Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH:8]1([C:14]2[C:15]3[CH:16]=[CH:17][C:18]([C:50]([O:52]C(C)(C)C)=[O:51])=[CH:19][C:20]=3[N:21]3[CH2:27][C:26]([C:28]4[N:32]([CH:33]5[CH2:35][CH2:34]5)[N:31]=[C:30]([CH:36]([CH3:38])[CH3:37])[C:29]=4[C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:25][C:24]4[CH:44]=[C:45]([O:48][CH3:49])[CH:46]=[CH:47][C:23]=4[C:22]=23)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>ClC(Cl)C>[CH:8]1([C:14]2[C:15]3[CH:16]=[CH:17][C:18]([C:50]([OH:52])=[O:51])=[CH:19][C:20]=3[N:21]3[CH2:27][C:26]([C:28]4[N:32]([CH:33]5[CH2:34][CH2:35]5)[N:31]=[C:30]([CH:36]([CH3:37])[CH3:38])[C:29]=4[C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:25][C:24]4[CH:44]=[C:45]([O:48][CH3:49])[CH:46]=[CH:47][C:23]=4[C:22]=23)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: CCOC(=O)c1c(C(C)C)nn(C2CC2)c1C1=Cc2cc(OC)ccc2-c2c(C3CCCCC3)c3ccc(C(=O)OC(C)(C)C)cc3n2C1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(Cl)Cl
Product: CCOC(=O)c1c(C(C)C)nn(C2CC2)c1C1=Cc2cc(OC)ccc2-c2c(C3CCCCC3)c3ccc(C(=O)O)cc3n2C1
Reaction time: 2.5 h
Yield: 99.8 %

Procedure:
TFA (2.8 mL, 37 mmol) was added to a stirring solution of tert-butyl 13-cyclohexyl-6-(1-cyclopropyl-4-(ethoxycarbonyl)-3-isopropyl-1H-pyrazol-5-yl)-3-methoxy-7H-indolo[2,1-a][2]benzazepine-10-carboxylate (350 mg, 0.527 mmol) in dichloroethane (5 mL) at room temperature. The reaction was allowed to stir for 2.5 hrs and then was concentrated to dryness to give expected product (320 mg, 0.526 mmol, quant) consistent by LCMS.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.C(NC(C)C)(C)C.[F:13][CH:14]([C:20]1[N:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([O:28][CH3:29])[N:21]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16].IC(C)C>CCCCCC.O1CCCC1.C(OCC)C.CN(C)P(=O)(N(C)C)N(C)C>[CH3:27][O:26][C:24]1[CH:23]=[C:22]([O:28][CH3:29])[N:21]=[C:20]([C:14]([F:13])([CH:2]([CH3:3])[CH3:1])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:25]=1
Reactant: [Li]CCCC
Reactant: CCOC(=O)C(F)c1nc(OC)cc(OC)n1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: CC(C)I
Product: CCOC(=O)C(F)(c1nc(OC)cc(OC)n1)C(C)C
Temperature: -60 °C
Reaction time: 0.5 h

Procedure:
Butyllithium (12.8ml of a 1.6M solution in hexane) was added to di-isopropylamine (3.05ml) in dry tetrahydrofuran (120ml) under nitrogen at a temperature of -78° C. and the mixture was stirred for 30 minutes. The product of Example 1 (3.4g) in dry tetrahydrofuran (20ml) was then added at a temperature of -65° C., and the mixture was stirred for 1 hour, during which the temperature rose to -30° C. After cooling to -60° C., 3.18 g of hexamethylphosphoric triamide were added, and the mixture was stirred for 15 minutes. Then 2-iodopropane (3.4 g) was added, and the mixture was stirred at room temperature for 72 hours, after which it was diluted with 100ml diethyl ether, and washed with a saturated ammonium chloride and sodium chloride solution. The aqueous phase was extracted with diethyl ether, and the organic layer was dried over magnesium sulfate and evaporated. The yellow oil obtained was finally chromatographed on silica gel using hexane/ethyl acetate (0-5% ethyl acetate) to give 1.46 g of the desired product, refractive index at 20° C. =1.4756.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8]([CH:14]=[O:15])=[N:9]2)([O-:3])=[O:2].O1CCCC1.[BH4-].[Na+].O>CO>[OH:15][CH2:14][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[CH:13][C:4]=2[N+:1]([O-:3])=[O:2])[N:9]=1
Reactant: O=Cc1ccc2c([N+](=O)[O-])cccc2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=[N+]([O-])c1cccc2nc(CO)ccc12
Reaction time: 5 h

Procedure:
700 mg (3.46 mmol) of 5-nitroquinoline-2-carbaldehyde are dissolved in 13 ml of methanol and 7.0 ml of tetrahydrofuran and mixed at 0° C. with 523 mg (13.9 mmol) of sodium borohydride. After 5 hours, the reaction is brought to a halt by adding water. The solvent is removed in a vacuum, the residue is taken up in dichloromethane and water, the aqueous phase is extracted with dichloromethane, and the combined organic phases are dried on sodium sulfate. After the solvent is removed, and after purification on silica gel with hexane-ethyl acetate (0–100%), 390 mg (55% of theory) of the product is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1F)[C:5]#[N:6].C1(OC2C=CC=CC=2)C=CC=CC=1.[K].[CH3:26][O:27][C:28](=[O:39])[C:29]1[CH:34]=[C:33]([OH:35])[CH:32]=[CH:31][C:30]=1[N+:36]([O-:38])=[O:37]>CN1CCCC1=O>[CH3:26][O:27][C:28](=[O:39])[C:29]1[CH:34]=[C:33]([O:35][C:9]2[C:8]([F:11])=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=2[Cl:1])[CH:32]=[CH:31][C:30]=1[N+:36]([O-:38])=[O:37]
Reactant: N#Cc1cc(F)c(F)c(Cl)c1
Reactant: COC(=O)c1cc(O)ccc1[N+](=O)[O-]
Agent: [K]
Solvent: CN1CCCC1=O
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COC(=O)c1cc(Oc2c(F)cc(C#N)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
The product 3-chloro-4,5-difluorobenzonitrile, prepared for example as set forth in Example 3, above, is a useful intermediate for the preparation of various end products especially for the preparation of diphenyl ether herbicides. Thus, for example, this compound may be further reacted with the potassium salt of methyl-5-hydroxy-2-nitrobenzoate in a solvent, such as N-methyl-2-pyrrolidone at a temperature of about 120° to 180° Celsius to form methyl-5-(2-chloro-4-cyano-6-fluoro-phenoxy)-2-nitro-benzoate. The ester may be hydrolyzed in a conventional manner to the corresponding carboxylic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]([C:29]2[CH:34]=[C:33]([O:35][CH3:36])[C:32]([O:37][CH3:38])=[C:31]([O:39][CH3:40])[CH:30]=2)[CH:24]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:22][C:23]2[CH:28]=[CH:27][N:26]=[C:25]([C:29]3[CH:34]=[C:33]([O:35][CH3:36])[C:32]([O:37][CH3:38])=[C:31]([O:39][CH3:40])[CH:30]=3)[CH:24]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2)CC1
Product: COc1cc(-c2cc(CN(c3ccccc3)C3CCN(C(=O)OC(C)(C)C)CC3)ccn2)cc(OC)c1OC

Procedure:
1-(tert-Butoxycarbonyl)-4-phenylaminopiperidine (553 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1.Cl.[C:16]1([CH3:23])[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=1>>[CH3:23][C:16]1[CH:21]=[CH:20][C:19]([C:10](=[O:11])[C:9]2[CH:13]=[CH:14][C:6]([F:5])=[CH:7][CH:8]=2)=[C:18]([CH3:22])[CH:17]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Cc1cccc(C)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1ccc(C(=O)c2ccc(F)cc2)c(C)c1
Reaction time: 3 h
Yield: 99 %

Procedure:
To a suspension of anhydrous aluminum chloride (19.5 g) dispersed in m-xylene (150 ml) was added dropwise 4-fluorobenzoyl chloride (21.1 g) under ice-cooling. The mixture was stirred at 0–10° C. for 3 hr and poured into 6N hydrochloric acid. The reaction mixture was partitioned and the obtained organic layer was washed successively with water, 10% aqueous sodium hydroxide solution and water. The solvent was evaporated to give a 96:4 mixture (30.2 g, 99%) of 1,3-dimethyl-4-(4′-fluorobenzoyl)benzene and 1,3-dimethyl-2-(4,-fluorobenzoyl)benzene as pale-yellow oil. 1,3-Dimethyl-4-(4′-fluorobenzoyl)benzene
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([N:11]([CH2:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])[CH:8]=[CH:9][CH:10]=1)=O.CC(C[AlH]CC(C)C)C.CO>C1COCC1.CCOCC.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>[OH:2][CH2:3][C:5]1[CH:6]=[C:7]([N:11]([CH2:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])[CH:8]=[CH:9][CH:10]=1
Reactant: CCS(=O)(=O)N(Cc1cccnc1)c1cccc(C(=O)OC)c1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CO
Product: CCS(=O)(=O)N(Cc1cccnc1)c1cccc(CO)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.9 %

Procedure:
Into a −78° C. solution of N-(3-methoxycarbonylphenyl)-N-(ethanesulfonyl)pyrid-3-ylmethylamine (75 g, 0.224 mole, 1 eq) in THF was added slowly DIBAl-H (561 mL, 1M in toluene, 2.5 eq). The mixture was stirred for 1 hour and then was warmed to 0° C. with an ice water bath and stirred for 2 h. The reaction was carefully quenched with methanol (18.50 mL, 0.396 mole, 1.8 eq). It was then diluted with ether (4650 mL) and Saturated Rochelle's salt (2775 mL) and stirred vigorously overnight. The layers were separated and the aqueous extracted with EtOAc (2000 mL). The combined organics were washed with brine, dried with MgSO4, filtered and concentrated. The residue was chromatographed, eluting with 1:1 DCM/EtOAc to give the title compound as a white solid (51.4 g, 43% Yield).
Reaction SMILES: B1C2CCCC1CCC2.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][C:20](=[CH2:23])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].Br[C:25]1[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][N:26]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl.O>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][C:25]2[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][N:26]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: Brc1ccc(Br)nc1
Reactant: C=C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: B1C2CCCC1CCC2
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Cc2ccc(Br)cn2)CC1
Temperature: 25 °C

Procedure:
A solution of 9-BBN (0.5 N in THF, 100 mL) was added 4-methylenepiperidine-1-carboxylic acid tert-butyl ester (1.23 g, 1.5 mmol) the reaction mixture was stirred at reflux for 1 h. The reaction mixture was cooled to RT and added via a syringe to a solution of 2,5-dibromopyridine (11.3 g, 47.5 mmol) and Pd(dppf)Cl2 dichloromethane (1.23 g, 1.5 mmol) dissolved in DMF (100 mL) and water (9.9 mL) and K2CO3 (8.29 g). This mixture was heated at 60° C. for 3 hours. The DMF was the removed in vacuo. Addition of Ethylactetate/heptane afforded only some crystallisation. Therefore was the crude mixture evaporated once more to an oil. Further purification on a CombiFlash with Ethyl actetate/heptane (9:1) as eluent afforded 4-(5-bromopyridin-2-ylmethyl)piperidine-1-carboxylic acid tert-butyl ester as a brown oil. Yield: 8 g, (45%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[C:13](Cl)[N:12]=[C:11]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]1([OH:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)C(C)C)(C)C>ClCCl>[CH2:1]([O:8][C:9]1[N:14]=[C:13]([O:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:12]=[C:11]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccccc1
Reactant: Clc1nc(OCc2ccccc2)nc(Oc2ccccc2)n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc(COc2nc(Oc3ccccc3)nc(Oc3ccccc3)n2)cc1
Yield: 98.5 %

Procedure:
Next, a synthesis method of the hydroxy group-protecting agent 2 will be explained. To a 30 mL eggplant flask, 470.6 mg (1.50 m mol) of 6-benzyloxy-2-chloro-4-phenoxy-1,3,5-triazine, 3.00 mL of dichloromethane, 178.8 mg (1.90 m mol) of phenol and 0.390 mL (1.90 m mol) of N,N-diisopropylethylamine were added, and reacted at 0 degree under a nitrogen atmosphere for 4 hours. After the reaction, 50 mL of dichloromethane was added, which was washed with 20 mL of 1 N hydrochloric acid, 20 mL of 1 N hydrochloric acid, 20 mL of water and 20 mL of saturated salt water. A resulting organic phase was dried by magnesium sulfate, from which dichloromethane was distilled away to obtain 548.5 mg of 6-benzyloxy-2,4-diphenoxy-1,3,5-triazine (yield: 99%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:31])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1[C:16](NC1C=C2OCOC2=CC=1C(=O)C)=[O:17])(=[O:10])=[O:9].[CH3:32][O:33][C:34](=[O:46])[C:35]1[CH:40]=[C:39]([O:41][CH3:42])[C:38]([O:43][CH3:44])=[CH:37][C:36]=1[NH2:45]>>[Cl:1][C:2]1[C:3]([CH3:31])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1[C:16]([NH:45][C:36]1[CH:37]=[C:38]([O:43][CH3:44])[C:39]([O:41][CH3:42])=[CH:40][C:35]=1[C:34]([O:33][CH3:32])=[O:46])=[O:17])(=[O:9])=[O:10]
Reactant: COC(=O)c1cc(OC)c(OC)cc1N
Reactant: CC(=O)c1cc2c(cc1NC(=O)c1sccc1S(=O)(=O)Nc1onc(C)c1Cl)OCO2
Product: COC(=O)c1cc(OC)c(OC)cc1NC(=O)c1sccc1S(=O)(=O)Nc1onc(C)c1Cl
Yield: 13 %

Procedure:
The title compounds were prepared by the method set forth for N-(4-chloro-3-methyl-5-isoxazolyl)2-{[2-acetyl-4,5-(methylenedioxy)phenyl]aminocarbonyl}thiophene-3-sulfonamide (EXAMPLE 148) except that methyl-2-amino-4,5-dimethoxybenzoate was used instead of 2'-amino-4',5=-(methylenedioxy)acetophenone. The crude product was purified via HPLC to give N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(4,5-dimethoxy-2-methoxycarbonylphenyl)aminocarbonyl]thiophene-3-sulfonamide as a yellow powder (13% yield, m.p. 167-168° C.) and N-(4-chloro-3-methyl-5-isoxazolyl)-2-{{2-[(4,5-dimethoxy-2-methoxycarbonyl)phenylaminocarbonyl]-4,5-dimethoxy}phenylaminocarbonyl}thiophene-3-sulfonamide as a dull yellow solid (1% yield, m.p. 228-230° C.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=1)[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:24][OH:25]>CN(C=O)C.CC(=O)OCC>[C:1]([O:5][C:6]([N:8]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:21](=[NH:22])[NH:24][OH:25])=[CH:19][CH:20]=1)[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CN(Cc1ccc(C#N)cc1)C(=O)OC(C)(C)C
Reactant: NO
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)CN(Cc1ccc(C(=N)NO)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 85 %

Procedure:
Prepared using General Procedure 19. To a stirring solution of methyl 2-((tert-butoxycarbonyl)(4-cyanobenzyl)amino)acetate INT-74 (1.35 g, 4.44 mmol) in DMF (8 mL) was added TEA (1.546 mL, 11.09 mmol) followed by hydroxylamine hydrochloride (0.771 g, 11.1 mmol). After stirring at room temperature for 48 h the reaction mixture was diluted with EA (100 mL) and the washed with brine (2×150 mL). The crude product was purified by chromatography (MeOH/DCM) to afford 1.28 g (85%) of methyl 2-((tert-butoxycarbonyl)(4-(N-hydroxycarbamimidoyl)benzyl)amino)acetate INT-75 as a viscous oil. LCMS-ESI (m/z) calculated for C16H23N3O5: 337; found 338 [M+H]+, tR=1.17 min (Method 10).
Reaction SMILES: [CH2:1]=C1CCC2(OCCO2)CC1.O=[C:13]1[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]1.O1C2(CCC(=O)CC2)OCC1>>[CH2:1]=[C:13]1[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]1
Reactant: C=C1CCC2(CC1)OCCO2
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: O=C1CCC2(CC1)OCCO2
Product: C=C1CCC(C(=O)OCC)CC1
Yield: 68.7 %

Procedure:
This intermediate was prepared following the procedure described Compound 31a. As starting material ethyl 4-oxocyclohexane-1-carboxylate replaced 1,4-dioxaspiro[4.5]decan-8-one. After the usual work-up procedure, the residue was purified by means of automated flash chromatography (SP01®TM-Biotage; gradient Petroleum Ether-EtOAc from 95:5 to 4:6) to give the title compound as a colorless oil. Yield: 68.7%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]2[N:9]=[CH:10][CH:11]=[C:4]2[N:3]=1.[Br:12]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:12][C:11]1[CH:10]=[N:9][N:5]2[C:6]([Cl:8])=[CH:7][C:2]([Cl:1])=[N:3][C:4]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: Clc1cc(Cl)n2nccc2n1
Solvent: ClC(Cl)Cl
Product: Clc1cc(Cl)n2ncc(Br)c2n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.3 %

Procedure:
To a solution of 5.3 g of 5,7-dichloropyrazolo(1,5-a)pyrimidine in 70 ml of chloroform was added portionwise 6 g of N-bromosuccinimide while keeping the temperature below 40° C. The resulting solution was refluxed for 30 minutes and was then stirred at room temperature for 12 hours. The suspension was then filtered. The filtrate was washed with 50 ml of cold 10% sodium hydroxide aqueous solution twice and was then dried over MgSO4. The chloroform solution was then concentrated under reduced pressure to give 7.47 g of the desired product, m.p. 73°-75° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5](O)=[O:6].Cl.[CH2:28]([NH:30][CH2:31][CH3:32])[CH3:29]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([N:30]([CH2:31][CH3:32])[CH2:28][CH3:29])=[O:6])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Reactant: CCNCC
Agent: Cl
Product: CCN(CC)C(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
75 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to diethylamine hydrochloride via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4,N4-diethylterephthalamide. MS (Q1) 443 (M)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].Cl[C:17]1[N:22]=[C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:20]=[CH:19][CH:18]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:17]2[N:22]=[C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:20]=[CH:19][CH:18]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Reactant: CCOC(=O)c1cccc(Cl)n1
Product: CCOC(=O)c1cccc(-c2cc(OC)c(OC)c(OC)c2)n1

Procedure:
3,4,5-Trimethoxyphenylboronic acid (837 mg) and ethyl 6-chloropicolinate (733 mg) were reacted in the same manner as in Preparation Example 1 to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:11]=2[C:12]#[N:13])=[CH:4][CH:3]=1>COCCOC.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:11]=2[C:12]#[N:13])=[CH:4][CH:3]=1
Reactant: N#Cc1cc(F)ccc1C=Cc1ccc(F)cc1
Agent: [Pd]
Solvent: COCCOC
Product: N#Cc1cc(F)ccc1CCc1ccc(F)cc1
Reaction time: 1 h
Yield: 99.2 %

Procedure:
2-[2-(4-Fluorophenyl)ethenyl]-5-fluorobenzonitrile (2.1 g, 8.7 mmol) was dissolved in ethylene glycol dimethyl ether (100 mL). Palladium on charcoal (10% Pd; 0.20 g) was added, and the reaction mixture was shaken under 60 psig H2 for 1 h. The reaction mixture was then filtered through Celite®, and the filtrate was rotary evaporated (75° C.) to provide 2.1 g (99%) of product as a light-yellow oil.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-])=O.C(N)CC(C)C.[Cl:20][C:21]1[CH:58]=[CH:57][C:24]([C:25]2[C:30]([C:31]3[CH:40]=[CH:39][C:38]4[C:33](=[CH:34][CH:35]=[C:36]([C:41]5N(CC)C6C=[CH:49][C:50]([C:52](O)=O)=[CH:51][C:43]=6[N:42]=5)[CH:37]=4)[N:32]=3)=[CH:29][C:28]([O:55][CH3:56])=[CH:27][CH:26]=2)=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:58]=[CH:57][C:24]([C:25]2[C:30]([C:31]3[CH:40]=[CH:39][C:38]4[C:33](=[CH:34][CH:35]=[C:36]([C:41]5[N:42]([CH2:43][CH2:51][CH:50]([CH3:52])[CH3:49])[C:2]6[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=6[N:11]=5)[CH:37]=4)[N:32]=3)=[CH:29][C:28]([O:55][CH3:56])=[CH:27][CH:26]=2)=[CH:23][CH:22]=1
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CCn1c(-c2ccc3nc(-c4cc(OC)ccc4-c4ccc(Cl)cc4)ccc3c2)nc2cc(C(=O)O)ccc21
Agent: CC(C)CCN
Product: COc1ccc(-c2ccc(Cl)cc2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4CCC(C)C)ccc3n2)c1

Procedure:
The title compound was prepared from Resin 534a and isoamylamine according to the procedure described in the preparation Compound 534.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[CH3:22])=[O:10].Br[CH2:24][C:25]1[CH:26]=[C:27]([C:30]#[N:31])[S:28][CH:29]=1>>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[CH3:22])=[O:10])[O:8][CH2:24][C:25]1[CH:26]=[C:27]([C:30]#[N:31])[S:28][CH:29]=1
Reactant: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(O)cc1F
Reactant: N#Cc1cc(CBr)cs1
Product: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(OCc2csc(C#N)c2)cc1F

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure C from (2-Fluoro-4-hydroxy-phenyl)-[2-(S)-(2-(R)-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-methanone and 4-bromomethyl-thiophene-2-carbonitrile [CAS 186552-07-8]. MS (ES+) m/e 428.3
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:11]=3[N:10]=[C:9]2[C:18]([OH:21])([CH3:20])[CH3:19])[CH2:4][CH2:3]1.[C:22]([C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[CH2:29][C@H:28]([CH:33]=O)[CH2:27]2)#[N:23]>>[Cl:17][C:15]1[CH:14]=[CH:13][C:12]2[N:8]([C@@H:5]3[CH2:4][CH2:3][C@H:2]([NH:1][CH2:33][C@@H:28]4[CH2:27][C:26]5[C:30](=[CH:31][CH:32]=[C:24]([C:22]#[N:23])[CH:25]=5)[CH2:29]4)[CH2:7][CH2:6]3)[C:9]([C:18]([OH:21])([CH3:19])[CH3:20])=[N:10][C:11]=2[CH:16]=1
Reactant: N#Cc1ccc2c(c1)C[C@@H](C=O)C2
Reactant: CC(C)(O)c1nc2cc(Cl)ccc2n1[C@H]1CC[C@@H](N)CC1
Product: CC(C)(O)c1nc2cc(Cl)ccc2n1[C@H]1CC[C@@H](NC[C@H]2Cc3ccc(C#N)cc3C2)CC1

Procedure:
This compound was prepared from the hydrochloride salt of cis-2-[1-(4-amino-cyclohexyl)-5-chloro-1H-benzoimidazol-2-yl]-propan-2-ol and (S)-5-cyano-indan-2-carbaldehyde. LC-MS showed a single peak, C27H31ClN4O (m/e) calcd 462.2186, obsd 463.2 (M+H). 1H-NMR (CD3OD) □ 7.96 (d, 1H), 7.59 (s, 1H), 7.57 (s, 1H), 7.49 (d, 1H), 7.38 (d, 1H), 7.18 (d, 1H), 5.38 (m, 1H), 3.22 (m, 2H), 2.75-2.97 (m, 8H), 2.01 (m, 2H), 1.72 (s, 6H), 1.68 (m, 4H).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:8][C:9]1([CH3:23])[C:13]([CH3:15])([CH3:14])[O:12][B:11]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)[O:10]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(OCC)(=O)C>[CH3:14][C:13]1([CH3:15])[C:9]([CH3:8])([CH3:23])[O:10][B:11]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:18][CH:17]=2)[O:12]1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Ethyl bromoacetate (0.60 mL) was added to a mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1.0 g) and potassium carbonate (0.94 g) in N,N-dimethylformamide (5 mL), and the mixture was stirred overnight at 80° C. Water and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=10/1) to afford the title compound (1.33 g).