Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:16])[NH:10][C@@H:11]1[CH2:15][CH2:14][NH:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:18]1[N:26]=[C:25]2[C:21]([N:22]=[CH:23][N:24]2[C@@H:27]2[CH2:31][C@H:30]([NH:32][C:33](=[O:36])[CH2:34][CH3:35])[C@@H:29]([OH:37])[C@H:28]2[OH:38])=[C:20]([NH:39][CH2:40][CH:41]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[N:19]=1>CN1C(=O)CCC1>[CH2:1]([O:8][C:9](=[O:16])[NH:10][C@@H:11]1[CH2:15][CH2:14][N:13]([C:18]2[N:26]=[C:25]3[C:21]([N:22]=[CH:23][N:24]3[C@@H:27]3[CH2:31][C@H:30]([NH:32][C:33](=[O:36])[CH2:34][CH3:35])[C@@H:29]([OH:37])[C@H:28]3[OH:38])=[C:20]([NH:39][CH2:40][CH:41]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=3)[N:19]=2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@@H]1CCNC1)OCc1ccccc1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Solvent: CN1CCCC1=O
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)OCc5ccccc5)C4)nc32)[C@H](O)[C@@H]1O

Procedure:
A solution of (R)-pyrrolidin-3-yl-carbamic acid benzyl ester hydrochloride (0.88 g, 3.45 mmol) in DCM is free-based using sodium hydrogen carbonate solution to yield (R)-pyrrolidin-3-yl-carbamic acid benzyl ester (0.487 g, 2.22 mmol). This amine is added to N-{(1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-propionamide (Intermediate J) (0.5 g, 0.96 mmol) and TEA (0.224 g, 2.22 mmol) and then dissolved in NMP (7 ml). The reaction mixture is heated using microwave radiation in a Personal Chemistry Emrys™ Optimizer microwave reactor at 190° C. for 1 hour. The resulting mixture is purified by chromatography on silica eluting with 5% MeOH in DCM to yield the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:5]=[C:6]([Br:20])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12](OC)=[C:11]([N+:17]([O-:19])=[O:18])[CH:10]=1.[NH3:26].O.Cl>COCCOCCO>[Br:1][C:2]1[CH:3]=[C:4]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:5]=[C:6]([Br:20])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:26])=[C:11]([N+:17]([O-:19])=[O:18])[CH:10]=1
Reactant: N
Reactant: COC(=O)Cc1cc(Br)c(Oc2ccc(OC)c([N+](=O)[O-])c2)c(Br)c1
Agent: Cl
Solvent: COCCOCCO
Solvent: O
Product: COC(=O)Cc1cc(Br)c(Oc2ccc(N)c([N+](=O)[O-])c2)c(Br)c1
Reaction time: 24 h
Yield: 84 %

Procedure:
To methyl [3,5-dibromo-4-(4-methoxy-3-nitrophenoxy)phenyl]acetate (5 g), dissolved in 2-(2-methoxyethoxy)ethanol (50 mL) was added an aqueous solution of ammonia (32%, 7 mL). The reaction mixture was heated at 150° C. for, with continuos refill of ammonia. After 24 hours, water was added followed by an aqueous solution of hydrochloric acid. This was continued until the acidity of the solution reached pH 2. The aqueous phase was extracted with chloroform, washed with brine and dried over magnesium sulphate. After concentration of the organic phase, 4.1 g (84%) of methyl [3,5-dibromo-4-(4-amino-3-nitrophenoxy)phenyl]acetate was obtained as an yellow solid mass.
Reaction SMILES: CS[S:3][CH3:4].S(Cl)(Cl)(=O)=O.[Br:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[N:18]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:17]=[C:16]2[CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Br:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[N:18]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:17]([S:3][CH3:4])=[C:16]2[CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: CSSC
Reactant: CCOC(=O)CCCc1cn(CC(=O)OCC)c2c(Br)cccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O=S(=O)(Cl)Cl
Product: CCOC(=O)CCCc1c(SC)n(CC(=O)OCC)c2c(Br)cccc12
Temperature: -5 °C
Reaction time: 1.5 h

Procedure:
To a chloroform (0.8 mL) solution of dimethyl disulfide (30 mg), sulfuryl chloride (34 mg) was added at −15° C. and the mixture was stirred at −5° C. for 1.5 hours. To the reaction mixture, a chloroform (0.5 mL) solution of the compound prepared in Example 43, namely, ethyl 4-{7-bromo-1-[2-(ethyloxy)-2-oxoethyl]-1H-indol-3-yl}butanoate (100 mg) was added at −78° C., followed by stirring at room temperature for 3 hours. To the reaction mixture, an aqueous saturated sodium hydrogen carbonate solution was added under ice cooling, followed by extraction with ethyl acetate. The organic layer was washed in turn with an aqueous saturated sodium hydrogen carbonate solution, water and saturated saline, dried over anhydrous magnesium sulfate and then concentrated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=95:5→91:9) to obtain the titled compound having the following physical properties (70 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[CH3:10][O:11][P:12]([O:15]C)[O:13][CH3:14]>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][P:12](=[O:15])([O:13][CH3:14])[O:11][CH3:10]
Reactant: COP(OC)OC
Reactant: Clc1ccccc1CBr
Product: COP(=O)(Cc1ccccc1Cl)OC

Procedure:
Following the procedure of Compound 11, 2-chlorobenzyl bromide is reacted with trimethylphosphite.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.CC(C)([O-])C.[K+].[Cl:15][C:16]1[CH:21]=[C:20](Cl)[CH:19]=[CH:18][N:17]=1>CC(N(C)C)=O>[Cl:15][C:16]1[CH:21]=[C:20]([O:8][C:5]2[CH:4]=[N:3][C:2]([NH2:1])=[N:7][CH:6]=2)[CH:19]=[CH:18][N:17]=1
Reactant: Clc1ccnc(Cl)c1
Reactant: Nc1ncc(O)cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Nc1ncc(Oc2ccnc(Cl)c2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.5 %

Procedure:
A solution of 2-amino-5-hydroxypyrimidine (1.00 g, 9.00 mmol) in DMA (25 mL) was treated with potassium tert-butoxide (1.24 g, 11.05 mmol). The thick mixture was stirred at RT for 1 h. To this was added a solution of 2,4-dichloropyridine (1.21 g, 8.18 mmol) in DMA (10 mL) and the reaction was stirred at RT overnight under Ar. The mixture was partitioned into EtOAc (100 mL) and water (100 mL). The organic phase was separated and the aqueous was extracted with EtOAc (100 mL). The combined EtOAc layers were washed with 5% LiCl (100 mL) and brine (100 mL) and then dried over sodium sulfate. The solvents were evaporated at reduced pressure to give 5-((2-chloropyridin-4-yl)oxy)pyrimidin-2-amine as a pale yellow solid (592 mg, 32%). MS (ESI) m/z: 223.0 (M+H+).
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH2:3][CH3:4].[Br:7][CH2:8][CH2:9][CH2:10][Sn:11](Br)(Br)[CH3:12].[NH4+].[Cl-]>C(OCC)C>[Br:7][CH2:8][CH2:9][CH2:10][Sn:11]([CH3:12])([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: CCCC[Mg]Br
Reactant: C[Sn](Br)(Br)CCCBr
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCCC[Sn](C)(CCCC)CCCBr
Yield: 88 %

Procedure:
A solution of 115 ml of 2.7 N butylmagnesium bromide in diethyl ether was added in about one hour to a solution of 62.5 g (0.15 mol) of (3-bromopropyl)methyltin dibromide in 200 ml of diethyl ether. After reflux for 1 h the mixture was treated with a saturated aqueous solution of NH4Cl and distilled to give 48.79 g (88%) of (3-bromopropyl)methyldibutyltin; b.p. 88°-90° C./0.1 mm Hg, nD20 =1.5001.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[CH:12]=[C:13]([CH:25]=[CH:26][CH:27]=2)[C:14]([NH:16][C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])=[O:15])=O)[CH:5]=[CH:4][N:3]=1.C1C(=O)N(Br)C(=O)C1.[F:36][C:37]([F:46])([F:45])[C:38]1[CH:43]=[CH:42][N:41]=[C:40]([NH2:44])[CH:39]=1.CCCCCC>C(Cl)Cl.CCOC(C)=O.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[N:41]3[CH:42]=[CH:43][C:38]([C:37]([F:45])([F:36])[F:46])=[CH:39][C:40]3=[N:44][C:9]=2[C:11]2[CH:12]=[C:13]([CH:25]=[CH:26][CH:27]=2)[C:14]([NH:16][C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])=[O:15])[CH:5]=[CH:4][N:3]=1
Reactant: O=C(Cc1ccnc(Cl)n1)c1cccc(C(=O)Nc2c(F)cccc2F)c1
Reactant: Nc1cc(C(F)(F)F)ccn1
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3cc(C(F)(F)F)ccn3c2-c2ccnc(Cl)n2)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 45.6 %

Procedure:
To a stirred solution of 3-[(2-chloro-4-pyrimidinyl)acetyl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1, step B) (0.4 g, 1.03 mmol) in DCM (10 mL) at rt under N2 was added NBS (0.193 g, 1.09 mmol). The reaction was stirred approximately 30 min, then concentrated under vacuum to a foam like solid. The solid was dissolved in dioxane (10 mL) and 4-(trifluoromethyl)-2-pyridinamine (0.5 g, 3.10 mmol) was added. The reaction was stirred under nitrogen, heated to 80° C., and stirred for approximately 48 h, then cooled to rt. The reaction was diluted with EtOAc and half-saturated aqueous NaHCO3. The organic layer was separated and washed brine. The combined aqueous layers were extracted with EtOAc (3×). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography to give a yellow solid. The solid was dissolved in minimal DCM and hexane was added until a precipitate formed. The slurry was filtered, washing the solids with cold hexane. The solids were dried under vacuum, however proton NMR indicates impurities so the solid was dissolved in minimal DCM and ether was added until a precipitate formed. The slurry was filtered, washing the solids with cold ether. The solids were dried under vacuum to give the title compound of step A (0.250 g, 0.47 mmol, 46%) as a white solid. MS (ESI): 530 [M+H]+.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=[O:12])[CH:9]=2)[N:4]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[C:21]([F:24])([F:23])[F:22])[N:3]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:4]2[C:5]3[C:10](=[CH:9][C:8]([CH:11]=[O:12])=[CH:7][CH:6]=3)[C:2]([C:29]3[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=3)=[N:3]2)=[C:15]([C:21]([F:24])([F:23])[F:22])[CH:16]=1
Reactant: O=Cc1ccc2c(c1)c(Br)nn2Cc1ccc(Cl)cc1C(F)(F)F
Reactant: OB(O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=Cc1ccc2c(c1)c(-c1ccc(F)cc1)nn2Cc1ccc(Cl)cc1C(F)(F)F
Temperature: 100 °C
Reaction time: 6 h

Procedure:
A mixture of 3-bromo-1-(4-chloro-2-trifluoromethylbenzyl)-1H-indazole-5-carbaldehyde (0.311 mmol from Example 407), 4-fluorophenylboronic acid (0.498 mmol), Pd(dppf)Cl2 dichloromethane complex (0.0311 mmol) and sodium carbonate (0.933 mmol) in DME/H2O (4 mL; 4:1) under argon was stirred at 100° C. for 6 h, then concentrated. The residue was purified by chromatography (silica gel, hexanes to hexanes:EtOAc, 1:1) to afford 1-(4-chloro-2-trifluoromethylbenzyl)-3-(4-fluorophenyl)-1H-indazole-5-carbaldehyde as white solid.
Reaction SMILES: [NH:1]([CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:14])[CH:12]=2)/[C:7](=[CH:15]\[C:16]2[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][CH:17]=2)/[C:6]=1[CH3:24])[OH:2].[CH3:25][N:26]=[C:27]=[O:28]>C1COCC1>[F:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:15]\[C:16]1[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][CH:17]=1)/[C:6]([CH3:24])=[C:5]2[CH2:4][CH2:3][N:1]([OH:2])[C:27]([NH:26][CH3:25])=[O:28]
Reactant: CSc1ccc(/C=C2/C(C)=C(CCNO)c3cc(F)ccc32)cc1
Reactant: CN=C=O
Solvent: C1CCOC1
Product: CNC(=O)N(O)CCC1=C(C)/C(=C/c2ccc(SC)cc2)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (Z)-3-(2-hydroxaminoethyl)-5-fluoro-2-methyl-1-(4-methylthiobenzylidene)indene from Example 3, Method A, Step 4 (34 mg, 0.1 mmol) in THF (0.5 mL), there was added methyl isocyanate (11.4 mg, 0.2 mmol) and the mixture stirred at room temperature for 1 hour. The solvent was evaporated and the residue triturated with hexane and filtered to afford the title product as a yellow-orange solid, mp: dec 138° C.
Reaction SMILES: [C:1]1([S:7]([CH3:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li][CH2:12][CH2:13][CH2:14][CH3:15].B(F)(F)F.[CH3:20][CH2:21][O:22][CH2:23][CH3:24]>C1COCC1>[CH2:24]1[CH2:23][O:22][CH2:21][CH2:20]1.[C:1]1([S:7]([C:10]2[CH:20]=[CH:12][CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)c1ccccc1
Reactant: [Li]CCCC
Reactant: CCOCC
Agent: FB(F)F
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h
Yield: 254.8 %

Procedure:
To a solution of methyl phenyl sulfone (470 mg, 3.0 mmole) in dry THF (10.0 mL) at -78° C. was dropwise added n-BuLi (1.2 mL, 3.0 mmole, 2.5 M solution in hexanes) under nitrogen and the resulting mixture was stirred at this temperature for 30 min followed by the addition of boron trifluoride diethyl etherate (0.092 mL, 1.0 mmole). A solution of the THR-epoxide (234 mg, 1.0 mmole) in dry THF (5.0 mL) was added and the resulting mixture was stirred at -78° C. for 3 h and quenched with saturated ammonium chloride (5.0 mL). The product was extracted with EtOAc (3×20 mL) and the combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, and concentrated using rotatory evaporation. The oily residue was purified by flash column chromatography (hexane/EtOAc=1/1) to yield 370 mg (95%) of the desired product as a colorless oil. This material (307 mg, 0.787 mmole) was then dissolved in dry dichloromethane (15 mL) and cooled down to 0° C. N-N-diisopropylethylamine (0.82 mL, 4.7 mmole) and chloromethyl methyl ether (0.15 mL, 2.0 mmole) were added and the resulting mixture was stirred at room temperature for 24 h. The reaction mixture was concentrated using rotary evaporation and the oily residue was purified by flash column chromatography (hexane/EtOAc=2/1) to yield 325 mg (95%) of the desired protected alcohol as a colorless oil.
Reaction SMILES: O[CH2:2][C@H:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4].C(Br)(Br)(Br)[Br:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C(Cl)Cl>[Br:14][CH2:2][C@H:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4]
Reactant: BrC(Br)(Br)Br
Reactant: C[C@H](CO)NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: C[C@H](CBr)NC(=O)OC(C)(C)C
Reaction time: 14 h
Yield: 50.1 %

Procedure:
(R)-tert-Butyl 1-hydroxypropan-2-ylcarbamate (1 g, 5.71 mmol) and carbon tetrabromide (2.84 g, 8.56 mmol) were stirred in CH2Cl2 (20 mL) at −20° C. under argon. A solution of triphenylphosphine (2.40 g, 9.13 mmol) in CH2Cl2 (5 mL) was added dropwise. The reaction was allowed to reach rt and stirred for 14 h. H2O (50 mL) was added to the reaction mixture and the aqueous layer was removed and the CH2Cl2 layer was dried over Na2SO4, filtered, and evaporated. The residue was applied to a silica ISCO column and eluted with 5:1 hexanes/EtOAc. Intermediate 5A (0.68 g, 2.86 mmol, 50.0% yield) was isolated as a white solid. LC-MS (ESI) 183.9 (M−tBu+H), RT=1.76 min (Method B).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][C:13](=[O:15])[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)[C:11]([CH3:26])=[C:10]2[C:27]([OH:29])=[O:28])=[CH:5][CH:4]=1)#[N:2].C1N=CN(C(N2C=NC=C2)=O)C=1.O[CH2:43][CH2:44][NH:45][C:46](=[O:48])[CH3:47].C(N(CC)CC)C>CN(C)C=O.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][C:13](=[O:15])[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:24])([F:25])[F:23])[CH:17]=3)[C:11]([CH3:26])=[C:10]2[C:27]([O:29][CH2:43][CH2:44][NH:45][C:46](=[O:48])[CH3:47])=[O:28])=[CH:7][CH:8]=1)#[N:2]
Reactant: CC1=C(C(=O)O)C(c2ccc(C#N)cc2)CC(=O)N1c1cccc(C(F)(F)F)c1
Reactant: CC(=O)NCCO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)NCCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)CC1c1ccc(C#N)cc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 40 mg (0.1 mmol) of the compound of Example 47 in 0.3 ml dry dimethylformamide are added 48.6 mg (0.3 mmol) N,N-carbonyldiimidazole. After allowing the reaction mixture to stand for one hour, the reaction mixture is diluted with water and extracted with ethyl acetate. After drying with magnesium sulfate, the solvent is evaporated off in vacuo. To the residue are added 0.5 ml (560 mg, 5.44 mmol) N-2-hydroxyethyl-acetamide and 10 μl (0.07 mmol) triethylamine. The reaction mixture is stirred at 100° C. for one hour. Then the reaction mixture is filtered and purified by preparative HPLC (column: Nucleosil 100-5 C 18 Nautilus 20 mm×50 mm, 5 μm; solvent A: acetonitrile, solvent B: water+0.1% formic acid; gradient: 0 min 10% A, 2 min 10% A, 6 min 90% A, 7 min 90% A, 7.1 min 10% A, 8 min 10% A; wavelength: 220 nm; injection volume: approx. 550 μl; number of injections: 1). The product containing fractions are combined and concentrated in vacuo.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH:6]([N:13]1[C:17]2[CH:18]=[CH:19][C:20]([C:22](O)=[O:23])=[CH:21][C:16]=2[N:15]=[CH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[N:57]1[CH:62]=[CH:61][N:60]=[CH:59][C:58]=1[N:63]1[CH2:68][CH2:67][NH:66][CH2:65][CH2:64]1>CN(C=O)C>[C:7]1([CH:6]([N:13]2[C:17]3[CH:18]=[CH:19][C:20]([C:22]([N:66]4[CH2:65][CH2:64][N:63]([C:58]5[CH:59]=[N:60][CH:61]=[CH:62][N:57]=5)[CH2:68][CH2:67]4)=[O:23])=[CH:21][C:16]=3[N:15]=[CH:14]2)[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:25])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: c1cnc(N2CCNCC2)cn1
Reactant: CCOC(=O)CC(c1ccccc1)n1cnc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CC(c1ccccc1)n1cnc2cc(C(=O)N3CCN(c4cnccn4)CC3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(3-ethoxy-3-oxo-1-phenylpropyl)-1H-benzimidazole-5-carboxylic acid (70 mg, 207 μmol) in DMF (4 mL) was added N,N-diisopropylethylamine (40 μL, 229 μmol) and TBTU (80 mg, 249 μmol). The solution was stirred at room temperature for 0.5 hour, 1-(2-pyrazinyl) piperazine (41 mg, 249 μmol) was added, and stirring continued at room temperature for 24 hours. The solution was evaporated in vacuo, and the residue was purified by flash column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (95:5) to afford the title compound, [LCMS (Method A, Mobile Phase I) RT=4.33 min, MH+ 485].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][S:9]([C:12]2[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=2)[C:15]([O:17]CC)=[O:16])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.C(O)C.[OH-].[Na+].Cl>O>[F:1][C:2]1[CH:3]=[C:4]([NH:8][S:9]([C:12]2[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=2)[C:15]([OH:17])=[O:16])(=[O:10])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cccc(S(=O)(=O)Nc2cccc(F)c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cccc(S(=O)(=O)Nc2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the product of Step A was added ethanol (6.4 mL) followed by a solution of NaOH (0.483 g, 12.1 mmol) in water (6.4 mL). The reaction was stirred at ambient temperature for 1 hour. To the mixture was added 1 N HCl (22.8 mL), and the mixture stirred at ambient temperature overnight. The solids were collected by filtration, washed with water (2×4 mL) and dried in a vacuum oven at 45° C. overnights to give 3-{[(3-fluorophenyl)amino]sulfonyl}benzoic acid: 1H NMR (400 MHz, DMSO-d6) δ ppm 13.51 (bs, 1H), 10.68 (bs, 1H), 8.30 (t, J=1.8, 1H), 8.14 (dt, J=7.7, 1.4, 1H), 7.99 (ddd, J=7.8, 2.0, 1.1, 1H), 7.70 (t, J=7.8, 1H), 7.27 (m, 1H), 6.94-6.82 (m, 3H); MS (ESI) m/z 294 (M−H)−.
Reaction SMILES: [CH3:1]/[CH:2]=[CH:3]\[CH3:4].[CH3:5]/[CH:6]=[CH:7]/[CH3:8].[CH2:9]=[C:10](C)C.C=CC=C.C=CCC.CCCC>C1C=CC=CC=1>[CH:2]([C:6]1[CH:5]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH2:3][CH3:4])[CH3:1]
Reactant: C/C=C/C
Reactant: C/C=C\C
Reactant: C=C(C)C
Agent: C=CC=C
Agent: C=CCC
Solvent: CCCC
Solvent: c1ccccc1
Product: CCC(C)c1ccccc1
Reaction time: 24 h

Procedure:
A 1.0 gram sample of the MCM-22 catalyst (65 wt % MCM-22/35% alumina binder) from Example 1 was used for the alkylation of benzene with Raffinate-2 type feed. The Raffinate-2 type feed was a synthetic blend with the following weight composition: 53.43% cis-butene, 41.29% trans-butene, 4.54% isobutene, 0.48% butadiene, 0.09% 1-butene, 0.09% n-butane, and 0.1% others. The catalyst was in the form of a 1.6 mm ( 1/16 inch) diameter cylindrical extrudate and was diluted with sand to 3 cc and loaded into an isothermal, down-flow, fixed-bed, tubular reactor having an outside diameter of 4.76 mm ( 3/16 inch). The catalyst was dried at 150° C. and 1 atm with 100 cc/min flowing nitrogen for 2 hours. The nitrogen was turned off and benzene was fed to the reactor at 60 cc/hr until reactor pressure reached the desired 2068 kPag (300 psig). Benzene flow was then reduced to 7.63 cc/hr (6.67 WHSV) and Raffinate-2 type feed was introduced from a syringe pump at 2.57 cc/hr (1.6 WHSV). The reactor temperature was adjusted to 160° C. Feed benzene/butene molar ratio was maintained at 3:1 for the entire run. Liquid product was collected in a cold-trap and analyzed off line. Butene conversion was determined by measuring unreacted butene relative to feed butene. The catalyst was on stream for 6 days at 1.6 WHSV of butene with 98% 2-butene conversion, 1 day at 4.8 WHSV with 80% conversion, 1 day at 7.2 WHSV with 62% conversion, and followed by 4 days again at 1.6 WHSV with 97% conversion. Representative data are shown in Table 6. Relative activity of MCM-22 based on first-order butene conversion was 0.5.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[NH:11][C:12](=O)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH2:3][CH2:2]1.C(O)(=O)C>C1(C)C=CC=CC=1>[CH:1]1([N:4]2[C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N:11]=[C:12]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH2:3][CH2:2]1
Reactant: COC(=O)CCCCCCC(=O)Nc1ccccc1NC1CC1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COC(=O)CCCCCCc1nc2ccccc2n1C1CC1
Temperature: 110 °C
Yield: 67.7 %

Procedure:
To a solution of methyl 8-(2-(cyclopropylamino)phenylamino)-8-oxooctanoate (390 mg) in toluene was added a drop of acetic acid. The reaction was heated to 110° C. overnight and concentrated. The residue was purified by biotage column chromatography to give methyl 7-(1-cyclopropyl-1H-benzo[d]imidazol-2-yl)heptanoate (249 mg)
Reaction SMILES: C1(N2C=C(Cl)C(Cl)[C:9](=[O:15])N2)C=CC=CC=1.[C:16]1([N:22]2[C:27](=[O:28])[C:26]([Cl:29])=[C:25](Cl)[CH:24]=[N:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>CO>[C:16]1([N:22]2[C:27](=[O:28])[C:26]([Cl:29])=[C:25]([O:15][CH3:9])[CH:24]=[N:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=c1c(Cl)c(Cl)cnn1-c1ccccc1
Reactant: O=C1NN(c2ccccc2)C=C(Cl)C1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1cnn(-c2ccccc2)c(=O)c1Cl
Yield: 95 %

Procedure:
The title compound was prepared according to the method of (S. Cho et al. described in J. Het. Chem., (1996), 33, 1579–1582), starting with the N-phenyl-dichloropyridazinone. A mixture of 2-phenyl-4,5-dichloro-3(2H)-pyridazinone (1 g, 4.1 mmol) and finely powdered, anhydrous K2CO3 (580 mg, 4.2 mmol) in 50 mL of methanol was heated at reflux for 5 hours and concentrated in vacuo. The residue was partitioned between water and ethyl acetate. The acetate layer was washed with water, and brine to provide 2-phenyl-4-chloro-5-methoxy-3(2H)-pyridazinone (yield: 920 mg, 95%). 1H NMR (300 MHz, DMSO-d6) δ 4.15 (s, 3H), 7.50 (m, 5H), 8.43 (s, 1H). MS (DCI/NH3) m/z 237 (M+H)+, 254 (M+NH4)+.