Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2([C:17]([OH:19])=O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=[O:4].C(Cl)(=O)C([Cl:23])=O>ClCCl.CN(C)C=O>[Cl:23][C:17]([C:11]1([C:8]2[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:19]
Reactant: COC(=O)c1ccc(C2(C(=O)O)CCCCC2)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1ccc(C2(C(=O)Cl)CCCCC2)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 100.9 %

Procedure:
To a solution of 1-[4-(methoxycarbonyl)phenyl]-cyclohexanecarboxylic acid (E14) (0.174 g, 0.66 mmol) in dry dichloromethane (4 ml) under argon atmosphere at ice bath temperature oxalyl chloride (0.648 g, 5.10 mmol) and one drop of dimethylformamide were added. The reaction mixture was stirred at room temperature for 15 minutes and at 40° C. for one hour, then concentrated under reduced pressure to give crude title compound (0.187 g, ca. 100%). The crude product was immediately utilized in the next step of the synthesis without further purification.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[Cl:8][C:9]1[CH:18]=[C:17]2[C:12]([N:13]=[CH:14][C:15](=[O:19])[NH:16]2)=[CH:11][CH:10]=1.Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>O>[Cl:8][C:9]1[CH:18]=[C:17]2[C:12]([N:13]=[CH:14][C:15](=[O:19])[N:16]2[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:11][CH:10]=1
Reactant: CCOC(=O)CBr
Reactant: O=c1cnc2ccc(Cl)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(=O)cnc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under a nitrogen gas flow, to a mixture of NaH (55% in oil, 515 mg) and DMF (5 mL) was added a mixture of 7-chloroquinoxalin-2(1H)-one (2.00 g) and DMF (35 mL) under ice-cooling, followed by stirring at room temperature for 30 minutes. The reaction mixture was ice-cooled and ethyl bromoacetate (1.3 mL) was added thereto, followed by stirring at room temperature for 7 hours. The reaction mixture was added to water, followed by extraction with EtOAc. The organic layer was washed with water and brine in this order, dried over Na2SO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/MeOH=100/0-98/2). The obtained solid was washed with Hex to obtain ethyl (7-chloro-2-oxoquinoxalin-1(2H)-yl)acetate (2.21 g).
Reaction SMILES: [CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=2)=[N:3]1.C([Li])CCC.CN(C)[CH:21]=[O:22].[Cl-].[NH4+]>O1CCCC1>[CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:21]=[O:22])=[CH:9][CH:8]=2)=[N:3]1
Reactant: Cn1nnc(-c2ccc(Br)cc2)n1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cn1nnc(-c2ccc(C=O)cc2)n1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 29.5 %

Procedure:
A stirred solution of 2.2 grams (0.009 mole) 4-(2-methyl-2H-tetrazol-5-yl)phenyl bromide in 70 mL of dry tetrahydrofuran was cooled to −70° C., and 7.4 mL (0.018 mole) of n-butyllithium (2.5M in hexanes) was added dropwise from a syringe. The resulting reaction caused the reaction mixture temperature to rise to about −50° C. The reaction mixture was again cooled to −70° C., and stirring was continued for about 30 minutes. After this time 0.8 mL (0.010 mole) of N,N-dimethylformamide was added during a 90 second period. The reaction mixture was then stirred for 30 minutes at ice-water bath temperature, after which time it was allowed to warm to ambient temperature. The reaction mixture was poured into 200 mL of an aqueous solution saturated with ammonium chloride. The mixture was stirred for about 90 minutes and then extracted with three 150 mL portions of ethyl acetate. The combined extracts were washed with one 400 mL portion of an aqueous solution saturated with sodium chloride. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil, which was subjected to column chromatography on silica gel, with 3:7 ethyl acetate:heptane as the eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding 0.5 gram of 4(2-methyl-2H-tetrazol-5-yl)benzaldehyde. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.C[N:18](C=O)C>C1COCC1>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:18])=[O:6]
Reactant: O=C(O)c1cccc(I)c1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: NC(=O)c1cccc(I)c1
Reaction time: 2 h
Yield: 99 %

Procedure:
3-Iodobenzoic acid (2.00 g, 8.06 mmol) was dissolved in THF (20 mL) then oxalyl chloride (1.4 mL, 16 mmol) and DMF (0.05 mL) were added and the resulting mixture stirred for 2 hours. The volatiles were evaporated under reduced pressure and the residue was dissolved in THF (20 mL) and concentrated aqueous ammonia (10 mL). After 60 minutes water (200 mL) was added and after a further 30 minutes the resulting precipitate was collected by filtration and air dried to give the title compound (I142) (1.97 g, 99% yield) as a white powder; 1H NMR (400 MHz, d4-MeOH) δ 8.23 (t, J=1.8 Hz, 1H), 7.90 (ddd, J=7.9, 1.7, 1.0 Hz, 1H), 7.86 (ddd, J=7.8, 1.7, 1.0 Hz, 1H), 7.24 (t, J=7.8 Hz, 1H). LCMS Method C: rt 5.29 min, m/z 248.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([CH2:19][N:20]3[CH:24]=[C:23]([C:25]([OH:32])([CH2:30][CH3:31])[C:26]([F:29])([F:28])[F:27])[N:22]=[N:21]3)=[CH:7][CH:8]=2)[N:3]=1.C[N:34]1C(=O)CCC1>[OH-].[NH4+]>[NH2:34][C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([CH2:19][N:20]3[CH:24]=[C:23]([C@@:25]([OH:32])([CH2:30][CH3:31])[C:26]([F:29])([F:28])[F:27])[N:22]=[N:21]3)=[CH:7][CH:8]=2)[N:3]=1
Reactant: CCC(O)(c1cn(Cc2ccc3c(-c4ccc(F)cc4)cc(Cl)nc3c2)nn1)C(F)(F)F
Reactant: CN1CCCC1=O
Agent: [NH4+]
Agent: [OH-]
Product: CC[C@](O)(c1cn(Cc2ccc3c(-c4ccc(F)cc4)cc(N)nc3c2)nn1)C(F)(F)F

Procedure:
A solution of 2-(1-{[2-chloro-4-(4-fluorophenyl)quinolin-7-yl]methyl}-1H-1,2,3-triazol-4-yl)-1,1,1-trifluorobutan-2-ol (85 mg, 0.18 mmol) in NMP (1 mL) and ammonium hydroxide (15 M, 1 mL) was stirred at 175° C. in a microwave for 10 min. The reaction was quenched with saturated aqueous NaHCO3 and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification on silica gel (eluting with ethanol/dichloromethane, 1:9) gave the title compound. MS (+ESI): 445 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[O:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Cl:12][C:10]1[CH:11]=[C:2]([NH:1][CH:17]2[CH2:18][CH2:19][O:14][CH2:15][CH2:16]2)[C:3]([CH3:13])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C1CCOCC1
Reactant: COC(=O)c1cc(Cl)cc(N)c1C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1cc(Cl)cc(NC2CCOCC2)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.1 %

Procedure:
To a stirred solution of methyl 3-amino-5-chloro-2-methylbenzoate (1 g, 5.02 mmol) and tetrahydropyran-4-one (2.5 g, 25 mmol) in methanol (10 mL), acetic acid (0.3 g, 5.02 mmol) was added and reaction stirred at room temperature for 3 h. Then sodium cyanoborohydride (0.63 g, 10.05 mmol) was added and reaction stirred overnight. On completion, solvent was removed under reduced pressure and crude material was purified by column chromatography to afford methyl 5-chloro-2-methyl-3-((tetrahydro-2H-pyran-4-yl)amino)benzoate (0.5 g, 35.5%).
Reaction SMILES: [H-].[Na+].[CH2:3](Br)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:11][C:12]1[N:17]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[C:15]([Br:22])=[CH:14][CH:13]=1>CN(C)C=O.C(OCC)C>[Br:22][C:15]1[C:16]([C:18]([O:20][CH3:21])=[O:19])=[N:17][C:12]([N:11]([CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:13][CH:14]=1
Reactant: COC(=O)c1nc(N)ccc1Br
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)c1nc(N(Cc2ccccc2)Cc2ccccc2)ccc1Br
Reaction time: 0.5 h
Yield: 73.2 %

Procedure:
To a suspension of 60% sodium hydride (880 mg, 22.0 mmol) and benzyl bromide (6.24 mL, 52.5 mmol) in N,N-dimethylformamide (80 mL) was added a solution of methyl 6-amino-3-bromopyridine-2-carboxylate (2.42 g, 10.5 mmol) in N,N-dimethylformamide (25 mL) under ice-cooling and the mixture was stirred for 30 min. The reaction solution was diluted with diethyl ether, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=0/100→20/80) to give the title compound (3.16 g, yield 73%).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:12]1[CH:13]=[CH:14][C:15]([N+:23]([O-:25])=[O:24])=[C:16]([CH:22]=1)[C:17]([N:19]([CH3:21])[CH3:20])=[O:18]>CN(C=O)C>[CH2:3]([O:10][C:12]1[CH:13]=[CH:14][C:15]([N+:23]([O-:25])=[O:24])=[C:16]([CH:22]=1)[C:17]([N:19]([CH3:21])[CH3:20])=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCc1ccccc1
Reactant: CN(C)C(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cc(OCc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.8 %

Procedure:
Sodium hydride (210 mg) was suspended in DMF (10 mL), and the suspension was cooled to 0° C. and thereto were added benzyl alcohol (568 mg) and a solution of 5-chloro-N,N-dimethyl-2-nitrobenzamide (1.00 g) in DMF (2 mL). The mixture was stirred at 50° C. for 0.5 hour and then concentrated. The residue was acidified with 2N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:2→2:3) to give 5-benzyloxy-N,N-dimethyl-2-nitrobenzamide (1.18 g)
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[S:11][C:10]([NH2:12])=[N:9][C:8]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:4][N:3]=1.[C:19](Cl)(=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>>[CH3:1][C:2]1[N:6]=[C:5]([C:7]2[S:11][C:10]([NH:12][C:19](=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[N:9][C:8]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[O:4][N:3]=1
Reactant: Cc1noc(-c2sc(N)nc2-c2ccccc2)n1
Reactant: CCCCCC(=O)Cl
Product: CCCCCC(=O)Nc1nc(-c2ccccc2)c(-c2nc(C)no2)s1

Procedure:
Prepared from 5-(3-methyl-[1,2,4]oxadiazol-5-yl)-4-phenyl-thiazol-2-ylamine and hexanoyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-])=O)[C:4]=1[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([OH:16])[CH:14]=2)[CH2:9][CH2:8][N:7]1[CH3:19].[H][H]>C(O)C.[Pd]>[NH2:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:3]([O:2][CH3:1])[C:4]=1[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([OH:16])[CH:14]=2)[CH2:9][CH2:8][N:7]1[CH3:19]
Reactant: [H][H]
Reactant: COc1cc2c(cc1O)C(Cc1c(OC)cccc1[N+](=O)[O-])N(C)CC2
Agent: [Pd]
Solvent: CCO
Product: COc1cc2c(cc1O)C(Cc1c(N)cccc1OC)N(C)CC2
Yield: 96.6 %

Procedure:
A mixture of the 1-(2'-methoxy-6'-nitrobenzyl)-2-methyl-6-methoxy-7-hydroxy-1,2,3,4-tetrahydroisoquinoline (3b) (1 g) and 5% palladium-charcoal (0.2 g) in absolute ethanol (150 ml) was shaken with hydrogen at room temperature and atmospheric pressure overnight (19 hours). The mixture was filtered through celite, and the filtrate was evaporated to dryness to leave a transparent brown oil. This crystallized from methanol-ether to give 1-(2'-amino-6'-methoxybenzyl)-2-methyl-6-methoxy-7-hydroxy-1,2,3,4-tetrahydroisoquinoline (4b) (0.885 g, 93%), mp 158°-160°. Recrystallization from absolute ethanol gave feathery needles, mp 161°-162°; λmaxKBr 2.88 and 2.96 μ (OH and NH2); λmaxEtOH (c) 285.5 nm (5480); nmr τ 3.02-3.87 (5H, aromatic H), 6.24 (6H, s, O--CH3), and 7.66 (3H, s, N--CH3); mass spectrum m/e 327 (M+ - 1), 296, 205, 192, 177, and 148.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1Br)([CH3:3])[CH3:2].C([Li])CCC.[CH2:18]([N:20]([CH2:24][CH3:25])[C:21](Cl)=[O:22])[CH3:19]>C(OCC)C>[CH:1]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C:21]([N:20]([CH2:24][CH3:25])[CH2:18][CH3:19])=[O:22])([CH3:3])[CH3:2]
Reactant: CCN(CC)C(=O)Cl
Reactant: COc1ccc(Br)c(C(C)C)c1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCN(CC)C(=O)c1ccc(OC)cc1C(C)C
Temperature: 0 °C
Reaction time: 5 h
Yield: 79.3 %

Procedure:
To a solution of 40.0 g (0.174 mol) of 2-isopropyl-4-methoxybromobenzene in 600 ml of diethyl ether at 0° C. was added 103.68 ml (0.175 mol) of a 1.69M solution of butyl lithium in diethyl ether. When the addition was complete the solution was cooled to 0° C. for one hour and stirred for an additional five hours at ambient temperature, then recooled to -78° C. and treated with a solution of 23.68 g (0.175 mol) of N,N-diethylcarbamyl chloride in 80 ml of diethyl ether. The resulting solution was stirred for about 12 hours while the reaction temperature was allowed to rise and then quenched with saturated ammonium chloride solution. The aqueous and organic layers were separated, the aqueous layer back extracted with ethyl acetate and the combined organic extracts washed once with brine, then dried and the solution taken to dryness to give a crude product which was flash chromatographed on silica gel, eluting with 30% ethyl acetate/hexane to give 34.4 g (79%) of 2-isopropyl-4-methoxy-N,N-diethylbenzamide as an oil which was used as such in the next step without further purification. The oil can be distilled, if desired, and boils at 123°-129/0.2-0.3 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([Cl:17])[CH:16]=1)[O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=O.[CH3:18][CH:19]([CH3:35])[C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:24]=1)=[O:21]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([Cl:17])[CH:16]=1)[O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH2:9][N:32]1[CH2:33][CH2:34][CH:29]([C:25]2[CH:24]=[C:23]([NH:22][C:20](=[O:21])[CH:19]([CH3:18])[CH3:35])[CH:28]=[CH:27][CH:26]=2)[CH2:30][CH2:31]1
Reactant: O=Cc1cccc(Oc2cc(Cl)cc(Cl)c2)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc(Oc4cc(Cl)cc(Cl)c4)c3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 3-(3,5-dichlorophenoxy)benzaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 497.2 (M+H)+.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)=[CH:10][C:9]([CH2:19][CH2:20][CH:21]=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:27][CH:26]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:23][O:24][C:25]1[CH:26]=[CH:27][C:28]([N:31]2[CH2:36][CH2:35][N:34]([CH2:21][CH2:20][CH2:19][C:9]3[CH:10]=[C:11]([C:12]4[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=4)[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=3)[CH2:33][CH2:32]2)=[CH:29][CH:30]=1
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: Cc1ccc(-c2cc(CCC=O)nn2-c2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N2CCN(CCCc3cc(-c4ccc(C)cc4)n(-c4ccccc4)n3)CC2)cc1

Procedure:
108 mg (78%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-5-p-tolyl-1H-pyrazol-3-yl)propanal (80 mg, 0.276 mmol), 1-(4-methoxyphenyl)piperazine (53 mg, 0.276 mmol), DIPEA (0.072 mL, 0.414 mmol) and NaBH(OAc)3 (175 mg, 0.828 mmol).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH3:9])[C:3]=1[F:10].C([Mg]Cl)(C)C.C(O[B:20]1[O:24][C:23]([CH3:26])([CH3:25])[C:22]([CH3:28])([CH3:27])[O:21]1)(C)C>O1CCCC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([B:20]2[O:24][C:23]([CH3:26])([CH3:25])[C:22]([CH3:28])([CH3:27])[O:21]2)=[C:3]([F:10])[C:4]=1[CH3:9]
Reactant: Cc1c(Cl)ccc(Br)c1F
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: Cc1c(Cl)ccc(B2OC(C)(C)C(C)(C)O2)c1F
Temperature: -10 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
To a stirred solution of 1-bromo-4-chloro-2-fluoro-3-methylbenzene (1.70 g, 7.61 mmol) in tetrahydrofuran (45 mL) cooled to −10° C. was added isopropylmagnesium chloride (2.9 M in THF) (3.0 mL, 8.75 mmol) dropwise. The reaction mixture was stirred at −10° C. for 1 h then allowed to warm to 0° C. and stirred for 1 h. The reaction mixture was cooled to −10° C. followed by the addition of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.785 mL, 8.75 mmol) dropwise. The reaction was allowed to warm to room temperature and stirred for 14 h. The reaction mixture was quenched with 1 N aqueous sodium hydroxide solution and stirred for 10 min. The pH of the reaction was adjusted to 3 with concentrated HCl and the solution was extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over sodium sulphate, and concentrated under reduced pressure to afford 2-(4-chloro-2-fluoro-3-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.75 g, 6.47 mmol, 85% yield) which was taken to the next step without purification. 1H NMR (400 MHz, CDCl3) δ 7.47 (m, 1H), 7.14 (d, J=8 Hz, 1H), 2.29 (d, J=2 Hz, 3H), 1.36 (s, 12H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH:10]([OH:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:23][C:24]1[CH:33]=[C:32]([O:34][CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)[CH:10]([O:21][CH2:23][C:24]2[CH:33]=[C:32]([O:34][CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:40])([CH3:42])[CH3:41])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1CN(Cc2ccccc2)CCC1c1ccc(F)cc1
Reactant: C[Si](C)(C)CCOCOc1cc(CCl)cc2ccccc12
Product: C[Si](C)(C)CCOCOc1cc(COC2CN(Cc3ccccc3)CCC2c2ccc(F)cc2)cc2ccccc12

Procedure:
In an analogous manner to that described in Example 1 (g), by alkylating (3RS,4RS)-1-benzyl-4-(4-fluoro-phenyl)-piperidin-3-ol with 2-chloromethyl-4-(β-trimethylsilylethoxymethoxy)-naphthalene there was obtained (3RS,4RS)-1-benzyl-4-(4-fluoro-phenyl)-3-[4-(2-trimethylsilyl-ethoxymethoxy)-naphthalen-2-ylmethoxy]-piperidine as a light yellow oil; MS: 572 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][C:10]2[CH:15]=[C:14]([CH3:16])[C:13]([OH:17])=[C:12]([CH3:18])[CH:11]=2)=[CH:4][C:3]=1[CH3:19].C[OH:21]>>[OH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]([C:10]2[CH:15]=[C:14]([CH3:16])[C:13]([OH:17])=[C:12]([CH3:18])[CH:11]=2)=[O:21])=[CH:4][C:3]=1[CH3:19]
Reactant: Cc1cc(Cc2cc(C)c(O)c(C)c2)cc(C)c1O
Reactant: CO
Product: Cc1cc(C(=O)c2cc(C)c(O)c(C)c2)cc(C)c1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 20 ml methanol was dissolved 500 mg/2.0 mmol of bis(4-hydroxy-3,5-dimethylphenyl)methane, and 886 mg/4.0 mmol of dicyanodichloroquinone was added to the solution at once in a stream of argon. After stirring at room temperature for 1 hour, the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate, and the insoluble matter was separated by filtration and re-concentrated. The resulting crude product was purified by silica gel column chromatography using methylene chloride for the eluting solution to obtain 230 mg of the desired 4,4'-dihydroxy-3,3',5,5'-tetramethylbenzophenone. MS: 270 (M+), 1H-NMR (CDCl3 /DMSO-d6): δ2.29 (12H, s), 7.41 (4H, s), 7.96 (2H, s).
Reaction SMILES: Cl[C:2]1[C:11]2[CH:10]=[C:9]3[N:12]=[CH:13][N:14]=[C:8]3[CH2:7][C:6]=2[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[Br:17][C:18]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:19]=1[NH2:20].Cl.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(OCCO)C>[Br:17][C:18]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:19]=1[NH:20][C:2]1[C:11]2[CH:10]=[C:9]3[N:12]=[CH:13][N:14]=[C:8]3[CH2:7][C:6]=2[N:5]=[CH:4][C:3]=1[C:15]#[N:16]
Reactant: N#Cc1cnc2c(c1Cl)C=C1N=CN=C1C2
Reactant: Nc1ccc(Cl)cc1Br
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOCCO
Product: N#Cc1cnc2c(c1Nc1ccc(Cl)cc1Br)C=C1N=CN=C1C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.8 %

Procedure:
A mixture of 0.25 g (1.10 mmol) of 8-chloroimidazo[4,5-g]quinoline-7-carbonitrile, 0.27 g (1.3 mmol) of 2-bromo-4-chloroaniline, and 0.13 g (1.12 mmol) of pyridine hydrochloride in 7.0 mL of 2-ethoxyethanol is heated at reflux temperature for 1 hour, cooled to room temperature, poured into a saturated solution of sodium bicarbonate and stirred for 0.5 hour. The solid is collected by filtration, washed with water and dried. The solid is purified by silica gel chromatography utilizing a gradient of methylene chloride/methanol (97:3 to 90:10) to yield 0.10 g of 8-(2-bromo-4-chloro-phenylamino)imidazo[4,5-g]quinoline-7-carbonitrile as an yellow solid, mp 244–246° C. (shrinks at 200° C.).
Reaction SMILES: [C:1]([CH2:3][S:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:6]=1[NH:15][C:16](=[O:18])[CH3:17])#[N:2].I([O-])(=O)(=O)=[O:20].[Na+].[K+].[Br-]>O1CCOCC1.O>[C:1]([CH2:3][S:4]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:12])([F:14])[F:13])=[CH:7][C:6]=1[NH:15][C:16](=[O:18])[CH3:17])=[O:20])#[N:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CC(=O)Nc1cc(C(F)(F)F)ccc1SCC#N
Agent: [Br-]
Agent: [K+]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)Nc1cc(C(F)(F)F)ccc1S(=O)CC#N
Temperature: 40 °C

Procedure:
A solution of N-(2-cyanomethylsulfanyl-5-trifluoromethylphenyl)acetamide(0.42 g) in dioxane (2.50 ml) was added dropwise to a stirred solution of sodium periodate (0.69 g) in a mixture of water (6 ml) and dioxane (1.50 ml) at ambient temperature. An additional amount of dioxane (2.50 ml) was added. The mixture was stirred at 40° C. for 6½ h, then at room temperature overnight. A precipitate was removed by filtration and washed on the filter with dichlorometane (20 ml). The two phases of the filtrate were shaken and separated. The aqueous phase was extracted with dichloromethane (2×10 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The more polar component of the residue was isolated by flash chromatography on silica gel eluted with 1) ether and 2) ethyl acetate to give a slowly crystallizing oil. Trituration with petroleum ether and subsequent drying gave white crystals. Yield 0.16 g (38%); mp 149-151° C.; 1H-NMR(CDCl3) δ (ppm): 9.9 (br, 1H), 8.70 (d, J=2 Hz, 1H), 7.68-7.46 (d+dd, J=8Hz and 8 Hz/2 Hz, 1H+1H), ABX-system at 4.13 (d, J=16 Hz, 1H) and 3.98 (d, J=16 Hz, 1H), 2.25 (s, 3H); 13C-NMR (DMSO-d6) δ (ppm): 170.1, 141.3, 135.8, 132.7 (q, J=32 Hz), 127.0, 123.5 (CF3, J=273 Hz), 123.1 (J=3.6 Hz), 122.0 (J=3.6 Hz), 113.3 (C≡N), 42.6 (CH2), 23.2 (CH3); IR (KBr) ν (cm−1): 3220 (NH), 2252 (C≡N), 1691 (C═O), 1532, 1476, 1337, 1273, 1176, 1128, 1033, 888, 675.
Reaction SMILES: [CH2:1]([C:3]1[C:9]([CH3:10])=[CH:8][C:6]([NH2:7])=[C:5]([N+:11]([O-])=O)[CH:4]=1)[CH3:2].[Sn](Cl)(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>CO>[CH2:1]([C:3]1[C:9]([CH3:10])=[CH:8][C:6]([NH2:7])=[C:5]([NH2:11])[CH:4]=1)[CH3:2]
Reactant: CCc1cc([N+](=O)[O-])c(N)cc1C
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCc1cc(N)c(N)cc1C
Temperature: 25 °C
Yield: 92.7 %

Procedure:
A stirred solution of 4-ethyl-5-methyl-2-nitro-aniline [484 mg, Reference Example 31(b)] in methanol (20 ml) was treated with tin chloride (5.09 g), then heated at reflux for 16 hours and then cooled to ambient temperature. The pH of the reaction mixture was adjusted to pH 8 by addition of aqueous sodium bicarbonate and then this mixture was extracted with ethyl acetate. The organic extracts were dried over magnesium sulfate and then evaporated to give 4-ethyl-5-methyl-phenylene diamine (374 mg) as an off-white solid. LC-MS (METHOD B): RT=1.80 minutes; 151.25 (M+H)+.