Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:10]=2[CH2:11][N:12]2[CH2:16][CH:15]([CH2:17][CH2:18][CH3:19])[CH2:14][C:13]2=[O:20])[CH:7]=1.[CH:25]1(B(O)O)[CH2:27][CH2:26]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.O.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.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:21]([C:9]1[C:10]([CH2:11][N:12]2[CH2:16][CH:15]([CH2:17][CH2:18][CH3:19])[CH2:14][C:13]2=[O:20])=[C:5]2[N:4]=[CH:3][C:2]([CH:25]3[CH2:27][CH2:26]3)=[CH:7][N:6]2[N:8]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CCCC1CC(=O)N(Cc2c(C(C)(C)C)nn3cc(Br)cnc23)C1
Reactant: OB(O)C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CCCC1CC(=O)N(Cc2c(C(C)(C)C)nn3cc(C4CC4)cnc23)C1
Temperature: 90 °C
Reaction time: 4 h
Yield: 29.2 %

Procedure:
To a solution of 1-[(6-bromo-2-tertbutylpyrazolo(1,5-a)pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one 190 (0.56 mmol, 1 eq, 0.2 g) in 5 ml of DME is added successively palladium-tetrakis-triphenylphosphine (0.019 mmol, 0.03 eq, 22 mg), cyclopropyl-boronic acid (0.727 mmol, 1.1 eq, 62 mg), and K3PO4 (1.98 mmol, 3 eq, 0.42 g) dissolved in 4 ml of water. The mixture is degassed and stirred vigorously at 90° C. for 4 hours. The solvent is removed under reduce pressure, water is added and the resulting mixture is extracted with dichloromethane. The organic phases are combined, washed with brine and dried over MgSO4. Volatiles are removed under reduce pressure. The crude product is purified by chromatography on silicagel (CH2Cl2/MeOH/NH4OH: 99/1/0.1) to afford 58 mg of pure 1-[(2-tert-butyl-6-cyclopropylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one 192 the compound in pure form.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH2:19][CH:18]([C:22]2[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=2[C:24]([O:26]C)=[O:25])[CH2:17]1.[OH-].[Na+]>CO>[O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH2:19][CH:18]([C:22]2[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=2[C:24]([OH:26])=[O:25])[CH2:17]1
Reactant: COC(=O)c1ccccc1C1CCCN(CCc2ccccc2N2CCCCC2=O)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccccc1C1CCCN(CCc2ccccc2N2CCCCC2=O)C1
Temperature: 80 °C
Yield: 99.6 %

Procedure:
Methyl 2-(1-{2-[2-(2-oxopiperidin-1-yl)phenyl]ethyl}piperidin-3-yl)benzoate a6-1 (0.35 g, 0.84 mmol, 1 eq) is dissolved in methanol (5 ml). NaOH 5N (0.84 ml, 4.20 mmol, 5 eq) is added and the mixture is heated at 80° C. for 16 h. The reaction mixture is concentrated under reduced pressure and the residue obtained is taken up in MeOH, filtered, and evaporated to afford 0.34 g of crude 2-(1-{2-[2-(2-oxopiperidin-1-yl)phenyl]ethyl}piperidin-3-yl)benzoic acid a6-5 which is used in the next step without further purification.
Reaction SMILES: [CH:1]([C@@H:3]([N:7]([CH3:15])[C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH:4]([CH3:6])[CH3:5])=O.C1(P(=[CH:35][C:36]#[N:37])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[C:36](/[CH:35]=[CH:1]/[C@@H:3]([N:7]([CH3:15])[C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH:4]([CH3:6])[CH3:5])#[N:37]
Reactant: CC(C)[C@@H](C=O)N(C)C(=O)OC(C)(C)C
Reactant: N#CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CC(C)[C@@H](/C=C/C#N)N(C)C(=O)OC(C)(C)C
Yield: 74.2 %

Procedure:
To a solution of tert-butyl (1S)-1-formyl-2-methylpropyl(methyl)carbamate (WO 99/32509) (500 mg, 202 mmol) in dicloromethane (5 mL) is added (triphenylphosphoranylidene)acetonitrile (700 mg, 2.32 mmol). After 1 h additional (triphenylphosphoranylidene)acetonitrile is added (350 mg, 1.16 mmol). After 24 h the reaction mixture is concentrated in vacuo and chromatographed (silica gel, hexane/ether) to give the title compound as an oil (410 mg). Analysis for C13H22N2O2: Calc'd: C, 65.52; H, 9.3; N 11.75. Found: C, 65.3; H, 9.05; N,11.51. MS (ES): m/z 239.1 (M+H)
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:8](=[O:16])[C:7]2[CH:17]=[N:18][CH:19]=[N:20][C:6]1=2)=[O:4].[CH3:21][NH:22][CH3:23]>C(O)C>[CH3:21][N:22]([CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:8](=[O:16])[C:7]2[CH:17]=[N:18][CH:19]=[N:20][C:6]1=2)=[O:4])[CH3:23]
Reactant: CNC
Reactant: O=C1Nc2ccccc2N(C(=O)CCl)c2ncncc21
Solvent: CCO
Product: CN(C)CC(=O)N1c2ccccc2NC(=O)c2cncnc21
Reaction time: 0.25 h

Procedure:
5.0 g (0.0174 mol) of 11-chloroacetyl-5,6-dihydropyrimido[4,5-b][1,5]benzodiazepin-5-one are added at 10° C. to 150 ml of a saturated solution of dimethylamine in absolute ethanol, the mixture is stirred for a further 15 minutes at the same temperature and the volatile constituents are then removed on a rotary evaporator. 50 ml of saturated sodium bicarbonate solution are added to the residue, the mixture is extracted several times with chloroform and the organic phase is dried and concentrated. The residue is recrystallized from 6:4 ethyl acetate/methylene chloride; yield: 2.2 g, m.p. 208° to 210° C.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][CH2:10][C:11]1[C:20]2[CH2:19][S:18][N:17]=[C:16]([NH:21]C(=O)OC(C)(C)C)[C:15]3=[N:29][N:30]([CH2:32][C:33]4[C:38]([CH3:39])=[C:37]([O:40][CH3:41])[C:36]([CH3:42])=[CH:35][N:34]=4)[N:31]=[C:13]([C:14]=23)[CH:12]=1.ClCCl>O1CCOCC1>[NH2:8][CH2:9][CH2:10][C:11]1[C:20]2[CH2:19][S:18][N:17]=[C:16]([NH2:21])[C:15]3=[N:29][N:30]([CH2:32][C:33]4[C:38]([CH3:39])=[C:37]([O:40][CH3:41])[C:36]([CH3:42])=[CH:35][N:34]=4)[N:31]=[C:13]([C:14]=23)[CH:12]=1
Reactant: COc1c(C)cnc(Cn2nc3cc(CCN)c4c-3c(n2)C(NC(=O)OC(C)(C)C)=NSC4)c1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1c(C)cnc(Cn2nc3cc(CCN)c4c-3c(n2)C(N)=NSC4)c1C
Temperature: 25 °C
Reaction time: 6 h
Yield: 69.2 %

Procedure:
Trifluoroacetic acid (0.5 ml) was added to a mixture composed of the above tert-butyl {8-(2-aminoethyl)-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-2,7-dihydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-4-yl}carbamate (17 mg) and dichloromethane (2 ml), and then the mixture was stirred at room temperature for six hours. The solvent in the reaction mixture was evaporated, and a 0.2 N sodium hydroxide solution was added to the resulting residue, followed by extraction with chloroform. The organic layer was dried over sodium sulfate and filtered, and then the solvent in the filtrate was evaporated under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (chloroform-methanol) to obtain an oil. The oil was dissolved in dioxane (0.5 ml), followed by lyophilization to obtain the title compound (9.4 mg) as an amorphous.
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[C:15]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[N:16][C:17]4[C:22]([C:23]=3[C:24]([OH:26])=O)=[CH:21][CH:20]=[C:19]([O:27][CH3:28])[C:18]=4[Br:29])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[C:67]1([C@@H:73]([NH2:76])[CH2:74][CH3:75])[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1>>[C:67]1([C@@H:73]([NH:76][C:24]([C:23]2[C:22]3[C:17](=[C:18]([Br:29])[C:19]([O:27][CH3:28])=[CH:20][CH:21]=3)[N:16]=[C:15]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:14]=2[CH2:13][N:10]2[CH2:11][CH2:12][CH:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH2:8][CH2:9]2)=[O:26])[CH2:74][CH3:75])[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1
Reactant: CC[C@H](N)c1ccccc1
Reactant: COc1ccc2c(C(=O)O)c(CN3CCC(N4CCCCC4)CC3)c(-c3ccccc3)nc2c1Br
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: CC[C@H](NC(=O)c1c(CN2CCC(N3CCCCC3)CC2)c(-c2ccccc2)nc2c(Br)c(OC)ccc12)c1ccccc1
Yield: 16.5 %

Procedure:
Prepared as described in Example 2 from 2 g (3.7 mmol) of 3-[1,4′]bipiperidinyl-1′-ylmethyl-8-bromo-7-methoxy-2-phenyl-quinoline-4-carboxylic acid (compound of Description 29), 1.55 ml (11.1 mmol) of triethylamine (TEA) 1.82 g (4.8 mmol) of O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumhexa-fluorophosphate (HBTU) and 0.75 g (5.5 mmol) of (S)-1-phenyl-propylamine The crude material was purified by flash column chromatography on 230-400 mesh silica gel, utilising a mixture of EtOAc/MeOH 95:5 containing 0.05% NH4OH (28%) affording 0.4 g of title compound. After trituration with iPr2O, 0.3 g of the title compound were recovered as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[C@@H:5]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]1=[O:16])[CH2:6][N+:7]([O-])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.O>O1CCCC1>[NH2:7][CH2:6][C@H:5]([C@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[OH:16])[C:4]1[CH:17]=[CH:18][C:19]([Cl:20])=[C:2]([Cl:1])[CH:3]=1
Reactant: O=C1CCCCC1[C@@H](C[N+](=O)[O-])c1ccc(Cl)c(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NC[C@@H](c1ccc(Cl)c(Cl)c1)[C@H]1CCCC[C@H]1O
Reaction time: 15 h

Procedure:
A solution of 28.5 g (0.09 mol) of rac-(2S*)-2-[(R*)-3,4-dichloro-α-(nitromethyl)benzyl]cyclohexanone in 500 ml of dry tetrahydrofuran is added dropwise to a suspension of 8.53 g (0.22 mol) of lithium aluminum hydride in 200 ml of dry tetrahydrofuran under argon so that temperature does not exceed 50°, whereupon the mixture is stirred at 50° for 15 hours. After cooling the reaction mixture is treated with tetrahydrofuran/water (1:1), the separated precipitate is filtered off under suction while washing with methylene chloride and the filtrate is evaporated. The thus-obtained oil is treated with 3N hydrochloric acid, whereupon the mixture is extracted twice with 500 ml of ether each time. The aqueous phase is made alkaline with 3N sodium hydroxide solution and extracted twice with 500 ml of methylene chloride each time. The organic phase is washed twice with 100 ml of water each time, dried over magnesium sulphate and evaporated. There is obtained a viscous oil which crystallizes from isopropyl ether/hexane. There is obtained rac-(1S*)-cis-2-[(R*)-α-(aminomethyl)-3,4-dichlorobenzyl]cyclohexanol in the form of colourless crystals of m.p. 117°-118°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:13][N:12]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:11](=[O:27])[C:10]=2[C:28](O)=[O:29])=[CH:5][CH:4]=1.[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:13][N:12]([CH2:23][CH:24]([CH3:25])[CH3:26])[C:11](=[O:27])[C:10]=2[C:28](=[O:29])[NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:5][CH:4]=1
Reactant: Nc1ccccc1
Reactant: COc1ccc(-c2nn(CC(C)C)c(=O)c(C(=O)O)c2-c2ccc(OC)cc2)cc1
Product: COc1ccc(-c2nn(CC(C)C)c(=O)c(C(=O)Nc3ccccc3)c2-c2ccc(OC)cc2)cc1
Yield: 89 %

Procedure:
Using 5,6-bis(4-methoxyphenyl)-4-carboxy-2-isobutyl-2H-pyridazin-3-one and aniline as starting materials, the procedures of Example 22 were repeated likewise, whereby the title compound was obtained in a yield of 89.0%.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:11]([CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH3:12])[CH:6]=[C:7]([O:9]C)[CH:8]=1.C(O)(=O)C.Br>O>[OH:2][C:3]1[CH:4]=[C:5]([CH:11]([CH2:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[CH3:12])[CH:6]=[C:7]([OH:9])[CH:8]=1
Reactant: COc1cc(OC)cc(C(C)CCCc2ccc(F)cc2)c1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: CC(CCCc1ccc(F)cc1)c1cc(O)cc(O)c1
Reaction time: 17 h

Procedure:
Fifty grams of the above prepared 2-(3,5-dimethoxyphenyl)-5-(4-fluorophenyl)pentane, 450 ml. of acetic acid and 180 ml. of 48% HBr in water were mixed. While cooling, the mixture was saturated with hydrogen bromide gas (approximately 1/2 hour). The reaction was placed in an 87° bath and stirred for 17 hours. The reaction was then concentrated in vacuo and the residue neutralized with K2CO3 and NaHCO3, extracted with ether, treated with charcoal and MgSO4 and filtered to yield 45 g. of 2-(3,5-dihydroxyphenyl)-5-(4-fluorophenyl)pentane as a brown oil which distills at 180°/0.01 mmHg.
Reaction SMILES: [NH2:1][CH:2]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[OH-].[Na+].[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(#N)C>[C:24]([NH:1][CH:2]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)CCCCC(N)c1ccc2ccccc2c1
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: CCOC(=O)CCCCC(NC(=O)c1ccccc1)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
While a solution (5 ml) of ethyl 6-amino-6-(2-naphthyl)hexanoate in acetonitrile (1.0 g) and a 1N aqueous solution of sodium hydroxide (4 ml) were vigorously stirred together under ice-cooling, benzoyl chloride (0.54 g) was added dropwise and the mixture was further stirred at room temperature for 1 hour. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The extract and the organic layer were combined, dried, and concentrated to provide ethyl 6-benzoylamino-6-(2-naphthyl)hexanoate (1.5 g).
Reaction SMILES: [C:1]([O:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])(OC(C)(C)C)=O.OC1[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:23]=[C:22]([CH3:30])[C:18]=1[C:19]([OH:21])=[O:20]>C(O)(C)(C)C.O1CCCC1>[C:12]([O:11][C:9]([O:8][C:1]1[C:25]([C:26]([F:27])([F:28])[F:29])=[CH:24][CH:23]=[C:22]([CH3:30])[C:18]=1[C:19]([O:21][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:20])=[O:10])([CH3:13])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: Cc1ccc(C(F)(F)F)c(O)c1C(=O)O
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: Cc1ccc(C(F)(F)F)c(OC(=O)OC(C)(C)C)c1C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 3 h
Yield: 87.2 %

Procedure:
N,N-Dimethylaminopyridine (0.7 g, 5.7 mmol) and di-tert-butyl dicarbonate [(tBuOCO)2O] (16.7 g, 76.5 mmol) were added to a solution of 2-hydroxy-6-methyl-3-(trifluoromethyl)benzoic acid (4.21 g, 19.1 mmol) obtained in Example (28-3) in a mixture of tert-butyl alcohol-tetrahydrofuran (2:1, 60 ml), and the mixture was stirred at 60° C. for 3 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=9/1) to give tert-butyl 2-[(tert-butoxycarbonyl)oxy]-6-methyl-3-(trifluoromethyl)benzoate (6.27 g, yield: 87%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2[CH:19]=[CH:18][C:11]3[C:12](O)=[N:13][S:14](=[O:16])(=[O:15])[C:10]=3[CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:20]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][NH2:32])=[CH:26][CH:25]=1)([CH3:23])([CH3:22])[CH3:21]>>[C:20]([C:24]1[CH:25]=[CH:26][C:27]([CH2:30][CH2:31][NH:32][C:12]2[C:11]3[CH:18]=[CH:19][C:8]([C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=4)=[CH:9][C:10]=3[S:14](=[O:16])(=[O:15])[N:13]=2)=[CH:28][CH:29]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: O=S1(=O)N=C(O)c2ccc(-c3ncccc3Cl)cc21
Reactant: CC(C)(C)c1ccc(CCN)cc1
Product: CC(C)(C)c1ccc(CCNC2=NS(=O)(=O)c3cc(-c4ncccc4Cl)ccc32)cc1

Procedure:
The title compound was prepared by reacting the product of Example 1B (0.1523 g, 0.52 mmol) and 2-(4-tert-butylphenyl)ethylamine (0.1210 g, 0.68 mmol) using the procedure as described in Example 1C. MS (ESI+) m/z 454 (M+H)+; (ESI−) m/z 452 (M−H)−; 1H NMR (300 MHz, CDCl3) δ 1.33 (s, 9H), 3.04 (t, J=7.0 Hz, 2H), 3.92 (q, J=6.6 Hz, 2H), 6.15 (s, 1H), 7.19 (m, 2H), 7.33 (dd,J=8.1, 4.7 Hz, 1H), 7.38 (m, 2H), 7.51 (d, J=7.8 Hz, 1H), 7.86 (dd, J=8.1, 1.0 Hz, 1H), 8.03 (dd, J=8.1, 1.4 Hz, 1H), 8.33 (d, J=1.4 Hz, 1H), 8.62 (dd, J=4.6, 0.8 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C(Cl)=O>CO>[Cl:1][C:2]1[C:3]([CH2:4][OH:5])=[CH:7][CH:8]=[C:9]([Cl:11])[N:10]=1
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CO
Product: OCc1ccc(Cl)nc1Cl
Temperature: 60 °C
Reaction time: 1 h
Yield: 70.1 %

Procedure:
To a solution of 2,6-dichloronicotinic acid (10 g) in MeOH (300 mL) was added oxalyl chloride (5.5 mL) dropwise at 0° C. The mixture was heated to 60° C. for a couple of hours until reaction complete. Upon concentration, the residue was dissolved in ether and added lithium aluminum hydride (2.3 g) slowly at 0° C. The reaction was stirred at 0° C. for 1 h and added water (2.3 mL) dropwise to quench excess lithium aluminum hydride. The resulting mixture was added 15% NaOH (2.3 mL) slowly, water (6.9 mL) and stirred at 0° C. for an additional 1 h. The slush solution was filtered through celite and washed with ether. The filtrate was concentrated to give the title compound (6.5 g).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C[O:12][C:13](=O)[CH2:14][C:15]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[O:17][C:16]=1[C:27]([F:30])([F:29])[F:28]>C1(C)C=CC=CC=1.O1CCCC1>[Cl:26][C:23]1[CH:22]=[CH:21][C:20]([C:18]2[O:17][C:16]([C:27]([F:28])([F:29])[F:30])=[C:15]([CH2:14][CH2:13][OH:12])[CH:19]=2)=[CH:25][CH:24]=1
Reactant: COC(=O)Cc1cc(-c2ccc(Cl)cc2)oc1C(F)(F)F
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OCCc1cc(-c2ccc(Cl)cc2)oc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
1.5 M Diisobutylaluminium hydride in toluene (0.8 ml) was added to a solution of methyl[5-(4-chlorophenyl)-2-(trifluoromethyl)-3-furyl]acetate (intermediate 86, 0.10 g) in tetrahydrofuran (5 ml) at 0° C. under nitrogen. The solution was allowed to stir thus for 2.5 hours then was quenched with methanol and allowed to warm to room temperature. Silica was added and the solvent was removed in vacuo. The crude product was purified using SPE (silica cartridge): the product was eluted using cyclohexane:ethyl acetate (5:1) and concentrated to form a colourless oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9](Cl)[C:8]=2[N:7]=[CH:6]1.[NH3:19]>CO>[NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:19])[C:8]=2[N:7]=[CH:6]1
Reactant: NCCCn1cnc2c(Cl)nc3ccccc3c21
Reactant: N
Solvent: CO
Product: NCCCn1cnc2c(N)nc3ccccc3c21

Procedure:
14 mg (0.0536 mmol) of 1-(3-aminopropyl)-4-chloro-1H-imidazo[4,5-c]quinoline, 5 ml of methanol and 3 ml of liquid ammonia were stirred in an autoclave overnight at 150° C. under heating. The reaction mixture was concentrated under reduced pressure and 0.3 ml of a 1N sodium hydroxide solution was added to the residue. The precipitate thus formed was collected by filtration to obtain 8 mg (0.0331 ml) of 1-(3-aminopropyl)-1H-imidazo[4,5-c]quinoline-4-amine shown below. ##STR38## The physicochemical data of this compound was in agreement with the compound of Example 5.
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]1[O:6][C@H:5]1[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.[NH3:16]>CO>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([C@@H:5]2[O:6][C@H:4]2[C:3]([NH2:16])=[O:2])=[CH:8][CH:9]=1
Reactant: N
Reactant: COC(=O)[C@@H]1O[C@H]1c1ccc(OC)cc1
Solvent: CO
Product: COc1ccc([C@@H]2O[C@H]2C(N)=O)cc1
Reaction time: 2 h

Procedure:
(2R,3S)-3-(4-Methoxyphenyl)-2,3-epoxypropionic acid methyl ester (10.4 g) is mixed with 15.3 wt % solution of ammonia in methanol (56 g), and the mixture is reacted at 15° C. for 2.5 hours. The mixture is concentrated under reduced pressure until the total weight of the mixture becomes 44 g. To the mixture is added ice-water (112 g), and the mixture is stirred for two hours under ice-cooling. The precipitated crystals are collected by filtration, washed with water, and dried at 50° C. to give (2R,3S)-3-(4-methoxyphenyl)-2,3-epoxypropionamide (8.99 g).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])=[CH:6][CH:7]=1.[OH:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>C(O)CCC>[OH:15][CH:16]1[CH2:21][CH2:20][N:19]([C:2]2[N:3]=[N:4][C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[Cl:14])=[CH:6][CH:7]=2)[CH2:18][CH2:17]1
Reactant: Clc1ccc(-c2ccccc2Cl)nn1
Reactant: OC1CCNCC1
Solvent: CCCCO
Product: OC1CCN(c2ccc(-c3ccccc3Cl)nn2)CC1

Procedure:
Operation is carried out in accordance with the methods mentioned for preparing 3-chloro-6-(2-chloro-phenyl)pyridazine (m.p.: 146°-147° C.). 5 g of this product are dissolved in 120 ml of normal butanol and mixed with 6.74 g of 4-hydroxy-piperidine, then heated to reflux. By following the modus operandi described for the previous Example, 5 g of CM 40907 are obtained after recrystallization in absolute ethanol.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6](Cl)=[N:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([C:21]#[N:22])=[CH:10][C:9]=2[CH3:23])=[O:4].[CH2:25]([NH:27][CH3:28])[CH3:26]>>[C:21]([C:11]1[CH:12]=[C:13]2[C:8](=[C:9]([CH3:23])[CH:10]=1)[N:7]=[C:6]([N:27]([CH2:25][CH3:26])[CH3:28])[C:5]([C:3]([OH:2])=[O:4])=[C:14]2[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)#[N:22]
Reactant: COC(=O)c1c(Cl)nc2c(C)cc(C#N)cc2c1-c1ccccc1
Reactant: CCNC
Product: CCN(C)c1nc2c(C)cc(C#N)cc2c(-c2ccccc2)c1C(=O)O

Procedure:
The title compound was prepared in analogy to example 60 step C from 2-chloro-6-cyano-8-methyl-4-phenyl-quinoline-3-carboxylic acid methyl ester (prepared as described in example 60 step B) and ethyl-methyl-amine. Off-white solid. MS (ESI): 346.2 (M+H)+.
Reaction SMILES: [Cu][C:2]#N.C[Li].C(OCC)C.Br[CH2:12][C:13]1[C:17]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=2)=[N:16][N:15]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)[N:14]=1>O1CCCC1>[CH2:12]([C:13]1[C:17]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=2)=[N:16][N:15]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)[N:14]=1)[CH3:2]
Reactant: FC(F)(F)Oc1cccc(Oc2nn(-c3ccc(C(F)(F)F)cc3)nc2CBr)c1
Reactant: N#C[Cu]
Agent: [Li]C
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCc1nn(-c2ccc(C(F)(F)F)cc2)nc1Oc1cccc(OC(F)(F)F)c1
Temperature: 0 °C

Procedure:
To a suspension of copper(I) cyanide (0.037 g, 0.41 mmol) in anhydrous tetrahydrofuran (2 mL) at −78° C. under a nitrogen atmosphere was added a solution of methyllithium in diethyl ether (1.6 M, 0.54 mL, 0.86 mmol). The mixture was stirred at 0° C. until a clear, colorless solution formed, and then the solution was cooled back to −78° C. To the methylcuprate solution was added a solution of 4-(bromomethyl)-5-[3-(trifluoromethoxy)phenoxy]-2-[4-(trifluoromethyl)phenyl)-2H-1,2,3-triazole (i.e. the product of Example 6, Step A, 0.100 g, 0.21 mmol) in anhydrous tetrahydrofuran (4 mL). The mixture was stirred for 1 h. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (5 mL) and stirred vigorously at 23° C. until the solution turned deep blue in color. The reaction mixture was extracted with ethyl acetate (2×10 mL). The organic layer was dried (MgSO4) and concentrated under reduced pressure to afford the crude product which was purified by chromatography on silica gel eluting with 0 to 10% ethyl acetate in hexanes to obtain the title compound (0.038 g) as a clear, colorless oil.