Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[F:14][C:15]1[CH:20]=CC=[C:17](OC)[C:16]=1B(O)O.CO[CH2:28][CH2:29][O:30][CH3:31].O>>[F:14][C:15]1[CH:20]=[CH:28][C:29]([O:30][CH3:31])=[C:17]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:16]=1
Reactant: COc1cccc(F)c1B(O)O
Reactant: Brc1ccccc1-c1ccccc1
Reactant: COCCOC
Solvent: O
Product: COc1ccc(F)cc1-c1ccccc1-c1ccccc1
Yield: 89 %

Procedure:
Treatment of 2-bromobiphenyl (6.85 g, 29.4 mmol) with 2-fluoro-6-methoxybenzene boronic acid (5.0 g, 29.4 mmol) in DME-water (5:1, 150 mL) according to the procedure described for Example 69, Step 1 provided 7.3 g (89%) of 5-fluoro-2-methoxy-2′-phenylbiphenyl as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=1.C1C(=O)N([Br:23])C(=O)C1>O1CCCC1>[Br:23][C:11]1[CH:12]=[N:13][N:14]([CH3:15])[C:10]=1[C:3]1[CH:4]=[C:5]([C:7]([OH:9])=[O:8])[S:6][C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cn1nccc1-c1cc(C(=O)O)sc1Cl
Solvent: C1CCOC1
Product: Cn1ncc(Br)c1-c1cc(C(=O)O)sc1Cl
Yield: 76.2 %

Procedure:
A solution of 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (50 mg, 0.21 mmol) [prepared in Example 95] and NBS (36.7 mg, 0.21 mmol) in tetrahydrofuran (2.06 ml) was stirred in a sealed tube for 1 h at 70° C. The reaction mixture was then partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4 and concentrated yielding 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-2-thiophenecarboxylic acid (82 mg, 0.16 mmol, 79% yield) as a yellow oil: LCMS (ES) m/e 257, 259 (M, M+2)+.
Reaction SMILES: N1([NH:7][C:8]([C:10]2[CH:40]=[CH:39][C:13]3[N:14]([CH:33]4[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]4)[C:15]([C:17]4[CH:18]=[C:19]5[C:24](=[CH:25][CH:26]=4)[N:23]=[C:22]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:21]=[N:20]5)=[N:16][C:12]=3[CH:11]=2)=[O:9])CCOCC1.N[C:42]1[CH:43]=[CH:44][CH:45]=[C:46]2[C:51]=1[CH:50]=[C:49]([OH:52])[CH:48]=[CH:47]2>>[OH:52][C:49]1[CH:50]=[C:51]2[C:46]([CH:45]=[CH:44][CH:43]=[C:42]2[NH:7][C:8]([C:10]2[CH:40]=[CH:39][C:13]3[N:14]([CH:33]4[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]4)[C:15]([C:17]4[CH:18]=[C:19]5[C:24](=[CH:25][CH:26]=4)[N:23]=[C:22]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:21]=[N:20]5)=[N:16][C:12]=3[CH:11]=2)=[O:9])=[CH:47][CH:48]=1
Reactant: Nc1cccc2ccc(O)cc12
Reactant: O=C(NN1CCOCC1)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)cnc3c1)n2C1CCCCC1
Product: O=C(Nc1cccc2ccc(O)cc12)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)cnc3c1)n2C1CCCCC1
Yield: 20 %

Procedure:
The general procedure described for Compound 574 was used with 8-amino-naphthalen-2-ol (15.9 mg), producing 5 mg of the title compound (20% yield). MS: 590.25 (M+H+) HPLC Procedure A, retention time=15.31 min.
Reaction SMILES: C[C:2]1[NH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:3]=1[CH2:4][CH2:5][NH2:6].[Cl:14][C:15]1[N:16]=[C:17]2[N:21]([C:22]=1[S:23](Cl)(=[O:25])=[O:24])[CH:20]=[CH:19][S:18]2.[CH3:27]C(C)([O-])C.[K+].C([O-])(O)=O.[Na+]>C1COCC1>[ClH:14].[Cl:14][C:15]1[N:16]=[C:17]2[N:21]([C:22]=1[S:23]([N:13]1[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:3]([CH2:4][C@@H:5]([NH2:6])[CH3:27])=[CH:2]1)(=[O:25])=[O:24])[CH:20]=[CH:19][S:18]2
Reactant: CC(C)(C)[O-]
Reactant: O=S(=O)(Cl)c1c(Cl)nc2sccn12
Reactant: Cc1[nH]c2ccccc2c1CCN
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H](N)Cc1cn(S(=O)(=O)c2c(Cl)nc3sccn23)c2ccccc12
Product: Cl
Yield: 35 %

Procedure:
A mixture of (S)-2-(1H-Indol-3-yl)-1-methylethylamine (0.43 g, 2.5 mmol) and di-t-butyl dicarbonate (0.60 g, 2.75 mmol) in acetone is treated dropwise with aqueous K2CO3 (3.5 g, 25 mmol) at OC, allowed to warm to room temperature for 16 h, concentrated to an aqueous residue and extracted with EtOAc. The extracts are combined, dried over MgSO4 and concentrated in vacuo to dryness. This residue is chromatographed (silica gel, 10%–50% EtOAc in hexanes as gradient eluent) to give the protected ®-2-methyl tryptamine. A mixture of the protected tryptamine (0.17 g, 0.62 mmol) and 6-chloroimidazo[2,1-b]thiazole-5-sulfonyl chloride (0.16 g, 0.62 mmol) in THF is treated with potassium t-butoxide (77 mg, 0.68 mmol) at room temperature, stirred for 1H, poured into saturated NaHCO3 and extracted with EtOAc. The extracts are combined, dried over Na2SO4 and concentrated in vacuo. The resultant residue is dispersed in THF and 4N HCl in dioxane, stirred for 16 h, concentrated in vacuo and purified by HPLC1 to afford the title product as a beige solid, 0.62 mg (35% yield), identified by NMR and mass spectral analyses. 1HPLC conditions: Hewlett Packard 1100 HPLC system; Waters Xterra C18, 2 mm×30 mm ID, 3 uM column; 5 uL injection; Solvent A: 0.02% TFA/water; Solvent B: 0.02% TFA/acetonitrile; Gradient: Time 0: 95% A; 0.2 min: 95% A; 3 min: 5% A; Flow rate 1.2 mL/min; Detection: 254 nm DAD.
Reaction SMILES: N[C@H](C=[O:8])CCSC.[NH2:9][C:10]([NH2:12])=S.[CH3:13][CH:14]([CH3:32])[CH:15]([C:21](=O)[CH2:22][C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[CH:24]=1)[C:16](OCC)=[O:17]>C(O)C>[CH3:30][C:25]1[CH:24]=[C:23]([CH:28]=[C:27]([CH3:29])[CH:26]=1)[CH2:22][C:21]1[NH:12][C:10](=[O:8])[NH:9][C:16](=[O:17])[C:15]=1[CH:14]([CH3:32])[CH3:13]
Reactant: CSCC[C@H](N)C=O
Reactant: NC(N)=S
Reactant: CCOC(=O)C(C(=O)Cc1cc(C)cc(C)c1)C(C)C
Solvent: CCO
Product: Cc1cc(C)cc(Cc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Temperature: 25 °C
Yield: 3.6 %

Procedure:
Metal sodium (23.8 g, 1.034 mol) was reacted with anhydrous ethanol (500 ml). To the clear obtained solution, was added thiourea (54.35 g, 714 mmol) and ethyl 3-methyl-2(3,5-dimethylphenylacetyl)butanoate (13.14 g, 47.6 mol). The reaction medium was maintained under reflux for 6 h, and then was concentrated in vacuo at 40.50° C. To the obtained residue was added concentrated hydrochloric acid (100 ml) and then the solution was brought to pH 4 with acetic acid. The obtained 6-dimethylbenzyl-5-isopropyl-2-thiouracil was dissolved in an aqueous 10% chloroacetic acid solution (200 ml) and the solution was maintained under reflux for 24 h and then cooled to ambient temperature and the obtained precipitates were separated by filtration and washed with cold ethanol and then with ether, and then dried in vacuo at 40° C. to give 6-(3,5-dimethylbenzyl)-5-isopropyluracil (7 g, 54%). Melting point: 213-214° C.
Reaction SMILES: I[C:2]1[C:3]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH:15]([CH3:17])[CH3:16])[C:4]=2[S:5][C:6]=1[CH3:7].IC1C2C=CC(OC)=CC=2SC=1C>>[CH:15]([O:14][C:8]1[C:4]2[S:5][C:6]([CH3:7])=[CH:2][C:3]=2[CH:11]=[CH:10][C:9]=1[O:12][CH3:13])([CH3:17])[CH3:16]
Reactant: COc1ccc2c(I)c(C)sc2c1OC(C)C
Agent: COc1ccc2c(I)c(C)sc2c1
Product: COc1ccc2cc(C)sc2c1OC(C)C
Yield: 67 %

Procedure:
When 3-iodo-7-isopropoxy-6-methoxy-2-methylbenzo[b]thiophene was substituted for 3-iodo-6-methoxy-2-methylbenzo[b]thiophene in Step C of Comparator D, the identical process provided the title compound in 67% yield, as a heavy colourless syrup. 1H-NMR (CDCl3) 1.33 (d, 6H, J=6.14 Hz); 2.51 (s, 3H); 3.88 (s, 3H); 4.69 (m, 1H, J=6.14 Hz); 6.84 (, 1H); 6.96 (d, 1H, J=8.51 Hz); 7.27 (d, 1H, J=8.51 Hz).
Reaction SMILES: C(O[C:4](=[N:6][C:7](=O)[C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=1)[CH3:5])C.[CH3:16][S:17]([C:20]1[CH:21]=[CH:22][C:23]([NH:26][NH2:27])=[N:24][CH:25]=1)(=[O:19])=[O:18].O>ClCCl.CO>[Br:14][C:11]1[CH:10]=[CH:9][C:8]([C:7]2[N:26]([C:23]3[CH:22]=[CH:21][C:20]([S:17]([CH3:16])(=[O:19])=[O:18])=[CH:25][N:24]=3)[N:27]=[C:4]([CH3:5])[N:6]=2)=[CH:13][CH:12]=1
Reactant: CCOC(C)=NC(=O)c1ccc(Br)cc1
Reactant: CS(=O)(=O)c1ccc(NN)nc1
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: Cc1nc(-c2ccc(Br)cc2)n(-c2ccc(S(C)(=O)=O)cn2)n1
Reaction time: 8 h
Yield: 61.1 %

Procedure:
N-(1-ethoxy-ethylidene)-4-bromo-benzamide 565 mg (2.09 mmol) was dissolved in a mixed solvent of dichloromethane 20 ml and methanol 10 ml, (5-methansulfonyl-pyridine-2-yl)-hydrazine 431 mg(2.23 mmol) was added to the solution and the solution was stirred for 8 hours. After completing the reaction, water 20 ml was added to the reacting solution and extracted two times with dichloromethane, and then, the collected organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the resulting product was re-crystallized in acetone and hexane phase. As a result, 2-[5-(4-bromo-phenyl)-3-methyl-[1,2,4]triazole-1-yl]-5-methanesulfonyl-pyridine (502 mg, yield: 61%) was obtained as a solid phase.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH2:19][CH2:20][CH3:21])[N:13]=2)[CH:3]=1.[NH2:22][C@@H:23]1[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]1[NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33]>CN1C(=O)CCC1.C(OCC)(=O)C.[Cl-].[Na+].O>[C:8]([C:5]1[N:6]=[N:7][C:2]([NH:22][C@@H:23]2[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]2[NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[CH:3][C:4]=1[NH:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH2:19][CH2:20][CH3:21])[N:13]=1)(=[O:9])[NH2:10]
Reactant: CCCc1cc(C)cc(Nc2cc(Cl)nnc2C(N)=O)n1
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1N
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCCc1cc(C)cc(Nc2cc(N[C@@H]3CCOC[C@@H]3NC(=O)OC(C)(C)C)nnc2C(N)=O)n1
Temperature: 140 °C
Reaction time: 48 h
Yield: 23.4 %

Procedure:
To a solution of 6-chloro-4-(4-methyl-6-propylpyridin-2-ylamino)pyridazine-3-carboxamide (73 mg, 239 μmol, prepared as described in example 38) in NMP (796 μL) was added tert-butyl (3R,4R)-4-aminotetrahydro-2H-pyran-3-ylcarbamate (206.4 mg, 956 μmol) in 4 portions approximately every 12 h over 48 h and heated at 140° C. in the periods between additions. After 48 h, the mixture was diluted with ethyl acetate and brine. The phases were separated then the organic phase was washed with brine (3×), concentrated in vacuo, and purified by chromatography (silica, 1 to 5% methanol in dichloromethane) to give tert-butyl (3R,4R)-4-(6-carbamoyl-5-(4-methyl-6-propylpyridin-2-ylamino)pyridazin-3-ylamino)tetrahydro-2H-pyran-3-ylcarbamate (27 mg, 56 μmol, 23%) as a light brown solid. MS (EI/CI) m/z: 486.2 [M+H].
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][NH2:9])[CH2:3][CH2:2]1.[Cl:10][C:11]1[CH:16]=[C:15](Cl)[CH:14]=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[Cl:10][C:11]1[CH:16]=[C:15]([CH:14]=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19])[NH:9][CH2:8][CH2:7][N:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: NCCN1CCOCC1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(NCCN2CCOCC2)cc1Cl
Temperature: 25 °C
Yield: 50.4 %

Procedure:
A suspension of 2-morpholinoethanamine (5.34 g, 41 mmol), 2,4-dichloro-1-nitrobenzene (7.87 g, 41 mmol) and Cs2CO3 (26.73 g, 82 mmol) in acetonitrile (100 mL) was refluxed for 6 h under N2, then cooled to rt, filtered and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=4:1) to give the title compound as a yellow solid (5.90 g, 50%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[O:38]=[S:39]1(=[O:45])[CH2:43][CH2:42][CH:41]([NH2:44])[CH2:40]1>>[O:38]=[S:39]1(=[O:45])[CH2:43][CH2:42][CH:41]([NH:44][C:21]2[N:20]=[C:19]([O:18][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:29]=[C:30]([N:32]5[CH2:33][CH2:34][O:35][CH2:36][CH2:37]5)[CH:31]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)[CH:24]=[CH:23][N:22]=2)[CH2:40]1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Reactant: NC1CCS(=O)(=O)C1
Product: O=C(Nc1ccc(Oc2ccnc(NC3CCS(=O)(=O)C3)n2)c2ccccc12)c1cc(F)cc(N2CCOCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and 1,1-Dioxo-tetrahydro-1λ6-thiophen-3-ylamine according to conditions described in general procedure C. Mp: 150-151° C.; 1H NMR (400 MHz, DMSO-d6) δ 2.04 (s, 2 H), 2.30 (s, 1 H), 2.88 (s, 2 H), 3.07 (s, 2 H), 3.26 (t, J=4.4 Hz, 4 H), 3.77 (t, J=4.8 Hz, 4 H), 4.56 (s, 1 H), 6.49 (s, 1 H), 7.04 (d, J=12.4 Hz, 1 H), 7.26 (d, J=8.8 Hz, 1 H), 7.43 (d, J=8.0 Hz, 1 H), 7.47 (s, 1 H), 7.56-7.61 (m, 3 H), 7.81-7.84 (m, 1 H), 7.99 (d, J=7.6 Hz, H), 8.30 (d, J=4.0 Hz, 1H), 10.46 (s, 1 H).
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[CH2:8][O:7][C:6]=2[CH:12]=1.[ClH:13].N([O-])=O.[Na+].[S:18](=[O:20])=[O:19]>CC#N.O.C(O)(=O)C>[O:11]=[C:9]1[CH2:8][O:7][C:6]2[CH:12]=[C:2]([S:18]([Cl:13])(=[O:20])=[O:19])[CH:3]=[CH:4][C:5]=2[NH:10]1
Reactant: Cl
Reactant: Nc1ccc2c(c1)OCC(=O)N2
Reactant: O=S=O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CC#N
Product: O=C1COc2cc(S(=O)(=O)Cl)ccc2N1
Temperature: 0 °C

Procedure:
Into a 500 mL 3-necked round bottom flask was placed a solution of 7-amino-2H-benzo[b][1,4]oxazin-3(4H)-one (5 g, 28.96 mmol) in CH3CN (200 mL). To the above was added acetic acid (24.9 g) dropwise with stirring, while cooling to a temperature of 0° C. To the above was added HCl (16.2 g) dropwise with stirring, while cooling to a temperature of 0° C. This was followed by the addition of a solution of NaNO2 (2.52 g, 36.52 mmol) in H2O (2 mL), which was added dropwise with stirring, while cooling to a temperature of 0° C. The resulting solution was allowed to react, with stirring, for 30 minutes while the temperature was maintained at 0-5° C. in a bath of H2O/ice. This was followed by and maintained with an atmosphere of sulfur dioxide, the resulting solution was allowed to react, with stirring, for an additional 2 hours while the temperature was maintained at 0-5° C. in a bath of H2O/ice. To the mixture was added CuCl2.2H2O (5.11 g, 29.97 mmol), while cooling to a temperature of 0-5° C. The resulting solution was allowed to react, with stirring, maintained with an atmosphere of sulfur dioxide for an additional 2 hours while the temperature was maintained at 0-5° C. in a bath of H2O/ice. The resulting solution was allowed to react, with stirring, overnight while the temperature was maintained at room temperature. The reaction progress was monitored by TLC (petroleum ether/ethyl acetate=1:1). The reaction mixture was then quenched by the adding 200 mL of H2O/ice. The resulting solution was extracted one time with 500 mL of ethyl acetate and the organic layers combined. Then the mixture was washed 3 times with 200 mL of brine. The mixture was dried over MgSO4 and concentrated by evaporation under vacuum using a rotary evaporator. The residue was dissolved in 100 mL of CH2Cl2. A filtration was performed. The filtrate was concentrated by evaporation under vacuum using a rotary evaporator. This resulted in 0.9 g (11%) of 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonyl chloride as a yellow solid. 1HNMR (400 MHz, CDCl3) δ 4.73 (s, 2H), 7.00 (m, 1H), 7.28 (d, 1H), 7.71 (d, 1H), 8.27 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH:9][CH:10]([CH3:12])[CH3:11])[CH:3]=1.[CH2:13](OC(OCC)OCC)C.C(O)(C(F)(F)F)=O>>[Br:1][C:2]1[N:7]=[CH:6][C:5]2[N:8]=[CH:13][N:9]([CH:10]([CH3:12])[CH3:11])[C:4]=2[CH:3]=1
Reactant: CCOC(OCC)OCC
Reactant: CC(C)Nc1cc(Br)ncc1N
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1cnc2cnc(Br)cc21
Temperature: 125 °C

Procedure:
A mixture of 6-bromo-N4-isopropylpyridine-3,4-diamine (intermediate 257, 1.2 g, 5.22 mmol), triethylorthoformate (26.6 ml, 156 mmol) and TFA (0.24 ml, 3.12 mmol) was heated at 125° C. for 3.5 h and then concentrated. The residue was diluted with sat. aq. NaHCO3 and extracted with
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH2:24])[CH:7]=1)[CH3:2].N1C=CC=CC=1.[Cl:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=1>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][C:14]=2[CH2:23][NH:24][C:37](=[O:38])[C:36]2[CH:40]=[CH:41][C:33]([Cl:32])=[CH:34][CH:35]=2)[CH:7]=1)[CH3:2]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2CN)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2CNC(=O)c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To [3-(2-aminomethyl-4-trifluoromethyl-phenoxy)-phenyl]-acetic acid ethyl ester (0.084 g, 0.24 mmol) and pyridine (2.0 mL) in CH2Cl2 (2.5 mL) was added 4-chlorobenzoyl chloride (0.04 mL, 0.29 mmol), and the reaction was stirred for 30 minutes at room temperature. The mixture was partitioned between CH2Cl2 and 1N aqueous HCl, and the organic layer was separated and washed twice with 1N aqueous HCl. The organic layer was dried and concentrated, resulting in the formation of a white precipitate. The precipitate was filtered off, and the filtrate was concentrated to give the title compound.
Reaction SMILES: C(OC([N:8]1[C@H:12]([CH2:13][CH2:14][S:15][CH2:16][CH3:17])[CH:11]([C:18]([OH:20])=[O:19])[O:10]C1(C)C)=O)(C)(C)C.[CH2:23](O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl.CN(C)CCCN=C=NCC.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1>ClCCl.ClCCl.CN(C=O)C>[NH2:8][C@H:12]([CH2:13][CH2:14][S:15][CH2:16][CH3:17])[CH:11]([OH:10])[C:18]([O:20][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:19]
Reactant: OCc1ccccc1
Reactant: CCSCC[C@@H]1C(C(=O)O)OC(C)(C)N1C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCSCC[C@@H](N)C(O)C(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
A solution of Example 22B (0.11 g, 0.33 mmol), benzyl alcohol (0.07 mL, 0.7 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.080 g, 0.41 mmol), HOAT (0.045 g, 0.33 mmol), and N-methylmorpholine (0.055 mL, 0.50 mmol) in 3:1 dichloromethane/DMF (4 mL) at room temperature was stirred for 16 hours, diluted with dichloromethane, washed sequentially with aqueous NaHCO3, brine, 0.5M citric acid, and brine, dried (MgSO4), filtered, and concentrated. The residue was dissolved in 4M HCl in dioxane (2 mL), stirred for 1 hour, treated with water (1 mL), stirred for 1 hour, concentrated, and purified by reverse phase HPLC with acetonitrile/water to provide the desired product. MS (ESI) m/e 284 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 7.43–7.37 (m, 5H), 5.20 (s, 1.4H), 5.19 (m, 0.6H), 4.44 (m, 0.3H), 4.32 (m, 0.7H), 3.53 (m, 1H), 2.63 (m, 2H), 2.43 (m, 2H), 1.90–1.75 (m, 2H), 1.20–1.12 (m, 3H).
Reaction SMILES: O.Cl[C:3]1[C:4]([F:13])=[C:5]([C:8]([F:12])=[C:9](Cl)[CH:10]=1)[C:6]#[N:7].[H][H]>[C].[Pd].C(N(CC)CC)C>[F:12][C:8]1[CH:9]=[CH:10][CH:3]=[C:4]([F:13])[C:5]=1[C:6]#[N:7]
Reactant: N#Cc1c(F)c(Cl)cc(Cl)c1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: O
Product: N#Cc1c(F)cccc1F
Reaction time: 7 h
Yield: 95.8 %

Procedure:
To 45 ml of water 15 g of 3,5-dichloro-2,6-difluorobenzonitrile was added and 0.05 g of palladium-carbon catalyst and 17.5 g of triethylamine were added to it. The reaction was carried out in an autoclave at 120° C. for 7 hours while introducing hydrogen gas into it so that the pressure of hydrogen gas in the reaction system was kept at 30 kg/cm2. In the same manner as in the process of the reduction step of Example 1, the reaction mixture was refined to obtain 9.6 g of 2,6-difluorobenzonitrile (yield: 95.8%) and 15.6 g of triethylamine was recovered (recovery rate: 89.1%).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]2[S:18][C:11]3[N:12]=[CH:13][N:14]=[C:15](SC)[C:10]=3[CH:9]=2)=[C:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:5]=[CH:4]1)[CH3:2].C([NH2:27])C.[CH:28]1(CN)[CH2:33][CH2:32]C[CH2:30][CH2:29]1>>[CH:2]1([CH2:1][N:3]2[C:7]([C:8]3[S:18][C:11]4[N:12]=[CH:13][N:14]=[C:15]([NH2:27])[C:10]=4[CH:9]=3)=[C:6]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:5]=[CH:4]2)[CH2:32][CH2:33][CH2:28][CH2:29][CH2:30]1
Reactant: CCn1cnc(-c2ccccc2)c1-c1cc2c(SC)ncnc2s1
Reactant: CCN
Reactant: NCC1CCCCC1
Product: Nc1ncnc2sc(-c3c(-c4ccccc4)ncn3CC3CCCCC3)cc12

Procedure:
The title compound was prepared using the general method of Example 56 and Intermediate 70 but replacing ethylamine with the cyclohexylmethylamine. Solid (20 mg, 19%);
Reaction SMILES: [F:1][CH:2]([F:33])[C:3]1[N:7]([C:8]2[CH:13]=[C:12]([S:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([CH3:20])=[CH:10][C:9]=2[F:21])[N:6]=[C:5]([O:22][C:23]([F:32])([F:31])[CH:24]([F:30])[O:25][C:26]([F:29])([F:28])[F:27])[CH:4]=1.ClC1C=CC=C(C(OO)=[O:42])C=1>C(Cl)(Cl)Cl>[F:33][CH:2]([F:1])[C:3]1[N:7]([C:8]2[CH:13]=[C:12]([S:14]([CH2:15][C:16]([F:17])([F:18])[F:19])=[O:42])[C:11]([CH3:20])=[CH:10][C:9]=2[F:21])[N:6]=[C:5]([O:22][C:23]([F:32])([F:31])[CH:24]([F:30])[O:25][C:26]([F:29])([F:28])[F:27])[CH:4]=1
Reactant: Cc1cc(F)c(-n2nc(OC(F)(F)C(F)OC(F)(F)F)cc2C(F)F)cc1SCC(F)(F)F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Cc1cc(F)c(-n2nc(OC(F)(F)C(F)OC(F)(F)F)cc2C(F)F)cc1S(=O)CC(F)(F)F
Reaction time: 1 h
Yield: 97 %

Procedure:
0.35 g of 5-difluoromethyl-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-{1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy}pyrazole was dissolved in 10 mL of chloroform, and 150 mg of m-chloroperbenzoic acid (purity: 75%) was added under cooling with ice. After stirring for one hour under cooling with ice, the solution was washed with an aqueous sodium thiosulfate solution and then washed with an aqueous sodium hydrogen carbonate solution, and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:2) to obtain 0.35 g of 5-difluoromethyl-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylsulfinyl)phenyl}-3-{1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy}pyrazole.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])=[CH:14][CH:13]=2)=[N:10][C:9]([Br:24])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].N([O-])=O.[Na+].[N-:29]=[N+:30]=[N-].[Na+].CCOCC>C(O)(C(F)(F)F)=O>[N:1]([C:2]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([O:20][CH:21]([CH3:22])[CH3:23])=[O:19])=[CH:14][CH:13]=2)=[N:10][C:9]([Br:24])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])=[N+:29]=[N-:30]
Reactant: COC(=O)c1cc(Br)nc(-c2ccc(C(=O)OC(C)C)cc2)c1N
Reactant: [N-]=[N+]=[N-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: COC(=O)c1cc(Br)nc(-c2ccc(C(=O)OC(C)C)cc2)c1N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.6 %

Procedure:
Methyl 3-amino-6-bromo-2-(4-(isopropoxycarbonyl)phenyl)isonicotinate (1.0 g, 2.54 mmol) was dissolved in TFA (15 mL) and the yellow solution was cooled in an ice bath. Sodium nitrite (0.351 g, 5.09 mmol) was added with stirring to give a dark yellow mixture. After 30 min, sodium azide (1.65 g, 25.4 mmol) was added followed immediately by Et2O (15 mL). The light yellow mixture was stirred in the ice bath for 30 min. It was partitioned between EtOAc and sufficient sat. aq. NaHCO3 solution to neutralize the acid. The organic phase was washed with brine, dried with sodium sulfate, and the solvent removed to leave methyl 3-azido-6-bromo-2-(4-(isopropoxycarbonyl)phenyl)isonicotinate (1.0 gm, 2.3 mmole, 92% yield). 1H NMR (500 MHz, chloroform-d) δ ppm 8.13 (2H, d, J=8.24 Hz), 7.82 (2H, d, J=4.58 Hz), 7.80 (1H, s), 5.24-5.30 (1H, m), 4.01 (3H, s), 1.38 (6H, d, J=6.10 Hz).