Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10](Cl)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[NH2:18][C:19]1[C:26]([OH:27])=[C:25]([F:28])[C:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:23]([CH3:35])[C:20]=1[C:21]#[N:22].C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[CH2:1]([O:8][CH2:9][C:10]([NH:18][C:19]1[C:26]([OH:27])=[C:25]([F:28])[C:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:23]([CH3:35])[C:20]=1[C:21]#[N:22])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)COCc1ccccc1
Reactant: Cc1c(C#N)c(N)c(O)c(F)c1-c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c(C#N)c(NC(=O)COCc2ccccc2)c(O)c(F)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.2 %

Procedure:
Under nitrogen atmosphere, benzyloxyacetyl chloride (489 μl, 3.10 mmol) was dropwise added to a tetrahydrofuran solution (10 ml) of 2-amino-5-phenyl-4-fluoro-3-hydroxy-6-methylbenzonitrile (I-41) (500 mg, 2.06 mmol) and sodium hydrogencarbonate (520 mg, 6.19 mmol) cooled with ice, followed by stirring at room temperature for 18 hours. Ethyl acetate was added to the reaction liquid, followed by washing with water and saturated brine. The obtained organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated away under reduced pressure. The resulting residue was recrystallized and purified with n-hexane/ethyl acetate to obtain the entitled compound (621 mg, 1.59 mmol, 77%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:8]=2)[N:5]=[C:4]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:3]=1.[Cl:26][C:27]1[CH:35]=[CH:34][C:33]([Br:36])=[CH:32][C:28]=1[C:29](O)=[O:30]>>[CH2:14]([O:13][C:9]1[CH:8]=[C:7]([N:6]2[C:2]([NH:1][C:29](=[O:30])[C:28]3[CH:32]=[C:33]([Br:36])[CH:34]=[CH:35][C:27]=3[Cl:26])=[CH:3][C:4]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:5]2)[CH:12]=[CH:11][CH:10]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1cc(N)n(-c2cccc(OCc3ccccc3)c2)n1
Reactant: O=C(O)c1cc(Br)ccc1Cl
Product: CCOC(=O)c1cc(NC(=O)c2cc(Br)ccc2Cl)n(-c2cccc(OCc3ccccc3)c2)n1

Procedure:
The title compound was prepared according to the method described for Preparation 16 using ethyl 5-amino-1-(3-(benzyloxy)phenyl)-1H-pyrazole-3-carboxylate (Preparation 54) and 2-chloro-5-bromobenzoic acid. The residue was purified using silica gel column chromatography eluting with 30-40% EtOAc in heptanes.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.C(N(C(C)C)C(C)C)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C1COCC1>[Cl:10][C:7]1[CH:6]=[CH:5][C:4]([CH:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])[CH2:2][NH:1][S:29]([CH3:28])(=[O:31])=[O:30])=[CH:9][CH:8]=1
Reactant: CC(C)(C)OC(=O)NC(CN)c1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC(CNS(C)(=O)=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of tert-butyl 2-amino-1-(4-chlorophenyl)ethylcarbamate (Intermediate 73) (220 mg, 0.81 mmol) and N-ethyldiisopropylamine (0.281 mL, 1.63 mmol) in THF (5 mL) was treated with methanesulfonyl chloride (0.075 mL, 0.98 mmol). The resulting solution was stirred at ambient temperature for 2 hours. The mixture was partitioned between DCM and sodium bicarbonate solution. The organic layer was concentrated and the residue was purified by flash column chromatography on silica using gradient elution (10% ethyl acetate/DCM to 30% ethyl acetate/DCM). The desired product, tert-butyl 1-(4-chlorophenyl)-2-(methylsulfonamido)ethylcarbamate, was thus isolated as a colourless solid (154 mg, 54.3%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10]C.B(Br)(Br)Br>C(Cl)Cl>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[OH:10]
Reactant: COc1cc(C=O)ccc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=Cc1ccc(F)c(O)c1
Reaction time: 1 h
Yield: 0.1 %

Procedure:
To a solution of 4-fluoro-3-methoxybenzaldehyde (1.5 g, 10 mmol), 10 mL CH2Cl2 at 0° C., was added BBr3 (30 mL, 1N, 30 mmol) dropwise. The mixture was allowed to warn up to rt over 1 h, then quenched with ice water and diluted with EtOAc. The organic phase was washed with sat. NaHCO3 and brine, dried (Na2SO4), filtered and concentrated. The crude product was purified by flash chromatography (0 to 5% EtOAc/hexanes, gradient) to afford 1.2 mg (85%) of Intermediate 255.1.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][N:3]1[CH2:18][C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=1)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Cl[CH2:41][CH2:42][CH2:43][N:44]1[C:49](=[O:50])[CH2:48][O:47][C:46]2[CH:51]=[CH:52][CH:53]=[CH:54][C:45]1=2>CC(=O)CC>[O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:41][CH2:42][CH2:43][N:44]3[C:49](=[O:50])[CH2:48][O:47][C:46]4[CH:51]=[CH:52][CH:53]=[CH:54][C:45]3=4)[CH2:8][CH2:7]2)[N:5]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:4][N:3]1[CH2:18][C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=1)[C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23]
Reactant: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCNCC3)C2=O)c1
Reactant: O=C1COc2ccccc2N1CCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(CCCN4C(=O)COc5ccccc54)CC3)C2=O)c1
Temperature: 78 °C
Reaction time: 18 h
Yield: 34.8 %

Procedure:
To a solution of tert-butyl 3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.2 g, 0.47 mmol), potassium carbonate (0.097 g, 0.7 mmol) and sodium iodide (0.021 g, 0.14 mmol) in 2-butanone (5 mL), was added 4-(3-chloropropyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (0.107 g, 0.47 mmol). After stirring at 78° C. for 18 hours, the reaction mixture was filtered, concentrated and isolated by preparatory TLC (10% methanol/dichloromethane) to obtain the title compound (0.1 g, 35%); 1H NMR (DMSO-d6): δ 1.52 (s, 9H), 1.62 (d, 2H, J=12.8 Hz), 1.75 (t, 2H, J=6.8 Hz), 2.40 (t, 2H, J=7.2 Hz), 2.45-2.62 (m, 2H), 2.66-2.73 (m, 4H), 3.99 (t, 2H, J=7.2 Hz), 4.58-4.63 (m, 6H), 6.76 (t, 1H, J=7.2 Hz), 6.85 (d, 2H, J=8.4 Hz), 7.00 (m, 3H), 7.21 (t, 2H, J=7.2 Hz), 7.33-7.34 (m, 1H), 7.48-7.55 (m, 2H), 7.79 (s, 1H), 7.83 (d, 1H, J=7.2 Hz); MS for C36H42N4O5 m/z 611.12 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[C:17]([Cl:19])[C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:14]([CH3:16])[CH3:15])[C:10](=[O:13])[NH:11][N:12]=2)=[C:4]([Cl:20])[CH:3]=1.O.[C:22]([OH:26])(=[O:25])[CH:23]=O.C(O)(=O)C.S([O-])([O-])(=O)=O.[Mg+2].C([BH3-])#N>C(Cl)Cl.CO>[Cl:20][C:4]1[CH:3]=[C:2]([NH:1][CH2:23][C:22]([OH:26])=[O:25])[CH:18]=[C:17]([Cl:19])[C:5]=1[O:6][C:7]1[CH:8]=[C:9]([CH:14]([CH3:16])[CH3:15])[C:10](=[O:13])[NH:11][N:12]=1
Reactant: CC(C)c1cc(Oc2c(Cl)cc(N)cc2Cl)n[nH]c1=O
Reactant: O=CC(=O)O
Agent: O=S(=O)([O-])[O-]
Agent: [BH3-]C#N
Agent: [Mg+2]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CC(C)c1cc(Oc2c(Cl)cc(NCC(=O)O)cc2Cl)n[nH]c1=O
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 16.7 %

Procedure:
A solution of 6-(4-amino-2,6-dichloro-phenoxy)-4-isopropyl-2H-pyridazin-3-one (25) (500 mg, 1.59 mmol) in methylene chloride (22 mL) and methanol (22 mL) at room temperature was treated with glyoxylic acid monohydrate (292 mg, 3.17 mmol), glacial acetic acid (0.10 mL, 1.74 mmol), a small spatula tip of magnesium sulfate, and resin bound cyanoborohydride (Argonaut Technologies Inc. MP-(CN)BH3, 0.97 g, 2.39 mmol). The reaction mixture was heated to 50° C. for 24 h. The reaction mixture was then cooled to room temperature, filtered through celite, and rinsed with chloroform. A 1N aqueous hydrochloric acid solution (150 mL) was added to the filtrate. The resulting mixture was stirred for 30 min. The organic layer was separated. The water layer was extracted with chloroform (100 mL). The organic layers were combined, methanol (10 mL) was added to dissolve insoluble material and the organic layer was dried with magnesium sulfate, filtered and concentrated under vacuum. The resulting solid was slurried with ether (3 mL) and diluted with petroleum ether (10 mL). The mixture was stirred for 45 min. The solids were collected by filtration and rinsed with petroleum ether. A small amount of higher Rf impurity was present by TLC. The solid was purified by flash chromatography (Biotage 40L) using silica gel eluted with 100% ethyl acetate followed by 0.4% glacial acetic acid in ethyl acetate. The desired fractions were collected and concentrated under vacuum. The solid was diluted with 1:1 methylene chloride:hexanes and concentrated under vacuum. The solid was slurried in petroleum ether, filtered, rinsed with petroleum ether and dried under high vacuum overnight to afford [3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenylamino]-acetic acid (26) (98.7 mg, 17%) as a white solid; LRMS for C15H15Cl2N3O4 (M+) m/z=372. Molecular Weight=372.2105; Exact Mass=371.0440
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[N:8]=2)[CH:6]=1.[C:27]([NH:31][S:32]([C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)(=[O:34])=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([NH:31][S:32]([C:35]1[CH:40]=[CH:39][C:38]([C:2]2[N:3]=[CH:4][N:5]([C:7]3[N:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:19][CH:18]=4)[N:8]=3)[CH:6]=2)=[CH:37][CH:36]=1)(=[O:34])=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-n3cnc(I)c3)n2)cc1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B(O)O)cc1
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cn(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)cn2)cc1

Procedure:
N-tert-Butyl-4-{1-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide was prepared from 2-(4-iodo-imidazol-1-yl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example E.68) (0.48 g, 1.0 mmol) and commercially available 4-(tert.-butylsulfamoyl)-phenylboronic acid (0.31 g, 1.2 mmol) according to the general procedure VI. Obtained as a light brown solid (0.043 g) which was subsequently deprotected.
Reaction SMILES: ClC1C=C(Cl)C=CC=1C([C:13]1[C:21]2[C:16](=[C:17]([CH2:23][S:24][CH3:25])[CH:18]=[C:19]([F:22])[CH:20]=2)[NH:15][CH:14]=1)CCO.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([CH:36]2[CH2:38][CH2:37]2)(O)[CH3:34])=[C:29]([F:39])[CH:28]=1.C1(C(C2C3C(=C(CSC)C=CC=3)NC=2)(C2C=CC(F)=CC=2)C)CC1>>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([C:13]2[C:21]3[C:16](=[C:17]([CH2:23][S:24][CH3:25])[CH:18]=[C:19]([F:22])[CH:20]=3)[NH:15][CH:14]=2)([CH:36]2[CH2:38][CH2:37]2)[CH3:34])=[C:29]([F:39])[CH:28]=1
Reactant: CC(O)(c1ccc(Cl)cc1F)C1CC1
Reactant: CSCc1cc(F)cc2c(C(CCO)c3ccc(Cl)cc3Cl)c[nH]c12
Agent: CSCc1cccc2c(C(C)(c3ccc(F)cc3)C3CC3)c[nH]c12
Product: CSCc1cc(F)cc2c(C(C)(c3ccc(Cl)cc3F)C3CC3)c[nH]c12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The title compound was prepared starting from 500 mg (2.56 mmol) of the compound from Example 8 and 605 mg (2.82 mmol) of the compound from Example 79A in analogy to the synthesis of the compound from Example 95. As a difference, the reaction mixture was stirred at 0° C. for 2 h and then warmed to RT. 67 mg (7% of theory) of the target compound were obtained.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[CH2:6][CH:7]([C:12]([O:14][CH3:15])=[O:13])[C:8]([O:10][CH3:11])=[O:9].[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>>[CH3:20][O:19][C:18]1[CH:17]=[CH:16][C:5]([CH2:6][CH:7]([C:8]([O:10][CH3:11])=[O:9])[C:12]([O:14][CH3:15])=[O:13])=[CH:4][C:3]=1[CH2:2][O:1][C:30]([NH:29][C:26]1[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=1)=[O:31]
Reactant: COC(=O)C(Cc1ccc(OC)c(CO)c1)C(=O)OC
Reactant: COc1ccc(N=C=O)cc1
Product: COC(=O)C(Cc1ccc(OC)c(COC(=O)Nc2ccc(OC)cc2)c1)C(=O)OC

Procedure:
Using dimethyl 2-[3-(hydroxymethyl)-4-methoxybenzyl]malonate and 4-methoxyphenylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.C([BH3-])#N.[Na+].[CH:24](=O)[CH2:25][CH2:26][CH2:27][CH3:28]>CO>[CH2:24]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:18][CH:19]=1)[CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: Nc1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: CCCCC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCCCCNc1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
12.5 g (0.05 mol) of the compound from Example 1 were dissolved in methanol. 2.0 g (0.03 mol) of sodium cyanoborohydride were then added in portions. 5.3 ml (0.05 mol) of pentanal were cautiously added dropwise to the solution. After stirring for 48 h at room temperature, the solution was concentrated in vacuo, the residue was dissolved in methylene chloride and the solution was washed with 2N hydrochloric acid. The organic phase was separated off, dried and concentrated in vacuo, and the residue was put through a 1000 cm3 silica gel 60 column. The system methylene chloride/ethyl acetate 7:3 was employed as the eluent.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][CH:23]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(S(C)(=O)=O)cc3)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(Nc3ccc(S(C)(=O)=O)cc3)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.6 %

Procedure:
N-tert-butyl-2-(4-(methylsulfonyl)phenylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (90 mg, 174 μmol) was dissolved in dichloromethane (3 mL) and treated with trifluoroacetic acid (396 mg, 268 μL, 3.48 mmol). After stirring at room temperature for 16 h, the mixture was concentrated in vacuo then re-dissolved in dichloromethane (3 mL), methanol (1.5 mL) and ammonium hydroxide (0.35 mL) and the mixture stirred at room temperature for 1 h. The mixture was concentrated in vacuo then diluted with water, triturated and filtered. The solid obtained was washed with ether then dried to give N-tert-butyl-2-(4-(methylsulfonyl)phenylamino)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (65 mg, 168 μmol, 97%) as a yellow solid. 1H NMR (400 MHz, DMSO-d) δ ppm: 12.55 (s, 1H), 10.12 (s, 1H), 8.19 (d, J=2.8, 1 H), 8.16 (s, 1H), 7.95 (d, J=8.8, 2 H), 7.88 (d, J=8.8, 2 H), 7.75 (s, 1H), 3.22 (s, 3H), 1.54 (s, 9H); MS (EI/CI) m/z: 388.2 [M+H].
Reaction SMILES: [C:1](Cl)(=O)C(Cl)=O.[F:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]([I:17])[C:9]=1[C:10]([OH:12])=[O:11].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.CN(C=O)C.CO>[F:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]([I:17])[C:9]=1[C:10]([O:12][CH3:1])=[O:11]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1c(F)cccc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1c(F)cccc1I
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Oxalyl chloride (2.5 ml, 28.66 mmol, 1.5 eq.) was added at room temperature to a suspension of 2-fluoro-6-iodobenzoic acid (5.1 g, 19.17 mmol, 1 eq.) in 40 ml of dry DCM under nitrogen atmosphere. A few drops of dry DMF were added and the mixture was stirred at room temperature for 1 h. The solvent was removed by distillation. The obtained residue was taken up in acetonitrile, which was distilled again, to remove excess acidity. The resulting brown oil was dissolved in dry DCM and the resulting solution was dropwise added to a suspension of potassium carbonate (7 g, 50.6 mmol, 2.6 eq.) in 20 ml of dry methanol. The reaction mixture was then stirred at room temperature overnight.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])[CH:5]=[CH:6][CH:7]=1.C(OC(C1(C(OC(C)C)=O)CC(OC)(OC)C1)=O)(C)C>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:8]2)=[CH:6][CH:7]=1
Reactant: O=C(C=C(Nc1cccc(Cl)c1)c1ccccc1)C(F)(F)F
Agent: COC1(OC)CC(C(=O)OC(C)C)(C(=O)OC(C)C)C1
Product: FC(F)(F)c1cc(-c2ccccc2)nc2cc(Cl)ccc12
Temperature: 0 °C

Procedure:
4-(3-Chloro-phenylamino)-1,1,1-trifluoro-4-phenyl-but-3-en-2-one (2.8 g, 0.0086 mole) and polyphosphoric acid (60 mL) in a 250 mL 3 neck round bottom flask was stirred mechanically under an atmosphere of Nitrogen at 165° C. internal temperature for 3 h. The reaction was poured over stirring ice water (600 ml). The product precipitated, and was collected by suction filtration, washed with water, and air dried overnight. The solids remaining in the Buchner funnel, and beaker from aqueous quench were rinsed into a flask concentrated in vacuo, then combined with the filtered sample and chromatographed on silica gel with 3:1 Hexanes/methylene chloride to afford the title compound as a white solid; 1H NMR (CDCl3, 400 MHz) δ 7.53-7.59 (m, 3 H), 7.60-7.63 (dd, 1 H, J=2.2 & J=9.1 Hz), 8.06-8.09 (dq, 1 H, J=1.9 & J=9.0 Hz), 8.16-8.20 (m, 3 H), 8.29 (d, 1H, J=2.1 Hz); 19F NMR 5-61.48; MS (ES+): 308.0 (100) [MH+], 310.0 (30) [M+2H+].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]([O:14]C)=[N:9][CH:10]=[C:11](Br)[CH:12]=1.[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8](=[O:14])[NH:9][CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1ncc(Br)cc1-c1ccccn1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Product: O=c1[nH]cc(-c2ccccc2)cc1-c1ccccn1
Temperature: 70 °C
Yield: 53.4 %

Procedure:
A mixture of 1.0 g of 3-(2-pyridyl)-5-bromo-2-methoxypyridine, 0.9 g of phenylboronic acid, 0.3 g of dichlorobistriphenylphosphine palladium and 2 ml of triethylamine was stirred at 120° C. for 1.5 hours in 30 ml of xylene in nitrogen atomosphere. The mixture was returned to room temperature, diluted with ethyl acetate, washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated, and the residue was incorporated with 47% hydrobromic acid and heated at 70° C. for 1 hour. The reaction solution was ice-cooled, diluted with water, and neutralized with potassium carbonate. The resulting precipitates were collected by filtration, washed with water and ether, and then air-dried, to give 0.5 g of the title compound as a pale yellow powder.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][N+:12]([O-:15])=[C:11]([CH3:16])[C:10]=1[CH3:17].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Cl:3][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][N+:12]([O-:15])=[C:11]([CH3:16])[C:10]=1[CH3:17]
Reactant: Cc1c(OCCO)cc[n+]([O-])c1C
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1c(OCCCl)cc[n+]([O-])c1C

Procedure:
1.0 ml of thionyl chloride was gradually added to a solution of 0.92 g (5 mmol) of 4-(2-hydroxyethoxy)-2,3-dimethylpyridine N-oxide in 10 ml of chloroform under cooling with ice. The obtained mixture was heated under reflux for 2 hours, cooled by allowing to stand, neutralized with a saturated aqueous solution of sodium hydrogencarbonate and extracted with 100 ml of methyl ethyl ketone twice. The extract was dried over magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography (solvent: chloroform/methanol=19:1) to obtain 0.56 g of 4-(2-chloroethoxy)-2,3-dimethylpyridine N-oxide as a colorless crystal.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][C@H:18]([N:31]2[C:35](=[O:36])[CH:34]([C:37]3[CH:46]=[CH:45][C:40]4[O:41][CH2:42][CH2:43][O:44][C:39]=4[CH:38]=3)[NH:33][C:32]2=[O:47])[C:19](=[O:30])[NH:20][C:21]2[S:22][CH:23]=[C:24]([C:26]([O:28][CH3:29])=[O:27])[N:25]=2)=[CH:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:29][O:28][C:26]([C:24]1[N:25]=[C:21]([NH:20][C:19](=[O:30])[C@@H:18]([N:31]2[C:35](=[O:36])[CH:34]([C:37]3[CH:46]=[CH:45][C:40]4[O:41][CH2:42][CH2:43][O:44][C:39]=4[CH:38]=3)[NH:33][C:32]2=[O:47])[CH2:17][C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:8][CH:9]=2)[S:22][CH:23]=1)=[O:27]
Reactant: COC(=O)c1csc(NC(=O)[C@H](Cc2cn(C(=O)OC(C)(C)C)c3ccccc23)N2C(=O)NC(c3ccc4c(c3)OCCO4)C2=O)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1csc(NC(=O)[C@H](Cc2c[nH]c3ccccc23)N2C(=O)NC(c3ccc4c(c3)OCCO4)C2=O)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.8 %

Procedure:
To a cold solution of 3-[(S)-2-[4-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-2,5-dioxo-imidazolidin-1-yl]-2-(4-methoxycarbonyl-thiazol-2-ylcarbamoyl)-ethyl]-indole-1-carboxylic acid tert-butyl ester (78 mg, 0.118 mmol) in dichloromethane (10 mL), was added trifluoroacetic acid (2 mL, 26.0 mmol). The reaction mixture was stirred at room temperature for 1 hour. The volatiles were removed in vacuo and the residue was dissolved in ethyl acetate (100 mL), washed once with cold saturated aqeous sodium bicarbonate, water, brine and dried over sodium sulfate. The solvent was removed and the residue was purified by chromatographed over silica gel gradient eluted between 50% and 75% ethyl acetate in hexanes to afford 2-[(S)-2-[4-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-2,5-dioxo-imidazolidin-1-yl]-3-(1H-indol-3-yl)-propionylamino]-thiazole-4-carboxylic acid methyl ester (37 mg, 55%).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][C:8]=2[CH2:9][N:10]([CH3:18])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:6])=[O:5])[CH2:3][CH2:2]1>CO.CCOC(C)=O.[Pd]>[NH2:23][C:20]1[CH:21]=[CH:22][C:7]([S:4]([CH:1]2[CH2:2][CH2:3]2)(=[O:6])=[O:5])=[C:8]([CH:19]=1)[CH2:9][N:10]([CH3:18])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:14])[CH3:15]
Reactant: CN(Cc1cc([N+](=O)[O-])ccc1S(=O)(=O)C1CC1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CN(Cc1cc(N)ccc1S(=O)(=O)C1CC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.2 %

Procedure:
To Intermediate 8A (10.0 g, 27.0 mmol) in MeOH (250 ml) and EtOAc (150 ml) was added 10% Pd/C (0.5 g, 4.70 mmol) under a stream of nitrogen. The system was purged and degassed 3× with nitrogen, then the hydrogen balloon was introduced. The system was purged and degassed with hydrogen 3×. The mixture was stirred at rt overnight after addition of 0.5 mL of conc. HCl. The catalyst was filtered carefully over CELITE® under a stream of nitrogen and washed with methanol. The filtrate was concentrated and dried to give Intermediate 8B as an off-white solid (9.3 g). MS (ESI) (m/z) 341 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.85-1.08 (m, 4H) 1.38 (d, J=48.37 Hz, 9H) 2.67-2.78 (m, J=4.40 Hz, 1H) 2.84 (s, 3H) 4.68 (s, 2H) 5.94-6.30 (m, 2H) 6.39 (s, 1H) 7.44 (d, J=8.79 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([N:12]1[CH:20]=[C:19]2[C:14]([C:15]([Cl:21])=[CH:16][CH:17]=[CH:18]2)=[N:13]1)[CH2:9][C:10]#[CH:11]>>[Cl:21][C:15]1[C:14]2[C:19](=[CH:20][N:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[N:13]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: Brc1ccccn1
Reactant: C#CCCn1cc2cccc(Cl)c2n1
Product: Clc1cccc2cn(CCC#Cc3ccccn3)nc12
Yield: 19.5 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (36 mg, 0.23 mmol) and 2-but-3-ynyl-7-chloro-2H-indazole (44 mg, 0.21 mmol). Reaction time: 1 day. The crude residue was purified by flash chromatography (DCM/MeOH 98:2) to yield 11 mg (41 μmol, 19%) of 7-chloro-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-indazole as a brown oil.