Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[SH:2][CH2:3][CH2:4][OH:5].[Br-].[Br-].[Br-].[Br-].O[CH2:11][C:12]([CH2:17]O)([CH2:15]O)[CH2:13]O>C(O)C>[OH:5][CH2:4][CH2:3][S:2][CH2:17][C:12]([CH2:11][S:2][CH2:3][CH2:4][OH:5])([CH2:13][S:2][CH2:3][CH2:4][OH:5])[CH2:15][S:2][CH2:3][CH2:4][OH:5]
Reactant: OCCS
Reactant: OCC(CO)(CO)CO
Agent: [Br-]
Agent: [Na]
Solvent: CCO
Product: OCCSCC(CSCCO)(CSCCO)CSCCO

Procedure:
To 400 parts of ethanol were successively added 9.2 parts of metallic sodium, 31.2 parts of 2-mercaptoethanol amd 38.8 parts of pentaerythritol tetrabromide, and the resulting mixture was heated under reflux. Thereafter, the deposited sodium bromide was removed, and the ethanol was removed by distillation to obtain tetrakis(2-hydroxyethylthiomethyl)methane. This compound was added to 80 parts of chloroform, and 60 parts of thionyl chloride was dropped into the resulting mixture. Subsequently, the mixture was heated under reflux, and then the solvent chloroform and unreacted thionyl chloride were removed by distillation under reduced pressure. The residual oily substance was poured into ice water and extracted with ether, and the ether extract was dehydrated over anhydrous sodium sulfate and then freed from the ether by distillation to obtain tetrakis(2-chloroethylthiomethyl)methane. To this compound were successively added 0.4 part of phosphoric acid and 80 parts of 30% aqueous hydrogen peroxide, and the resulting mixture was heated under reflux and then cooled to deposit tetrakis(2-chloroethylsulfonylmethyl)methane. The deposited compound was recovered by filtration and dissolved in 200 parts of acetone, and the resulting solution was incorporated with 40 parts of triethylamine and then stirred at room temperature to deposit triethylamine hydrochloride. This hydrochloride was removed, and the acetone was removed by distillation to deposit solids. The deposited solids were recrystallized from acetone-ethanol to obtain tetrakis(vinylsulfonylmethyl)methane.
Reaction SMILES: [CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:14]([NH:16][CH2:17][C:18]([O:20]CC)=[O:19])=[O:15])[C:10](=[O:23])[NH:9][C:8]2=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[Br:31][C:32]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:33]=1[CH2:34]Br.Cl>CC(N(C)C)=O>[Br:31][C:32]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:33]=1[CH2:34][N:9]1[C:10](=[O:23])[C:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])=[C:12]([OH:13])[N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]1=[O:24]
Reactant: COc1ccc(Br)c(CBr)c1
Reactant: CCOC(=O)CNC(=O)c1c(O)n(C2CCCCC2)c(=O)[nH]c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1ccc(Br)c(Cn2c(=O)c(C(=O)NCC(=O)O)c(O)n(C3CCCCC3)c2=O)c1
Reaction time: 8 h
Yield: 29.4 %

Procedure:
A mixture of ethyl N-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate (340 mg, 1.0 mmoles), pulv. potassium carbonate (750 mg, 5.35 mmoles) and 2-bromo-5-methoxybenzyl bromide (560 mg, 2.0 mmoles) in dimethylacetamide (6 mL) was vigorously stirred at 100° C. for 3 hours. The mixture was poured into 1 molar hydrochloric acid and extracted with ethyl acetate (×2). The combined organic solutions were washed with 1 molar hydrochloric acid and evaporated. The residue was purified by flash chromatography (10-50% ethyl acetate in hexane), the required fractions evaporated, dissolved in ethanol (5 mL) and 1 molar sodium hydroxide solution (3.0 mL) added. The mixture was stirred overnight, acidified and extracted with ethyl acetate (×2), the combined extracts washed with 1 molar hydrochloric acid, dried and evaporated. Recrystallization from acetic acid-water gave the title compound (150 mg, 29%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.04 (br. s., 1 H), 10.12 (br. s., 1 H), 7.55 (d, J=8.84 Hz, 1 H), 6.84 (dd, J=8.84, 3.03 Hz, 1 H), 6.50 (d, J=2.78 Hz, 1 H), 4.94 (s, 2 H), 4.65 (t, J=11.75 Hz, 1 H), 4.13 (d, J=5.81 Hz, 2 H), 3.69 (s, 3 H), 2.25 (q, 2 H), 1.79 (d, J=13.14 Hz, 2 H), 1.54-1.74 (m, 3 H), 1.28 (q, J=12.72 Hz, 2 H), 1.10 (q, J=12.88 Hz, 1 H)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[CH2:13][CH2:14][NH:15][C:16]([O:18][C:19](C)([CH3:21])[CH3:20])=[O:17].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[CH2:13][CH2:14][NH:15][C:16]([O:18][CH:19]([CH3:20])[CH3:21])=[O:17]
Reactant: COC(=O)CCc1ccc(O)cc1CCNC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CCc1ccc(O)cc1CCNC(=O)OC(C)C
Reaction time: 1 h
Yield: 66.4 %

Procedure:
A solution of 3-[2-(2-tert-butoxycarbonylamino-ethyl)-4-hydroxy-phenyl]-propionic acid methyl ester (282 mg, 0.876 mmol; Example 544, Step E) in CH2Cl2 (10 mL) at ambient temperature was treated with TFA (5.0 mL), stirred for 60 min, and concentrated. The residue in CH2Cl2 (10 mL) was treated with triethyl amine (2.0 mL) and iso-propyl chloroformate (0.97 mL, 1.0 M in toluene). The reaction mixture was stirred at ambient temperature for 16 h and concentrated. The crude material was purified using silica gel chromatography (50% EtOAc/hexanes) to yield the title compound (180 mg, 67%).
Reaction SMILES: Cl.Cl.[Br:3][C:4]1[C:9]2[N:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:11]([C@@H:13]([NH2:15])[CH3:14])=[N:12][C:8]=2[CH:7]=[CH:6][C:5]=1[O:22][CH3:23].Cl[C:25]1[N:33]=[CH:32][N:31]=[C:30]2[C:26]=1[N:27]=[CH:28][N:29]2[CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][O:35]1.CCN(C(C)C)C(C)C>CC(O)C>[Br:3][C:4]1[C:9]2[N:10]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:11]([C@@H:13]([NH:15][C:25]3[N:33]=[CH:32][N:31]=[C:30]4[C:26]=3[N:27]=[CH:28][N:29]4[CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][O:35]3)[CH3:14])=[N:12][C:8]=2[CH:7]=[CH:6][C:5]=1[O:22][CH3:23]
Reactant: COc1ccc2nc([C@H](C)N)n(-c3ccccc3)c2c1Br
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COc1ccc2nc([C@H](C)Nc3ncnc4c3ncn4C3CCCCO3)n(-c3ccccc3)c2c1Br
Temperature: 90 °C
Yield: 45.9 %

Procedure:
To a solution of (S)-1-(7-bromo-6-methoxy-1-phenyl-1H-benzoimidazol-2-yl)ethylamine dihydrochloride (0.75 g, 1.8 mmol) in IPA (10 mL) was added 6-chloro-9-(tetrahydro-pyran-2-yl)-9H-purine (0.56 mg, 2.34 mmol) and DIPEA (1.2 mL, 7.2 mmol) and the reaction mixture heated at 90° C. for 16 h. The reaction mixture was concentrated in vacuo and the resultant residue subjected to flash chromatography (SiO2, eluting with 0-10% methanol in EtOAc) to give the title compound as a white solid (453 mg, 44%). LCMS (Method C): RT=3.22 min, [M+H]+=548 & 550.
Reaction SMILES: O[CH2:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:13][C:14](=[O:26])[C:15]3[C:20]([CH:21]=2)=[CH:19][C:18]([O:22][CH3:23])=[CH:17][C:16]=3[O:24][CH3:25])=[CH:7][C:6]=1[CH3:27].[C:28]1(=[O:38])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30](=[O:37])[NH:29]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:23][O:22][C:18]1[CH:19]=[C:20]2[C:15](=[C:16]([O:24][CH3:25])[CH:17]=1)[C:14](=[O:26])[NH:13][C:12]([C:8]1[CH:9]=[C:10]([CH3:11])[C:5]([O:4][CH2:3][CH2:2][N:29]3[C:30](=[O:37])[C:31]4[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:28]3=[O:38])=[C:6]([CH3:27])[CH:7]=1)=[CH:21]2
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCO)c(C)c3)cc2c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCN4C(=O)c5ccccc5C4=O)c(C)c3)cc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of 3-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-6,8-dimethoxy-2H-isoquinolin-1-one (0.80 g, 2.16 mmol), isoindole-1,3-dione (0.35 g, 2.38 mmol), and triphenylphosphine (0.85 g, 3.25 mmol) in THF (30 mL), was added diethyl azodicarboxylate (0.56 g, 3.25 mmol) and the reaction mixture was stirred at room temperature for 16 hours. The solvent was evaporated in vacuo and the residue was washed with ether to give the title compound as an off-white solid. Yield: 1.11 g (crude). 1H NMR (400 MHz, CDCl3): δ 8.34 (s, 1H), 7.89 (m, 2H), 7.77 (m, 2H), 7.21 (s, 2H), 6.49 (br s, 2H), 6.44 (s, 1H), 4.16 (m, 2H), 4.08 (m, 2H), 3.97 (s, 3H), 3.89 (s, 3H), 2.25 (s, 6H). MS (ES) m/z: 499.06 (M+1) (100%).
Reaction SMILES: [NH2:1][C@@H:2]([C@@H:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:6])[CH2:3][OH:4].[F:12][C:13]1[N:18]=[C:17](F)[C:16]([F:20])=[CH:15][N:14]=1.CCN(C(C)C)C(C)C>C(#N)C>[C:8]([O:7][C@@H:5]([CH3:6])[C@H:2]([NH:1][C:15]1[C:16]([F:20])=[CH:17][N:18]=[C:13]([F:12])[N:14]=1)[CH2:3][OH:4])([CH3:10])([CH3:9])[CH3:11]
Reactant: C[C@H](OC(C)(C)C)[C@H](N)CO
Reactant: Fc1ncc(F)c(F)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@H](OC(C)(C)C)[C@@H](CO)Nc1nc(F)ncc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.2 %

Procedure:
To a round bottom flask containing (2R,3S)-2-amino-3-(tert-butoxy)butan-1-ol (1.25 g, 7.75 mmol) and a stir bar was added acetonitrile (50 mL) followed by the addition of 2,4,5-trifluoropyrimidine (1.04 g, 7.75 mmol) and DIEA (4.1 mL, 23.3 mmol). The resulting reaction mixture allowed to stir 1 hr at room temperature. The volatiles were then removed. Reaction mixture was then partitioned between EtOAc and water. Aqueous layer extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na2SO4), filtered and concentrated to a viscous yellow oil of (2R,3S)-3-(tert-butoxy)-2-((2,5-difluoropyrimidin-4-yl)amino)butan-1-ol (1.56 g, 5.67 mmol, 73% yield). 1H NMR (400 MHz, CDCl3) δ 1.15 (s, 9H) 1.32 (d, J=6.26 Hz, 3H) 3.45 (br. s., 1H) 3.67 (d, J=11.35 Hz, 1H) 3.85-3.92 (m, 1H) 4.27 (d, J=11.74 Hz, 1H) 6.29 (d, J=5.48 Hz, 1H) 7.87 (d, J=2.35 Hz, 1H). LCMS m/z 276.4 (M+H)+, Rt 0.71 min.
Reaction SMILES: [CH2:1]([CH:3]1[CH:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][N:17](COCC[Si](C)(C)C)[C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][CH:5]([O:28][C:29]2[N:30]=[CH:31][C:32]([C:35]#[N:36])=[N:33][CH:34]=2)[CH2:4]1)[CH3:2].C(O)(C(F)(F)F)=O.[OH-].[NH4+].O>C(Cl)Cl>[CH2:1]([CH:3]1[CH:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][NH:17][C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][CH:5]([O:28][C:29]2[N:30]=[CH:31][C:32]([C:35]#[N:36])=[N:33][CH:34]=2)[CH2:4]1)[CH3:2]
Reactant: CCC1CC(Oc2cnc(C#N)cn2)CC1c1nnc2cnc3c(ccn3COCC[Si](C)(C)C)n12
Agent: [NH4+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CCC1CC(Oc2cnc(C#N)cn2)CC1c1nnc2cnc3[nH]ccc3n12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 88.3 %

Procedure:
To 5-(3-ethyl-4-(6-((2-(trimethyl silyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyloxy)pyrazine-2-carbonitrile (0.097 g, 0.19 mmol, Preparation #11.1) in DCM (2.5 mL) was added TFA (0.7 mL, 10 mmol). The reaction mixture was stirred at ambient temperature for about 1.5 h. The solvents were removed under reduced pressure and the residue was dissolved in 1,4-dioxane (1.3 mL). Ammonium hydroxide (28-30% aqueous ammonia, 2.5 mL, 24 mmol) was added and the reaction mixture was heated at about 60° C. for about 30 min then cooled to ambient temperature. Water (4 mL) was added and the precipitate was collected by filtration to give 5-(-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyloxy)pyrazine-2-carbonitrile (0.0628 g, 87%): LC/MS (Table 1, Method b) Rt=1.99 min; MS m/z: 375 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12](OC)=[C:11]([C:17]3[CH:22]=[CH:21][C:20]([Se:23][CH3:24])=[CH:19][CH:18]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C[Se]C1C=CC(B(O)O)=CC=1.[F:36][C:37]1[CH:42]=[CH:41][C:40](N2C(=O)C(OC)=C(C3C=CC(SC)=CC=3)C=N2)=[CH:39][CH:38]=1.FC1C=CC([Mg]Br)=CC=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([C:40]3[CH:41]=[CH:42][C:37]([F:36])=[CH:38][CH:39]=3)=[C:11]([C:17]3[CH:22]=[CH:21][C:20]([Se:23][CH3:24])=[CH:19][CH:18]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: COc1c(-c2ccc([Se]C)cc2)cnn(-c2ccc(F)cc2)c1=O
Reactant: COc1c(-c2ccc(SC)cc2)cnn(-c2ccc(F)cc2)c1=O
Agent: C[Se]c1ccc(B(O)O)cc1
Agent: Fc1ccc([Mg]Br)cc1
Product: C[Se]c1ccc(-c2cnn(-c3ccc(F)cc3)c(=O)c2-c2ccc(F)cc2)cc1

Procedure:
The title compound was prepared according to the method of Example 228, substituting 2-(4-fluorophenyl)-4-methoxy-5-[4-(methylseleno)phenyl]-3(2H)-pyridazinone (prepared according to the method of Example 194C, substituting 4-(methylseleno)benzeneboronic acid from Example 1 in place of 4-(methylthio)benzeneboronic acid) in place of 2-(4-fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone and substituting 4-fluorophenyl magnesium bromide in place of cyclohexylmagnesium chloride (yield: 44 mg, 69%). 1H NMR (300 MHz, CDCl3) δ 2.37 (s, 3H), 6.98 (dd, J=8.8, 8.8 Hz, 2H), 7.05 (d, J=8.7 Hz, 2H), 7.17 (dd, J=8.7, 8.7 Hz, 2H), 7.23-7.31 (m, 2H), 7.32 (d, J=8.7 Hz, 2H), 7.65-7.72 (m, 2H), 8.00 (s, 1H). MS (APCI+) m/z 455 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[C:11]([C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12]>>[C:11]([C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH:1][C:2]2[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([NH2:6])=[O:5])(=[O:23])=[O:22])=[CH:17][CH:16]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: NC(=O)c1ccccc1N
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccccc2C(N)=O)cc1

Procedure:
prepared by reaction of 2-amino-benzamide with 4-tert-butyl-benzenesulfonyl chloride
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:10]=[C:11]([C:20]#[N:21])[N:12]3[C:17]([SH:18])=[CH:16][C:15]([CH3:19])=[N:14][C:13]=23)=[C:4]([CH3:22])[CH:3]=1.[CH3:23]I>[OH-].[Na+]>[Br:1][C:2]1[CH:3]=[C:4]([CH3:22])[C:5]([C:9]2[CH:10]=[C:11]([C:20]#[N:21])[N:12]3[C:17]([S:18][CH3:23])=[CH:16][C:15]([CH3:19])=[N:14][C:13]=23)=[C:6]([CH3:8])[CH:7]=1
Reactant: CI
Reactant: Cc1cc(S)n2c(C#N)cc(-c3c(C)cc(Br)cc3C)c2n1
Agent: [Na+]
Agent: [OH-]
Product: CSc1cc(C)nc2c(-c3c(C)cc(Br)cc3C)cc(C#N)n12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 8-(4-bromo-2,6-dimethyl-phenyl)-4-mercapto-2-methyl-pyrrolo[1,2-a]pyrimidine-6-carbonitrile (7.50 g), MeI (12.5 mL) in 1 M NaOH aqueous solution (100 mL) was stirred at room temperature for 1 h. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give crude 8-(4-bromo-2,6-dimethyl-phenyl)-2-methyl-4-methylsulfanyl-pyrrolo[1,2-a]pyrimidine-6-carbonitrile (5.75 g). This product was used in the next step without further purification.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[N:8]=1)=O.[NH:26]([C:28]1[CH:33]=[CH:32][N:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=1)[NH2:27]>>[F:23][C:21]([F:22])([F:24])[O:20][C:17]1[CH:16]=[CH:15][C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:26]([C:28]4[CH:33]=[CH:32][N:31]=[C:30]([C:34]([F:37])([F:35])[F:36])[CH:29]=4)[N:27]=[CH:3][CH:4]=3)=[N:8]2)=[CH:19][CH:18]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)(F)F)cc2)ccc1=O
Reactant: NNc1ccnc(C(F)(F)F)c1
Product: O=c1ccn(-c2ccc(OC(F)(F)F)cc2)nc1-c1ccnn1-c1ccnc(C(F)(F)F)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-8) and 4-hydrazino-2-trifluoromethylpyridine according to the method described for example 91. MS: M=468.1 (M+H)+
Reaction SMILES: [CH:1]([C:4]1[CH:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[CH:9]=[C:8]([CH:15]([CH3:17])[CH3:16])[C:5]=1[CH2:6]Br)([CH3:3])[CH3:2].[CH:18]([C:21]1[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]([CH3:36])[CH3:35])[C:22]=1[O:23][S:24]([N:27]=C=O)(=[O:26])=[O:25])([CH3:20])[CH3:19].[NH4+].[Cl-].C[CH2:40][O:41]C(C)=O>C1COCC1>[CH3:2][CH:1]([C:4]1[CH:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[CH:9]=[C:8]([CH:15]([CH3:17])[CH3:16])[C:5]=1[CH2:6][C:40]([C:33]1[C:21]([CH:18]([CH3:19])[CH3:20])=[C:22]([O:23][S:24](=[O:25])(=[O:26])[NH2:27])[C:30]([CH:34]([CH3:35])[CH3:36])=[CH:31][CH:32]=1)=[O:41])[CH3:3]
Reactant: CCOC(C)=O
Reactant: CC(C)c1cccc(C(C)C)c1OS(=O)(=O)N=C=O
Reactant: CC(C)c1cc(C(C)C)c(CBr)c(C(C)C)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)c1cc(C(C)C)c(CC(=O)c2ccc(C(C)C)c(OS(N)(=O)=O)c2C(C)C)c(C(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
A solution of 2,4,6 - triisopropylbenzyl bromide (12 g, 40.4 mmol) in dry THF (160 mL) was added to a suspension of Mg powder (1.96 g, 80.8 mmol) (4hours) in THF (20 mL) heated under reflux. 2,6-Diisopropylphenoxysulfonyl isocyanate (ROSO2NCO) (see Phos. and Sulf., 19:167 (1984) for preparation) (11.45 g, 40.4 mmol) was added neat, and after the addition was completed, the reflux was continued for another 2 hours. The reaction was stirred at room temperature for 16 hours. Saturated NH4Cl and EtOAc were added. The EtOAc layer was separated, dried over MgSO4, filtered, and evaporated to dryness. After purification by column chromatography (4:1 hexane:EtOAc), the compound was isolated as white solid (13.5 g, 67%), mp 178°-180° C.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11](N1C2C(=CC=CC=2)CCC1)=[O:12].[N:28]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[NH2:40])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[C:6]([C:11]([NH:40][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[O:12])=[CH:7][N:8]=[CH:9][CH:10]=1
Reactant: Nc1ccccc1N1CCCCC1
Reactant: O=C(c1cnccc1Oc1cc(Cl)ccc1Cl)N1CCCc2ccccc21
Product: O=C(Nc1ccccc1N1CCCCC1)c1cnccc1Oc1cc(Cl)ccc1Cl

Procedure:
The title compound was prepared in analogy to Example 1, from 4-(2,5-dichloro-phenoxy)-nicotinic acid (Example 1, intermediate) and 2-piperidin-1-yl-phenylamine (commercially available; CAS RN 39643-31-7). White foam (90%). MS (ESI): 442.108 [M+H]+.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH:36]=[CH:37][CH:38]=1)[C:12]([NH:14][CH:15]([C:17]1[N:22]=[N:21][C:20]([NH:23][C:24]2[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=2)=[N:19][CH:18]=1)[CH3:16])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O>ClCCCl.CN(C)C=O>[CH3:16][C:15]1[N:14]=[C:12]([C:11]2[CH:10]=[C:9]([C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:8])[CH:38]=[CH:37][CH:36]=2)[N:22]2[C:17]=1[CH:18]=[N:19][C:20]([NH:23][C:24]1[CH:25]=[C:26]([O:34][CH3:35])[C:27]([O:32][CH3:33])=[C:28]([O:30][CH3:31])[CH:29]=1)=[N:21]2
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3cccc(C(=O)c4ccccc4)c3)nn2)cc(OC)c1OC
Solvent: ClCCCl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc(Nc2ncc3c(C)nc(-c4cccc(C(=O)c5ccccc5)c4)n3n2)cc(OC)c1OC
Temperature: 50 °C
Yield: 9 %

Procedure:
To a solution of 3-benzoyl-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)benzamide (Intermediate 28) (95 mg, 0.18 mmol) in 1,2-dichloroethane was added catalytic dimethylformamide (3 drops) and thionyl chloride (0.36 mL, 5.0 mmol). The mixture was heated at 50° C. for 14 hours. After cooling to room temperature the mixture was concentrated under vacuum. The resulting solid was taken up in a mixture of dichloromethane and methanol, then concentrated ammonium hydroxide was added until the solution was basic. The solution was then concentrated under vacuum and purified by reverse-phase HPLC to give (3-{5-methyl-2-[(3,4,5-trimethoxyphenyl)-amino]imidazo[5,1-f][1,2,4]triazin-7-yl}phenyl)(phenyl)-methanone (8 mg) as a yellow solid. 1H NMR (DMSO-d6): δ9.63 (s, 1H), 9.26 (s, 1H), 8.80 (d, J=7.87 Hz, 1H), 8.61 (s, 1H), 7.74-7.80 (m, 3H), 7.63 (t, J=7.69 Hz, 2H), 7.68 (t, J=7.69 Hz, 2H), 7.05 (s, 2H), 3.68 (s, 6H), 3.62 (s, 3H), 2.52 (s, 3H). MS m/z 495 (M+1).
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH2:13])[CH:11]=2)[NH:6][CH:5]=1)(=[O:3])[CH3:2].[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>N1C=CC=CC=1>[C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][S:20]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:22])=[O:21])[CH:11]=2)[NH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1c[nH]c2ccc(N)cc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)c1c[nH]c2ccc(NS(=O)(=O)c3ccccc3)cc12
Reaction time: 16 h
Yield: 99 %

Procedure:
A solution of 3-acetyl-5-aminoindole (1.57 g, 9 mmol) in pyridine is treated dropwise at 0° C. with benzenesulfonyl chloride (1.25 g, 9.9 mmol), stirred for 16 h at ambient temperatures, poured into dilute aqueous HCl and extracted with ethyl acetate. The combined extracts are washed sequentially with water and brine, dried over Na2SO4 and concentrated in vacuo to afford the title product as a white solid, 2.8 g (99% yield), identified by NMR and mass spectral analyses.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:31][CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22]3[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=3)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.[NH2:51][CH2:52][CH2:53][CH2:54][OH:55]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:31][CH:32]2[CH2:33][CH2:34][CH2:35][CH2:36]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([C:26]([NH:51][CH2:52][CH2:53][CH2:54][OH:55])=[O:27])=[CH:29][CH:30]=3)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: NCCCO
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(Cc3ccc(C(=O)O)cc3)n2)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(Cc3ccc(C(=O)NCCCO)cc3)n2)cc1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 29.8 %

Procedure:
4-{3-[2-(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-ylmethyl}-benzoic acid (prepared in example 45, 40 mg, 0.08 mmol) was suspended in methylene chloride (1 mL) and a 2.0 M solution of oxalyl chloride in methylene chloride (38 μL, 0.08 mmol) was added and the reaction stirred at 25° C. for 20 min. The solution was chilled to 0° C. and 2,6-lutidine (18 μL, 0.15 mmol) was added. The reaction continued to stir at 0° C. for 20 min. 3-Amino-propan-1-ol (7 μL, 0.09 mmol) was added, the ice bath was removed and the reaction continued to stir at 25° C. for 16 h. The reaction was diluted with methylene chloride (10 mL), washed with water (2×4 mL), saturated aqueous brine solution (1×4 mL), dried over magnesium sulfate and concentrated in vacuo to a beige foam. Purification by reverse phase preparative HPLC (Column: Thomson C18 ODSA, 5 micron, 50×21.2 mm ID; 30% acetonitrile/water to 100% acetonitrile/water; 30 mL/min flow rate for 15 min run) followed by preparative thin layer chromatography (Merck Silica gel 60 F254, 500 μm, 20×20 cm; 100% ethyl acetate) afforded 4-{3-[2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-ylmethyl}-N-(3-hydroxy-propyl)-benzamide (14 mg, 32%) as a white waxy solid: ESI-LRMS m/e calcd for C29H35ClN4O5S [M+] 586.2, found 587.29 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.08-1.22 (m, 2H, CH2), 1.43-1.93 (m, 10H, 5×CH2), 2.15-2.31 (m, 1H, CH), 3.26 (s, 3H, SO2CH3), 3.57-3.67 (m, 3H, CH2 and CH), 3.73 (t, J=5.5 Hz, 2H, CH2), 5.18 (s, 2H, NCH2), 6.74 (d, J=2.3 Hz, 1H, Ar), 6.82 (brm, 1H, NH), 7.12 (d, Jo=8.1 Hz, 2H, Ar), 7.36 (d, J=2.3 Hz, 1H, Ar), 7.43 (dd, Jo=8.1, Jm=1.6 Hz. 1H, Ar), 7.59 (d, Jm=1.6 Hz, 1H, Ar), 7.67 (d, Jo=8.1 Hz, 2H, Ar), 8.04 (d, Jo=8.1 Hz, 1H, Ar), 8.32 (s, 1H, NH).