Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=O)[C:7]3[C:15](=[O:16])[N:14]([C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=4)[N:13]=[C:12]([OH:24])[C:8]=3[NH:9][C:10]=2[CH:11]=1.FC(F)(F)C(O)=O.[BH4-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][C:7]3[C:15](=[O:16])[N:14]([C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=4)[N:13]=[C:12]([OH:24])[C:8]=3[NH:9][C:10]=2[CH:11]=1
Reactant: Cc1ccc(-n2nc(O)c3[nH]c4cc(Cl)ccc4c(=O)c3c2=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: Cc1ccc(-n2nc(O)c3c(c2=O)Cc2ccc(Cl)cc2N3)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 97.1 %

Procedure:
To a suspension of 7-chloro-4-hydroxy-2-(4′-methylphenyl)-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione (495 mg, 1.4 mmol) in tetrahydrofuran (25 mL) was added trifluoroacetic acid (4.5 ml, 58 mmol). The mixture was cooled to 0° C. with an ice bath and sodium borohydride (290 mg, 7.7 mmol) was added. The resulting solution was stirred at 0° C. for 15 minutes, the cooling bath removed, and the reaction mixture was allowed to warm to room temperature. This was then stirred at room temperature for 3 hours after which the reaction was diluted with cold water (65 mL) and stirred for an additional 10 minutes. After this time, the resulting white mixture was extracted with ethyl acetate (120 mL). The organic phase was washed with water (25 mL), brine (25 mL), dried over Na2SO4 and evaporated to dryness. The resulting residue was triturated and filtered twice from warm ethyl acetate/hexane (2:1, 15 mL) and ethyl acetate (6 mL). After drying, this afforded the title compound as a white solid (462 mg, 97%). MP=208-210° C. (d) MS(CI)340(m/e+1) NMR(d6-DMSO): 2.33(s,3H),3.79(s,2H), 6.92(dd,1H,J1=8.1Hz,J2=1.9Hz), 7.11(d,1H,J=8.2 Hz),7.24(app d, 3H), 7.43(d,2H,J=8.2Hz), 9.05(s,1H),11.99(s, 1H);
Reaction SMILES: [C:1]([CH2:3][C:4]1[N:5]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[S:7][CH:8]=1)#[N:2].C([Li])CCC.[CH3:20][N:21]1[C:25]([Cl:26])=[C:24]([C:27](Cl)=[O:28])[C:23]([Cl:30])=[N:22]1.Cl>C1COCC1>[CH3:20][N:21]1[C:25]([Cl:26])=[C:24]([C:27]([OH:28])=[C:3]([C:4]2[N:5]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[S:7][CH:8]=2)[C:1]#[N:2])[C:23]([Cl:30])=[N:22]1
Reactant: Cn1nc(Cl)c(C(=O)Cl)c1Cl
Reactant: N#CCc1csc(-c2ccccc2)n1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1nc(Cl)c(C(O)=C(C#N)c2csc(-c3ccccc3)n2)c1Cl
Temperature: -60 °C
Reaction time: 0.33 h

Procedure:
0.72 g of 4-cyanomethyl-2-phenylthiazole was dissolved in 10 ml of dry THF, and 4.6 ml of n-butyl lithium (1.56 M hexane solution) was dropwise added thereto at −60° C. or lower in an argon atmosphere. After the resulting product was stirred at −60° C. or lower for 20 minutes, 0.84 g of 1-methyl-3,5-dichloropyrazole-4-carbonyl chloride as dissolved in 3 ml of dry THF was dropwise added thereto at −60° C. or lower. Then, the resulting product was gradually heated, and stirred for 4 hours at room temperature. The reaction mixture was poured into ice water, acidified with diluted hydrochloric acid, extracted with ethyl acetate, and washed with saturated saline. The resulting product was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residual product was purified through silica gel column chromatography to obtain the intended product from the fraction eluted with chloroform. The resulting product was crystallized and washed with diethyl ether to obtain 0.8.6 g of 3-(1-methyl-3,5-dichloropyrazol-4-yl)-2-(2-phenylthiazol-4-yl)-3-hydroxyacrylonitrile.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[Se:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][CH:5]=1)[CH2:2][CH3:3].[Li][CH2:16]CCC.CI.[Cl-].[NH4+].N>C(OCC)C>[CH3:16][C:12]1[Se:11][C:10]([C:7]2[CH:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=2)=[CH:14][CH:13]=1
Reactant: CCCc1ccc(-c2ccc[se]2)cc1
Reactant: [Li]CCCC
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CI
Product: CCCc1ccc(-c2ccc(C)[se]2)cc1
Temperature: -70 °C
Reaction time: 3 h

Procedure:
3.0 g (12.0 mmol) of 2-(4-propylphenyl)selenophene are initially introduced in 30 ml of diethyl ether, and 9.4 ml (15.0 mmol, 15% soln. in hexane) of n-BuLi are metered in rapidly. The mixture is heated under reflux for 30 min and subsequently cooled to −70° C. 3.0 ml (48.2 mol) of methyl iodide are added in one portion, and the mixture is warmed to RT and stirred for 3 h. Sat. ammonium chloride soln. and conc. ammonia soln. are added, and the batch is stirred vigorously for a few minutes. The organic phase is separated off, and the aqueous phase is extracted with MTBE. The combined organic phases are washed with 2 N hydrochloric acid and sat. sodium chloride soln. and dried using sodium sulfate. The solution is concentrated to dryness, and the residue is purified by column chromatography (SiO2, n-heptane:EtOAc=20:1→10:1→5:1). The further purification is carried out by flash chromatography (SiO2 RP-18, ACN:water=9:1); 2-methyl-5-(4-propylphenyl)selenophene is obtained as a colourless solid (m.p. 31° C.).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([Cl:30])[N:3]=1.[CH3:31][O:32][C:33]1[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[CH:35][C:34]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O.O1CCOCC1>[Cl:30][C:4]1[N:3]=[C:2]([C:34]2[CH:35]=[CH:36][C:37]([C:39]([F:42])([F:41])[F:40])=[CH:38][C:33]=2[O:32][CH3:31])[C:11]2[C:6]([CH:5]=1)=[CH:7][C:8]([S:12]([N:15]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1)[C:16]1[S:17][CH:18]=[CH:19][N:20]=1)(=[O:14])=[O:13])=[CH:9][CH:10]=2
Reactant: COc1cc(C(F)(F)F)ccc1B(O)O
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Br)nc(Cl)cc3c2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4OC)nc(Cl)cc3c2)cc1
Temperature: 90 °C
Yield: 741.3 %

Procedure:
This reaction was conducted in two separate vials. For the first reaction, a vial was charged with 1-bromo-3-chloro-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (57.11 mg, 0.109 mmol), (2-methoxy-4-(trifluoromethyl)phenyl)boronic acid (25.1 mg, 0.114 mmol), Pd(AmPhos)2Cl2 (3.85 mg, 5.44 μmol), potassium phosphate (69.3 mg, 0.326 mmol), 1,4-dioxane (408 μl), and water (136 μl). The vial was flushed with Ar (g), then sealed and heated in a microwave reactor for 15 min at 90° C. A second vial was charged with 1-bromo-3-chloro-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (422 mg, 0.804 mmol), (2-methoxy-4-(trifluoromethyl)phenyl)boronic acid (186 mg, 0.844 mmol), Pd(AmPhos)2Cl2 (28.5 mg, 0.040 mmol), potassium phosphate (512 mg, 2.412 mmol), 1,4-dioxane (3015 μl), and water (1005 μl). The vial was flushed with Ar (g), then sealed and heated in a Biotage Initiator microwave reactor for 15 min at 90° C. The reaction mixtures from each vial were combined, and the combined mixture was extracted with EtOAc (3×). The combined organic extracts were concentrated, and the residue was purified by chromatography on silica gel (40-g column, 20 to 60% EtOAc/Heptane) to give 3-chloro-1-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (Intermediate RRR; 500.9 mg, 0.808 mmol, 89% yield) as an off-white foam: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm=8.15 (t, J=1.1 Hz, 1H), 7.77 (s, 1H), 7.68-7.65 (m, 2H), 7.50 (s, 1H), 7.44-7.38 (m, 2H), 7.30 (d, J=8.8 Hz, 2H), 7.27 (s, 1H), 7.04 (d, J=3.6 Hz, 1H), 6.73 (d, J=8.8 Hz, 2H), 5.11 (s, 2H), 3.76 (s, 3H), 3.73 (s, 3H); m/z (ESI) 620.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:11])[CH:3]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:8])=[C:4]([F:11])[CH:3]=1
Reactant: C1CCNC1
Reactant: O=C(O)c1ccc(Br)cc1F
Product: O=C(c1ccc(Br)cc1F)N1CCCC1

Procedure:
The sub-title compound was prepared by the method of example 18 step a) using 4-bromo-2-fluoro-benzoic acid and pyrrolidine.)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:8][C:9]1[N:14]=[C:13](Cl)[CH:12]=[C:11]([CH3:16])[N:10]=1.Cl.[OH-].[K+]>O>[C:2]1([NH:1][C:13]2[CH:12]=[C:11]([CH3:16])[N:10]=[C:9]([NH2:8])[N:14]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(Cl)nc(N)n1
Reactant: Nc1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(Nc2ccccc2)nc(N)n1
Yield: 34.5 %

Procedure:
Compound No. 45. (CNI-4594) A mixture of aniline (0.93 g) and 2-amino-4-chloro-6-methylpyrimidine (1.44 g) in 36 mL water was treated with 0.84 mL conc HCl and heated at reflux for 1 hr. Addition of 20 mL 1N KOH gave a light buff solid, which was filtered out, dried, and recrystallized from ethyl acetate/2-methoxyethanol and ethyl acetate/hexane to give 0.69 g 4-phenylamino-2-amino-6-methylpyrimidine, mp 179°-180° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[CH:16]=[C:17]([C:20]([OH:22])=O)[NH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[CH:4][CH:3]=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[CH:16]=[C:17]([C:20]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[O:22])[NH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: C1COCCN1
Reactant: Cc1onc(-c2ccc(F)cc2)c1/C=C/c1cc(C(=O)O)[nH]n1
Product: Cc1onc(-c2ccc(F)cc2)c1/C=C/c1cc(C(=O)N2CCOCC2)[nH]n1
Yield: 33 %

Procedure:
As described for example 131 (step 3), 5-{(E)-2-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-vinyl}-2H-pyrazole-3-carboxylic acid was converted, using morpholine instead of thiomorpholine S,S-dioxide, to the title compound (18 mg, 33%) which was obtained as an off white solid. MS: m/e=383.2 [M+H]+.
Reaction SMILES: [O:1]=[C:2]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.CC(O[CH:28](N(C)C)[N:29]([CH3:31])[CH3:30])(C)C>>[CH3:28][N:29]([CH3:31])[CH:30]=[C:3]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)[C:2](=[O:1])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: CC(C)(C)OC(=O)N1CCN(CC(=O)c2ccccc2)CC1
Product: CN(C)C=C(C(=O)c1ccccc1)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 55 °C

Procedure:
To the compound tert-butyl 4-(2-oxo-2-phenylethyl)piperazine-1-carboxylate (18 g) taken in round bottom flask, Bredereck's reagent (1 1.33 g) was added very slowly under nitrogen atmosphere. The reaction mixture was stirred at 55° C. for over-night. The progress of reaction was monitored by TLC. After consumption of starting material, diethyl ether was added to the reaction mixture. The resulting solid was filtered and dried under reduced pressure to afford tert-butyl 4-(1-(dimethylamino)-3-oxo-3-phenylprop-1-en-2-yl)piperazine-1-carboxylate as pure product.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:8]=[C:7]2[OH:20])([O-:3])=[O:2].[CH2:21]([N:23]([CH2:27][CH3:28])[C:24](Cl)=[O:25])[CH3:22].C(N(CC)CC)C>O1CCCC1.CN(C)C1C=CN=CC=1>[CH2:21]([N:23]([CH2:27][CH3:28])[C:24](=[O:25])[O:20][C:7]1[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:10]=[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=1)[CH3:22]
Reactant: CCN(CC)C(=O)Cl
Reactant: O=[N+]([O-])c1ccc2nc(-c3ccccc3)cc(O)c2c1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)Oc1cc(-c2ccccc2)nc2ccc([N+](=O)[O-])cc12
Yield: 77.7 %

Procedure:
The procedure is as in Example 70, starting with 6-nitro-2-phenyl-4-hydroxyquinoline (6 g) in tetrahydrofuran (60 cc), N,N-diethylcarbamoyl chloride (6.1 g), triethylamine (6.3 cc) and 4-dimethylaminopyridine (1.3 g). The residue is recrystallized twice in ethyl acetate. 6-Nitro-2-phenyl-4-quinolyl diethylcarbamate (6.4 g), m.p. 140° C., is thereby obtained.
Reaction SMILES: [ClH:1].[C:2]1(=[O:32])[N:6]([CH:7]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]3[CH:26]=[CH:25][C:20]([C:21](=[NH:24])OC)=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)[CH3:8])[C:5](=[O:27])[C:4]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:3]12.[NH3:33].CCOCC>CO>[ClH:1].[C:5]1(=[O:27])[N:6]([CH:7]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]3[CH:26]=[CH:25][C:20]([C:21]([NH2:33])=[NH:24])=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)[CH3:8])[C:2](=[O:32])[C:3]2=[CH:31][CH:30]=[CH:29][CH:28]=[C:4]12
Reactant: COC(=N)c1ccc(CCc2ccc(C(C)N3C(=O)c4ccccc4C3=O)cc2)cc1
Reactant: N
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CC(c1ccc(CCc2ccc(C(=N)N)cc2)cc1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 1.8 g of methyl 4-{2-[4-(1-phthalimidoethyl)phenyl]ethyl}benzimidate hydrochloride in 30 ml of anhydrous methanol, was added 2.3 ml of a solution of anhydrous ammonia in anhydrous methanol (0.036 g/ml). The mixture was stirred at room temperature for 15 hours. The reaction mixture was stripped of the solvent under reduced pressure. Ether was added to the residue and the precipitated crystals were collected by filtration to yield 1.6 g of 4-{2-[4-(1-phthalimidoethyl)phenyl]ethyl}benzamidine hydrochloride; m.p. 110°-115° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:3][CH:4]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)c1ccc(Br)cc1
Reactant: C1CNCCN1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(N2CCNCC2)cc1
Temperature: 100 °C
Yield: 48.1 %

Procedure:
1-Bromo-4-t-butylbenzene (2.38 mL, 14 mmol), piperazine (1.8 g, 21 mmol), sodium t-butoxide (1.95 g, 20.3 mmol) and dichlorobis(tri-o-tolylphosphine)palladium(II) (330.1 mg, 0.42 mmol) were dissolved in anhydrous toluene and reacted for 3 hours while heating at 100° C. After identifying complete disappearance of 1-bromo-4-t-butylbenzene by TLC, the reaction solution was filtered with celite. The filtrate was concentrated and purified by separation through column chromatography (CH2Cl2/MeOH, 1:1). A target compound (1.47 g, 6.732 mmol, 48.2%) was yielded.
Reaction SMILES: C[C:2]([C:4](=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=1[Cl:17])[C:5]([O:7][CH3:8])=[O:6])=O.C1(C)C=CC(S([CH2:27][N+:28]#[C-])(=O)=O)=CC=1.C[O-].[Na+].O>CO>[CH3:8][O:7][C:5]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=2[Cl:17])=[CH:27][NH:28][CH:2]=1)=[O:6]
Reactant: COC(=O)C(=Cc1cccc(Cl)c1Cl)C(C)=O
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1c[nH]cc1-c1cccc(Cl)c1Cl
Yield: 58 %

Procedure:
With stirring, 20 g of methyl α-methylcarbonyl-2,3-dichlorocinnamate are added at 0° C. to a 22 % by weight solution of (p-tolylsulfonyl)methyl isocyanide prepared according to Example P1 (a). Then 26.3 g of a 30% solution of sodium methylate in methanol are added dropwise over 2 hours. The mixture is stirred for 2 hours and then 35 ml of water are added dropwise. The reaction mixture is concentrated at +50° C. under vacuum. After addition of 70 ml of water, the reaction mixture is concentrated once more under vacuum and then filtered. The filter residue is washed with toluene and recrystallised from ethanol, affording 10.8 g (58% of theory) of 4-methoxycarbonyl-3-(2,3-dichlorophenyl)-pyrrole which melts at 200°-201° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[C:12]([CH:14]=[C:15](OCC)[NH:16][CH3:17])#[N:13]>>[C:12]([CH:14]=[C:15]([NH:16][CH3:17])[NH:11][CH2:10][CH2:9][S:8][CH2:7][C:6]1[NH:5][CH:4]=[N:3][C:2]=1[CH3:1])#[N:13]
Reactant: Cc1nc[nH]c1CSCCN
Reactant: CCOC(=CC#N)NC
Product: CNC(=CC#N)NCCSCc1[nH]cnc1C
Reaction time: 5 h

Procedure:
4-Methyl-5-[(2-aminoethyl)thiomethyl]imidazole (3.5 g) was added to a solution of 1-cyano-2-ethoxy-2-methylaminoethylene (3.1 g) and the solution was stirred for 5 hours at 100°. The product was chromatographed on a column of neutral alumina with elution by chloroform/ethyl acetate (1:1) to give the title compound as a glass.
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.Cl[CH2:13][CH2:14][C:15]([OH:17])=[O:16].Cl>O>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:7][CH:6]=1
Reactant: COc1ccc(O)cc1
Reactant: O=C(O)CCCl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(OCCC(=O)O)cc1
Yield: 18.1 %

Procedure:
Solid KOH 6.80 g, (0.122 mol) and H2O (10 ml) are added to para-methoxyphenol 7.0 g (0.0564 mol), the resultant mixture is stirred at the room temperature while 3-chloropropanoic acid (6.12 g, 0.0564 mol) is added to thereof. Then the mixture is stirred and heated to reflux for 3 h. The reaction solution is acidified to pH 2 by adding concentrated aqueous HCl and extracted with ether. The combined ether extracts is then washed with 10% aqueous NaHCO3 and acidified to pH 3-4 by adding concentrated aqueous HCl, and precipitate is formed. The residue is filtered and recrystallized by benzene to provide needle crystal 2.0 g. m.p.: 102-103° C., yield: 18.1%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[NH:11][CH2:12][CH2:13][CH2:14][OH:15].[H][H]>[Ni].C(O)C>[NH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[NH:11][CH2:12][CH2:13][CH2:14][OH:15]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cccc(Cl)c1NCCCO
Agent: [Ni]
Solvent: CCO
Product: Nc1cccc(Cl)c1NCCCO
Yield: 20 %

Procedure:
A mixture of 115 parts of 3-[(2-chloro-6-nitrophenyl)amino]-1-propanol and 400 parts of ethanol is hydrogenated at normal pressure and at room temperature with 12 parts of a Raney-nickel catalyst. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated, yielding 20 parts (20%) of 3-[(2-amino-6-chlorophenyl)amino]-1-propanol as a residue.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18].CCN(CC)CC>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[Br:11]
Reactant: OB(O)c1cccc(F)c1
Reactant: Oc1ccccc1Br
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Fc1cccc(Oc2ccccc2Br)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 47.9 %

Procedure:
To a stirred solution of 3-fluorophenylboronic acid (2.10 g, 15 mmol), 2-bromophenol (1.77 g, 10 mmol) and Cu(OAc)2 (0.93 g, 5 mmol) in anhydrous CH2Cl2 (25 mL) was added activated 4 Å molecular sieves (˜0.1 g), followed by anhydrous Et3N (3.5 mL, 25 mmol). The resulting dark green solution was stirred at rt for 48 h. The mixture was evaporated under reduced pressure and the residue was washed several times with Et2O (˜150 mL). The Et2O solution was washed with sat'd aq NH4Cl, and 1 N aq HCl. The organic layer was evaporated and the crude product was purified by flash column chromatography to give 1-(3-fluorophenoxy)-2-bromobenzene (1.28 g, 48%) as clear oil.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(O)(=O)/C=C/C(O)=O.[CH2:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:39][CH2:38][CH:37]1[CH2:46][CH:47]1[CH2:51][NH:50][CH:49]=[N:48]1>C1C=CC=CC=1>[CH2:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:39][CH2:38][CH:37]1[CH2:46][CH:47]1[CH2:51][N:50]([C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:49]=[N:48]1
Reactant: C1=NC(CC2CCc3ccccc3C2)CN1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: C1=NC(CC2CCc3ccccc3C2)CN1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 20 °C
Reaction time: 15 h

Procedure:
1.25 ml (9 mmol) of triethylamine and 2.36 g (8.50 mmol) of trityl chloride are added, in succession, at 20° C., to a solution of the compound obtained in Example 16 (Step 4) in the form of the free amine (1.80 g, 8.40 mmol) in 50 ml of benzene, under nitrogen. After stirring for 15 hours at 20° C., the mixture is washed with H2O, and the organic phase is dried and concentrated in vacuo to yield an oily residue. Chromatography on a chiral column, eluting with a solution of triethylamine in toluene (0.5%), allows the 4 isomers to be separated in the form of white solids.
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][C:11](=[O:32])[CH2:12][C:13]1[CH:14]=[CH:15][C:16]2[O:20][C:19]([C:21]([F:30])([F:29])[C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[F:24])=[N:18][C:17]=2[CH:31]=1.CI>O1CCCC1>[F:28][C:22]([F:27])([C:23]([F:24])([F:25])[F:26])[C:21]([F:30])([F:29])[C:19]1[O:20][C:16]2[CH:15]=[CH:14][C:13]([CH:12]([CH3:1])[C:11]([O:10][CH3:9])=[O:32])=[CH:31][C:17]=2[N:18]=1
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)Cc1ccc2oc(C(F)(F)C(F)(F)C(F)(F)F)nc2c1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C(C)c1ccc2oc(C(F)(F)C(F)(F)C(F)(F)F)nc2c1
Temperature: -70 °C
Reaction time: 1 h
Yield: 101.6 %

Procedure:
A solution of lithium diisopropylamide (2.0M solution in tetrahydrofuran/ethyl benzene/heptane, 15.32 ml, 0.0306 mol) was added dropwise to a solution of methyl(2-heptafluoropropylbenzoxazol-5-yl)acetate (11.0 g, 0.0306 mol) in tetrahydrofuran (175 ml) at −70° C. under a nitrogen atmosphere and the mixture was stirred at −70° C. for 1 hour. A solution of methyl iodide (39.1 g, 0.275 mol) in tetrahydrofuran (25 ml) was added dropwise and the mixture was stirred at −70° C. for a further 1 hour. The cooling bath was removed and the mixture was allowed to warm to room temperature over a period of 3 hours. The reaction was quenched with water, acidified with dilute aqueous hydrochloric acid and extracted with ethyl acetate. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated in vacuo to give methyl 2-(2-heptafluoropropylbenzoxazol-5-yl)propionate (11.6 g) as a reddish oil, which was used without further purification in the next step.