.CO>[Pd].O1CCOCC1>[NH2:29][C:17]1[CH:16]=[CH:15][C:14]([O:13][C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:33][CH:32]=2)=[CH:19][C:18]=1[N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(OCc3ccccc3)cc2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CO
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(O)cc2)ccc1N
Yield: 98.6 %

Procedure:
By using 3.32 g of t-butyl N-[5-(4-benzyloxyphenoxy)-2-nitrophenyl]-N-methylcarbamate, 0.39 g of 10% palladium on carbon, 100 ml of methanol and 100 ml of 1,4-dioxane, reaction and purification were carried out in a similar manner to that described in Reference Example 7, whereby 2.40 g of the title compound were obtained.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].[C@@H:13]12[C:22](=O)[O:21][C:19](=[O:20])[C@@H:14]1[CH2:15][CH2:16][CH2:17][CH2:18]2>C(O)(=O)C>[C:22]1(=[O:21])[N:1]([CH:2]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:3][C:4]([OH:6])=[O:5])[C:19](=[O:20])[C@H:14]2[CH2:15][CH2:16][CH2:17][CH2:18][C@@H:13]12
Reactant: NC(CC(=O)O)c1ccccc1
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Solvent: CC(=O)O
Product: O=C(O)CC(c1ccccc1)N1C(=O)[C@H]2CCCC[C@H]2C1=O
Temperature: 25 °C
Yield: 58 %

Procedure:
A stirred mixture 3-amino-3-phenylpropionic acid and cis-1,2-cyclohexanedicarboxylic anhydride in 10 mL of acetic acid under nitrogen was heated to reflux for 4 h and then allowed to cool to room temperature. The resulting mixture was concentrated to an orange yellow oil. This oil was crystallized from a 1/1 mixture of ethyl acetate/hexane to afford 1.77 g (58%) of 3-(cis-hexahydrophthalimido)-3-phenylpropionic acid as white crystals: 1H NMR (DMSO-d6) δ 12.45 (br s, 1 H, COOH), 7.33 (m, 5 H, Ph), 5.48 (dd, 1 H, J=6.3, 9.6, CH), 3.41 (dd, 1 H, J=16.5, 9.6 Hz), 3.14 (dd, 1H, J=16.5, 6.3 Hz), 2.50 (m, 2 H), 1.8-1.1 (m, 8 H); 13C NMR (DMSO-d6) δ 179.3, 179.2, 171.7, 138.7, 128.4, 127.5, 126.8, 50.1, 38.7, 38.6, 35.2, 23.0, 22.9, 21.1. Anal. Calcd for C17H19NO4. Theory: C, 67.76; H, 6.36; N, 4.65. Found: C, 67.52; H, 6.20; N, 4.60.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[N:14]1[NH:15][C:16]([CH2:23][CH2:24][C:25](O)=O)=[C:17]2[C:22]=1[CH2:21][CH2:20][CH2:19][CH2:18]2.Cl[C:29]1C=CC(C2CCNCC2)=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:25][CH2:24][CH2:23][C:16]3[N:15]([CH3:29])[N:14]=[C:22]4[C:17]=3[CH2:18][CH2:19][CH2:20][CH2:21]4)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: O=C(O)CCc1[nH]nc2c1CCCC2
Reactant: Clc1ccc(C2CCNCC2)cc1
Product: Cn1nc2c(c1CCCN1CCN(c3ccc(Cl)cc3)CC1)CCCC2

Procedure:
In the same manner as in Example 102 except that 3-(4,5,6,7-tetrahydro-2-methyl-2H-indazol-3-yl)propionic acid obtained in Staring Material Synthesis Example 9 and 1-(4-chlorophenyl)piperazine were used instead of 3-(4,5,6,7-tetrahydro-2H-indazol-3-yl)propionic acid obtained in Starting Material Synthesis Example 1 and 4-(4-chlorophenyl)piperidine, 3-(3-(4-(4chlorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-2-methyl-2H-indazole was obtained.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.CC1(C)C(C)(C)OB([C:40]2[CH:48]=[C:47]3[C:43]([CH2:44][C:45](=[O:49])[NH:46]3)=[CH:42][CH:41]=2)O1>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:16][C:6]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:2]([C:40]2[CH:48]=[C:47]3[C:43]([CH2:44][C:45](=[O:49])[NH:46]3)=[CH:42][CH:41]=2)[N:3]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:5]=1
Reactant: CC1(C)OB(c2ccc3c(c2)NC(=O)C3)OC1(C)C
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1Cl
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccc2c(c1)NC(=O)C2
Yield: 63.5 %

Procedure:
This compound was prepared according to general method E from methyl 2-(4-chloro-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (0.08 g; 0.25 mmol), tetrakis(triphenylphosphine) palladium(0) (0.029 mg; 0.025 mmol), N,N-diisopropylethylamine (0.173 mL; 1 mmol) and intermediate 17 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one (0.133 g; 0.75 mmol) in DME-water (2 mL) for 30 min. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (10-80%) in heptane furnished 0.066 g (56%) of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1.C(N(CC)CC)C.C(C1NC=CN=1)(C1NC=CN=1)=O.Cl.[Br:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][CH:46]=1)[CH:43]=[C:42]([S:47]([N:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1)(=[O:49])=[O:48])[CH:41]=[CH:40]2>CN(C=O)C>[Br:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][CH:46]=1)[CH:43]=[C:42]([S:47]([N:50]1[CH2:51][CH2:52][N:53]([C:11](=[O:13])[C:10]3[CH:9]=[CH:8][C:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[CH:15][CH:14]=3)[CH2:54][CH2:55]1)(=[O:48])=[O:49])[CH:41]=[CH:40]2
Reactant: O=S(=O)(c1ccc2cc(Br)ccc2c1)N1CCNCC1
Reactant: O=C(O)c1ccc(-c2ccccn2)cc1
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1ccc(-c2ccccn2)cc1)N1CCN(S(=O)(=O)c2ccc3cc(Br)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 17.2 %

Procedure:
4-(2-Pyridyl)benzoic acid (199 mg,1 mmol) was suspended in DMF (5 mL) and triethylamine (0.14 mL, 1 mmol) was added. The reaction mixture was stirred at room temperature for 15 minutes then cooled to 5° C. Carbonyl diimidazole (162 mg, 1 mmol) was added and the reaction mixture allowed to warm slowly to room temperature over one hour. 1-(6-Bromonaphth-2-ylsulphonyl)piperazine hydrochloride (393 mg, 1 mmol) was added as a solid in one portion and the reaction mixture was stirred overnight at room temperature then concentrated in vacuo. The crude product was dissolved in ethyl acetate (50 mL) and washed with aqueous sodium bicarbonate solution (2×50 mL). The tube organic layer was dried over MgSO4, filtered and concentrated in vacuo. The resulting off white solid was subjected to chromatography (SiO2; 100% EtOAc) to yield 1-(6-bromonaphth-2-ylsulphonyl)-4-[4-(2-pyridyl)benzoyl]piperazine as a white solid (92 mg); 1H NMR (DMSO-d6) δ=3.09 ppm (s,4H), δ=3.62 ppm (s,4H), δ=7.37 ppm (t,1H), δ=7.51 to 7.99 ppm (m,4H), δ=7.42 and 8.08 ppm (dd,4H), δ=8.17 ppm (dd,2H), δ=8.40 ppm (d,1H), δ=8.47 ppm (s,1H), δ=8.66 ppm (dd,1H); MS (M+H)+ 536.