Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([C:8]1[C:9]([CH3:18])=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[O:12][CH2:11]2)=[CH2:7])CCC.C1C(=O)N([Br:26])C(=O)C1.Br>O.C1COCC1>[Br:26][CH2:5][C:6]([C:8]1[C:9]([CH3:18])=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[O:12][CH2:11]2)=[O:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=C(OCCCC)c1ccc2c(c1C)COC2=O
Agent: Br
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C(=O)CBr)ccc2c1COC2=O
Temperature: 19 °C
Reaction time: 1 h

Procedure:
To a 1 L 3-neck flask equipped with overhead stirrer was added crude 5-(1-butoxy-vinyl)-4-methyl-3H-isobenzofuran-1-one (55.8 g) and THF (315 mL). The solution was cooled to <5° C. after which water (79 mL) was added and the solution was maintained at <5° C. NBS (41.6 g) was then added portionwise while maintaining Tmax=19° C. The solution was then warmed to RT for 30 minutes. HBr (48%, 0.241 mL) was added and the reaction was aged at RT for approximately 1 h after which 236 mL water was then added to the batch. A water bath is used to maintain temp at 20° C. Another 315 mL of water was added (solvent composition 1:2 THF:water) and the slurry was cooled to 15° C. The resulting solids were filtered and washed with cold 1:2 THF:water (15° C.): 150 mL displacement wash followed by 100 mL slurry wash. The solids were dried under vacuum at RT to provide 5-(2-bromo-acetyl)-4-methyl-3H-isobenzofuran-1-one. 1H NMR (400 MHz, DMSO-d6): δ 7.99 (d, J=7.8 Hz, 1H), 7.82 (d, J=7.8 Hz, 1H), 5.49 (s, 2H), 4.92 (s, 2H), 2.33 (s, 3H)
Reaction SMILES: [Br:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][C:5]([OH:10])=[C:4]([F:11])[CH:3]=1.[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1>C(Cl)Cl.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>[Br:1][C:2]1[C:7]([CH2:8][O:9][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][O:12]2)=[CH:6][C:5]([O:10][CH:17]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([F:11])[CH:3]=1
Reactant: OCc1cc(O)c(F)cc1Br
Reactant: C1=COCCC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: ClCCl
Product: Fc1cc(Br)c(COC2CCCCO2)cc1OC1CCCCO1
Temperature: 25 °C
Reaction time: 21 h
Yield: 83 %

Procedure:
Protection of the alcohol was carried out by making a solution of 4-bromo-2-fluoro-5-(hydroxymethyl)phenol (1.37 g, 6.19 mmol), 3,4 dihydro-2H-pyran (1.4 mL, 15 mmol) in 20 mL of CH2Cl2. The reaction mixture was then treated with camphor sulfonic acid (58 mg, 0.25 mmol) before stirring at room temperature for 21 hr. The reaction mixture was then quenched with equal volumes of 0.2 M NaOH and EtOAc (1:1, 20 mL) before the layers were separated. The water phase was further extracted with equal volume of EtOAc before the organic layers were combined and dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure. The residue was purified by silica gel column using Combiflash to give 2-(4-bromo-2-fluoro-5-((tetrahydro-2H-pyran-2-yloxy)methyl)phenoxy)tetrahydro-2H-pyran (2.0 g, 83%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:20]1([C:14]2([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: [H][H]
Reactant: c1ccc(CN2CCN(C3(c4ccccc4)CCCCC3)CC2)cc1
Agent: [Pd]
Solvent: CO
Product: c1ccc(C2(N3CCNCC3)CCCCC2)cc1

Procedure:
1 benzyl 4 (1-phenylcyclohexyl)piperazine (0.47 q) was dissolved in 86 mL methanol and 14 mL 0.2 N HCI in methanol. The mixture was hydrogenated over palladium black (0.1175 g) and 3 atm. of hydrogen at room temperature for 1 hour. The reaction was filtered and the solvent was removed in vacuo. The residue was chromatographed on silica gel eluted with the appropriate mixture of methanol and chloroform to yield pure 1 (1-phenylcyclohexyl)piperazine.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([O:13][CH3:14])=[C:7]([CH3:15])[C:4]=1[CH:5]=O.[C:16]([O-:21])(=[O:20])[C:17]([CH3:19])=[O:18].[Na+].[OH-].[K+]>CO>[CH3:1][O:2][C:3]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([O:13][CH3:14])=[C:7]([CH3:15])[C:4]=1[CH:5]=[CH:19][C:17](=[O:18])[C:16]([OH:21])=[O:20]
Reactant: COc1c(C)c(C)c(OC)c(C=O)c1C
Reactant: CC(=O)C(=O)[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1c(C)c(C)c(OC)c(C=CC(=O)C(=O)O)c1C
Temperature: 0 °C
Yield: 100 %

Procedure:
A suspension of 3.7 g (17.6 mmol) of 2,5-dimethoxy-3,4,6-trimethylbenzaldehyde and 5.0 g (53.2 mmol) of sodium pyruvate in 20 ml of methanol is treated with 0.1 g (1.8 mmol) of potassium hydroxide and the mixture is subsequently heated at reflux for 5 hours, whereby a yellow solution is obtained. The reaction mixture is poured on to ice-water and the resulting 4-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-2-keto-3-butenoic acid is precipitated by the addition of sulphuric acid while stirring. The suspension is stirred for 1 hour, filtered, the filter residue is washed with water and dried. In this manner there are obtained 4.9 g of 4-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-2-keto-3-butenoic acid in the form of a yellow powder of melting point 126°-127° C.
Reaction SMILES: [O-2].[O-2].[O-2].[O-2].[O-2].[V+5:6].[V+5].[Fe:8].[CH2:9]([CH:11]([CH2:15][CH2:16][CH2:17][CH3:18])[C:12]([OH:14])=[O:13])[CH3:10].C(O)CCCCCO>O>[CH2:9]([CH:11]([CH2:15][CH2:16][CH2:17][CH3:18])[C:12]([O-:14])=[O:13])[CH3:10].[Fe+2:8].[V+5:6].[CH2:9]([CH:11]([CH2:15][CH2:16][CH2:17][CH3:18])[C:12]([O-:14])=[O:13])[CH3:10].[CH2:9]([CH:11]([CH2:15][CH2:16][CH2:17][CH3:18])[C:12]([O-:14])=[O:13])[CH3:10].[CH2:9]([CH:11]([CH2:15][CH2:16][CH2:17][CH3:18])[C:12]([O-:14])=[O:13])[CH3:10].[CH2:9]([CH:11]([CH2:15][CH2:16][CH2:17][CH3:18])[C:12]([O-:14])=[O:13])[CH3:10].[CH2:9]([CH:11]([CH2:15][CH2:16][CH2:17][CH3:18])[C:12]([O-:14])=[O:13])[CH3:10].[CH2:9]([CH:11]([CH2:15][CH2:16][CH2:17][CH3:18])[C:12]([O-:14])=[O:13])[CH3:10]
Reactant: CCCCC(CC)C(=O)O
Reactant: [Fe]
Agent: [V+5]
Agent: OCCCCCCO
Agent: [O-2]
Solvent: O
Product: CCCCC(CC)C(=O)[O-]
Product: [Fe+2]
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A mixture of 18 grams (0.196 mole) of vanadium pentoxide, 51.1 grams (0.895 mole) of iron powder (97.8% iron), 348.2 grams (2.402 moles) of 2-ethylhexanoic acid (acid number 387), 30 grams of hexylene glycol (stabilizer), 25 grams of water and 60 grams of mineral spirits was agitated for 1 hour with an air sparge. The mixture was then heated to 70° C. and held for 11.5 hours. The reaction product was heated to 135° C. under vacuum to remove water, filtered and diluted with mineral spirits to 6.0% iron and 1.0% vanadium.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl-].[CH3:8][O:9][CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[F:30][C:31]([F:41])([F:40])[C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1.O>C1COCC1>[CH3:8][O:9][CH:10]=[CH:36][C:35]1[CH:38]=[CH:39][C:32]([C:31]([F:41])([F:40])[F:30])=[CH:33][CH:34]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC=Cc1ccc(C(F)(F)F)cc1
Reaction time: 1 h
Yield: 60.4 %

Procedure:
Potassium tert butoxide (13.46 g, 0.120 mol) was added to methoxymethyl triphenyl phosphonium chloride (38.30 g, 0.112 mol) in 150 ml dry THF at −30° C. under argon atmosphere and stirred for 1 h. 4-trifluoromethylbenzaldehyde (15.0 g, 0.086 mol) in 60 ml THF was added dropwise at the same temperature and stirring continued for 3 h at room temperature. The reaction mixture was treated with 100 ml water, 150 ml petroleum ether and filtered through celite. Organic layer was separated and the aq. layer was extracted with petroleum ether (2×100 ml). Combined organic layer was washed with brine and dried over sodium sulfate. Solvent evaporation under reduced pressure followed by purification over silica gel using petroleum ether as eluent afforded (10.5 g) of the sub-title compound as a colorless liquid. This was directly taken for next step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[Br:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16]>>[Br:12][C:13]1[CH:14]=[C:15]([NH:16][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])[CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)Cc1ccccc1Br
Reactant: Nc1cccc(Br)c1
Product: O=C(O)Cc1ccccc1Nc1cccc(Br)c1

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 3-bromoaniline to yield 2-[(3-bromophenyl)amino]phenylacetic acid.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[C:7]([C:10]1[NH:11][C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1)(=[O:9])[CH3:8].C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[C:7]([C:10]1[N:11]([CH:6]2[CH2:5][CH2:4][CH2:3][CH2:2][O:1]2)[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1)(=[O:9])[CH3:8]
Reactant: C1=COCCC1
Reactant: CC(=O)c1nc2ccccc2[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CC(=O)c1nc2ccccc2n1C1CCCCO1
Reaction time: 24 h

Procedure:
Dihydropyran (20.5 mL) as added dropwise to a solution of 2-acetylbenzoimidazole (32 g) and p-toluenesulfonic acid (2 g) in dichloromethane (280 mL) at reflux. The reaction mixture was stirred at this temperature for 24 hours, then cooled and the insoluble materials were filtered off. The filtrate was concentrated to give 2-acetyl-1-(tetrahydropyran-2-yl)-benzoimidazole as an amber oil (51.8 g). TLC: dichloromethane:methanol, 97:3) RF=0.80.
Reaction SMILES: C([Li])CCC.[C:6]1([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:21]([O:25][CH2:26][CH3:27])(=[O:24])[CH:22]=[O:23].C1(C)C=CC=CC=1>O1CCCC1>[OH:23][CH:22]([C:13]1[N:12]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:20]2[C:15]([CH:14]=1)=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:21]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: c1ccc(-n2ccc3ccccc32)cc1
Reactant: CCOC(=O)C=O
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C(O)c1cc2ccccc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 19 %

Procedure:
A solution of butyllithium (1.6 M, 1.19 mL, 1.9 mmol) was added at −78° C. to a solution of 1-phenyl-1H-indole (5a) (350 mg, 1.81 mmol) in tetrahydrofuran (10 mL) under a nitrogen atmosphere. After 45 minutes, a solution of ethyl glyoxylate in toluene (50%, 400 μL, 2 mmol) was added. The reaction mixture was slowly warmed to room temperature for 12 hours, quenched with water (2 mL) and concentrated in vacuo. The residue was partitioned between dichloromethane (30 mL) and water (10 mL). The organic layer was washed with water (2×10 mL), brine (10 mL), dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 90/10) to afford the desired alcohol (5b) as a white solid (100 mg, 0.33 mmol, 19%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([N:10]2[CH2:22][CH2:21][N:13]3[C:14]4[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=4[CH:20]=[C:12]3[C:11]2=[O:23])[N:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][N:5]=[C:6]([N:10]2[CH2:22][CH2:21][N:13]3[C:14]4[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=4[CH:20]=[C:12]3[C:11]2=[O:23])[C:7]=1[CH2:8][OH:9]
Reactant: O=Cc1c(Cl)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C1c2cc3c(n2CCN1c1nccc(Cl)c1CO)CCCC3
Reaction time: 0.5 h
Yield: 90.4 %

Procedure:
To a solution of 4-chloro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-nicotinaldehyde 103b (1.0 g, 3.0 mmol) in methanol (30 mL) was added sodium borohydride (380 mg, 9.0 mmol) at 10° C. The reaction mixture was stirred for 30 minutes and quenched with water (10 mL). It was then concentrated under reduced pressure and the residue was dissolved in dichloromethane (50 mL). The mixture was washed with water (10 mL), dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to afford 190f as a yellow solid (900 mg, 90%). MS-ESI: [M+H]+ 332.
Reaction SMILES: O[CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1.S(Cl)([Cl:17])=O>C(Cl)Cl>[ClH:17].[Cl:17][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: OCCNc1cccc(C(F)(F)F)c1
Solvent: ClCCl
Product: Cl
Product: FC(F)(F)c1cccc(NCCCl)c1
Temperature: 0 °C

Procedure:
20.5 g (0.1 mole of N-(2-hydroxy-ethyl)-3-trifluoromethyl-aniline were taken up in 100 ml of absolute methylene chloride, and the solution was cooled to 0° C. At this temperature 14.3 g (0.12 mol) of thionyl chloride were added dropwise. The reaction mixture was allowed to warm to room temperature while stirring, whereupon it was refluxed, while monitoring by chromatography, until the reaction had gone to completion. After the solvent and the residual thionyl chloride had been removed, the crude product thus obtained was used for further reaction.
Reaction SMILES: [C:1]([CH2:3][C:4]1[S:8][CH:7]=[C:6]([C:9]2[C:13]3[C:14](=[O:20])[NH:15][CH:16]=[C:17]([C:18]#[N:19])[C:12]=3[N:11]([CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:10]=2)[CH:5]=1)#[N:2].C(=O)([O-])[O-:27].[K+].[K+].OO.O>CS(C)=O>[C:18]([C:17]1[C:12]2[N:11]([CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:10]=[C:9]([C:6]3[CH:5]=[C:4]([CH2:3][C:1]([NH2:2])=[O:27])[S:8][CH:7]=3)[C:13]=2[C:14](=[O:20])[NH:15][CH:16]=1)#[N:19]
Reactant: O=C([O-])[O-]
Reactant: N#CCc1cc(-c2cn(C3CCCC3)c3c(C#N)c[nH]c(=O)c23)cs1
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1c[nH]c(=O)c2c(-c3csc(CC(N)=O)c3)cn(C3CCCC3)c12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 3-(5-(cyanomethyl)-3-thienyl)-1-cyclopentyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-7-carbonitrile (80 mg) obtained in Example 93 and 2M aqueous potassium carbonate solution (0.574 mL) in DMSO (3 mL) was added 30% hydrogen peroxide aqueous solution (0.235 mL) at 0° C., and the mixture was stirred at room temperature for 5 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (13 mg).
Reaction SMILES: [CH2:1]([N:5]([CH2:22][CH:23]([OH:26])[CH2:24][Cl:25])[CH2:6][CH:7]([OH:21])[CH2:8][O:9][CH:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[N:13]([OH:18])[C:12]([CH3:20])([CH3:19])[CH2:11]1)[CH2:2][CH2:3][CH3:4]>O>[Cl-:25].[CH2:1]([N+:5]1([CH2:6][CH:7]([OH:21])[CH2:8][O:9][CH:10]2[CH2:15][C:14]([CH3:17])([CH3:16])[N:13]([OH:18])[C:12]([CH3:20])([CH3:19])[CH2:11]2)[CH2:24][CH:23]([OH:26])[CH2:22]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CC(O)CCl)CC(O)COC1CC(C)(C)N(O)C(C)(C)C1
Solvent: O
Product: CCCC[N+]1(CC(O)COC2CC(C)(C)N(O)C(C)(C)C2)CC(O)C1
Product: [Cl-]

Procedure:
The compound of Example 12A is heated at 100° C. in water to form the title compound.
Reaction SMILES: [CH3:1][OH:2].C[O-].[Na+].Cl[C:7]1[C:8]2[CH:16]=[C:15]([CH3:17])[O:14][C:9]=2[N:10]=[C:11]([NH2:13])[N:12]=1>FC(F)(F)C(O)=O>[CH3:1][O:2][C:7]1[C:8]2[CH:16]=[C:15]([CH3:17])[O:14][C:9]=2[N:10]=[C:11]([NH2:13])[N:12]=1
Reactant: CO
Reactant: Cc1cc2c(Cl)nc(N)nc2o1
Agent: C[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: COc1nc(N)nc2oc(C)cc12
Reaction time: 24 h

Procedure:
To 100 ml of anhydrous methanol was added 0.9 g sodium methoxide plus 1.7 g of 4-chloro-6-methylfuro[2,3-d]pyrimidin-2-amine and the mixture was heated to boiling for 24 hours. The methanol was then removed under reduced pressure and the product was triturated with water and filtered to afford a yield of 1.5 g, m.p. 173°-175°. An NMR (60 MHz) spectrum in trifluoroacetic acid solution exhibited absorptions at 2.5, 4.4 and 6.5 ppm in a 3:3:1 ratio indicating the title compound.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH:7]([CH3:12])[C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:3]=1.C1C(=O)N([Br:20])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.BrC(C1OC=C(CBr)N=1)(C)C(OC)=O>C(Cl)(Cl)(Cl)Cl>[Br:20][C:7]([C:5]1[O:6][C:2]([CH3:1])=[CH:3][N:4]=1)([CH3:12])[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C(C)c1ncc(C)o1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: COC(=O)C(C)(Br)c1nc(CBr)co1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(C)(Br)c1ncc(C)o1
Temperature: 25 °C

Procedure:
A mixture of the intermediate from Step B (0.322 g, 1.903 mmol), NBS (0.373 g, 2.09 mmol), and AIBN (0.016 g, 0.095 mmol) in 15 mL of CCl4 was refluxed for 1 hour. The mixture was cooled to room temperature, filtered, and concentrated. The residue was purified by silica gel chromatography using a hexanes/EtOAc gradient to give a 7:1 mixture of the indicated product and methyl 2-bromo-2-[4-(bromomethyl)-1,3-oxazol-2-yl]propanoate (pale yellow oil). The mixture was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH3:9])=[C:6](Cl)[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:13][CH:12]=2)[N:3]=1.C(O)C.O.C(N(CC)CC)C>[H][H].[Pd]>[CH3:9][O:8][C:7]1[CH:6]=[N:5][C:4]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:13][CH:12]=2)=[N:3][CH:2]=1
Reactant: CCCCCCCCc1ccc(-c2nc(Cl)c(OC)c(Cl)n2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: CCCCCCCCc1ccc(-c2ncc(OC)cn2)cc1

Procedure:
To 4,6-dichloro-5-methoxy-2-(4-octylphenyl)pyrimidine (74.2 g, 0.202 mol) were added ethanol (310 ml), water (15.5 ml), 5% Pd-activated carbon (5.7 g) and triethylamine (61.3 g, 0.606 mol), followed by agitating the mixture at about 40° C. in hydrogen current, filtering off the Pd-activated carbon, adding toluene, sufficiently washing the mixture with 2N--NaOH aqueous solution, further washing it with water, distilling off toluene and recrystallizing the residue from ethanol (70 ml) to obtain 5-methoxy-2-(4-octylphenyl)pyrimidine in the form of colorless acicular crystals (54.9 g) having a m.p. of 40.1°-41.8° C.
Reaction SMILES: [F:1][C:2]1([F:36])[CH2:5][CH:4]([CH2:6][O:7][C:8]2[CH:35]=[CH:34][C:11]3[N:12]=[C:13]([C:15]4[N:20]=[CH:19][C:18]([O:21][CH2:22][C@@H:23]([NH:25]C(=O)OC(C)(C)C)[CH3:24])=[CH:17][C:16]=4[F:33])[O:14][C:10]=3[CH:9]=2)[CH2:3]1.Cl.[C:38](OCC)(=[O:40])[CH3:39]>C(OCC)(=O)C>[F:36][C:2]1([F:1])[CH2:5][CH:4]([CH2:6][O:7][C:8]2[CH:35]=[CH:34][C:11]3[N:12]=[C:13]([C:15]4[N:20]=[CH:19][C:18]([O:21][CH2:22][C@@H:23]([NH:25][C:38](=[O:40])[CH3:39])[CH3:24])=[CH:17][C:16]=4[F:33])[O:14][C:10]=3[CH:9]=2)[CH2:3]1
Reactant: CCOC(C)=O
Reactant: C[C@@H](COc1cnc(-c2nc3ccc(OCC4CC(F)(F)C4)cc3o2)c(F)c1)NC(=O)OC(C)(C)C
Agent: Cl
Product: CC(=O)N[C@@H](C)COc1cnc(-c2nc3ccc(OCC4CC(F)(F)C4)cc3o2)c(F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of tert-butyl {(1S)-2-[(6-{6-[(3,3-difluorocyclobutyl)methoxy]-1,3-benzoxazol-2-yl}-5-fluoropyridin-3-yl)oxy]-1-methylethyl}carbamate (390 mg), 4 M hydrogen chloride/ethyl acetate (3 mL), and ethyl acetate (3 mL) was stirred at room temperature for 4 hr. The mixture was concentrated under reduced pressure. The residue was mixed with pyridine (3 mL) and acetic anhydride (1 mL). The mixture was stirred at room temperature for 3 days. 1 M hydrochloric acid was added, and the mixture was extracted with ethyl is acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate/methanol) and recrystallization (ethyl acetate) to give the title compound (218 mg) as white crystals.
Reaction SMILES: O=P(Cl)(Cl)Cl.[NH:6]1[C:10]2[CH:11]=[C:12]([C:15]([NH2:17])=O)[CH:13]=[CH:14][C:9]=2[N:8]=[CH:7]1.[OH-].[Na+]>CN(C=O)C>[NH:6]1[C:10]2[CH:11]=[C:12]([C:15]#[N:17])[CH:13]=[CH:14][C:9]=2[N:8]=[CH:7]1
Reactant: NC(=O)c1ccc2nc[nH]c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1ccc2nc[nH]c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.4 %

Procedure:
Under ice-cooling, to DMF (30 ml) was slowly added dropwise POCl3 (6.68 g, 4.06 ml), followed by reaction at room temperature for 2 hours, and then a solution of 1H-benzimidazole-6-carboxamide (2.38 g) in DMF (47.6 ml) was added thereto, followed by stirring at room temperature for 2 hours. To the solution was added a 1M aqueous NaOH solution (pH 6 to 7), followed by stirring at room temperature for 0.5 hour. The solution was extracted with EtOAc, and the organic layer was combined, washed with saturated brine, dried over anhydrous MgSO4, and then filtered, and the filtrate was concentrated. The residue was purified by silica gel chromatography, and powdered/washed with IPE to obtain 1H-benzimidazole-6-carbonitrile (0.58 g) as a pale red crystal.
Reaction SMILES: [Li][C:2]([N-]C(C)C)(C)C.[CH2:9]([O:16][C:17]1[CH:22]=[C:21]([C:23]([CH3:31])([CH3:30])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:20]=[CH:19][C:18]=1[CH:32]1[CH2:37][C:36](=[O:38])[CH:35]=[C:34]([O:39][CH3:40])[CH2:33]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CN(C)P(N(C)C)(N(C)C)=O.CI>O1CCCC1>[CH2:9]([O:16][C:17]1[CH:22]=[C:21]([C:23]([CH3:31])([CH3:30])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:20]=[CH:19][C:18]=1[CH:32]1[CH:37]([CH3:2])[C:36](=[O:38])[CH:35]=[C:34]([O:39][CH3:40])[CH2:33]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCCCCCC(C)(C)c1ccc(C2CC(=O)C=C(OC)C2)c(OCc2ccccc2)c1
Reactant: [Li]C(C)(C)[N-]C(C)C
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Solvent: CI
Product: CCCCCCC(C)(C)c1ccc(C2CC(OC)=CC(=O)C2C)c(OCc2ccccc2)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a -78° C. solution of 0.5 mole of lithiodiisopropylamide in 500 ml of tetrahydrofuran (from 50.5 g, 0.5 mole diisopropylamine and 417 ml of 1.2 M n-butyllithium in hexane) is added dropwise (30 mm) a solution of 217 g (0.5 mole) of 5-(2-benzyloxy-4-(1,1-dimethylheptyl)phenyl)-3-methoxy-2-cyclohexen-1-one in 250 ml of tetrahydrofuran. The reaction is stirred 30 minutes longer at -78° C. followed by the addition of 179 g (1.0 mole) of hexamethylphosphoramide and 78.1 g (0.55 mole) of methyl iodide. The reaction is allowed to slowly warm to room temperature, stirred one hour and quenched by the addition of 10 ml of water. The reaction is evaporated under reduced pressure to remove the tetrahydrofuran and added to one liter ice water-one liter ether. The ether extract is washed with three one liter portions of water, dried over magnesium sulfate and evaporated to yield the title compound in nearly pure form. The title compound is purified via column chromatography on 2 kg of silica gel eluted with ether-pentane.
Reaction SMILES: Cl[CH:2]([O:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:3].[NH:9]1[CH:13]=[N:12][CH:11]=[N:10]1>C(#N)C>[N:9]1([CH:2]([O:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:3])[CH:13]=[N:12][CH:11]=[N:10]1
Reactant: c1nc[nH]n1
Reactant: CCCCOC(C)Cl
Solvent: CC#N
Product: CCCCOC(C)n1cncn1

Procedure:
Crude n-butyl 1-chloroethyl ether (Straus and Weber, Ann, 1932, 498, 124) was treated with 1,2,4-triazole (2.4 g) in acetonitrile (50 ml) to give at once a precipitate. The mixture was refluxed for 2 hours. The solvent was removed under reduced pressure. The residue was treated with water and extracted with diethyl ether. The ethereal layer was washed with water and dried over magnesium sulphate, and the solvent was removed to give the title product as a colourless oil, which was shown by GLC to be 95% pure.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:5]([CH3:23])=[C:6]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][C:19]=2[F:20])[N:16]([CH3:21])[C:15](=[O:22])[CH2:14][CH2:13]3)[CH:7]=[N:8][CH:9]=1.[Cl:24][C:25]1[C:26]([C:31](O)=[O:32])=[N:27][CH:28]=[CH:29][CH:30]=1>>[F:20][C:19]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][C:15](=[O:22])[N:16]2[CH3:21])=[CH:11][C:10]=1[C:6]1[C:5]([CH3:23])=[C:4]([CH2:3][NH:2][C:31]([C:26]2[C:25]([Cl:24])=[CH:30][CH:29]=[CH:28][N:27]=2)=[O:32])[CH:9]=[N:8][CH:7]=1
Reactant: O=C(O)c1ncccc1Cl
Reactant: Cc1c(CN)cncc1-c1cc2c(cc1F)N(C)C(=O)CC2
Agent: Cl
Product: Cc1c(CNC(=O)c2ncccc2Cl)cncc1-c1cc2c(cc1F)N(C)C(=O)CC2

Procedure:
In analogy to the procedure described for the preparation of example 75, 6-(5-aminomethyl-4-methyl-pyridin-3-yl)-7-fluoro-1-methyl-3,4-dihydro-1H-quinolin-2-one hydrochloride (example 226) has been coupled with 3-chloro-pyridine-2-carboxylic acid to give the title compound as a colorless solid. MS: 439.4 (M+H+).