Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].S(Cl)([Cl:15])=O.CN(C)C=O>C(Cl)Cl>[CH:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([Cl:15])=[O:9])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)c1ccc(C(=O)Cl)cc1
Reaction time: 1 h

Procedure:
In 5 ml of methylene chloride was suspended 0.25 g of 4-isopropylbenzoic acid. Then, at ambient temperature, 0.12 ml of thionyl chloride and 0.03 ml of N,N-dimethylformamide were added. After stirring the mixture at the same temperature as above for one hour, the solvent was distilled off under reduced pressure, and an azeotropic distillation treatment using toluene was carried out to obtain 0.25 g of 4-isopropylbenzoic acid chloride. To a suspension of 0.50 g of trifluoroacetic acid salt of 2-(4-benzyl-3-oxo-1-thia-4,8-diazaspiro[4.5]decan-2-yl]-acetic acid in 5 ml methylene chloride were successively added dropwise at 0-5° C. 0.64 ml of triethylamine and a solution of 0.25 g of 4-isopropylbenzoic acid chloride in 5 ml methylene chloride. The resulting mixture was stirred at ambient temperature for 24 hours. The reaction mixture was poured into ice water, pH was adjusted to 1.0 with 2 mol/L hydrochloric acid, and the organic layer was separated. The organic layer was washed successively with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification of the residue by column chromatography [eluents: toluene:ethyl acetate=1:1, followed by chloroform] gave 0.30 g of 2-[4-benzyl-8-(4-isopropylbenzoyl)-3-oxo-1-thia-4,8-diazaspiro[4.5]-decan-2-yl]-acetic acid as a light yellow solid product.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=2)[CH2:13]1)[CH3:2].[C:24](Cl)(=[O:28])[C:25](Cl)=[O:26]>C(OCC)C>[CH2:1]([N:3]1[C:4]2[C:9](=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=2[CH:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=3)[CH2:13]2)[C:25](=[O:26])[C:24]1=[O:28])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCNc1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Solvent: CCOCC
Product: CCN1C(=O)C(=O)c2c(OC)ccc(C3CCc4cc(OC)ccc4C3)c21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl [5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (260 mg) in diethyl ether (30 ml) was added dropwise oxalyl chloride (0.21 ml) on an ice bath, and the solution was stirred for 30 minutes at room temperature. The reaction solution was concentrated in vacuo, the total amount of the resulting {ethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amino}oxoacetyl chloride (crude product) was stirred in dichloromethane (5 ml), a solution of aluminum chloride (220 mg) in dichloromethane (20 ml) was added dropwise thereto on an ice bath, and the solution was stirred overnight at room temperature. The reaction mixture was diluted with ice water, extracted with chloroform, then washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (160 mg).
Reaction SMILES: [NH:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[CH:3]1[NH:14][C:15]([NH:17][C:18]([O:20][CH3:21])=[O:19])=[S:16].I[CH2:23][CH2:24][CH2:25][CH3:26].CN(C)C=O.[OH-].[Na+]>O>[NH:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[CH:3]1[NH:14][C:15](=[N:17][C:18]([O:20][CH3:21])=[O:19])[S:16][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCI
Reactant: COC(=O)NC(=S)NC1C(=N)C=CC=C1Cc1ccco1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCSC(=NC(=O)OC)NC1C(=N)C=CC=C1Cc1ccco1
Reaction time: 0.5 h

Procedure:
To 5.0 g (0.0165 mole) of 1-imino(2-furylmethyl)-2-(3-carbomethoxythioureido)benzene and 3.6 g (0.01975 mole) of iodobutane in 80 ml. of N,N-dimethylformamide is added 0.7 g (0.0175 mole) of sodium hydroxide in 20 ml of water. The resulting mixture is stirred for 1/2 hour and the yellow precipitate that formed is separated by filtration, washed with 50 ml of water and dried to give 3.4 g of crude product, m.p. 86°-7° C. Recrystallization from ether-hexane affords 1-imino(2-furylmethyl)-2-(3-carbomethoxy-S-butylisothioureido)benzene m.p. 84°-85° C.
Reaction SMILES: [NH:1]([C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([NH:18][CH2:19][C:20]([O:22]C)=[O:21])=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[OH-].[Na+].Cl>CO.O>[NH:1]([C:24]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:25])[C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1
Reactant: COC(=O)CNC(=O)[C@@H](C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1)C(=O)NCC(=O)O

Procedure:
To a solution of Z-Tyr-D-Ala-Gly-OMe (27) (4.57 g, 0.01 mol) in MeOH (10 ml) was added 1 N NaOH (20 ml, 0.02 mol) at 0° with stirring. The suspension was stirred for 2 hr at 0° C., diluted with water (80 ml), and neutralized with 1 N HCl (20 ml). The precipitated crystals were collected by suction, washed with water and dried under reduced pressure to give Z-Tyr-D-Ala-Gly.OH (28) (3.59 g, 81.0%), mp 102°-104° C. (AcOEt) (lit.* mp 124° C.); [α]D22 18.0° (C=1.0, DMF), (lit.* [α]D22 16.7° (c=0.54, DMF)); NMR (DMSO-d6)δ: 1.16 (3H, d, J=7 Hz, CH3), 2.60-2.90 (2H, m, CH2), 3.80 (2H, d, J=6 Hx, CH2PhOH), 4.10-4.45 (2H, m, 2CH), 5.02 (2H, s, CH2O), 6.63-7.20 (4H, m, HOPh-), 7.40 (5H, s, ArH), 8.10-8.30 (2H, br, 2 NH), 9.10-9.40 (1H, br, OH). Rf (IV)=0.20.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([O:9]C)=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=1.C1C(=O)N([Br:24])C(=O)C1.[OH-].[Na+]>O1CCCC1>[Br:24][C:12]1[CH:13]=[N:14][N:15]([CH3:16])[C:11]=1[C:3]1[CH:4]=[C:5]([C:7]([OH:9])=[O:8])[O:6][C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(-c2ccnn2C)c(C)o1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1oc(C(=O)O)cc1-c1c(Br)cnn1C
Temperature: 70 °C
Reaction time: 4 h
Yield: 47.4 %

Procedure:
A solution of methyl 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylate (600 mg, 2.72 mmol) [prepared in Example 116] and n-bromosuccinimide (485 mg, 2.72 mmol) in tetrahydrofuran (13.6 ml) was stirred in a sealed tube for 1 h at 70° C. The reaction mixture was divided and half of the solution was treated with 6N sodium hydroxide (4.54 ml, 27.2 mmol) which stirred at 70° C. in a sealed tube for 4 h. The solution was partitioned between H2O-DCM and the pH of the aqueous phase was adjusted to ˜4 and washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and used directly affording 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylic acid (369 mg, 1.29 mmol, 48% yield) as an orange oil: LCMS (ES) m/e 285, 287 (M, M+2)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.Cl[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][C:23]([OH:25])=[O:24]>[Cu].C1(C)C(C)=CC=CC=1>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:22][C:23]([OH:25])=[O:24])=[CH:10][CH:9]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: O=C(O)Cc1ccccc1Cl
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Product: O=C(O)Cc1ccccc1Oc1ccc(Cl)cc1
Temperature: 65 °C
Yield: 43.9 %

Procedure:
xylene (600 mL), potassium carbonate (53.75 g), 4-chlorophenol (46.25 g), and copper powder (2.7 g) are charged in to a round bottom flask at 25-35° C. The reaction mixture heated to 60-70° C., o-chlorophenyl acetic acid (50 g) is added in portions. The reaction mixture is heated to reflux, maintained for 2-3 hours and simultaneously water is removed by azeotropic distillation. The reaction mixture is cooled to below 90° C. Water (600 mL) is added, both layers are separated. The organic layer is washed with water (600 mL). The combined organic layer is cooled to 0-10° C. and conc. HCl (26 mL) is added until the pH reaches to 2.0. The reaction mass is maintained at 0-10° C. for 1 hour, the obtained solid is collected by filtration, washed with water (450 mL), and dried at 60° C. to afford 33.8 g of the title compound.
Reaction SMILES: [C:1](Cl)(=O)C.[OH:5][C:6]1[C:7]([CH3:15])=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10]>CO>[CH3:1][O:10][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][CH:14]=[C:6]([OH:5])[C:7]=1[CH3:15]
Reactant: Cc1c(O)cccc1C(=O)O
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)c1cccc(O)c1C
Temperature: 25 °C
Yield: 87.3 %

Procedure:
Acetyl chloride (5.4 ml, 5.96 g, 76 mmol) was added dropwise to methanol (15 ml) at 0° C. in a sealed 50 ml round-bottom flask. This solution was allowed to warm to room temperature for 1 hour while stirring. To this solution 3-hydroxy-2-methyl-benzoic acid (519 mg, 3.4 mmol) was added and the solution was stirred at room temperature for 42 hours. The reaction was quenched with saturated aqueous sodium bicarbonate and solid sodium bicarbonate. The volatiles were removed in vacuo and the basic aqueous solution was then extracted with dichloromethane (4×40 ml). The combined organic extracts were dried (MgSO4), filtered, and the solvent evaporated in vacuo affording 493 mg (87%) of 3-hydroxy-2-methyl-benzoic acid methyl ester as a solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([CH3:12])([CH3:11])[CH2:9][CH3:10])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:13]C=O.[OH-].[K+].CO>O>[CH3:12][C:8]([C:7]1[C:2]([CH3:1])=[C:3]([NH2:13])[CH:4]=[CH:5][CH:6]=1)([CH3:11])[CH2:9][CH3:10]
Reactant: CCC(C)(C)c1cccc(NC=O)c1C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCC(C)(C)c1cccc(N)c1C

Procedure:
2,21 g (10.77 mmol) N-(2-methyl-3-(1,1-dimethylpropyl)phenyl)form-amide, 1,42 g (21.54 mmol) 85% potassium hydroxide and 9 ml methanol are heated under stirring at reflux temperature for 15 hours. After cooling 100 ml of water is added and the reaction mixture is extracted with ethylacetate. After drying of the organic phase over sodium sulfate and evaporation of the solvent in a water jet vacuum, the product is purified by destillation (bp. ca. 70° C., 13,33 Pa). This gives 1.7 g of 2-Methyl-3-(1,1-dimethylpropyl)phenylamine in the form of a colourless oil (89% of theory).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][C@@H:16]([O:18][CH3:19])[C@H:15]([O:20][CH3:21])[CH2:14]3)=[O:12])[S:10][C:3]=12.[CH3:22][C:23]1[NH:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([OH:32])=[CH:27][CH:26]=2>>[CH3:21][O:20][C@H:15]1[C@H:16]([O:18][CH3:19])[CH2:17][N:13]([C:11]([C:9]2[S:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[O:32][C:28]3[CH:29]=[C:30]4[C:25](=[CH:26][CH:27]=3)[NH:24][C:23]([CH3:22])=[CH:31]4)[CH:8]=2)=[O:12])[CH2:14]1
Reactant: Cc1cc2cc(O)ccc2[nH]1
Reactant: CO[C@@H]1CN(C(=O)c2cc3nccc(Cl)c3s2)C[C@H]1OC
Product: CO[C@@H]1CN(C(=O)c2cc3nccc(Oc4ccc5[nH]c(C)cc5c4)c3s2)C[C@H]1OC

Procedure:
The title compound was prepared from (3R,4R)-(7-chloro-thieno[3,2-b]pyridin-2-yl)-(3,4-dimethoxy-pyrrolidin-1-yl)-methanone and 2-methyl-1H-indol-5-ol by a procedure analogous to Example 1F. MS 438.3 (MH+); HPLC Rf: 5.554 min.; HPLC purity: 97%.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1.[CH2:18]([O:20][C:21](=[O:31])[CH2:22][NH:23][C:24]1[C:29]([NH2:30])=[CH:28][CH:27]=[CH:26][N:25]=1)[CH3:19].C(OC(=O)CNC1C([N+]([O-])=O)=CC=CN=1)C>O1CCCC1.[Pd]>[CH2:18]([O:20][C:21](=[O:31])[CH2:22][NH:23][C:24]1[C:29]([NH:30][C:13](=[O:14])[C:12]2[CH:16]=[CH:17][C:9]([F:8])=[CH:10][CH:11]=2)=[CH:28][CH:27]=[CH:26][N:25]=1)[CH3:19]
Reactant: CCOC(=O)CNc1ncccc1N
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: [Pd]
Agent: CCOC(=O)CNc1ncccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CNc1ncccc1NC(=O)c1ccc(F)cc1
Yield: 5.6 %

Procedure:
Under a nitrogen atmosphere, triethylamine (31.8 g, 0.315 mole) and 4-fluorobenzoyl chloride (50 g, 0.315 mole) were added simultaneously, dropwise, to a stirred and chilled solution of freshly prepared N-[[3-amino]-2-pyridinyl]glycine ethyl ester (0.33 mole) by palladium/carbon reduction of N-[[3-nitro]-2-pyridinyl]glycine ethyl ester, (75.3 g, 0.33 mole) in dry tetrahydrofuran (~800 ml). The reaction mixture was stirred at room temperature overnight and the solvent was evaporated under reduced pressure. The residue was partitioned between ethyl acetate (300 ml) and water (300 ml), the insoluble material was filtered off, the layers were separated and the aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed three times with water, dried over magnesium sulfate, treated with charcoal, filtered and evaporated to give 76.8 g of crude solid (77% yield). A 6.8-g portion of the solid was recrystallized from isopropyl alcohol and water to give 5.63 g of title compound, mp 127° -128.5° C.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([S:6][CH2:7][CH2:8][OH:9])=[N:2]1.[H-].[Na+].Cl[C:13]1[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[CH:15][N:14]=1.Cl>CN(C=O)C>[NH:1]1[CH:5]=[N:4][C:3]([S:6][CH2:7][CH2:8][O:9][C:13]2[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[CH:15][N:14]=2)=[N:2]1
Reactant: N#Cc1ccnc(Cl)c1
Reactant: OCCSc1nc[nH]n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccnc(OCCSc2nc[nH]n2)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 33 %

Procedure:
A solution of 2-(1H-1,2,4-triazol-3-ylthio)ethanol obtained in Reference Example 16 (7.34 g, 50.6 mmol) in DMF (50 mL) was added to a solution of 60% sodium hydride (oil dispersion, 4.91 g, 123 mmol) in DMF (50 mL) at 0° C. The mixture was stirred at 0° C. for 15 min, and then at room temperature for 30 min. A solution of 2-chloropyridine-4-carbonitrile (6.80 g, 49.1 mmol) in DMF (50 mL) was added at 0° C., and the mixture was stirred at 0° C. for 15 min, and then at room temperature for 2 hr. The mixture was neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (10%-80% ethyl acetate/hexane) to give the title compound as a white powder (4.01 g, 33%).
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[S:10][C:11]([CH2:14][OH:15])=[CH:12][N:13]=2)[O:8][CH2:7][CH2:6][O:5]1.CCN(CC)CC.[S:23](Cl)([CH3:26])(=[O:25])=[O:24]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:26][S:23]([O:15][CH2:14][C:11]1[S:10][C:9]([C:4]2([CH3:3])[O:8][CH2:7][CH2:6][O:5]2)=[N:13][CH:12]=1)(=[O:25])=[O:24]
Reactant: CC1(c2ncc(CO)s2)OCCO1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(c2ncc(COS(C)(=O)=O)s2)OCCO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (2-(2-methyl-[1,3]dioxolan-2-yl)thiazol-5-yl)methanol (389 mg, 1.93 mmol) in dry CH2Cl2 (10 mL) was treated at 0° C. with Et3N (0.35 mL, 2.50 mmol) followed by DMAP (24 mg, 0.19 mmol) and Ms-Cl (0.19 mL, 2.40 mmol). After stirring at 0° C. for 1 h, the reaction was quenched with water (10 mL). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification by FC (1:1->1:2 hept-EA+1% Et3N) gave pure (2-(2-methyl-[1,3]dioxolan-2-yl)thiazol-5-yl)methyl methanesulfonate as a pale yellow oil. Part of this material (140 mg, 0.50 mmol) was dissolved in dry DMF (1 mL) and treated with NaN3 (35 mg, 0.53 mmol) at 80° C. for 1 h30. The reaction mixture was then cooled down to rt and partitioned between EA and water. The layers were separated and the org. layer dried over MgSO4, filtered and concentrated under reduced pressure to give crude 5-(azidomethyl)-2-(2-methyl-[1,3]dioxolan-2-yl)thiazole as a brown oil. LC-MS-conditions 01: tR=0.80 min; [M+H]+=226.96.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[F:8][C:9]([F:16])([F:15])[C:10]1[CH:14]=[CH:13][NH:12][N:11]=1.Cl[C:18]1[C:23]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=[C:22]([CH3:31])[N:21]=[N:20][C:19]=1[CH3:32]>C(OCC)(=O)C>[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([C:23]2[C:18]([N:12]3[CH:13]=[CH:14][C:10]([C:9]([F:16])([F:15])[F:8])=[N:11]3)=[C:19]([CH3:32])[N:20]=[N:21][C:22]=2[CH3:31])=[CH:29][CH:28]=1
Reactant: Cc1nnc(C)c(-c2ccc(Cl)cc2)c1Cl
Reactant: FC(F)(F)c1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nnc(C)c(-n2ccc(C(F)(F)F)n2)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 77.5 %

Procedure:
87 mg of sodium hydride (55% oil dispersion) was added to 5 ml of DMF, and to this was added 0.27 g of 3-trifluoromethylpyrazole, and the mixture was stirred for 5 hours at room temperature. To the resultant mixture was added 0.25 g of 4-chloro-5-(4-chlorophenyl)-3,6-dimethylpyridazine, and the mixture was stirred for 3 hours on an oil bath of 80° C. To the reaction mixture was added ethyl acetate, and the mixture was washed with brine four times. The organic layer was dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure. 0.57 g of the resultant residue was subjected to silica gel column chromatography, to obtain 0.27 g of 5-(4-chlorophenyl)-4-(3-trifluoromethyl-1-pyrazolyl)-3,6-dim ethylpyridazine (hereinafter, described as compound (4) of the present invention.).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH:32]([CH3:34])[CH3:33])=[CH:27][CH:26]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=1)=[CH:10][CH:9]=2)=[O:5])C.[OH-].[Na+].O.Cl>O1CCOCC1>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[N:7]([C:25]2[CH:26]=[CH:27][C:28]([O:31][CH:32]([CH3:33])[CH3:34])=[CH:29][CH:30]=2)[C:6]([C:4]([OH:5])=[O:3])=[CH:14]3)=[CH:16][CH:17]=1)([CH3:22])([CH3:24])[CH3:23]
Reactant: CCOC(=O)c1cc2cc(-c3ccc(C(C)(C)C)cc3)ccc2n1-c1ccc(OC(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)Oc1ccc(-n2c(C(=O)O)cc3cc(-c4ccc(C(C)(C)C)cc4)ccc32)cc1
Reaction time: 0.5 h
Yield: 67.7 %

Procedure:
A mixture of 5-(4-tert-butylphenyl)-1-(4-isopropoxyphenyl)indole-2-carboxylic acid ethyl ester (259 mg, 0.57 mmol; see step (b)), NaOH (114 mg, 2.85 mmol), water (0.6 mL) and dioxane (3 mL) was heated using microwave irradiation for 1 h at 120° C. An additional portion of NaOH (100 mg) was added and heating was continued for another 30 min at 120° C. After cooling, the reaction was acidified with HCl (1M) to pH 2 and extracted with EtOAc. The combined extracts were washed with water, brine and dried over Na2SO4 and purified by chromatography to give the title compound (165 mg, 60%).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:10][C:11]1[C:19]2[C:18](=O)[N:17]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:23]([F:33])[CH:22]=3)[CH:16]([OH:34])[C:15]=2[C:14]([O:35][CH2:36][CH3:37])=[C:13]2[CH:38]=[CH:39][CH:40]=[CH:41][C:12]=12)[CH3:9].C([SiH](CC)CC)C>ClCCl>[CH2:8]([O:10][C:11]1[C:19]2[CH2:18][N:17]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:23]([F:33])[CH:22]=3)[C:16](=[O:34])[C:15]=2[C:14]([O:35][CH2:36][CH3:37])=[C:13]2[CH:38]=[CH:39][CH:40]=[CH:41][C:12]=12)[CH3:9]
Reactant: CCOC(=O)Cc1ccc(N2C(=O)c3c(c(OCC)c4ccccc4c3OCC)C2O)cc1F
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)Cc1ccc(N2Cc3c(c(OCC)c4ccccc4c3OCC)C2=O)cc1F
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 94.7 %

Procedure:
Trifluoroacetic acid (1900 mL) was added to a stirred solution of ethyl {4-[4,9-bis(ethyloxy)-1-hydroxy-3-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl]-2-fluorophenyl}acetate (898 g, 1.92 mol) in dichloromethane (1900 mL) at 0° C. under a nitrogen atmosphere. Triethylsilane (465 mL, 2.92 mol) was added dropwise to the deep red solution ensuring that the temperature was maintained below 3° C. The reaction mixture was then stirred at 0° C. for 45 minutes, over which time the solution turned yellow and all ethyl {-4-[4,9-bis(ethyloxy)-1-hydroxy-3-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl]-2-fluorophenyl}acetate was shown to be consumed by TLC analysis (silica, dichloromethane:methanol, 99:1). The reaction mixture was evaporated to dryness under reduced pressure, slurried in hexane (2×2.5 L) and then isopropanol (2.5 L) at 40° C. and dried under vacuum to give the desired product as a white solid (821 g, 95% yield).
Reaction SMILES: Cl.Cl[C:3]1[N:8]2[N:9]=[C:10]([CH:12]3[CH2:17][CH2:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)[N:11]=[C:7]2[CH:6]=[C:5]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[N:4]=1.Cl.[NH2:30][C:31]1[C:36]([C:37](=[O:42])[C:38]([F:41])([F:40])[F:39])=[CH:35][CH:34]=[C:33]([NH:43][CH2:44][CH2:45][NH2:46])[N:32]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[NH2:30][C:31]1[C:36]([C:37](=[O:42])[C:38]([F:39])([F:41])[F:40])=[CH:35][CH:34]=[C:33]([NH:43][CH2:44][CH2:45][NH:46][C:3]2[N:8]3[N:9]=[C:10]([CH:12]4[CH2:17][CH2:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]4)[N:11]=[C:7]3[CH:6]=[C:5]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])[N:4]=2)[N:32]=1
Reactant: CC(C)N1CCC(c2nc3cc(-c4ccc(Cl)cc4Cl)nc(Cl)n3n2)CC1
Reactant: NCCNc1ccc(C(=O)C(F)(F)F)c(N)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)N1CCC(c2nc3cc(-c4ccc(Cl)cc4Cl)nc(NCCNc4ccc(C(=O)C(F)(F)F)c(N)n4)n3n2)CC1
Temperature: 130 °C

Procedure:
250 mg (0.59 mmol) of 5-chloro-7-(2,4-dichlorophenyl)-2-[1-(propan-2-yl)piperidin-4-yl][1,2,4]-triazolo[1,5-c]pyrimidine hydrochloride (Example 40A), 201 mg (0.71 mmol) of 1-{2-amino-6-[(2-aminoethyl)amino]pyridin-3-yl}-2,2,2-trifluoroethanone hydrochloride (Example 13A) and 0.615 ml (3.5 mmol) of N,N-diisopropylethylamine were initially charged in 4 ml of DMSO. The mixture was heated in the microwave at 130° C. for 30 min. This gave, after purification of the crude product by preparative HPLC (Method 11), 210 mg (56% of theory) of the product as a solid.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][C@H:15]2[CH2:20][CH2:19][CH2:18][NH:17][C@H:16]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:29](OC=O)(=[O:31])C>O1CCCC1>[CH:29]([N:17]1[CH2:18][CH2:19][CH2:20][C@H:15]([O:14][CH2:13][C:5]2[CH:4]=[C:3]([C:2]([F:27])([F:1])[F:28])[CH:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:6]=2)[C@@H:16]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:31]
Reactant: FC(F)(F)c1cc(CO[C@H]2CCCN[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Reactant: CC(=O)OC=O
Solvent: C1CCOC1
Product: O=CN1CCC[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1c1ccccc1

Procedure:
The title compound was prepared from (+)-cis-3-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-phenyl piperidine prepared from the hydrochloride salt, Example 5)(0.5 g) and formic-acetic anhydride (prepared from 90% formic acid (1.5 ml) and acetic anhydride (3 ml) at 60° C. for 30 minutes) in tetrahydrofuran for 48 h at 23° C. The solvent was evaporated in vacuo and the residue partitioned between diochloromethane and saturated aqueous sodium bicarbonate solution, dried (MgSO4), concentrated in vacuo and chromatographed on silica gel to give the title compound as an oil. Found: C, 57.79; H, 4.39; N, 3.13. Calcd for C21H19NO2F6.0.3(H2O), C, 57.75; H, 4.52; N, 3.21%.