Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]1[N:7](C(OC(C)(C)C)=O)[CH2:6][CH:5]([C:15]2[N:23]3[C:18]([C:19]([NH2:24])=[N:20][CH:21]=[N:22]3)=[C:17]([C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=4)=[C:27]([O:39][CH3:40])[CH:26]=3)[CH:16]=2)[CH2:4][CH2:3]1.C(O)(C(F)(F)F)=O.C(OCC)(=O)C.CCCCCC.C(Cl)[Cl:61]>>[Cl:61][C:16]1[C:17]([C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=3)=[C:27]([O:39][CH3:40])[CH:26]=2)=[C:18]2[N:23]([C:15]=1[CH:5]1[CH2:4][CH2:3][CH2:2][NH:7][CH2:6]1)[N:22]=[CH:21][N:20]=[C:19]2[NH2:24]
Reactant: ClCCl
Reactant: COc1cc(-c2cc(C3CCC(Cl)N(C(=O)OC(C)(C)C)C3)n3ncnc(N)c23)ccc1Oc1cccc(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1cc(-c2c(Cl)c(C3CCCNC3)n3ncnc(N)c23)ccc1Oc1cccc(Cl)c1
Reaction time: 2 h

Procedure:
The compound (40 mg, 0.068 mmol) prepared in Example 30 was taken up in DCM and treated with TFA (0.5 mL). The reaction was stirred for 2 hours and monitored by TLC (1:1 ethyl acetate/hexane). The solvent was removed under vacuum and the residue was taken up in ethyl acetate and the organic layer was washed with 1N sodium hydroxide. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with water, brine and dried over anhydrous sodium sulfate. The solution was filtered and solvent removed. The product is used in next reaction without further purification.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[O:10])=[CH:5][CH:4]=1.[CH:18]1([C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[CH:25]=2)=[O:22])[CH2:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+].[Na+].[I-]>CCOC(C)=O.CN(C)C=O>[CH:18]1([C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH:31]3[CH2:32][CH2:33][N:34]([CH2:2][C:3]4[CH:8]=[CH:7][C:6]([S:9]([C:11]5[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=5)=[O:10])=[CH:5][CH:4]=4)[CH2:35][CH2:36]3)[CH:25]=2)=[O:22])[CH2:19][CH2:20]1
Reactant: Cc1ccc(S(=O)c2ccc(CBr)cc2)cc1
Reactant: Cc1ccc(NC(=O)C2CC2)cc1C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)c2ccc(CN3CCC(c4cc(NC(=O)C5CC5)ccc4C)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.04 h
Yield: 38.9 %

Procedure:
Into a vial was added 4-(bromomethyl)-1-[(4-methylphenyl)sulfinyl]benzene (100 mg, 0.320 mmol), cyclopropyl-N-(4-methyl-3-(4-piperidyl)phenyl)carboxamide (50.0 mg, 0.190 mmol), potassium carbonate (60.0 mg, 0.430 mmol), NaI (30.0 mg, 0.200 mmol) and 2.50 mL of dimethylformamide. The mixture was stirred for 2-3 min at 25° C. and heated to 90° C. (oil bath). After stirring 12 h at 90° C., the mixture was allowed to cool to 25° C. and was diluted with 50 mL of EtOAc. The reaction solution was then washed with water (3×30 mL) and the aqueous solution was extracted with 30 mL of EtOAc. The organic solutions were combined and dried over MgSO4. Removal of solvent in vacuo gave crude product that was purified by flash column chromatography (eluent: 97% EtOAc: 3% methanol (2 M ammonia)) to afford cyclopropyl-N-{4-methyl-3-[1-({4-[(4-methylphenyl)sulfinyl]phenyl}methyl)(4-piperidyl)]phenyl}carboxamide (36.0 mg, 39.1% yield). 1H NMR (CDCl3) δ 7.62 (s, 1H), 7.54-7.43 (m, 4H), 7.42-7.31 (m, 3H), 7.24-7.10 (m, 3H), 7.05-6.91 (m, 1H), 3.47 (s, 2H), 2.92-2.81 (m, 2H), 2.66-2.52 (m, 1H), 2.29 (s, 3H), 2.18 (s, 3H), 2.08-1.97 (m, 2H), 1.76-1.54 (m, 4H), 1.48-1.38 (m, 1H), 1.02-0.91 (m, 2H), 0.75-0.68 (m, 2H). ESMS m/e: 487.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:17]([CH3:18])=[CH:16][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[O:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[C:17]([CH3:18])=[CH:16][C:5]2[N:6]([CH:10]3[CH2:11][CH2:12][N:13]([CH:22]4[CH2:23][CH2:24][O:19][CH2:20][CH2:21]4)[CH2:14][CH2:15]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1
Reactant: O=C1CCOCC1
Reactant: Cc1cc2c(cc1Br)[nH]c(=O)n2C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc2c(cc1Br)[nH]c(=O)n2C1CCN(C2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 25.9 %

Procedure:
5-Bromo-6-methyl-1-(4-piperidinyl)-1,3-dihydro-2H-benzimidazol-2-one (D37) (1.16 mmol, 359 mg) was dissolved in dichloromethane (20 mL) and tetrahydropyran-4-one (8.12 mmol, 7 eq, 813 mg), sodium triacetoxyborohydride (8.12 mmol, 1.72 g, 7 eq) and triethylamine (3.48 mmol, 352 mg, 3 eq, 0.48 ml) added. The reaction mixture was stirred at room temperature for 20 h. The reaction mixture was diluted with dichloromethane, washed with aqueous NaOH (pH 12), and the product extracted with dichloromethane (×2). The combined organic layers were washed with aqueous NaOH (pH 12), dried (MgSO4) and the solvent removed under reduced pressure to afford the crude product. The product was purified by chromatography, eluting with 12+M, DCM/50% MeOH in DCM, 00%-50%, 8CVs), to afford 5-bromo-6-methyl-1-[1-(tetrahydro-2H-pyran-4-yl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazol-2-one as a pale yellow solid (0.3 mmol, 111 mg, 26%). This was dissolved in dichloromethane (5 mL) and HCl (1M solution in ether) was added. The mixture was stirred at room temperature for 15 minutes. The solvents were removed under reduced pressure to afford the title compound as a white solid (0.02 mmol, 9 mg, 7%)
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]([F:16])[F:15])=[C:9]([O:17][CH2:18][CH:19]2[CH2:21][CH2:20]2)[CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].C(ON1[C:29](=[O:30])[CH:28]2[C:31](=C=O)[CH:32]=[CH:33][CH:34]=[C:27]2[C:26]1=[O:37])C.C(=O)([O-])[O-].[Na+].[Na+].Cl>O.C(#N)C>[CH:19]1([CH2:18][O:17][C:9]2[CH:8]=[C:7]([CH:2]([N:1]3[C:29](=[O:30])[C:28]4[C:27](=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:26]3=[O:37])[CH2:3][C:4]([OH:6])=[O:5])[CH:12]=[CH:11][C:10]=2[O:13][CH:14]([F:16])[F:15])[CH2:21][CH2:20]1
Reactant: CCON1C(=O)C2=CC=CC(=C=O)C2C1=O
Reactant: NC(CC(=O)O)c1ccc(OC(F)F)c(OCC2CC2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=C(O)CC(c1ccc(OC(F)F)c(OCC2CC2)c1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 87.9 %

Procedure:
To a solution of 3-amino-3-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-propionic acid (0.78 g, 2.9 mmol) and N-ethoxy-carbonyl-phthalimide (0.64 g, 2.9 mmol) in 30 ml of water and acetonitrile (1:1) was added sodium carbonate (0.33 g, 31 mmol). The mixture was stirred at room temperature for 5 hours. 1N HCl was added dropwise until pH=2. The mixture was extracted with ether (2×25 ml). The organic layer was washed with water (2×20 ml), brine (20 ml) and was dried over magnesium sulfate. The solvent was removed in vacuo to give 3-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propionic acid as a colorless oil (1.1 g, 91%). 1H NMR (CDCl3): δ 0.32-0.38 (m, 2H), 0.60-0.67 (m, 2H), 1.17-1.28 (m, 1H), 3.33 (dd, J=6, 17 Hz, 1H), 3.79 (dd, J=10, 17 Hz, 1H), 3.86 (d, J=8 Hz, 2H), 4.92 (broad, 1H), 5.74 (dd, J=6, 10 Hz, 1H), 6.58 (t, JH-F=75 Hz, 1H), 7.10 (s, 2H), 7.16 (s, 1H), 7.69-7.74 (m, 2H), 7.78-7.83 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[C:12]([OH:14])[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1.C1N2CCN(CC2)C1.[CH3:24][N:25]([CH3:29])[C:26](Cl)=[S:27]>CN(C=O)C>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[C:12]([O:14][C:26](=[S:27])[N:25]([CH3:29])[CH3:24])[CH:13]=[C:4]([C:3]([O:2][CH3:1])=[O:15])[CH:5]=1
Reactant: CN(C)C(=S)Cl
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OC(=S)N(C)C)cc(C(=O)OC)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
o a solution of 5-hydroxy-isophthalic acid dimethyl ester (D42) (21 g, 100 mmol, 1 equiv) in DMF (300 ml) at room temperature was added DABCO (14.6 g, 130 mmol, 1.3 equiv) followed by dimethylthiocarbamoyl chloride (14.8 g, 120 mmol, 1.2 equiv). The resulting mixture was stirred at room temperature for 16 h and at 60° C. for 2 h, then cooled to room temperature and concentrated in vacuo. The residue was partitioned between AcOEt and H2O and the aqueous phase re-extracted with AcOEt. The combined organic solution was washed sequentially with 5% aqueous citric acid solution, 2N aqueous NaOH solution and brine, then dried over MgSO4 and concentrated in vacuo to give 5-dimethylthiocarbamoyloxy-isophthalic acid dimethyl ester (D55) (23.5 g, 79%) as a pale yellow oil. [M+H]+=298.0, RT=3.06 min
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[F:15][C:16]([F:40])([F:39])[C:17]1[N:21]2[N:22]=[C:23]([N:26]3[CH2:31][CH2:30][N:29]([C:32]4[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=4)[CH2:28][CH2:27]3)[CH:24]=[CH:25][C:20]2=[N:19][N:18]=1.[CH3:41][N:42]1[C:46]([CH2:47][CH2:48]OC2C=CC(C3CCN(C4CCC5N(C(C(F)(F)F)=NN=5)N=4)CC3)=CC=2)=[CH:45][CH:44]=[N:43]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:41][N:42]1[C:46]([CH2:47][CH2:48][O:38][C:35]2[CH:36]=[CH:37][C:32]([N:29]3[CH2:28][CH2:27][N:26]([C:23]4[CH:24]=[CH:25][C:20]5[N:21]([C:17]([C:16]([F:15])([F:39])[F:40])=[N:18][N:19]=5)[N:22]=4)[CH2:31][CH2:30]3)=[CH:33][CH:34]=2)=[CH:45][CH:44]=[N:43]1
Reactant: Oc1ccc(N2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Reactant: Cn1nccc1CCOc1ccc(C2CCN(C3=Nn4c(nnc4C(F)(F)F)CC3)CC2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1nccc1CCOc1ccc(N2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 69.2 %

Procedure:
DIAD (20.73 mL, 105.27 mmol) was added dropwise to 4-[4-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]phenol (32.0 g, 87.72 mmol), 2-(1-methyl-1H-pyrazol-5-yl)ethanol (obtained as described in Example 15, preparation of starting materials) (16.6 g, 131.58 mmol) and triphenylphosphine (34.5 g, 131.58 mmol) in THF (320 mL) at 0° C. under nitrogen. The resulting solution was stirred at ambient temperature for 3 days. The reaction mixture was evaporated to dryness and re-dissolved in DCM (700 mL), and the solution was washed sequentially with 2M NaOH (200 mL×2) and saturated brine (200 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, eluting with a gradient of 80 to 100% EtOAc in isohexane followed by EtOAc, then a gradient of 0 to 3% MeOH in DCM. Pure fractions were evaporated to dryness to afford 6-[4-[4-[2-(1-methyl-1H-pyrazol-5-yl)ethoxy]phenyl]piperazin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (28.7 g, 69.3%) as a solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[C:16]([C:17]([NH:19][CH2:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]([CH3:32])([CH3:31])[C:28](O)=[O:29])=[CH:23][CH:22]=4)=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:33][N:34](C)C=O.C(Cl)(=O)C(Cl)=O>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[N:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([CH3:32])([C:28](=[O:29])[NH:34][CH3:33])[CH3:31])=[CH:23][CH:22]=3)=[O:18])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)(C(=O)O)c1ccc(CNC(=O)c2cccnc2Oc2ccc3c(c2)OCO3)cc1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CNC(=O)C(C)(C)c1ccc(CNC(=O)c2cccnc2Oc2ccc3c(c2)OCO3)cc1

Procedure:
2-[4-({[2-(Benzo[1,3]dioxol-5-yloxy)-pyridine-3-carbonyl]-amino}-methyl)-phenyl]-2-methyl-propionic acid (1.00 g) was suspended in anhydrous dichloromethane (20 mL). Anhydrous dimethylformamide (0.02 mL) was added to the suspension, followed by oxalyl chloride (0.391 mL). A 5 mL portion of this 1.15 M solution was transferred to a flame-dried, nitrogen purged round bottom flask. Anhydrous monomethyl amine gas was bubbled in for 5-10 min. The resulting white precipitate was washed with hot dichloromethane, and further purified by silica gel chromatography (ethyl acetate) to yield the title compound (0.127 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[S:10][CH:9]=[C:8]([C:11]([NH:13][C:14]3[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:15]=3[CH3:21])=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](Cl)=[O:28]>C1COCC1.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]2[S:10][CH:9]=[C:8]([C:11]([NH:13][C:14]3[CH:19]=[C:18]([NH:20][C:27](=[O:28])[C:26]4[CH:30]=[CH:31][CH:32]=[C:24]([C:23]([F:22])([F:33])[F:34])[CH:25]=4)[CH:17]=[CH:16][C:15]=3[CH3:21])=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Cc1ccc(N)cc1NC(=O)c1csc2c(N)ncnc12
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1NC(=O)c1csc2c(N)ncnc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 74.2 %

Procedure:
4-Amino-N-(5-amino-2-methylphenyl)thieno[3,2-d]pyrimidine-7-carboxamide (30 mg, 0.1 mmol) was dissolved in THF (1 mL) and TEA (42 μL, 0.30 mmol) was added thereto. 3-(trifluoromethyl)benzoyl chloride (19 μL, 0.13 mmol) was added to reaction mixture at 0° C. and stirred at room temperature for 6 hours. The reaction mixture was diluted with ethyl acetate (10 mL) and washed with brine. The organic layer was dried with MgSO4, filtered and concentrated under reduced pressure. The resulting mixture was purified by silica gel chromatography (3/97 MeOH/DCM) to obtain the title compound (35 mg, 74% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[CH:24]=[C:23]2[C:18]([CH2:19][CH2:20][NH:21][CH:22]2[CH3:25])=[CH:17][CH:16]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:21]3[CH2:20][CH2:19][C:18]4[C:23](=[CH:24][C:15]([F:14])=[CH:16][CH:17]=4)[CH:22]3[CH3:25])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2ccc(F)cc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC1c2cc(F)ccc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
A solution of 80 mg (0.33 mmol) of 6-Bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid, 66 mg (0.40 mmol) of 7-fluoro-1-methyl-1,2,3,4-tetrahydro-isoquinoline, 63 mg (0.33 mmol) of EDC and 50 mg (0.12 mmol) of HOBt in 2 mL of DMF is stirred at room temperature for 24 h. The mixture is concentrated in vacuo and the solid residue is partitioned between methylene chloride (3 mL) and saturated aqueous sodium hydrocarbonate solution (3 mL). The organic layer is separated, washed with 0.5 N HCl, water and brine and concentrated in vacuo.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[S:7][C:8]2[N:9]=[C:10]([NH:15][C:16]3[CH:17]=[C:18]([NH:23][C:24](=[O:36])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([C:34]#[N:35])([CH3:33])[CH3:32])[CH:26]=4)[CH:19]=[CH:20][C:21]=3[CH3:22])[N:11]=[CH:12][C:13]=2[N:14]=1)=[O:4].CN(C)C=O.C(N(CC)CC)C.[CH3:49][N:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1>O1CCCC1.O>[C:34]([C:31]([C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=1)[C:24]([NH:23][C:18]1[CH:19]=[CH:20][C:21]([CH3:22])=[C:16]([NH:15][C:10]2[N:11]=[CH:12][C:13]3[N:14]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:53]4[CH2:54][CH2:55][N:50]([CH3:49])[CH2:51][CH2:52]4)[S:7][C:8]=3[N:9]=2)[CH:17]=1)=[O:36])([CH3:32])[CH3:33])#[N:35]
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Nc1ncc2nc(NC(=O)CCl)sc2n1
Reactant: CN1CCNCC1
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Nc1ncc2nc(NC(=O)CN3CCN(C)CC3)sc2n1
Temperature: 60 °C
Reaction time: 3 h
Yield: 81.5 %

Procedure:
To a solution of N-[3-({2-[(chloroacetyl)amino][1,3]thiazolo[5,4-d]pyrimidin-5-yl}amino)-4-methylphenyl]-3-(1-cyano-1-methylethyl)benzamide (150 mg, 288 μmol) produced in Example D32(i) in tetrahydrofuran (4 mL)/N,N-dimethylformamide (0.5 mL) were added triethylamine (120 μL, 864 μmol) and 1-methylpiperazine (96 μL, 864 μmol), and the mixture was stirred at 60° C. for 3 hr. To the reaction mixture was added water (15 mL), and the mixture was extracted with ethyl acetate (20 mL, 5 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/methanol=97/3→92/8), and the fractions containing the object product were concentrated under reduced pressure. The obtained residue was recrystallized from tetrahydrofuran, ethyl acetate and hexane to give the title compound (137 mg, 82%) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:49]([CH3:51])[CH3:50])[N:11](/[CH:20]=[CH:21]/[C@@H:22]([OH:48])[CH2:23][C:24]([O:26][C@@H:27](C3C=CC=CC=3)C(O)(C3C=CC=CC=3)C3C=CC=CC=3)=[O:25])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[Na]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:49]([CH3:51])[CH3:50])[N:11](/[CH:20]=[CH:21]/[C@@H:22]([OH:48])[CH2:23][C:24]([O:26][CH3:27])=[O:25])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: CC(C)c1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)n1/C=C/[C@@H](O)CC(=O)O[C@@H](c1ccccc1)C(O)(c1ccccc1)c1ccccc1
Agent: [Na]
Solvent: CO
Product: COC(=O)C[C@H](O)/C=C/n1c(C(C)C)nc(-c2ccc(F)cc2)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 82 %

Procedure:
A stirred suspension of (S)-1-hydroxy-1,1,2-triphenyleth-2-yl (3S,E)-5-[4,5-bis(4-fluorophenyl)-2-(1-methylethyl)-1H-imidazol-1-yl]-3-hydroxy-4-pentenoate (3.11 g) in methanol (30 ml) was treated with a solution of sodium (110 mg) in methanol (20 ml) plus methanol washings (2×5 ml). The resulting orange solution was stirred at room temperature for 2.5 h then the reaction mixture was concentrate. This was dissolved in dichloromethane (150 ml) and the solution was washed with water (50 ml) and brine (2×50 ml). The combined washings were extracted with dichloromethane (50 ml) and the combined organic phases were dried and evaporated to a pale buff solid (3.13 g). This was purified by CC eluting with System A 1:1 to give the title compound (1.588 g) as a white crystalline solid, νmax (nujol) 1738 cm-1 (C=O).
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[O:9]2)=[CH:4][CH:3]=1.[Li]CCCC.B(OC)(OC)[O:24]C.OO.Cl>C1COCC1.O.C(O)(=O)C>[F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[O:9]2)=[CH:4][C:3]=1[OH:24]
Reactant: COB(OC)OC
Reactant: CCCCCC1CCc2ccc(F)c(F)c2O1
Agent: Cl
Agent: OO
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CCCCCC1CCc2cc(O)c(F)c(F)c2O1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
52.4 g (about 0.22 mol) of crude 7,8-difluoro-2-pentylchroman are initially introduced in 400 ml of THF, and 150.7 ml (0.24 mol) of n-BuLi (15% soln. in hexane) are added at −70° C. After 3 h at this temperature, 26.8 ml (0.24 mol) of trimethyl borate are added dropwise, and the batch is warmed to room temperature. 55 ml of dilute acetic acid (about 30%) are added, and 57 ml of hydrogen peroxide soln. (35%) are carefully added to the batch. When the addition is complete, the mixture is stirred for 17 h at room temperature. Water is added, and the batch is acidified using HCl. The solution is extracted a number of times with MTBE, and the combined organic phases are washed successively with water, sat. sodium chloride soln. and ammonium iron(II) sulfate soln. The solution is dried using sodium sulfate and concentrated to dryness. The crude product is purified by column chromatography (SiO2, n-heptane:MTBE=2:1).
Reaction SMILES: Br[C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([N:15]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:10][C:11]=3[CH2:12]2)=[CH:4][CH:3]=1.[CH:24]([C:26]1[S:30][C:29](B(O)O)=[CH:28][CH:27]=1)=[O:25].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CO>[CH2:16]([N:15]([CH2:20][CH2:21][CH2:22][CH3:23])[C:9]1[CH:10]=[C:11]2[C:6]([C:5]3[CH:4]=[CH:3][C:2]([C:29]4[S:30][C:26]([CH:24]=[O:25])=[CH:27][CH:28]=4)=[CH:14][C:13]=3[CH2:12]2)=[CH:7][CH:8]=1)[CH2:17][CH2:18][CH3:19]
Reactant: O=Cc1ccc(B(O)O)s1
Reactant: CCCCN(CCCC)c1ccc2c(c1)Cc1cc(Br)ccc1-2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CO
Product: CCCCN(CCCC)c1ccc2c(c1)Cc1cc(-c3ccc(C=O)s3)ccc1-2
Temperature: 60 °C

Procedure:
Under N2 atmosphere, 0.37 parts of (7-bromo-9H-fluoren-2-yl)-dibutyl amine (11), 0.19 parts of 5-formyl-2-thiopheneboronic acid, 0.41 parts of potassium carbonate, and 0.16 parts of PdCl2(dppf) were added into 5 parts of toluene and 5 parts of CH3OH, followed by stirring and mixing. Then, the reaction mixture was heated to 60° C. and reacted for 18 hours. After the reaction mixture was quenched by water, using the diethyl ether to extract the product, and magnesium sulfate was used for dehydration. After removing the solvent, the residual was purified with chromatography method column by using dichloromethane/hexane co-solvent as an eluent, to obtain a compound (12a) of the present example. This compound was in a form of a tangerine solid, and the yield of this compound was 61%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N:15]1[C:19]([C:20](OCC)=[O:21])=[CH:18][C:17]([O:25][C:26]([F:35])([F:34])[CH:27]([F:33])[O:28][C:29]([F:32])([F:31])[F:30])=[N:16]1.[H-].C([Al+]CC(C)C)C(C)C.[Cl-].[NH4+]>C1(C)C=CC=CC=1>[CH:20]([C:19]1[N:15]([C:3]2[CH:4]=[C:5]([S:9][CH2:10][C:11]([F:14])([F:13])[F:12])[C:6]([CH3:8])=[CH:7][C:2]=2[F:1])[N:16]=[C:17]([O:25][C:26]([F:35])([F:34])[CH:27]([F:33])[O:28][C:29]([F:30])([F:31])[F:32])[CH:18]=1)=[O:21]
Reactant: CCOC(=O)c1cc(OC(F)(F)C(F)OC(F)(F)F)nn1-c1cc(SCC(F)(F)F)c(C)cc1F
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: Cc1ccccc1
Product: Cc1cc(F)c(-n2nc(OC(F)(F)C(F)OC(F)(F)F)cc2C=O)cc1SCC(F)(F)F
Temperature: -78 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
1.1 g of ethyl 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-{1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy}pyrazole-5-carboxylate was dissolved in 30 mL of toluene, followed by cooling to −78° C., and 2.6 mL of a toluene solution (1.0 mol/L) of diisobutyl aluminum hydride was slowly dropwise added. After stirring for 3 hours, a saturated aqueous solution of ammonium chloride was added, extraction with ethyl acetate was carried out, the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:3) to obtain 0.95 g of 5-formyl-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-{1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy}pyrazole (1H-NMR (CDCL3/TMS δ (ppm) value) δ: 2.56 (3H, s), 3.39 (2H, q), 6.05 (1H, dt), 6.85 (1H, s), 7.17 (1H, d), 7.66 (1H, d), 9.72 (1H, d)).