Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl([O-])(=O)(=O)=O.[Li+].[CH3:7][Mg]Br.[CH3:10][C:11]1([CH3:23])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([Br:21])[CH:19]=2)[S:14]C(=O)[CH2:12]1.OS(O)(=O)=O.CC[O:31][CH2:32][CH3:33]>>[Br:21][C:18]1[CH:17]=[CH:16][C:15]([SH:14])=[C:20]([C:11]([CH3:12])([CH3:23])[CH2:10][C:32]([CH3:33])([OH:31])[CH3:7])[CH:19]=1
Reactant: CC1(C)CC(=O)Sc2ccc(Br)cc21
Reactant: CCOCC
Reactant: C[Mg]Br
Agent: O=S(=O)(O)O
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Product: CC(C)(O)CC(C)(C)c1cc(Br)ccc1S
Temperature: 0 °C

Procedure:
To 3.49 g (32.8 mmol) of lithium perchlorate was added under argon 35 ml of 3.0M (105 mmol) methyl magnesium bromide in ether. The above mixture was treated dropwise with stirring with a solution of 2.961 g (10.926 mmol) of 4,4-dimethyl-6-bromo-2-oxo-thiochroman (Compound 31) and the reaction mixture was then heated at reflux for 70 h. The reaction mixture was then allowed to cool and poured onto a mixture of 100 g of ice and 8 ml of conc. H2SO4. The organic layer was separated and the aqueous layer was extracted with 2×25 ml of ether. The organic layers were combined and washed successively with 2×25 ml of saturated NaHCO3 solution, 25 ml of water and 25 ml of saturated NaCl solution and then dried (MgSO4). The solvent was removed in-vacuo and the residue purified by flash chromatography to give the title compound as a pale yellow oil. PMR (CDCl3): & 1.05 (6H, s), 1.52 (6H, s), 2.30 (2H, s), 3.71 (1H, s), 7.22 (1H, dd, J-8.5 Hz, 2.1 Hz), 7.28 (1H, d, J-8.5 Hz), 7.35 (1H, d, J-2.1 Hz)
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[C:11]([C:12]#[N:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([CH2:14][CH2:15][C:16]([F:19])([F:18])[F:17])[NH:7]2.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:29][C:30]([NH2:32])=[O:31]>C(#N)C>[C:12]([C:11]1[C:3]([C:2]([F:1])([F:20])[F:21])=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:29][C:30]([NH2:32])=[O:31])[C:6]([CH2:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:5]2)#[N:13]
Reactant: N#Cc1ccc2[nH]c(CCC(F)(F)F)cc2c1C(F)(F)F
Reactant: NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: N#Cc1ccc2c(cc(CCC(F)(F)F)n2CC(N)=O)c1C(F)(F)F
Yield: 51 %

Procedure:
To a solution of 4-(trifluoromethyl)-2-(3,3,3-trifluoropropyl)-1H-indole-5-carbonitrile (Example 302A) (0.200 g, 0.653 mmol) in anhydrous acetonitrile (50 mL) was added Cs2CO3 (0.851 g, 0.2.612 mmol) and 2-bromoacetamide (0.300 g, 1.37 mmol). The mixture was heated under N2, for 2 h. Upon cooling, the mixture was partitioned between EtOAc and water. The organic phase was separated, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (0-20% EtOAc-hexanes gradient) to afford a pure product (0.121 g, 51% yield): MS (ES) m/z 363 (M+).
Reaction SMILES: [CH2:1]([C:3]1([CH2:24][CH3:25])[O:7][C:6]([C:9]2[CH:10]=[C:11]([S:14][C:15]3[CH:20]=[CH:19][C:18]([C:21](=O)[CH3:22])=[CH:17][CH:16]=3)[S:12][CH:13]=2)([CH3:8])[CH2:5][O:4]1)[CH3:2].Cl.[NH2:27][OH:28]>>[CH2:1]([C:3]1([CH2:24][CH3:25])[O:7][C:6]([C:9]2[CH:10]=[C:11]([S:14][C:15]3[CH:20]=[CH:19][C:18](/[C:21](=[N:27]/[OH:28])/[CH3:22])=[CH:17][CH:16]=3)[S:12][CH:13]=2)([CH3:8])[CH2:5][O:4]1)[CH3:2]
Reactant: NO
Reactant: CCC1(CC)OCC(C)(c2csc(Sc3ccc(C(C)=O)cc3)c2)O1
Agent: Cl
Product: CCC1(CC)OCC(C)(c2csc(Sc3ccc(/C(C)=N/O)cc3)c2)O1
Yield: 80 %

Procedure:
Using an analogous procedure to that described in Example 68, 4'-[4-(2,2-diethyl-4-methyl-1,3-dioxolan-4-yl)thien-2-ylthio]acetophenone was reacted with hydroxylamine hydrochloride to give (E)-4'-[4-(2,2-diethyl-4-methyl-1,3-dioxolan-4-yl)thien-2-ylthio]acetophenone oxime in 80% yield as a gum.
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH:13]1[CH:17]=[CH:16][CH:15]=[N:14]1>CN(C)C=O>[N:13]1([C:2]2[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:17]=[CH:16][CH:15]=[N:14]1
Reactant: c1cn[nH]c1
Reactant: CCOC(=O)c1ccccc1F
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccccc1-n1cccn1

Procedure:
As described for the general reaction of ethyl 2-fluorobenzoate with amines set forth in Tetrahedron, 53, 7557-7576 (1997), ethyl 2-fluorobenzoate was reacted with pyrazole by refluxing N, N-dimethylformamide to give ethyl 2-(1-pyrazolyl)benzoate, as a thick yellow oil. Anal. Calc'd: for C12H12N2O2 : C, 66.7; H, 5.6; N 13.0: Found: C, 66.5: H, 5.4: N, 12.9; Mass spectrum (ES) 217.2 (M+H). A sample (7.02 g) of this compound and 8.42 ml of 5N NaOH in 40 ml of ethanol-tetrahydrofuran (2:1) was refluxed for 2 hrs and the solvent removed. The residue was made acidic (pH6) with 2N citric acid and the precipated solid was filtered to obtain 3.7g of product. The pH of the filtrate was adjusted to 4:5 and extracted with ethyl acetate The extract was concentrated to dryness to give 1.5 g of product. The two crops were combined to give 5.2 g of 2-(1-pyrazolyl)benzoic acid, mp 140-142° C. To the preceding compound (2.07 g) in 5 ml CH2Cl2 (chilled in an ice bath )was added 11.1 ml of a 2 Molar solution of oxalyl chloride in CH2Cl2 and 0.085 ml of N,N-dimethylformamide. The mixture was allowed to warm to room temperature and stirred for 4 hours. The solvent was removed and 25 ml of toluene added (twice) and removed under vacuum to give 2-(1-pyrazolyl)benzoyl chloride as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH2:18]([O:20][C:21]([C:23]1[C:27]([CH2:28][CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)=[C:26]([CH:38]=O)[NH:25][C:24]=1[CH3:40])=[O:22])[CH3:19]>C(O)C.N1CCCCC1>[CH2:18]([O:20][C:21]([C:23]1[C:27]([CH2:28][CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)=[C:26]([CH:38]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[NH:12][C:11]2=[O:17])[NH:25][C:24]=1[CH3:40])=[O:22])[CH3:19]
Reactant: CCOC(=O)c1c(C)[nH]c(C=O)c1CCCN1CCN(C)CC1
Reactant: O=C1Cc2c(cccc2-c2cccc(F)c2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(F)c4)c32)c1CCCN1CCN(C)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 45.9 %

Procedure:
To a solution of 4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 5-formyl-2-methyl-4-[3-(4-methyl-piperazin-1-yl)-propyl]-1H-pyrrole-3-carboxylic acid ethyl ester (80.3 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(3-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2-methyl-4-[3-(4-methyl-piperazin-1-yl)-propyl]-1H-pyrrole-3-carboxylic acid ethyl ester as a yellow solid (60.9 mg, 53%).
Reaction SMILES: O=[C:2]([CH:18]([C:20](OCC)=O)C)[CH2:3][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].Cl.[OH2:26]>>[O:26]=[C:18]([CH3:20])[CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[C:7]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:8]
Reactant: CCOC(=O)C(C)C(=O)Cc1cccc(C(=O)c2ccccc2)c1
Reactant: O
Agent: Cl
Product: CC(=O)CCc1cccc(C(=O)c2ccccc2)c1
Temperature: 20 °C
Reaction time: 17 h

Procedure:
A mixture of 14.2 g of 3-(2'-oxo-3'-ethoxycarbonylbutyl)-benzophenone and 142 ml of 6N hydrochloric acid was refluxed with stirring of 17 hours and after cooling to 20° C, the mixture was diluted with 140 ml of water and extracted 3 times with 50 ml of methylene chloride. The organic phase was washed with 50 ml of an aqueous saturated sodium bicarbonate solution and twice with 50 ml of water, dried over sodium sulfate and evaporated to dryness under reduced pressure to obtain 10.76 g of 3-(3'-oxo-butyl)-benzophenone which was utilized as is for the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].[CH:26]1([NH2:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)=[CH:4][C:3]=1[NH:15][C:16](=[O:25])[C:17]1[CH2:24][CH2:23][CH2:22][CH2:21][C:18]=1[C:19]([NH:32][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:20]
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Reactant: NC1CCCCC1
Solvent: c1ccccc1
Product: O=C(Nc1cc(OC2CCCC2)c(Cl)cc1F)C1=C(C(=O)NC2CCCCC2)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.5 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (1.00 g, 2.75 mmol), cyclohexylamine (0.360 g, 3.63 mmol) and benzene (25 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-cyclohexyl-3,4,5,6-tetrahydrophthalamide as white crystals (0.579 g, 45.5% yield).
Reaction SMILES: CO[CH:3](OC)[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([O:13][CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])[CH:7]=1.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.C([O-])([O-])=O.[K+].[K+]>C(O)(C(F)(F)F)=O.CO>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:13][CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])[NH:5][CH:4]=[CH:3]2
Reactant: COC(CNc1ccc(Cl)c(OCCN(C)C)c1)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CCOc1cc2[nH]ccc2cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.5 %

Procedure:
A solution of N-[4-chloro-3-(2-dimethylaminoethoxy)phenyl]aminoacetaldehyde dimethyl acetal (D7, 0.61 g, 0.002 mol) in TFA (2.6 ml) at 0° C., was treated with TFAA (2.6 ml) under an argon atmosphere. More TFA (3.7 ml ) was added and the reaction was heated to reflux for 48 h. The solution was evaporated to dryness and the residue taken up in EtOAc. The extract was dried (Na2SO4) and concentrated in vacuo to leave a brown oil which was dissolved in MeOH (10 ml), treated with K2CO3 (1 g) and then stirred at room temperature for 3 h The mixture was concentrated in vacuo, and then the residue treated with water and extracted with EtOAc. The solution was dried (Na2SO4) and concentrated in vacuo to give the title compound as a brown solid (0.37 g , 76%)
Reaction SMILES: ClC1N=C(NC2C=CC3OCCOC=3C=2)C(F)=CN=1.[Cl:20][C:21]1[N:26]=[C:25](Cl)[C:24]([N+:28]([O-:30])=[O:29])=[C:23]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[N:22]=1.Cl.[CH2:37]([O:39][C:40](=[O:43])[CH2:41][NH2:42])[CH3:38]>>[CH2:37]([O:39][C:40](=[O:43])[CH2:41][NH:42][C:25]1[C:24]([N+:28]([O-:30])=[O:29])=[C:23]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[N:22]=[C:21]([Cl:20])[N:26]=1)[CH3:38]
Reactant: CCOC(=O)c1nc(Cl)nc(Cl)c1[N+](=O)[O-]
Reactant: CCOC(=O)CN
Agent: Cl
Agent: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Product: CCOC(=O)CNc1nc(Cl)nc(C(=O)OCC)c1[N+](=O)[O-]

Procedure:
In a manner similar to the preparation of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-6-ethoxycarbonyl-5-nitropyrimidine and glycine ethyl ester hydrochloride salt were reacted to yield N-(2-chloro-6-ethoxycarbonyl-5-nitro-4-pyrimidinyl)glycine Ethyl Ester. 1H NMR (CDCl3): δ 8.87 (bs, 1H), 4.48 (q, 2H, J=7.2 Hz), 4.39 (d, 2H, J=5.1 Hz), 1.40 (t, 3H, J=6.9 Hz), 1.33 (t, 3H, J=7.2 Hz); LCMS: ret. time: 28.27 min.; purity: 97%; MS (m/e): 332 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8]C)=[CH:4][CH:3]=1.[C:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19](Cl)=[O:20])[CH2:15][CH2:14]1)(=[O:12])[CH3:11]>>[C:10]([N:13]1[CH2:14][CH2:15][CH:16]([C:19]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=2[OH:8])=[O:20])[CH2:17][CH2:18]1)(=[O:12])[CH3:11]
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Reactant: COc1ccc(Cl)cc1
Product: CC(=O)N1CCC(C(=O)c2cc(Cl)ccc2O)CC1

Procedure:
Preparation took place by reacting 4-chloroanisole with 1-acetylpiperidine-4-carbonyl chloride to give the intermediate (1-acetylpiperidin-4-yl)-(5-chloro-2-hydroxyphenyl)methanone in analogy to Strupczewski et al., J. Med. Chem. 1985, 28, 761-69. Alkylation of the OH function with methyl bromoacetate was followed by cyclization in analogy to Kaltenbronn et al, Eur. J. Med. Chem. 1997, 32 (5), 425-431, to give methyl 3-(1-acetylpiperidin-4-yl)-5-methyl-1-benzofuran-2-carboxylate. Hydrolysis of the ester function, decarboxylation and subsequent hydrolysis of the acetyl group resulted in 4-(5-methyl-1-benzofuran-3-yl)piperidine (see also DE 2537837 for the preparation).
Reaction SMILES: [O:1]=[C:2]1[CH2:9][CH2:8][C:5]2([CH2:7][CH2:6]2)[CH2:4][CH:3]1[C:10]#[N:11].[BH4-].[Li+]>C1COCC1.O>[OH:1][CH:2]1[CH2:9][CH2:8][C:5]2([CH2:6][CH2:7]2)[CH2:4][CH:3]1[C:10]#[N:11]
Reactant: N#CC1CC2(CCC1=O)CC2
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: N#CC1CC2(CCC1O)CC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 6-oxospiro[2.5]octane-5-carbonitrile (130 mg, 0.87 mmol) in THF (4.3 mL) was stirred at ambient temperature and lithium borohydride (76 mg, 3.5 mmol) was added. The resulting mixture was stirred at ambient temperature for 16 hours. The mixture was diluted with water and extracted with EtOAc (2×). The combined organic extracts were washed with water, brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford the title compound. The material was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.C([Li])CCC.[C:16]([O:20][C:21](=[O:35])[N:22]([CH2:27][C:28]1[CH:29]=[N:30][C:31](Br)=[CH:32][CH:33]=1)[CH2:23][CH2:24][O:25][CH3:26])([CH3:19])([CH3:18])[CH3:17]>C1COCC1.[Cl-].[Zn+2].[Cl-]>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:31]3[N:30]=[CH:29][C:28]([CH2:27][N:22]([CH2:23][CH2:24][O:25][CH3:26])[C:21](=[O:35])[O:20][C:16]([CH3:17])([CH3:18])[CH3:19])=[CH:33][CH:32]=3)[S:10][C:3]=12
Reactant: COCCN(Cc1ccc(Br)nc1)C(=O)OC(C)(C)C
Reactant: Clc1ccnc2ccsc12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: C1CCOC1
Product: COCCN(Cc1ccc(-c2cc3nccc(Cl)c3s2)nc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.7 %

Procedure:
To a solution of 7-chlorothieno[3,2-b]pyridine (1) (8.84 g, 52.1 mmol) in THF (100 mL) at −78° C. was added n-butyllithium (20.86 mL, 52.1 mmol). After 30 min, zinc chloride (52.1 mL, 52.1 mmol) (1M in ether) was added at −78° C. and the reaction mixture was warmed to r.t. After 1 h, palladium tetrakistriphenylphosphine (1.004 g, 0.869 mmol) and 144 (6 g, 17.38 mmol) in THF (25 mL) were added and the mixture was heated to reflux for 1 h. It was then partitioned between saturated aqueous NaHCO3 solution and EtOAc. The organic layer was collected and the aqueous layer was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine and evaporated under reduce pressure. The residue was purified by flash column chromatography, eluents Hexane/EtOAc: 5/5, 3/7, 0/10, to afford compound 145 (5.41 g, 72% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.65 (d, J=5.1 Hz, 1H), 8.52 (d, J=1.6 Hz, 1H), 8.39 (s, 1H), 8.27 (d, J=8.0 Hz, 1H), 7.80 (dd, J=8.1, 2.1 Hz, 1H), 7.58 (d, J=5.1 Hz, 1H), 4.48 (s, 2H), 3.43-3.35 (m, 4H), 3.22 (s, 3H), 1.43-1.33 (m, 9H). MS (m/z): 434.2 (M+H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[C:7]([O:24][CH3:25])=[CH:8][C:9]([CH:21]([CH3:23])[CH3:22])=[C:10]([CH:20]=1)[O:11][C:12]1[CH:13]([NH2:19])[NH:14][C:15]([NH2:18])=[N:16][CH:17]=1.I[CH3:27].[OH-].[K+]>CC(C)=O>[CH:21]([C:9]1[CH:8]=[C:7]([O:24][CH3:25])[C:6]([C:2]2[N:1]([CH3:27])[CH:5]=[CH:4][N:3]=2)=[CH:20][C:10]=1[O:11][C:12]1[CH:13]([NH2:19])[NH:14][C:15]([NH2:18])=[N:16][CH:17]=1)([CH3:23])[CH3:22]
Reactant: COc1cc(C(C)C)c(OC2=CN=C(N)NC2N)cc1-c1ncc[nH]1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: COc1cc(C(C)C)c(OC2=CN=C(N)NC2N)cc1-c1nccn1C
Temperature: 30 °C
Yield: 52.2 %

Procedure:
To a solution of 5-[5-(1H-Imidazol-2-yl)-2-isopropyl-4-methoxy-phenoxy]-3,4-dihydro-pyrimidine-2,4-diamine (0.044 g, 0.129 mmols) and iodomethane (9 ul, 0.145 mmols) in acetone (5 ml) was added KOH (0.055 g, 0.98 mmols), the mixture was heated at 30° C. for 20 minutes, the mixture was filtered through celite, washed with CH2Cl2, the combined organic solution was concentrated in vacuo. The residue was purified via preparative TLC silica plates, eluted with 5% MeOH/CH2Cl2/NH4OH four times to give 5-[2-Isopropyl-4-methoxy-5-(1-methyl-1H-imidazol-2-yl)-phenoxy]-3,4-dihydro-pyrimidine-2,4-diamine (0.024 g, 52%). Mass Spec: M+H: 355.
Reaction SMILES: Cl.C[O:3][C:4](=[O:16])[C@H:5]([NH2:15])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1.[I:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[C:20]([NH:27][S:28]([C:31]2[C:32]3[N:33]=[CH:34][CH:35]=[N:36][C:37]=3[CH:38]=[CH:39][CH:40]=2)(=[O:30])=[O:29])[CH:19]=1>>[Cl:14][C:9]1[CH:8]=[C:7]([CH2:6][C@@H:5]([NH:15][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][C:18]([I:17])=[CH:19][C:20]=2[NH:27][S:28]([C:31]2[C:32]3[N:33]=[CH:34][CH:35]=[N:36][C:37]=3[CH:38]=[CH:39][CH:40]=2)(=[O:30])=[O:29])[C:4]([OH:3])=[O:16])[CH:12]=[CH:11][C:10]=1[Cl:13]
Reactant: COC(=O)[C@H](N)Cc1ccc(Cl)c(Cl)c1
Reactant: O=C(O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nccnc12
Agent: Cl
Product: O=C(N[C@H](Cc1ccc(Cl)c(Cl)c1)C(=O)O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nccnc12

Procedure:
(R)-2-(tert-Butoxycarbonylamino)-3-(3,4-dichloro-phenyl)-propionic acid was treated as in EXAMPLE 2, Part A, to produce (R)-2-amino-3-(3,4-dichloro-phenyl)-propionic acid methyl ester hydrochloride as a white solid. This ester was coupled to 4-iodo-2-(quinoxaline-5-sulfonylamino)-benzoic acid as in EXAMPLE 1, Part C. The resulting methyl ester was hydrolyzed as in EXAMPLE 2, Part E, to afford the title compound. HPLC: RT=10.06 min. MS (ESI−): mass calcd. for C24H17Cl2IN4O5S, 669.93; m/z found, 669/671 [M−H]−. 1H NMR (500 MHz, CDCl3): 10.85 (s, 1H), 9.00 (d, J=1.8, 1H), 8.92 (d, J=1.7, 1H), 8.54 (dd, J=7.4, 1.2, 1H), 8.33-8.31 (m, 1H), 8.07 (d, J=1.5, 1H), 7.91-7.87 (m, 1H), 7.47-7.22 (m, 3H), 6.98 (dd, J=8.2, 2.0, 1H), 6.87 (d, J=8.3, 1H), 6.37 (d, J=7.7, 1H), 4.92-4.88 (m, 1H), 3.23 (dd, J=14.2, 5.9, 1H), 3.14 (dd, J=14.1, 6.1, 1H).
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:19])=[C:6]([Br:18])[C:7](=[O:17])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:9]=1)(=[O:3])[CH3:2].[CH2:20](O)[CH2:21][OH:22].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Br:18][C:6]1[C:7](=[O:17])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:9]=[C:4]([C:1]2([CH3:2])[O:22][CH2:21][CH2:20][O:3]2)[C:5]=1[CH3:19]
Reactant: OCCO
Reactant: CC(=O)c1nn(-c2ccc(F)cc2)c(=O)c(Br)c1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1c(C2(C)OCCO2)nn(-c2ccc(F)cc2)c(=O)c1Br
Yield: 89.4 %

Procedure:
A suspension of 6-acetyl-4-bromo-2-(4-fluorophenyl)-5-methyl-3(2H)-pyridazinone (3.2 g), ethylene glycol (3.1 g) and p-toluenesulfonic acid (0.2 g) in toluene (35 ml) was heated under reflux for 10 hours with removing water formed. After cooling on standing, the reaction mixture was extracted with ethyl acetate. After washing with a saturated aqueous sodium hydrogen carbonate solution and a brine, the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by evaporation, the resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2), and the resulting crude crystals were washed with hexane to obtain 4-bromo-2-(4-fluorophenyl)-5-methyl-6-(2-methyl-1,3-dioxolan-2-yl)-3(2H)-pyridazinone (3.25 g).
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH:5]=[C:4]([C:7]([OH:9])=O)[O:3]1.[CH3:10][NH:11][CH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=2)=[O:21])[CH2:16][CH2:15]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[CH3:10][N:11]([CH2:12][CH2:13][CH:14]1[CH2:15][CH2:16][N:17]([C:20]([O:22][CH2:23][C:24]2[CH:25]=[C:26]([Cl:31])[CH:27]=[C:28]([Cl:30])[CH:29]=2)=[O:21])[CH2:18][CH2:19]1)[C:7]([C:4]1[O:3][C:2](=[O:1])[NH:6][CH:5]=1)=[O:9]
Reactant: O=C(O)c1c[nH]c(=O)o1
Reactant: CNCCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(CCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1)C(=O)c1c[nH]c(=O)o1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 2-oxo-2,3-dihydrooxazole-5-carboxylic acid (Example 21, step 1) (317 mg, 1.471 mmol) and 3,5-dichlorobenzyl 4-(2-(methylamino)ethyl)piperidine-1-carboxylate (Example 1, step 3)(508 mg, 1.471 mmol) in DMF (10 ml) was added DIPEA (0.257 ml, 1.471 mmol) and HATU (559 mg, 1.471 mmol). The orange suspension formed was stirred at RT for 16 hrs. The mixture was concentrated under reduced pressure and the residue was dissolved in EtOAc (100 ml). The mixture was filtered and the filtrate was dry loaded in MeOH onto silica (˜5 g). Purification was carried out by chromatography on silica (12 g silica cartridge) eluting with 0-100% EtOAc/iso-hexane. The product fractions were combined and concentrated to give a gum. This was dissolved in minimum volume of EtOAc and applied to a combined 10 g Isolute® PEAX/SCX-2 cartridge. The column was washed with MeOH and the fractions combined and concentrated under reduced pressure. The resultant solid was dissolved in DMSO (500 μl), MeCN (2 ml) and water and applied to a 13 g C18 cartridge which was eluted with 0-100% MeCN/water. The product fractions were combined and concentrated to give an aqueous suspension which was extracted with EtOAc (50 ml). The extracts were dried (MgSO4) and concentrated to give 3,5-dichlorobenzyl 4-(2-(N-methyl-2-oxo-2,3-dihydrooxazole-5-carboxamido)ethyl)piperidine-1-carboxylate as a white solid.
Reaction SMILES: OO.C(O[C:10]([C:12](F)(F)F)=[O:11])(C(F)(F)F)=O.C(NC1N=[N+:21]([O-:35])[C:22]2[CH:31]=[C:30]3[C:26]([CH2:27][CH:28](N(C)C)[CH2:29]3)=[CH:25][C:23]=2[N:24]=1)C.C(O)(C(F)(F)F)=[O:37]>C(Cl)Cl.N>[N+:21]([C:22]1[CH:31]=[C:30]2[C:26]([CH2:27][CH2:28][CH2:29]2)=[CH:25][C:23]=1[NH:24][C:10](=[O:11])[CH3:12])([O-:35])=[O:37]
Reactant: O=C(O)C(F)(F)F
Reactant: CCNc1nc2cc3c(cc2[n+]([O-])n1)CC(N(C)C)C3
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: N
Agent: OO
Solvent: ClCCl
Product: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])CCC2
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
H2O2 (70%, 0.35 mL, ca. 6.9 mmol) was added dropwise to a stirred solution of TFAA (1.0 mL, 6.9 mmol) in DCM (10 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a stirred solution of 1-oxide 113 (188 mg, 0.7 mmol) and TFA (0.26 mL, 3.4 mmol) in DCM (10 mL) at 0° C. The solution was stirred at 20° C. for 6 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCl3 (4×30 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give (i) starting material 113 (175 mg, 93%) and (ii) 1,4-dioxide 114 (8 mg, 4%) as a red gum: 1H NMR δ 8.11 (s, 1H, H-9), 8.08 (s, 1H, H-5), 6.98 (br s, 1H, NH), 3.63 (dq, J=7.2, 1.0 Hz, 2H, CH2N), 3.15-3.30 (m, 3H, CH, CH2), 2.95-3.07 (m, 2H, CH2), 2.33 [s, 6H, N(CH3)2], 1.36 (t, J=7.2 Hz, 3H, CH3); MS (FAB+) m/z 290 (MH+, 20%), 274 (5); HRMS (FAB+) calcd for C14H20N5O2 (MH+) m/z 290.1617, found 290.1607.