Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=4)=[C:14]([C:24]([NH:26][CH3:27])=[O:25])[C:13]=3[CH:28]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].N[C@@H:30]([CH:33]([CH3:35])[CH3:34])[CH2:31][OH:32]>C1(Cl)C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:15]2[O:16][C:12]3[CH:11]=[CH:10][C:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:1]5[O:32][CH2:31][C@H:30]([CH:33]([CH3:35])[CH3:34])[N:2]=5)[CH:4]=4)=[CH:28][C:13]=3[C:14]=2[C:24]([NH:26][CH3:27])=[O:25])=[CH:18][CH:19]=1
Reactant: CC(C)[C@H](N)CO
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C#N)c3)cc12
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Clc1ccccc1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C4=N[C@@H](C(C)C)CO4)c3)cc12
Yield: 18.3 %

Procedure:
Zinc chloride (8 mg, 0.054 mmol) was added to a stirring solution of 5-(3-cyanophenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (40 mg, 0.108 mmol) and (S)-2-amino-3-methylbutan-1-ol (111 mg, 1.080 mmol) in PhCl (3 mL) at rt. It was subjected for two 1 hr iterations to microwave irradiation at 200° C. The reaction was concentrated and purified by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give the titled compound (9 mg, 17%). 1H NMR (500 MHz, CD3OD) δ ppm 8.24 (1 H, s), 7.93-7.99 (2 H, m), 7.89-7.93 (2 H, m), 7.86 (1 H, d, J=7.63 Hz), 7.63-7.69 (2 H, m), 7.56 (1 H, t, J=7.78 Hz), 7.26 (2H, t, J=8.70 Hz), 4.52 (1 H, t, J=9.31 Hz), 4.30 (1 H, t, J=8.09 Hz), 4.15-4.22 (1 H, m), 2.98 (3 H, s), 1.86-1.96 (1 H, m), 1.04 (3 H, d, J=6.71 Hz), 0.97 (3 H, d, J=6.71 Hz). LC-MS retention time: 1.63 min; m/z (MH+): 457. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10 u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% CH3CN/95% H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 μm, Rt=10.06 min, purity=95%; Column: Waters Xbridge Phenyl column 4 6×150 mm, 3.5 μm, Rt=10.53 min, purity=95%.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:12])([F:11])[CH:5]([OH:10])[C:6]([F:9])([F:8])[F:7].Cl[C:14]1[CH:19]=[C:18]([CH3:20])[C:17]([N+:21]([O-:23])=[O:22])=[CH:16][N:15]=1.C(OCC)(=O)C>O1CCCC1.O>[CH3:20][C:18]1[C:17]([N+:21]([O-:23])=[O:22])=[CH:16][N:15]=[C:14]([O:10][CH:5]([C:6]([F:9])([F:8])[F:7])[C:4]([F:12])([F:11])[F:3])[CH:19]=1
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Reactant: OC(C(F)(F)F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(OC(C(F)(F)F)C(F)(F)F)ncc1[N+](=O)[O-]
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 85.1 %

Procedure:
After 1.33 g of 60% sodium hydride was introduced to 15 ml of tetrahydrofuran and cooled to 5° C., 5.84 g of 1,1,1,3,3,3-hexafluoro-2-propanol was added dropwise. The mixture was stirred at 5° C. for 30 minutes, and then 3.0 g of 2-chloro-4-methyl-5-nitropyridine dissolved in 10 ml of tetrahydrofuran was added dropwise, this being stirred at room temperature for 3 hours. After being left at room temperature for 3 days, ethyl acetate and water were added thereto, and the organic layer was separated and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Thus obtained residue was purified by silica gel column chromatography (eluent:hexane:ethyl acetate=10:1) to give 4.5 g (yield 80%) of the title compound as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[N:19](Cl)[S:18][NH:17][CH:16]=1>CN(C)C=O.C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:16]2[C:15]([Cl:14])=[N:19][S:18][N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: ClC1=CNSN1Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCN(c2nsnc2Cl)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Piperazine-1-carboxylic acid tert-butyl ester (10 g, 0.054 m) was dissolved in anhydrous dimethylformamide (DMF, 50 mL) under nitrogen in a single-necked round bottomed flask. The clear solution was placed in a preheated oil bath (50 C-60 C). 4,5-Dichloro-[1,2,5]thiadiazole (5.0 mL, 0.054 m) was added and the reaction mixture was allowed to stir for 24 h. A yellow solution containing a white solid was observed. After cooling to room temperature, the mixture was diluted with an equal volume of anhydrous ethyl ether and stirred for 5 minutes. The solid was removed by filtration and the yellow filtrate was concentrated under aspirator vacuum to remove ether and then evaporated under oil pump vacuum to remove DMF. The yellow residue was dried at oil pump vacuum overnight to give 9.91 g of 4-(4-chloro-[1,2,5]thiadiazol-3-yl)piperazine-1-carboxylic acid tert-butyl ester. Two recrystallizations of crude product from hexane gave white crystals: mp 83-86° C.
Reaction SMILES: [F:1][C:2]([F:7])([CH3:6])[CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17].O>C1COCC1>[CH3:15][S:16]([O:5][CH2:4][CH2:3][C:2]([F:7])([F:1])[CH3:6])(=[O:18])=[O:17]
Reactant: CC(F)(F)CCO
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(F)(F)CCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3,3-difluorobutan-1-ol (2.60 g) and triethylamine (6.58 mL) in THF (50 mL) was added dropwise methanesulfonyl chloride (2.74 mL) at 0° C., and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as a pale-yellow oil (2.69 g).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[O:15][C:14]([NH:16][CH2:17][C@@H:18]([NH:30]C(=O)OC(C)(C)C)[CH2:19][C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=4)=[N:13][N:12]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:30][C@@H:18]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:29])[F:28])=[CH:22][CH:21]=1)[CH2:17][NH:16][C:14]1[O:15][C:11]([C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[CH:1]=[N:2][CH:3]=[CH:4]3)=[N:12][N:13]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CNc1nnc(-c2ccc3cnccc3c2)o1)Cc1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H](CNc1nnc(-c2ccc3cnccc3c2)o1)Cc1ccc(C(F)(F)F)cc1
Yield: 62 %

Procedure:
tert-Butyl(S)-1-(5-(isoquinolin-6-yl)-1,3,4-oxadiazol-2-ylamino)-3-(4-(trifluoromethyl)phenyl)propan-2-ylcarbamate (0.04 g, 0.078 mmol) was treated with 2 mL TFA in 2 mL DCM for 30 minutes. After removing the solvent, the remaining residue was made basic with 2M ammonia in MeOH and loaded on a preparative TLC plate. The TLC plate was developed with 5% 2M ammonia in MeOH in DCM. A white solid was obtained as the desired product (20 mg, 63%). LCMS (API-ES) m/z (%): 414.0 (100%, M++H); 1H NMR (400 MHz, CD3OD) δ ppm 2.72 (dd, J=13.60, 7.53 Hz, 1H) 2.94 (dd, J=13.50, 5.28 Hz, 1H) 3.30-3.37 (m, 2H) 3.39-3.45 (m, 1H) 7.43 (d, J=8.02 Hz, 2H) 7.56 (d, J=8.22 Hz, 2H) 7.87 (d, J=5.87 Hz, 1H) 8.10-8.15 (m, 1H) 8.16-8.20 (m, 1H) 8.34 (s, 1H) 8.47 (d, J=5.87 Hz, 1H) 9.24 (s, 1H).
Reaction SMILES: [CH3:1]C1C=C(C2N=C3N(CC4CCOCC4)C(=O)NC3=NC=2)C=CC=1C1N=CNN=1.C[C:31]1[CH:32]=[C:33]([C:48]2[N:53]=[C:52]3[N:54]([CH2:58][CH2:59][CH:60]4[CH2:65][CH2:64][O:63][CH2:62][CH2:61]4)[C:55](=[O:57])[NH:56][C:51]3=[N:50][CH:49]=2)[CH:34]=[CH:35][C:36]=1[C:37]1[N:41]=[CH:40][N:39](C2CCCCO2)[N:38]=1.Cl>O1CCOCC1>[CH3:1][C:32]1[CH:31]=[C:36]([C:37]2[N:41]=[CH:40][NH:39][N:38]=2)[CH:35]=[CH:34][C:33]=1[C:48]1[N:53]=[C:52]2[N:54]([CH2:58][CH2:59][CH:60]3[CH2:65][CH2:64][O:63][CH2:62][CH2:61]3)[C:55](=[O:57])[NH:56][C:51]2=[N:50][CH:49]=1
Reactant: Cc1cc(-c2cnc3[nH]c(=O)n(CC4CCOCC4)c3n2)ccc1-c1nc[nH]n1
Reactant: Cc1cc(-c2cnc3[nH]c(=O)n(CCC4CCOCC4)c3n2)ccc1-c1ncn(C2CCCCO2)n1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(-c2nc[nH]n2)ccc1-c1cnc2[nH]c(=O)n(CCC3CCOCC3)c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-(3-Methyl-4-(1H-1,2,4-Triazol-3-yl)phenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-B]pyrazin-2(3H)-one. 6-(3-Methyl-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)phenyl)-1-((tetrahydro-2H-pyran-4-yl)ethyl)-1H-imidazo[4,5-B]pyrazin-2(3H)-one (0.283 g, 0.578 mmol) was added to 6.0 M hydrogen chloride in dioxane (4.0 mL) and stirred at 25° C. for 2 h. The solution was condensed under reduced pressure and purified using reverse-phase semi-preparatory HPLC (20-70% acetonitrile+0.1% TFA in H2O+0.1% TFA, over 30 min). Clean fractions were combined, neutralized with ammonium hydroxide, concentrated, diluted with water (20 mL). The desired product was collected by filtration to afford the title compound as an off white solid, 99.5% pure, (0.061 g, 26%). 1H NMR (400 MHz, CD3OD-d4) δ 8.40 (br. s., 1H), 8.07 (s, 1H), 8.00 (s, 1H), 7.94 (d, J=8.20, 1H), 7.55 (d, J=8.20, 1H), 4.04 (t, J=7.22, 2H), 3.90 (dd, J=11.32, 3.51, 2H), 3.34-3.42 (m, 3H), 2.49 (s, 3H), 1.70-1.87 (m, 4H), 1.58 (dddd, J=10.93, 7.32, 4.10, 3.81, 1H), 1.50-1.66 (m, 1H), 1.22-1.40 (m, 2H); MS (ESI) m/z 408.5 [M+1]+; mp 258-260° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]=O)[N:13]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Cl[C:21]([F:26])([F:25])C([O-])=O.[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]=[C:21]([F:26])[F:25])[N:13]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(-c2cccc(C=O)n2)ccc1Cl
Reactant: O=C([O-])C(F)(F)Cl
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-c2cccc(C=C(F)F)n2)ccc1Cl
Temperature: 120 °C

Procedure:
To a solution of methyl 2-chloro-5-(6-formylpyridin-2-yl)benzoate (Preparation 39, 302 mg, 1.10 mmol) in DMF (5.5 mL) was added sodium chlorodifluoroacetate (250 mg, 1.64 mmol) and triphenylphosphine (435 mg, 1.64 mmol) and heated to 120° C. for 40 minutes followed by cooling to room temperature for 2 hours. The reaction was concentrated in vacuo and partitioned between water and EtOAc. The aqueous layer was washed with EtOAc (2×10 mL) and the organic layers combined, washed with brine, dried over sodium sulphate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 0-20% EtOAc in heptanes to afford the title compound.
Reaction SMILES: C(O)(=O)C.[C:5]([NH2:8])(=[NH:7])[CH3:6].C([O:11][CH:12]=[C:13]([C:19](OCC)=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15])C>C(O)C.O.ClCCl>[CH3:6][C:5]1[NH:7][C:12](=[O:11])[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:19][N:8]=1
Reactant: CC(=N)N
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1cnc(C)[nH]c1=O
Temperature: 25 °C
Yield: 44.1 %

Procedure:
Acetamidine acetate (37.21 g, 0.31 mole) and diethyl ethoxymethylenemalonate (63 mL, 0.31 mole) were refluxed for 4 h in ethanol (60 mL). The reaction mixture was allowed to cool for 15 min., then acetamidine acetate (37.21 g, 0.31 mole) was added. The reaction mixture was refluxed for 22 hours, allowed to cool to room temperature, and diluted with water (200 mL) and dichloromethane (200 mL). The aqueous layer was extracted with 10% isopropanol/dichloromethane (2×200 mL). The combined organic extracts were washed with water (50 mL), brine (50 mL), dried over magnesium sulfate, filtered and the solvent was removed. The residue was recrystallized from chloroform/hexanes in two crops to afford the title compound (24.92 g) in 46% yield as yellowish crystals. Rf =0.27 (silica gel, 10% isopropanol in dichloromethane). m.p. 187°-188° C.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[C:30]([C:32]3[CH:36]=[CH:35][S:34][CH:33]=3)[CH:29]=[C:28]([C:37](=[O:41])N(C)C)[CH:27]=2)=[CH:17][CH:16]=[CH:15][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])([OH:3])=[O:2].C(OC(CCC1C(OCCCC(OCC)=O)=CC=CC=1CCCCCCOC1C=C(C=C(C2C=CSC=2)C=1)C(O)=O)=O)C.[CH:85]1([NH2:88])[CH2:87][CH2:86]1>>[C:1]([CH2:4][CH2:5][C:6]1[C:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[C:30]([C:32]3[CH:36]=[CH:35][S:34][CH:33]=3)[CH:29]=[C:28]([C:37](=[O:41])[NH:88][CH:85]3[CH2:87][CH2:86]3)[CH:27]=2)=[CH:17][CH:16]=[CH:15][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])([OH:3])=[O:2]
Reactant: NC1CC1
Reactant: CN(C)C(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccsc2)c1
Agent: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)O)cc(-c3ccsc3)c2)c1CCC(=O)OCC
Product: O=C(O)CCCOc1cccc(CCCCCCOc2cc(C(=O)NC3CC3)cc(-c3ccsc3)c2)c1CCC(=O)O

Procedure:
The title compound was prepared by the same method as 4-{2-(2-carboxy-ethyl)-3-[6-(3-dimethylcarbamoyl-5-thiophen-3-yl-phenoxy)-hexyl]-phenoxy}-butyric acid starting from 3-{6-[2-(2-ethoxycarbonyl-ethyl)-3-(3-ethoxycarbonyl-propoxy)-phenyl]-hexyloxy}-5-thiophen-3-yl-benzoic acid and cyclopropylamine.
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][CH2:8][N:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]3=[N:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[H][H]>[Pt]=O.CO>[NH2:11][C:5]1[CH:4]=[CH:3][CH:2]=[CH:1][C:6]=1[CH2:7][CH2:8][N:9]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:10]1
Reactant: [H][H]
Reactant: C1=CC2=Nc3ccccc3CCN2C=C1
Agent: O=[Pt]
Solvent: CO
Product: Nc1ccccc1CCN1CCCCC1
Yield: 105.7 %

Procedure:
Platinum oxide catalyst (1.0 g) is added to a solution of 11,12-dihydropyrido[2,1-b][1,3]benzodiazepine (20.0 g) in methanol (550 ml). Hydrogen gas (about 50 psig) is added and hydrogen uptake is completed in about 1 and 2 hours. The catalyst is filtered off, and the filtrate is concentrated to yield 22.0 g of material that crystallizes spontaneously, melting point 36°-38° C. Recrystallization from 150 ml of pentane yields 16.0 g of the title compound, melting point 39°-41° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1[NH2:10])=[O:4].I[CH3:18]>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1[NH:10][CH3:18])=[O:4]
Reactant: CI
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N
Solvent: CN(C)C=O
Product: CNc1cc(-c2ccccc2)sc1C(=O)OC
Reaction time: 18 h
Yield: 32.2 %

Procedure:
To a mixture of methyl-3-amino-5-phenylthiophene-2-carboxylate (200 mg, 0.855 mmol) in anhydrous N,N-dimethylformamide (4.6 ml) were added 4.2 ml (8.55 mmol) of 2M iodomethane solution in t-buthylmethylether. The mixture was stirred at 60 C for 18 hours, concentrated and purified using biotage technics (silica gel, hexane to hexane:ethyl acetate; 95:5 containing few drops of triethylamine) to give 68 mg (32% yield) of 3-methylamino-5-phenyl-thiophene-2-carboxylic acid methyl ester. 1H NMR (CDCl3, 400 MHz) 7.65-7.62 (m, 2H), 7.42-7.36 (m, 3H), 6.86 (broad s, 1H), 3.83 (s, 3H), 3.04 (d, 3H)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]([NH:12][C@H:13]([C:27]([O:29]C)=[O:28])[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([CH:24]([CH3:26])[CH3:25])[CH:16]=1)=[O:11].[OH-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]([NH:12][C@H:13]([C:27]([OH:29])=[O:28])[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([CH:24]([CH3:26])[CH3:25])[CH:16]=1)=[O:11]
Reactant: COC(=O)[C@H](Cc1cn(C(C)C)c2ccccc12)NC(=O)C=Cc1ccccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)n1cc(C[C@H](NC(=O)C=Cc2ccccc2F)C(=O)O)c2ccccc21
Yield: 70.8 %

Procedure:
The same procedures as in Example 149 were carried out from the compound obtained in Example 147 (0.98 g), 1 mol/L of an aqueous sodium hydroxide solution (3.6 mL), and methanol (40 mL), to give the captioned compound (0.67 g, 71%) as crystals.
Reaction SMILES: Br[CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:9]=2)[N:6]=[N:5][C:4]=1[C:19]([NH:21][CH:22]1[CH2:24][CH2:23]1)=[O:20].[P:25]([O:32]CC)([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28]>>[CH:22]1([NH:21][C:19]([C:4]2[N:5]=[N:6][N:7]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:9]=3)[C:3]=2[CH2:2][P:25]([O:29][CH2:30][CH3:31])([O:26][CH2:27][CH3:28])=[O:32])=[O:20])[CH2:24][CH2:23]1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CBr)cc1
Reactant: CCOP(OCC)OCC
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CP(=O)(OCC)OCC)cc1
Temperature: 120 °C
Reaction time: 72 h

Procedure:
5-(Bromomethyl)-N-cyclopropyl-1-{4-[(ethylamino)carbonyl]phenyl}-1H-1,2,3-triazole-4-carboxamide (890 mg) obtained in Example 321a) was dissolved in triethyl phosphite (2 ml), and the mixture was stirred at 120° C. for 3 days. An excess amount of triethyl phosphite was evaporated under reduced pressure, and the obtained residue was purified by silica gel column (ethyl acetate to ethyl acetate/methanol=4/1) to give the title compound as a colorless oil (640 mg).
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=2[F:23])=[N:9][S:10][C:11]=1[C:12]([F:15])([F:14])[F:13])(=O)=O.O[C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])=[C:27]([CH3:38])[C:26]=1[CH3:39]>>[F:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[C:8]1[C:7]([CH2:6][O:5][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[C:27]([CH3:38])[C:26]=2[CH3:39])=[C:11]([C:12]([F:15])([F:14])[F:13])[S:10][N:9]=1
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1C
Reactant: Cc1ccc(-c2nsc(C(F)(F)F)c2COS(C)(=O)=O)c(F)c1
Product: Cc1ccc(-c2nsc(C(F)(F)F)c2COc2ccc(CCC(=O)O)c(C)c2C)c(F)c1

Procedure:
The title compound was prepared according to the procedure described in Example 1 starting following Step 5 and 6 coupling (3-(2-fluoro-4-methylphenyl)-5-(trifluoromethyl)isothiazol-4-yl)methyl methanesulfonate and ethyl 3-(4-hydroxy-2,3-dimethylphenyl)propanoate followed by hydrolysis to afford the desired product as an off-white solid. 1H NMR (300 MHz, CD3OD) δ 7.36 (t, J=7.6 Hz, 1H), 7.10 (d, J=8.4 Hz, 1H), 7.07 (d, J=11.4 Hz, 1H), 6.90 (d, J=8.4 Hz, 1H), 6.50 (d, J=8.7 Hz, 2H), 5.05 (s, 2H), 2.85 (t, J=8.4 Hz, 2H), 2.42 (s, 3H), 2.34 (t, J=8.4 Hz, 2H), 2.18 (s, 3H), 1.88 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C23H21F4NO3S, 466.1 (M−H). found 466.2.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1B1OC(C)(C)C(C)(C)O1)[C:5]([O:7][CH3:8])=[O:6].Br[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH:28]([F:30])[F:29].[F-].[Cs+].O>O1CCOCC1.CC(OC)(C)C.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>[F:29][CH:28]([F:30])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[CH3:1]
Reactant: FC(F)c1ccccc1Br
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Solvent: COC(C)(C)C
Solvent: O
Product: COC(=O)c1ccc(-c2ccccc2C(F)F)c(C)c1
Temperature: 90 °C

Procedure:
A mixture of methyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (Combiblocks PN-8756, 1.86 g, 6.74 mmol), 1-bromo-2-difluoromethyl-benzene (Fluorochem 023878, 1.67 g, 8.08 mmol), cesium fluoride (3.07 g, 20.2 mmol) and PdCl2(PPh3)2 (142 mg, 0.20 mmol) was prepared in dioxane (20 mL) and water (10 mL) under nitrogen atmosphere. The resulting mixture was heated at 90° C. for 2 hours. The reaction mixture was diluted with MTBE (60 mL), and then washed with water (2×50 mL) and brine (50 mL). The aqueous layers were extracted with MTBE (50 mL). The organic layers were combined, dried (MgSO4) and concentrated under reduced pressure. After purification by flash chromatography (silica, DCM/heptane), the title compound was obtained as a colorless oil (1.42 g, 76%). HPLC (Method A) Rt 5.0 min (purity: 99.1%). 1H NMR (DMSO-d6, 300 MHz) δ 7.93 (s, 1H), 7.84 (dd, J=7.9, 1.4 Hz, 1H), 7.75 (m, 1H), 7.67-7.56 (m, 2H), 7.28 (m, 2H), 6.55 (t, J=54.7 Hz, 1H), 3.88 (s, 3H), 2.06 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11]N(C)C)=[CH:7][NH:8]2)=[CH:4][C:3]=1[F:15].[C-:16]#[N:17].[Na+]>C(OCC)(=O)C.CS(C)=O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][C:16]#[N:17])=[CH:7][NH:8]2)=[CH:4][C:3]=1[F:15]
Reactant: [C-]#N
Reactant: CN(C)Cc1c[nH]c2cc(Br)c(F)cc12
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#CCc1c[nH]c2cc(Br)c(F)cc12
Temperature: 80 °C
Yield: 43.9 %

Procedure:
A mixture of (6-Bromo-5-fluoro-1H-indol-3-ylmethyl)-dimethyl-amine (1.0 g) and sodium cyanide (0.54 g, 11.02 mmol) in ethyl acetate (1.8 ml) and methylsulfoxide (16 ml) was heated at 80° C. for 24 hrs then partitioned between ethyl acetate and water. The organic extract was washed with brine, dried (anhydrous sodium sulfate), concentrated under reduced pressure. The residue was purified by flash column chromatography over silica gel eluting with 20% ethyl acetate in hexane to give (6-Bromo-5-fluoro-1H-indol-3-yl)-acetonitrile as a yellow solid (0.41 g, 44%). 1H NMR (CDCl3) d: 3.78 (d, 2H, J=1.0 Hz), 7.27 (dd, 1H, J=1.2 Hz), 7.31 (d, 1H, J=8.8 Hz, 7.58 (d, 1H, J=5.5 Hz), 8.23 (bs, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Cl[C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)[N:11]=1>>[CH3:28][C:26]1[NH:25][N:24]=[C:23]([NH:22][C:12]2[N:11]=[C:10]([O:8][C:4]3[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][CH:5]=3)[C:19]3[C:14]([CH:13]=2)=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=3)[CH:27]=1
Reactant: Cc1cccc(O)c1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Product: COc1ccc2c(Oc3cccc(C)c3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 10 was used, starting from 3-methyl-phenol and (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give (5-methyl-1H-pyrazol-3-yl)-(1-m-tolyloxy-6-methoxy-isoquinolin-3-yl)-amine. LC-MS m/e 361(MH+).