Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[CH:10]([C:20]([OH:22])=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[CH2:59]([CH:66]1[CH2:70][CH2:69][CH2:68][NH:67]1)[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>C(Cl)Cl>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[CH:10]([C:20]([N:67]2[CH2:68][CH2:69][CH2:70][CH:66]2[CH2:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)=[O:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(CC2CCCN2)cc1
Reactant: Cc1ccccc1C1CN(Cc2ccccc2)CC1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1C1CN(Cc2ccccc2)CC1C(=O)N1CCCC1Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 1-Benzyl-4-(2-methylphenyl)pyrrolidine-3-carboxylic acid (0.088 g, 0.298 mmol) in CH2Cl2 (1.490 ml) was added BOP (0.138 g, 0.313 mmol), DIPEA (0.208 ml, 1.192 mmol), and 2-benzylpyrrolidine (0.050 g, 0.313 mmol). The solution was stirred at room temperature for 4 hours. Concentrate, filter, and purify on reverse phase HPLC. HRMS (M+H)=439.2739
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([F:9])[CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:20][O:21][C:22]([C:24]1[CH:29]=[CH:28][C:27](=[O:30])[N:26]([CH3:31])[C:25]=1Cl)=[O:23]>C1COCC1>[CH3:20][O:21][C:22]([C:24]1[CH:29]=[CH:28][C:27](=[O:30])[N:26]([CH3:31])[C:25]=1[NH:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[F:9])=[O:23]
Reactant: Nc1ccc(Br)cc1F
Reactant: COC(=O)c1ccc(=O)n(C)c1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(=O)n(C)c1Nc1ccc(Br)cc1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 65.3 %

Procedure:
To a solution of 4-bromo-2-fluorophenylamine (0.192 g, 1.01 mmol) in THF (5 mL) at −78° C. under N2 was added lithium bis(trimethylsilyl)amide (1.50 mL, 1.50 mmol, 1 M solution in hexanes) dropwise. The reaction mixture was stirred for one hour at −78° C. 2-Chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (0.202 g, 1.00 mmol) was then added dropwise as a solution in THF (5 mL) and the reaction mixture was stirred for one hour at −78° C. The reaction mixture was quenched by the addition of H2O and the pH was adjusted to pH 7 with saturated NH4Cl and then diluted with EtOAc. The organic layer was separated and washed with saturated NaCl, dried (Na2SO4), and concentrated under reduced pressure. Purification by flash column chromatography (methylene chloride/EtOAc, 15:1) gave 0.232 g (65%) pure desired product as a white crystalline solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH2:5][C:6](=O)[CH2:7]Cl)[CH3:2].[F:11][C:12]([F:24])([F:23])[C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH2:22])=[S:21])=[CH:15][CH:14]=1>C(O)C>[CH2:1]([O:3][C:4](=[O:10])[CH2:5][C:6]1[N:22]=[C:20]([NH:19][C:16]2[CH:15]=[CH:14][C:13]([C:12]([F:23])([F:11])[F:24])=[CH:18][CH:17]=2)[S:21][CH:7]=1)[CH3:2]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: NC(=S)Nc1ccc(C(F)(F)F)cc1
Solvent: CCO
Product: CCOC(=O)Cc1csc(Nc2ccc(C(F)(F)F)cc2)n1

Procedure:
4-Chloro-3-oxo-butyric acid ethyl ester was added to a suspension of (4-trifluoromethyl-phenyl)-thiourea (3 grams), obtained in step (ii), in ethanol (20 mL) and refluxed for about 12 hrs. The reaction mixture was cooled and the solid obtained was filtered and dried to give the pure product (4.1 grams).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:13][CH3:14])[N:12]=1)[C:6]([O:8]C)=[O:7])#[N:2].[Li+].[OH-].Cl>C1COCC1.CO.O>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:13][CH3:14])[N:12]=1)[C:6]([OH:8])=[O:7])#[N:2]
Reactant: COC(=O)c1cc(C#N)nc(OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1cc(C(=O)O)cc(C#N)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under N2, methyl 2-cyano-6-methoxyisonicotinate (0.433 g, 2.25 mmol, Eq: 1.00) was dissolved in THF (25.0 ml) and Methanol (3.03 ml). At 0° C., 1M LiOH in H2O (2.82 ml, 2.82 mmol, Eq: 1.25) was added and the RM was stirred at 0° C. for 30 minutes. Control with TLC: the reaction was finished. The reaction mixture was acidified with 1M HCl. The mixture was diluted with H2O and extracted with EtOAc. The organic phase was dried over MgSO4; filtered; concentrated in vacuo. Light yellow solid. MS (EIC): 176.8 ([M−H]−)
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:17](=[O:18])[C:16]3[NH:15][C:14](Br)=[N:13][C:12]=3[N:11]([CH2:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:9]2=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH:1]1([CH2:7][N:8]2[C:17](=[O:18])[C:16]3[NH:15][C:14]([N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)=[N:13][C:12]=3[N:11]([CH2:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:9]2=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=c1c2[nH]c(Br)nc2n(CC2CCCCC2)c(=O)n1CC1CCCCC1
Reactant: C1CCNCC1
Product: O=c1c2[nH]c(N3CCCCC3)nc2n(CC2CCCCC2)c(=O)n1CC1CCCCC1

Procedure:
The title compound was prepared from 1,3-di-cyclohexylmethyl-8-bromo xanthine (0.7 g, 0.0017 mol) and piperidine (0.28 g, 0.003 mol) using an analogous procedure to that described in Example 19. The title product was obtained as a crystalline solid, m.pt. 266° C.
Reaction SMILES: I[C:2]1[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][C@@H:15]([OH:17])[CH3:16])[N:8]=2)=[CH:5][N:4]([CH:18]([CH3:20])[CH3:19])[N:3]=1.[CH3:21][C:22]1[C:23]([NH2:37])=[N:24][CH:25]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:27]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:37][C:23]1[N:24]=[CH:25][C:26]([C:2]2[C:6]([C:7]3[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][C@@H:15]([OH:17])[CH3:16])[N:8]=3)=[CH:5][N:4]([CH:18]([CH3:20])[CH3:19])[N:3]=2)=[CH:27][C:22]=1[CH3:21]
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cnc1N
Reactant: CC(C)n1cc(-c2ccnc(NC[C@H](C)O)n2)c(I)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1cc(-c2nn(C(C)C)cc2-c2ccnc(NC[C@H](C)O)n2)cnc1N
Temperature: 85 °C
Reaction time: 8 h
Yield: 11.6 %

Procedure:
To a solution of (2S)-1-(4-(3-iodo-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol (B-1-3) (0.52 g, 1.34 mmol) in toluene (21 mL) and EtOH (7 mL) were added 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (B-3-2) (1 g, 2.68 mmol in theory) and 2 N aq. Na2CO3 (2 mL). The resulting mixture was degassed under N2 for 2 minutes. Then Pd(PPh3)4 (0.15 g, 0.134 mmol) was added and the mixture was degassed again. The reaction was heated to 80-90° C. and stirred overnight. The mixture was cooled. The organic layer was separated and concentrated. The residue was purified by prep. HPLC to afford (2S)-1-(4-(3-(6-amino-5-methylpyridin-3-yl)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol (B-3) (0.057 g, 11.6%) as a light yellow solid.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9]C)[C:4]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][CH:13]=1.Cl.N1C=CC=CC=1>O>[CH2:18]([C:15]1[CH:16]=[CH:17][C:12]([CH2:11][C:4]2[C:3]([OH:2])=[CH:8][CH:7]=[CH:6][C:5]=2[OH:9])=[CH:13][CH:14]=1)[CH3:19]
Reactant: CCc1ccc(Cc2c(OC)cccc2OC)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCc1ccc(Cc2c(O)cccc2O)cc1
Temperature: 180 °C
Reaction time: 15 h
Yield: 97.3 %

Procedure:
A mixture of 1,3-dimethoxy-2-(4-ethylbenzyl)benzene (6.0 g, 23.4 mmol) and pyridine hydrochloride (21.6 g, 187 mmol) was heated and stirred at 180° C. for 15 hours. After addition of water, the reaction mixture was extracted with ethyl acetate, and the organic phase was washed with diluted aqueous hydrochloric acid and saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate 80:20) to give 2-(4-ethylbenzyl)resorcinol (5.2 g, 97%) as a light-brown oil.
Reaction SMILES: Cl.[CH2:2]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([Cl:20])=[C:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH:12]=2)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]1)[CH3:3].[OH:25][CH:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:28](=O)[O:27]1.C(N(CC)CC)C>CN(C=O)C>[CH2:2]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([Cl:20])=[C:11]([N:14]3[CH2:19][CH2:18][N:17]([CH:28]4[C:30]5[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=5)[C:26](=[O:25])[O:27]4)[CH2:16][CH2:15]3)[CH:12]=2)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]1)[CH3:3]
Reactant: O=C1OC(O)c2ccccc21
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(Cl)c(N3CCNCC3)cc21
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCn1cc(C(=O)O)c(=O)c2cc(Cl)c(N3CCN(C4OC(=O)c5ccccc54)CC3)cc21
Yield: 76.9 %

Procedure:
A mixture of 1-ethyl-6-chloro-7-(1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid hydrochloride 1.9 g (0.005 mole), 3-hydroxyphthalide 0.75 g (0.005 mole), triethylamine 0.5 g (0.005 mole) and DMF 10 ml was heated at 100°-110° C. for 8 hours under stirring. After cooling, the reaction mixture was evaporated under vacuum. The residue was dissolved in dichloromethane, washed with water and dried with anhydrous Na2SO4. After removing the solvent, the residue was recrystallized from a mixed solvent of DMF and ethanol to obtain 1.8 g (78%) of 1-ethyl-6-chloro-7-(4-phthalidyl-1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid. Colorless powders.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[C:17](Cl)(=[O:21])/[CH:18]=[CH:19]/[CH3:20].Cl>C1COCC1.[Cl-].[Cl-].[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([C:17](=[O:21])/[CH:18]=[CH:19]/[CH3:20])=[CH:3][CH:4]=1
Reactant: FC(F)(F)c1ccc(I)cc1
Reactant: C/C=C/C(=O)Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: C/C=C/C(=O)c1ccc(C(F)(F)F)cc1
Reaction time: 0.67 h

Procedure:
To a solution of commercially available 4-iodobenzotrifluoride (11.76 mL, 80 mmol) in THF (70 mL) at −40° C. was added isopropylmagnesium chloride (2 M in THF, 41.2 mL, 88 mmol) within 5 min keeping the internal temperature below −20° C., stirring was continued at −20 to 0° C. for 40 min. ZnCl2 (1M in THF, 88 mL, 88 mmol) was added, the cooling bath was removed and replaced with a water bath, the mixture was allowed to reach 23° C. and stirred at 23° C. for 45 min resulting in a light yellow suspension. Pd(PPh3)4 (924 mg, 1 mol %) and trans-crotonyl chloride (90%, 9.38 mL, 88 mmol) were added dropwise at 23° C. (exothermic reaction (!), keeping the internal temperature at ˜35° C. by water bath cooling) and stirring was continued at 23° C. for 1 h. Poured into icecold 0.5 N HCl, extracted with EtOAc, washed with sat. NaHCO3-sol. and brine, dried over MgSO4. Removal of the solvent in vacuum left a red oil which was purified with chromatography with heptane to heptane:TBME (9:1) to give the (E)-1-(4-trifluoromethyl-phenyl)-but-2-en-1-one as a yellow liquid (18.37 g, quant., 93% purity).
Reaction SMILES: [CH3:1][C:2]1([CH3:35])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[CH:19]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([C:26](O)=[O:27])=[CH:22][CH:21]=4)[CH:17]=[CH:16][C:15]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].[K+].C[Si](C)(C)[O:40][NH2:41].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O.ClCCl.C(O)C>[CH3:1][C:2]1([CH3:35])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[CH:19]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([NH:41][OH:40])=[O:27])=[CH:22][CH:21]=4)[CH:17]=[CH:16][C:15]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: C[Si](C)(C)ON
Reactant: CC1(C)CCC(C)(C)c2cc(-c3cc(-c4ccc(C(=O)O)cc4)ccc3-c3ccccc3)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: CC1(C)CCC(C)(C)c2cc(-c3cc(-c4ccc(C(=O)NO)cc4)ccc3-c3ccccc3)ccc21
Temperature: 25 °C

Procedure:
2.00 g (4.3 mmol) of the acid obtained in Example 14, 30 ml of ethanol and 290 mg (5.2 mmol) of powdered potassium hydroxide are successively introduced into a three-necked flask under a stream of nitrogen. The reaction medium is stirred for thirty minutes at room temperature and is then evaporated to dryness. The residue is taken up in 80 ml of dichloromethane and 673 mg (4.8 mmol) of O-(trimethylsilyl)hydroxylamine and 645 mg (4.8 mmol) of 1-hydroxybenzotriazole (HOBT) are added. After cooling the reaction medium to 0° C., 915 mg (4.8 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) are added and the solution obtained is stirred for one hour at 0° C. and then for sixteen hours at room temperature. The reaction medium is poured into a water/dichloromethane mixture and extracted with dichloromethane, and the organic phase is washed with water to neutral pH, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a mixture composed of 20% ethyl acetate and 80% heptane. After evaporation of the solvents, 530 mg (22%) of the expected product are collected in the form of a beige-coloured solid with a melting point of 105–108° C.
Reaction SMILES: [H][H].C([O:10][C:11]1[CH:16]=[C:15]([CH3:17])[N:14]=[C:13]2[C:18]([C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH:32]=[CH:31][CH:30]=[N:29]4)=[CH:24][C:23]=3[CH3:33])=[N:19][N:20]([CH3:21])[C:12]=12)C1C=CC=CC=1>[Pd]>[CH3:21][N:20]1[C:12]2[C:13](=[N:14][C:15]([CH3:17])=[CH:16][C:11]=2[OH:10])[C:18]([C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH:32]=[CH:31][CH:30]=[N:29]3)=[CH:24][C:23]=2[CH3:33])=[N:19]1
Reactant: Cc1cc(OCc2ccccc2)c2c(n1)c(-c1ccc(-n3cccn3)cc1C)nn2C
Reactant: [H][H]
Agent: [Pd]
Product: Cc1cc(O)c2c(n1)c(-c1ccc(-n3cccn3)cc1C)nn2C
Yield: 76.9 %

Procedure:
To a solution of compound 3a (2.0 g in 30 mL ethanol) was added 10% palladium on carbon (0.3 g). The reaction was shaken for 2 hours under 40 psi hydrogen. The reaction mixture was filtered through a pad of Celite®, and the filter cake was washed with ethanol. The filtrate was concentrated to afford 1,5-dimethyl-3-(2-methyl-4-pyrazol-1-yl-phenyl)-1H-pyrazolo[4,3-b]pyridin-7-ol (compound 3e, 1.2 g, 77%) as an off white solid; LC/MS: [M+H]=319.0.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21](Cl)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:25]1[CH2:30][CH2:29][CH2:28][C@@H:27]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:26]1.CCN(C(C)C)C(C)C>ClCCCl>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21]([N:25]3[CH2:30][CH2:29][CH2:28][C@@H:27]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:26]3)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Reactant: CCOC(=O)[C@@H]1CCCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CCOC(=O)[C@@H]1CCCN(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)C)n3CC2CCOCC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (300 mg, 0.80 mmol) in DCE (5 mL) was slowly added to a solution of ethyl (3R)-piperidine-3-carboxylate (140 mg, 0.88 mmol) and DIPEA (1.4 mL, 8.0 mmol) in DCE (25 mL). The reaction mixture was stirred overnight at ambient temperature and the solvent was concentrated. The product was purified by MPLC on silica gel using 60-90% EtOAc/Heptane to provide the title compound as white solid. Yield: 265 mg (66%); 1H NMR (400 MHz, CDCl3) δ 1.26 (t, J=7.13 Hz, 3 H), 1.33 (td, J=12.55, 4.00 Hz, 1 H), 1.50-1.57 (m, 3 H), 1.59 (s, 9 H), 1.62-1.71 (m, 2 H), 1.72-1.84 (m, 1 H), 1.90-2.02 (m, 1 H), 2.22-2.38 (m, 2 H), 2.44 (t, J=11.03 Hz, 1 H), 2.57-2.69 (m, 1 H), 3.28-3.41 (m, 2 H), 3.70 (d, J=11.33 Hz, 1 H), 3.91 (dd, J=11.43, 3.81 Hz, 1 H), 4.01 (dd, J=11.23, 2.83 Hz, 2 H), 4.13 (q, J=7.16 Hz, 2 H), 4.25 (d, J=7.42 Hz, 2 H), 7.43 (d, J=8.59 Hz, 1 H), 7.64 (dd, J=8.40, 1.76 Hz, 1 H), 8.18 (d, J=1.17 Hz, 1 H); MS (ESI) (M+H)+=492.0.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:6]=1[S:12][C:13]1[C:18](=[O:19])[O:17][C:16]([C:28]2[CH:41]=[CH:40][C:31]([O:32][CH2:33][CH2:34]OS(C)(=O)=O)=[CH:30][CH:29]=2)([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:15][C:14]=1[OH:42])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[NH:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1.Cl>CN(C=O)C.O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:6]=1[S:12][C:13]1[C:18](=[O:19])[O:17][C:16]([C:28]2[CH:29]=[CH:30][C:31]([O:32][CH2:33][CH2:34][N:49]3[CH2:54][CH2:53][O:52][CH2:51][CH2:50]3)=[CH:40][CH:41]=2)([CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:15][C:14]=1[OH:42])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(C(C)(C)C)c(SC2=C(O)CC(CCc3ccccc3)(c3ccc(OCCOS(C)(=O)=O)cc3)OC2=O)c1
Reactant: C1COCCN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C(C)(C)C)c(SC2=C(O)CC(CCc3ccccc3)(c3ccc(OCCN4CCOCC4)cc3)OC2=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound was prepared by combining methanesulfonic acid 2-{4-[5-(2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-oxo-2-phenethyl-3,6-dihydro-2H-pyran-2-yl]-phenoxy}-ethyl ester (0.07 g, 0.115 mmol) from the previous paragraph, K2CO3 (0.08 g, 0.57 mmol), and morpholine (0.15 mL, 1.72 mmol) in DMF (2 mL). The reaction was stirred overnight at room temperature then combined with H2O and acidified to pH 6.0 with 1N HCl. The product was extracted with EtOAc, dried (MgSO4) and concentrated. Purification by silica gel chromatography, eluting with MeOH:CH2Cl2 :hexane (3:50:50) gave the title compound, m.p. 140°-150° C. 1H NMR (CDCl3) δ 1.48 (s, 9 H), 1.80 (s, 3 H), 2.17-2.29 (m, 3 H), 2.38 (m, 1 H), 2.63 (m, 4 H), 2.84 (m, 2 H), 3.21 (dd, 2 H), 3.74 (m, 4 H), 4.00 (m, 2 H), 6.15 (s, 1 H), 6.78 (m, 2 H), 7.05 (d, 2 H), 7.10-7.22 (m, 5 H), 7.32 (d, 2 H).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[S:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[CH:6][CH:7]=1.Cl.Cl.[CH3:16][N:17]1[C:21](=[O:22])[C:20]2([CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[N:19]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:18]1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:16][N:17]1[C:21](=[O:22])[C:20]2([CH2:23][CH2:24][N:25]([C:2]3[N:3]=[N:4][C:5]([C:8]4[S:12][N:11]=[C:10]([CH3:13])[N:9]=4)=[CH:6][CH:7]=3)[CH2:26][CH2:27]2)[N:19]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:18]1
Reactant: CN1CN(c2ccccc2)C2(CCNCC2)C1=O
Reactant: Cc1nsc(-c2ccc(Cl)nn2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1nsc(-c2ccc(N3CCC4(CC3)C(=O)N(C)CN4c3ccccc3)nn2)n1

Procedure:
The object product (85 mg, 33%) was obtained in the same manner as in Example 1 and using 3-chloro-6-(3-methyl-1,2,4-thiadiazol-5-yl)pyridazine (130 mg), 3-methyl-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one dihydrochloride (223 mg) and potassium carbonate (130 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([NH2:12])=[O:11])=[CH:4][CH:3]=1.[Br:13]N1C(=O)CCC1=O>C(Cl)Cl.CC#N.[Cl-].[Na+].O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([NH2:12])=[O:11])=[CH:6][C:7]=1[Br:13]
Reactant: NC(=O)CCc1ccc(N)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: NC(=O)CCc1ccc(N)c(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
To a mixture of 3-(4-amino-phenyl)-propionamide (as prepared in the previous step, 123 mg, 0.749 mmol) in 10 mL of 1:1 DCM/CH3CN at 0° C. was added N-bromosuccinimide (NBS) (133 mg, 0.749 mmol) in 4 mL of 1:1 DCM/CH3CN. The mixture was warmed to RT and stirred for 1 h under Ar. Treated with 20 mL of brine, the mixture was extracted with EtOAc (3×20 mL). The combined organic layers were concentrated in vacuo and the residue was purified by flash chromatography on silica gel (1-4% MeOH/DCM) giving 133 mg (81%) of the title compound as a white solid. Mass spectrum (ESI, m/z): Calcd. for C9H11BrN2O, 243.0 (M+H). found 242.9.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[C:5]([NH:7][C:8]1[C:13]([Br:14])=[CH:12][C:11]([C:15]([C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=2)([OH:20])[C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[Br:29])=[O:6].N1C=CC=CC=1.[C:39]([C:41]1[CH:49]=[CH:48][C:44]([C:45](Cl)=[O:46])=[CH:43][CH:42]=1)#[N:40].C(=O)([O-])O.[Na+]>O1CCCC1>[C:39]([C:41]1[CH:49]=[CH:48][C:44]([C:45]([NH:1][C:2]2[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=2)[C:5]([NH:7][C:8]2[C:9]([Br:29])=[CH:10][C:11]([C:15]([C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=3)([OH:20])[C:16]([F:19])([F:17])[F:18])=[CH:12][C:13]=2[Br:14])=[O:6])=[O:46])=[CH:43][CH:42]=1)#[N:40]
Reactant: Nc1cccc(C(=O)Nc2c(Br)cc(C(O)(c3cc(Cl)cc(Cl)c3)C(F)(F)F)cc2Br)c1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: N#Cc1ccc(C(=O)Nc2cccc(C(=O)Nc3c(Br)cc(C(O)(c4cc(Cl)cc(Cl)c4)C(F)(F)F)cc3Br)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-amino-N-{2,6-dibromo-4-[1-(3,5-dichloro-phenyl)-2,2,2-trifluoro-1-hydroxy-ethyl]-phenyl}-benzamide (Example I8) (0.147 mg, 0.24 mmol) in tetrahydrofuran (5 ml) were added successively pyridine (0.058 ml, 0.72 mmol) and 4-cyano-benzoyl chloride (48 mg, 0.29 mmol). The reaction mixture was stirred at ambient temperature for 2 hours. Aqueous sodium hydrogen carbonate (saturated) was added and the phases were separated. The aqueous phase was extracted twice with ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 1:1) to give the title compound.
Reaction SMILES: [N:1]1[C:6]([CH3:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].[OH:9]O>C(O)(=O)C>[N+:1]1([O-:9])[C:6]([CH3:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8]
Reactant: Cc1cccc(C)n1
Reactant: OO
Solvent: CC(=O)O
Product: Cc1cccc(C)[n+]1[O-]

Procedure:
A solution of 2,6-lutidine (19, 23 ml, 200 mmol) and 50% hydrogen peroxide (15 ml) in glacial acetic acid (100 ml) is refluxed at 110° C. for 3 hours. The solution is then concentrated in vacuo at 40° C. to approximately 60 ml. Water (20 ml) is added, and the concentration process is repeated three times. The concentrated solution is further dried by lyophilizer overnight, yielding 26 g of 2,6-Lutidine 1-oxide (20) that contains approximately 10% acetic acid. 1H NMR (300 MHz, CDCl3) δ 2.52 (s, 6H), 7.15 (m, 3H). MS, m/z 124 (M+1), 247 (2M+1).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:24])[C:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=O)[NH2:22])=[CH:17][CH:16]=2)=[O:13])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].COC1C=CC2C(=CC=C(C(C)C(OC3C=CC(C4[S:48]SC(=S)C=4)=CC=3)=O)C=2)C=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1>C1C=CC=CC=1>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:24])[C:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[S:48])[NH2:22])=[CH:17][CH:16]=2)=[O:13])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: COc1ccc2cc(C(C)C(=O)Oc3ccc(-c4cc(=S)ss4)cc3)ccc2c1
Reactant: CC(C)Cc1ccc(C(C)C(=O)Oc2ccc(C(N)=O)cc2)cc1
Agent: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: c1ccccc1
Product: CC(C)Cc1ccc(C(C)C(=O)Oc2ccc(C(N)=S)cc2)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 55 %

Procedure:
4-carbamoylphenyl 2-(4-isobutylphenyl)propanoate, 3 (2.48 g, 7.62 mmol) and Lawesson reagent (3.1 g, 7.62 mmol) were dissolved in 130 ml of anhydrous benzene. The reaction was warmed to 60° C. and stirred for 4 h. The solvent was removed under reduced pressure. The obtained compound was purified by a silica gel open column and eluted with CH2Cl2/MeOH (9.5/0.5) giving the pure compound 4 (1.45 g, 55% yield).