Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B([O-])=O.B([O-])=O.[Ba+2].[C:8]([O-:27])(=[O:26])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[Na+].[Al:29]>O>[C:8]([O-:27])(=[O:26])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[Al+3:29].[C:8]([O-:27])(=[O:26])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[C:8]([O-:27])(=[O:26])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: [Al]
Agent: CCCCCCCCCCCCCCCCCC(=O)[O-]
Agent: O=B[O-]
Agent: [Ba+2]
Solvent: O
Product: [Al+3]
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To 150 parts of water was added 50 parts of barium metaborate and the mixture was heated to 70±5° C. Then, 3 parts of sodium stearate and 3 parts of aluminum polychloride were added and the mixture was stirred at 70±5° C. for about 1 hour. It was then subjected to dehydration, drying and pulverization to give aluminum stearate-treated barium metaborate.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14](Br)=[N:13][C:12]=1[CH3:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:18]1[C:22](B(O)O)=[CH:21][CH:20]=[N:19]1.C(=O)([O-])[O-].[K+].[K+].CCCCCC>C1(C)C=CC=CC=1.O.C(O)C.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>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:22]2[NH:18][N:19]=[CH:20][CH:21]=2)=[N:13][C:12]=1[CH3:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccn[nH]1
Reactant: Cc1nc(Br)sc1C(=O)NCc1ccccc1
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: [K+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1nc(-c2ccn[nH]2)sc1C(=O)NCc1ccccc1
Temperature: 100 °C
Yield: 65.2 %

Procedure:
A solution of 2-bromo-4-methyl-thiazole-5-carboxylic acid, benzyl amide (2.0 g, 6.43 mmol) in toluene (30 mL), water (10 mL) and ethanol (10 mL) was added 1H-pyrazole-5-boronic acid (1.44 g, 12.86 mmol), Pd(PPh3)4 (0.74 g, 0.643 mmol), and potassium carbonate (2.67 g, 19.29 mmol). The resulting mixture was degassed three times and heated to 100° C. for 16 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 mL) and washed with brine (2×100 mL). The organic phase was dried (Na2SO4) and evaporated. The residue was purified by preparative thin layer chromatography over silica gel eluting with 1:1 ethyl acetate:hexane to provide 4-methyl-2-(2H-pyrazol-3-yl)-thiazole-5-carboxylic acid benzylamide (1.25 g, 66% yield) as a white solid. MS (M+H)+=299; Rt=1.06 min; HRMS (M+H)+=299.
Reaction SMILES: [H][H].BrC1C=C2C(C(C)(C)CCC2=O)=CC=1.[Br:17][C:18]1[CH:19]=[C:20]([CH2:24][C:25](OCC)=[O:26])[CH:21]=[CH:22][CH:23]=1.[H-].C([Al+]CC(C)C)C(C)C>>[Br:17][C:18]1[CH:19]=[C:20]([CH2:24][CH:25]=[O:26])[CH:21]=[CH:22][CH:23]=1
Reactant: [H][H]
Reactant: CCOC(=O)Cc1cccc(Br)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: CC1(C)CCC(=O)c2cc(Br)ccc21
Agent: [H-]
Product: O=CCc1cccc(Br)c1

Procedure:
In the preferred compounds of the invention the two R1 substituents are methyl, and the R2 and R3 substituents are hydrogen. Reaction Scheme 2 illustrates a synthetic process for preparing 7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1-one (Compound G) which serves as a starting material for the synthesis of several preferred compounds of the invention. Thus, referring now specifically to Reaction Scheme 2, ethyl 3-bromophenylacetate (Compound B, made by esterification of 3-bromophenylacetic acid) is reduced with diisobutylaluminum hydride (DIBAL--H) to yield (3-bromophenyl)acetaldehyde. (3-Bromophenyl)acetaldehyde is reacted in a Wittig reaction with (carbethoxymethylene)triphenylphosphorane to provide a mixture of E and Z ethyl 4-(3-bromophenyl)but-2-enoates. The latter compounds are hydrogenated to yield ethyl 4-(3-bromophenyl)butanoate (Compound D). Compound D is reacted with the Grignard reagent derived from methylbromide to give the tertiary alcohol 5-(3-bromophenyl)-2-methylpentan-2-ol (Compound E) (It should be apparent to those skilled in the art, that the choice of the Grignard reagent used in this reaction step determines the nature of the R1 substituent in the resulting compounds of the invention.) Compound E is then treated with acid to cyclize it and to form 6-bromo-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene (Compound F). Compound F is oxidized with chromium trioxide to yield 7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound G). Compound G is covered by Formula 10 and in accordance with Reaction Scheme 1 serves as a starting material in the synthesis of several preferred compounds of the invention.
Reaction SMILES: C([O:5][C:6](=[O:30])[C@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[S:12]([C:15]1[CH:24]=[C:23]2[C:18]([C:19]([Cl:29])=[CH:20][N:21]=[C:22]2[NH:25][C:26]([NH2:28])=[NH:27])=[CH:17][CH:16]=1)(=[O:14])=[O:13])(C)(C)C>CCOC(C)=O.Cl>[ClH:29].[Cl:29][C:19]1[C:18]2[C:23](=[CH:24][C:15]([S:12]([N:8]3[CH2:9][CH2:10][CH2:11][C@@H:7]3[C:6]([OH:30])=[O:5])(=[O:14])=[O:13])=[CH:16][CH:17]=2)[C:22]([NH:25][C:26]([NH2:28])=[NH:27])=[N:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1S(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Agent: Cl
Solvent: CCOC(C)=O
Product: N=C(N)Nc1ncc(Cl)c2ccc(S(=O)(=O)N3CCC[C@@H]3C(=O)O)cc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 167.3 %

Procedure:
N-[(4-Chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-D-proline t-butyl ester (50 mg, 0.11 mmol) was dissolved in a solution of EtOAc saturated with HCl (10 mL) and the mixture stirred at room temperature for 2.5 h. The mixture was concentrated in vacuo, azeotroping with CH2Cl2, to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-D-proline hydrochloride (40 mg, 0.092 mmol) as a white powder.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)=O.Cl>C1COCC1.CO>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:7][C:8]1[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=1
Reactant: O=C(CCCBr)Nc1ccc(O)cc1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: Oc1ccc(NCCCCBr)cc1
Reaction time: 0.25 h

Procedure:
A solution of 18.06 g (0.07 mol) of 4-bromo-N-(4-hydroxyphenyl)butanamide in about 120 mL of THF was filtered to remove 0.6 g of a solid and placed in a 2 L flask under nitrogen. It was stirred magnetically in an ice bath while 280 mL (0.28 mol) of 1M borane-THF complex was dripped in over 20 minutes. The reaction was stirred cold for 1/2 hour, then at room temperature for 15 minutes, then at reflux for two hours on a steam bath. The reaction was cooled with an ice bath and diluted with 275 mL of methanol followed by 20 mL of 8N ethanolic HCl. This solution was heated at reflux for six hours on a steam bath and then allowed to stand at room temperature overnight. The next morning the solution was evaporated and the residue was dissolved in acetonitrile and evaporated again. The oily residue was slurried three times with ether and the ether decanted after each addition. After the last decanting the solution was evaporated on a rotary evaporator to yield an oil which was taken to the next step without further purification.
Reaction SMILES: C[O-].[Na+].C[O:5][C:6](=O)[CH:7]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])[C:8](OC)=[O:9].[NH2:22][C:23]([NH2:25])=[S:24]>CO>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[O:12][CH:7]1[C:6](=[O:5])[NH:25][C:23](=[S:24])[NH:22][C:8]1=[O:9]
Reactant: NC(N)=S
Reactant: COC(=O)C(Oc1ccccc1OC)C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccccc1OC1C(=O)NC(=S)NC1=O
Temperature: 10 °C
Reaction time: 2.17 h
Yield: 89.6 %

Procedure:
12.15 g sodium methylate was dissolved in 200 ml methanol and 21.1 g dimethyl-(o-methoxyphenoxy)malonate was added. Stirring was continued for 130 min. The mixture was cooled to 10° C. and 7.6 g thiourea was added. Stirring was continued for 24 h. The solvent was evaporated in vacuo. The residue was stirred with diethyl ether. The ether layer was filtered off and the solid was dissolved in 60 ml water and acidified to pH=4 with conc. acetic acid. The precipitated product was filtered and washed with methanol and dried at 30° C. and reduced pressure to give 19.8 g 5-(o-methoxyphenoxy)-2-thioxo-dihydro-pyrimidine-4,6-dione (or a tautomere thereof.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]3[N:14]=[CH:15][C:16]([C:17]([NH2:19])=[O:18])=[C:12]3[NH:11][CH2:10][C:9]=2[CH3:20])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[C:23](N1C=CN=C1)(N1C=CN=C1)=[S:24]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]3[C:12]4[N:11]([C:23](=[S:24])[NH:19][C:17](=[O:18])[C:16]=4[CH:15]=[N:14]3)[CH2:10][C:9]=2[CH3:20])[CH:5]=[CH:6][CH:7]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CC1=C(c2cccc(Cl)c2)n2ncc(C(N)=O)c2NC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1=C(c2cccc(Cl)c2)n2ncc3c(=O)[nH]c(=S)n(c32)C1
Temperature: -78 °C
Reaction time: 2 h
Yield: 69.8 %

Procedure:
A mixture of 5.0 g of 7-(3-chlorophenyl)-4,5-dihydro-6-methylpyrazolo(1,5-a)pyrimidine-3-carboxamide (Example 36) and 0.2 liters of dry tetrahydrofuran is stirred and cooled to -78° C. in a dry ice-acetone bath, then 1.43 g of sodium hydride (60 percent dispersion in mineral oil) is added in one portion. This mixture is stirred at -78° C. for 1.5 hours then 3.19 g of 1,1'-thiocarbonyldiimidazole is added and stirring is continued at -78° C. for 2 hours. The mixture is allowed to warm to room temperature and is stirred for 48 hours and then the reaction is quenched with 0.5 liters of water and neutralized with 5 percent aqueous hydrochloric acid. The crystalline solid that forms is collected, washed with ether and dried to give 4.0 g of the desired product as cream colored crystals, mp 289-291° C.
Reaction SMILES: C(OC([N:8]1[C@H:13]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=O)(C)(C)C.[C:24]([OH:30])([C:26]([F:29])([F:28])[F:27])=[O:25]>C(Cl)Cl>[F:27][C:26]([F:29])([F:28])[C:24]([OH:30])=[O:25].[CH2:17]([O:16][C:14]([C@@H:13]1[CH2:12][C@@H:11]2[C@@H:9]([CH2:10]2)[NH:8]1)=[O:15])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(OCc1ccccc1)[C@@H]1C[C@H]2C[C@H]2N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (1R,3S,5R)-2-aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 3-benzyl ester 2-tert-butyl ester (3.27 g, 9.79 mmol) in CH2Cl2 (50 mL) was added was added TFA (7.54 mL, 98 mmol). The reaction mixture was stirred overnight at RT and subsequently concentrated under reduced pressure to give the desired material as a yellow oil. MS (UPLC): 218.1 [M+H]+; tR (HPLC conditions f): 1.24 min.
Reaction SMILES: [CH2:1]([N:8]([CH3:24])[C@H:9]([C:21]([OH:23])=O)[CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][NH2:34])=[CH:28][CH:27]=1>>[OH:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][NH:34][C:21](=[O:23])[C@H:9]([CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH3:24])=[CH:28][CH:27]=1
Reactant: CN(Cc1ccccc1)[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)O
Reactant: NCCc1ccc(O)cc1
Product: CN(Cc1ccccc1)[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)NCCc1ccc(O)cc1

Procedure:
This compound is prepared using Procedure C by coupling of Nα-benzyl-Nδ-Boc-Nα-methylornithine and (4-hydroxyphenyl)ethylamine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[C:11](=[O:23])[C:10]=1[C:24]#[C:25][Si](C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[C:11](=[O:23])[C:10]=1[C:24]#[CH:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C#Cc1c(OCc2ccccc2)ccn(Cc2cccc(F)c2)c1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC#N
Product: C#Cc1c(OCc2ccccc2)ccn(Cc2cccc(F)c2)c1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 73 %

Procedure:
To a solution of 4-(benzyloxy)-1-(3-fluorobenzyl)-3-[(trimethylsilyl)ethynyl]pyridin-2(1H)-one (1.31 g, 3.2 mmol) in anhydrous acetonitrile (25 mL) at 0° C. was added tetrabutylammonium fluoride (0.611 g, 1.93 mmol). The reaction was stirred at 0° C. for 15 min then for 1 h at room temperature. The reaction was concentrated under reduced pressure and the residue was diluted with EtOAc and washed with water. The organic extracts were combined, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel) using EtOAc in hexanes (1:1 v/v). The appropriate fractions were combined and concentrated under reduced pressure to afford the desired product (0.779 g, 72%) as a gold solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]([NH:12][C@H:13]([C:23]([O:25]C)=[O:24])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)=[O:11].[OH-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]([NH:12][C@H:13]([C:23]([OH:25])=[O:24])[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)=[O:11]
Reactant: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C=Cc1ccccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C[C@H](NC(=O)C=Cc2ccccc2F)C(=O)O)cc1
Yield: 75.4 %

Procedure:
The same procedures as in Example 90 were carried out from the compound obtained in Example 38 (5.8 g), 1 mol/L of an aqueous sodium hydroxide solution (24 mL), and methanol (200 mL), to give the captioned compound (4.2 g, 76%) as crystals.
Reaction SMILES: C[O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14]C)=[CH:10][C:9]=2[CH3:16])=[C:5]([CH3:19])[C:4]=1[CH:20]([CH3:22])[CH3:21].B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=2[CH3:16])=[C:5]([CH3:19])[C:4]=1[CH:20]([CH3:22])[CH3:21]
Reactant: COc1ccc(Cc2ccc(OC)c(C(C)C)c2C)c(C)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc(O)ccc1Cc1ccc(O)c(C(C)C)c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.5 %

Procedure:
To a stirring solution of 4-(4′-methoxy-2′-methyl-3′-iso-propylbenzyl)-3-methyl-anisole (0.8 g, 2.68 mmol) in CH2Cl2 (10 mL) at −20° C. was added BBr3 (10.7 mL, 1M in CH2Cl2). The reaction mixture was stirred at room temperature for 16 hrs. It was added ice and diluted with CH2Cl2. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate/hexanes (1:1) to afford 4-(4′-hydroxy-2′-methyl-3′-iso-propylbenzyl)-3-methylphenol as a yellow solid (0.54 g, 75%): 1H NMR (200 MHz, DMSO-d6): δ 9.03 (s, 1 H), 8.84 (s, 1 H), 6.41-6.60 (m, 5 H), 3.65 (s, 2 H), 3.33 (m, 1 H), 2.12 (s, 3 H), 2.08 (s, 3 H), 1.27 (d, J=6.9 Hz, 6 H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=20% ethyl acetate in hexanes; Rf-0.31.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[F:11].Br.Br[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1>>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:6][C:5]=1[F:11]
Reactant: COC(=O)c1ccc(O)cc1F
Reactant: BrCc1ccccn1
Agent: Br
Product: COC(=O)c1ccc(OCc2ccccn2)cc1F

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure E from 2-Fluoro-4-hydroxy-benzoic acid methyl ester and 2-(bromomethyl)pyridine hydrobromide. MS (ES+) 262
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[C:4]([F:21])[CH:3]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>>[F:21][C:4]1[CH:3]=[C:2]([C:26]2[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=2)[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:9]
Reactant: O=C(c1ccc(Br)cc1F)N1CCC[C@H]1CN1CCCC1
Reactant: OB(O)c1ccc(F)cc1
Product: O=C(c1ccc(-c2ccc(F)cc2)cc1F)N1CCC[C@H]1CN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure SS starting from (4-bromo-2-fluoro-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and 4-Fluorobenzene boronic acid. MS (M+H) 371.2
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.F[C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[C:12]#[N:13].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[C:7]([O:8][C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[C:12]#[N:13])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: N#Cc1ccccc1F
Reactant: Oc1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccccc1Oc1cccnc1Cl
Temperature: 90 °C

Procedure:
A 50 mLround bottom flask was charged with 2-chloropyridin-3-ol (2.5 g, 19 mmol), 2-fluorobenzonitrile (2.6 g, 21 mmol) and potassium carbonate (6.7 g, 48 mmol) in DMF (10 mL) and heated at 90° C. for 1.5 days. Water was added water, and the reaction mixture was extracted with ethyl acetate, dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography using 10-20% ethyl acetate in hexanes as eluent to afford the title compound as an off white solid (2.1 g, 47% yield).
Reaction SMILES: [CH2:1]1[CH2:5][C:4]2([CH2:12][C:10](=[O:11])[O:9][C:7](=O)[CH2:6]2)[CH2:3][CH2:2]1.[NH2:13][C:14]1[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21]C)=[O:19])=[CH:16][CH:15]=1.CC1(C)CC(=O)OC(=O)C1>>[O:11]=[C:10]1[N:13]([C:14]2[CH:15]=[CH:16][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:23][CH:24]=2)[C:7](=[O:9])[CH2:6][C:4]2([CH2:3][CH2:2][CH2:1][CH2:5]2)[CH2:12]1
Reactant: O=C1CC2(CCCC2)CC(=O)O1
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: CC1(C)CC(=O)OC(=O)C1
Product: COC(=O)c1ccc(N2C(=O)CC3(CCCC3)CC2=O)cc1

Procedure:
The desired product was prepared by substituting methyl 4-aminobenzoate and 3,3-tetramethyleneglutaric anhydride for ethyl 4-aminobenzoate and 3,3-dimethylglutaric anhydride, respectively, in Example 119A. MS (DCI) m/e 302 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6](Br)[N:5]=1)(=[O:3])[CH3:2].[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[Na+].[Na+].O.CO>C1(C)C=CC=CC=1.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.CCOCC>[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=1)(=[O:3])[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CC(=O)c1cccc(Br)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: CO
Solvent: O
Product: CC(=O)c1cccc(-c2ccccc2)n1
Temperature: 80 °C
Reaction time: 1 h
Yield: 89.2 %

Procedure:
To a Schlenk tube charged with a solutionof 200 mg (1.0 mmol) of 2-acetyl-6-bromopyridine and 23 mg (0.02 mmol) of (Ph3P)4Pd in 10 mL of degassed toluene was added a solution. of 150 mg (1.2 mmol) phenylboronic acid and 270 mg (2.5 mmol) Na2CO3 in 8 mL of degassed 4:1 H2O/MeOH. The biphasic mixture was heated to 80° C. with rapid stirring for 1 h. On cooling to RT, Et2O (50 mL) was added and the layers were separated. The organic layer was dried over Na2SO4 and the volatiles were removed by rotary evaporation. The resulting oil was chromatographed on silica with 10-50% CH2Cl2/hexanes eluent to provide 176 mg (89%) of 2-acetyl-6-phenylpyridine as a white powder. 1H NMR (CDCl3); δ 2.84 (s, 3H); 7.43-7.62 (m, 3 H); 7.91-8.08 (m, 3 H); 8.18 (d, J=6.6 Hz, 2H). Mass Spec.: m/e 197.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.[C:21]([C:24]1[CH:29]=[C:28]([Cl:30])[C:27]([NH:31][C:32](=[O:44])[CH2:33][N:34]2[CH2:39][CH2:38][NH:37][CH:36]([C:40]([NH:42][CH3:43])=[O:41])[CH2:35]2)=[C:26]([Cl:45])[CH:25]=1)(=[O:23])[CH3:22].C(N(CC)CC)C>COCCO>[C:21]([C:24]1[CH:29]=[C:28]([Cl:30])[C:27]([NH:31][C:32](=[O:44])[CH2:33][N:34]2[CH2:39][CH2:38][N:37]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[C:7]3[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=3)[CH:36]([C:40]([NH:42][CH3:43])=[O:41])[CH2:35]2)=[C:26]([Cl:45])[CH:25]=1)(=[O:23])[CH3:22]
Reactant: CNC(=O)C1CN(CC(=O)Nc2c(Cl)cc(C(C)=O)cc2Cl)CCN1
Reactant: Fc1ccc(N(CCCCCl)c2ccc(F)cc2)cc1
Solvent: COCCO
Solvent: CCN(CC)CC
Product: CNC(=O)C1CN(CC(=O)Nc2c(Cl)cc(C(C)=O)cc2Cl)CCN1CCCCN(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 70 °C
Reaction time: 72 h
Yield: 19 %

Procedure:
A mixture of 2.07 parts of N-(4-chlorobutyl)-4-fluoro-N-(4-fluorophenyl)benzenamine, 2.5 parts of N-(4-acetyl-2,6-dichlorophenyl)-3-[(methylamino)carbonyl]-1-piperazineacetamide, 1.3 parts of N,N-diethylethanamine and 97 parts of 2-methoxyethanol was stirred for 3 days at 70° C. The reaction mixture was evaporated and the residue was taken up in water. The product was extracted twice with dichloromethane. The combined extracts were washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The desired fraction was collected and the eluent was evaporated. The residue was crystallized from acetonitrlle. The product was filtered off and dried, yielding a first fraction of 0.74 parts (19.0%) of N-(4-acetyl-2.6-dichlorophenyl)-4-[4-[bis(4-fluorophenyl)amino]butyl]-3-[(methylamino)carbonyl]-1-piperazineacetamide mp. 87.1° C. The second fraction was collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding a second fraction of 0.78 parts (20.1%) of N-(4-acetyl-2,6-dichlorophenyl)-4-[4-[bis(4-fluorophenyl)amino]butyl]3-[(methylamino)carbonyl]-1-piperazineacetamide; mp. 85.0° C. Total yield: 1.52 parts (39.1%) of N-(4-acetyl-2,6-dichlorophenyl)-4-[4-[bis(4-fluorophenyl)amino]butyl]-3-[(methylamino)carbonyl]-1piperazineacetamide (compound 97).
Reaction SMILES: CC(C)(OC(N[C@H]([C:19]1[N:20](CC(=O)C2C=CC=CC=2)[CH:21]=[C:22](C2C=CC=CC=2)[N:23]=1)CC1C2C(=CC=CC=2)NC=1)=O)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH:20]1[C:21]2[N:20]=[CH:21][CH:22]=[N:23][C:22]=2[NH:23][CH2:19]1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)c1nc(-c2ccccc2)cn1CC(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cnc2c(n1)NCN2
Temperature: 20 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
A solution of 2-[1(S)-{(1,1-dimethylethoxy)carbonylamino}-2-(3-indolyl)ethyl]-1-(benzoylmethyl)-4-phenyl-1H-imidazole (prepared as described previously) (100 mg) in a mixture of 10% TFA in DCM (1.3 mL) was stirred for about 3 hours at about 20° C. and concentrated under reduced pressure to yield the expected dihydro-imidazo-pyrazine (yield=95%). LC/MS: calculated MW: 402.19, m/z=403.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([NH:12][NH2:13])=[N:4][N:3]=1.C(O)(=O)C.[N:18]([O-])=O.[Na+]>O>[Cl:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]2=[N:12][N:13]=[N:18][N:4]2[N:3]=1
Reactant: NNc1nnc(Cl)c2c1CCCC2
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Clc1nn2nnnc2c2c1CCCC2

Procedure:
To a suspension of 9.9 g of 1-chloro-4-hydrazino-5,6,7,8-tetrahydrophthalazine in 35 ml of aqueous 12% acetic acid was added a solution of 3.5 g of sodium nitrite in 30 ml of water. The mixture was kept at room temperature (about 22°-25° C.) for about 20 minutes. The solid present was then separated by filtration, air dried and recrystallized to give 6-chloro-7,8,9,10-tetrahydrotetrazolo[5,1-a]phthalazine melting at about 109°-110° C.