Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:17])=[C:3]([O:12][Si](C)(C)C)[O:4][CH2:5]CO[Si](C)(C)C.[C:18]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])(=[O:22])[C:19]([CH3:21])=[CH2:20].F[H-]F.CN([S+](N(C)C)N(C)C)C>C1COCC1>[C:3]([O:4][CH3:5])(=[O:12])[C:2]([CH3:17])=[CH2:1].[C:18]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])(=[O:22])[C:19]([CH3:21])=[CH2:20]
Reactant: CC(C)=C(OCCO[Si](C)(C)C)O[Si](C)(C)C
Agent: C=C(C)C(=O)OCCCC
Agent: CN(C)[S+](N(C)C)N(C)C
Agent: F[H-]F
Solvent: C1CCOC1
Product: C=C(C)C(=O)OC

Procedure:
Following the procedure of Example 26, hydroxyterminated methyl methacrylate (35%)n-butyl methacrylate (BMA) (65%) copolymer was prepared using the following amounts of materials: [(2-methyl-1-[2-(trimethylsiloxy)ethoxy]-1-propenyl)oxy]trimethylsilane, 0.51 g (1.85 mmol); MMA, 11 ml (103.7 mmol); BMA, 30 ml (188.5 mmol); tris(dimethylamino)sulfonium bifluoride, 20 mg (0.1 mmol); THF, 100 ml. Upon addition of the monomers the temperature rose to 48.6° from 20.6°. Evaporation of solvents and drying of the resultant residue gave 38.6 g of copolymer. GPC: Mn 22100, Mw 24500, D 1.11 (theor. Mw 20,215).
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.Cl.[NH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C([O-])([O-])=O.[K+].[K+]>CC#N.O.CO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[N:6]3[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:9]=[CH:10][C:5]3=[N:4][CH:3]=2)=[CH:26][CH:25]=1
Reactant: NCc1ccc(B(O)O)cc1
Reactant: Brc1cnc2ccc(NCCCc3ccccc3)nn12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: O
Solvent: CC#N
Product: NCc1ccc(-c2cnc3ccc(NCCCc4ccccc4)nn23)cc1
Temperature: 150 °C

Procedure:
A mixture of (3-bromo-imidazo[1,2-b]pyridazin-6-yl)-(3-phenyl-propyl)-amine (100 mg, 0.3 mmol), (4-aminomethylphenyl)boronic acid hydrochloride (67 mg, 0.36 mmol), K2CO3 (124 mg, 0.9 mmol) and dichlorobis(triphenylphosphine)palladium(II) (11 mg, 0.015 mmol) in MeCN/water (3.6 ml/0.9 ml) was heated in a microwave at 150° C. for 20 min. The reaction mixture was diluted with MeOH (2 ml) and filtered. The filtrate was subjected to preparative HPLC to give the titled compound as AcOH salt (29.9 mg). 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.93 (s, 3H) 1.99-2.09 (m, 2H) 2.70-2.80 (m, 2H) 3.41 (t, J=6.95 Hz, 2H) 4.14 (s, 2H) 6.74 (d, J=9.60 Hz, 1H) 7.15-7.29 (m, 5H) 7.53 (d, J=8.34 Hz, 2H) 7.64 (d, J=9.60 Hz, 1H) 7.80 (s, 1H) 8.24 (d, J=8.59 Hz, 2H).
Reaction SMILES: C(OI1(OC(=O)C)(OC(=O)C)C2C(=CC=CC=2)C(=O)O1)(=O)C.[CH3:23][O:24][C:25]([C:27]1[O:28][C:29]([CH3:34])=[C:30]([CH2:32][OH:33])[CH:31]=1)=[O:26].C(=O)(O)[O-].[Na+].O.O.O.O.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl.C(OCC)C>[CH3:23][O:24][C:25]([C:27]1[O:28][C:29]([CH3:34])=[C:30]([CH:32]=[O:33])[CH:31]=1)=[O:26]
Reactant: COC(=O)c1cc(CO)c(C)o1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: CCOCC
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1cc(C=O)c(C)o1
Temperature: 0 °C
Yield: 70.8 %

Procedure:
Acetic acid 1,1-diacetoxy-3-oxo-1λ5-ioda-2-oxa-indan-1-yl ester (Dess-Martin reagent) (549 mg, 1.293 mmoles) in dry dichloromethane was added to a solution of 4-hydroxymethyl-5-methyl-furan-2-carboxylic acid methyl ester (16) (200 mg, 1.176 mmoles) in dry dichloromethane (9 ml) with cooling to 0° C. under an argon atmosphere. After stirring for 20) minutes, the mixture was diluted with diethyl ether (40 ml) and was poured into saturated aqueous sodium bicarbonate (30 ml) containing sodium thiosulphate pentahydrate (4 g) and agitated vigorously for 5 minutes. The organic phase was washed with saturated aqueous sodium bicarbonate (40 ml), water (50 ml) and brine (50 ml) and dried. After removal of the solvent, the residue was purified by flash chromatography, using petrol/diethyl ether 4:1 v/v as eluent, to afford compound 157 (140 mg) as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:25]=1[C:31]1[C:35]([C:36](Cl)=[O:37])=[C:34]([CH3:39])[O:33][N:32]=1>>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:25]=1[C:31]1[C:35]([C:36]([O:1][CH2:2][CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:20])[CH3:21])[CH:12]=3)[CH2:7][CH2:6]2)=[O:37])=[C:34]([CH3:39])[O:33][N:32]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCO)CC2)c1
Reactant: Cc1onc(-c2c(F)cccc2Cl)c1C(=O)Cl
Product: Cc1onc(-c2c(F)cccc2Cl)c1C(=O)OCCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1

Procedure:
Prepared by Procedure Q1 and Scheme C2 (TEA) using N-{3-[1-(3-hydroxypropyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 3-(2-chloro-6-fluorophenyl)-5-methyl-4-isoxazolecarbonyl chloride: ESMS m/e: 542.2 (M+H)+.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[C:9](=[O:25])[O:10][C:11]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[C:12]=2[C:13]=1[CH3:14])(=O)=O.[C:26]1([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CC(OC)(C)C.C(O)(C)C>[CH3:24][O:23][C:15]1[C:12]2[C:13]([CH3:14])=[C:8]([CH2:7][CH2:6][N:35]3[CH2:36][CH2:37][N:32]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:33][CH2:34]3)[C:9](=[O:25])[O:10][C:11]=2[CH:18]=[C:17]([O:19][CH3:20])[C:16]=1[O:21][CH3:22]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: COc1cc2oc(=O)c(CCOS(C)(=O)=O)c(C)c2c(OC)c1OC
Solvent: CC(C)O
Solvent: COC(C)(C)C
Product: COc1cc2oc(=O)c(CCN3CCN(c4ccccc4)CC3)c(C)c2c(OC)c1OC
Yield: 49 %

Procedure:
Process B; starting materials: 3-[2-(methanesulphonyloxy)ethyl]-5,6,7-trimethoxy-4-methyl-2H-1-benzopyran-2-one (Example 34) and 1-phenylpiperazine; yield 49%; m.p. 136°-137° C. (from TBME/isopropanol).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([O:29][CH2:30][CH3:31])[C:17](N[C@H](C2C=CC=CC=2)CO)=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:33]>O.O1CCOCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C@H:16]([O:29][CH2:30][CH3:31])[C:17]([OH:18])=[O:33])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCO[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)N[C@@H](CO)c1ccccc1
Reactant: O=S(=O)(O)O
Solvent: O
Solvent: C1COCCO1
Product: CCO[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O

Procedure:
3-(4-Benzyloxyphenyl)-(S)-2-ethoxy-N-(2-hydroxy-(R)-1-phenylethyl)propanoic amide (8.9 g; 21.22 mmole) was hydrolyzed with concentrated sulfuric acid (27 ml) in water (104 ml) and dioxane (104 ml) at 90° C. for 5 hours. The reaction mixture was poured onto water (220 ml) and extracted with ethyl acetate. The organic phase was washed with brine, dried (sodium sulfate) and the solvent was evaporated in vacuo to give 6.85 g of a mixture of 3-(4-benzyloxyphenyl)-2-(S)-ethoxypropanoic acid and (S)-2-ethoxy-3-(4-hydroxyphenyl)-propanoic acid, which was used without further purification.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[CH2:6]([O:13][CH2:14][CH:15]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:16][NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C1COCC1>[CH2:6]([O:13][CH2:14][CH:15]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:16][N:17]([C:3](=[O:4])[CH2:2][Br:1])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(Br)CBr
Reactant: CC(C)(C)OC(=O)NC(CNCc1ccc(F)cc1)COCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(COCc1ccccc1)CN(Cc1ccc(F)cc1)C(=O)CBr
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Bromoacetyl bromide (588 μL, 6.75 mmol) was added slowly to a stirred solution of tert-butyl 2-(benzyloxy)-1-{[(4-fluorobenzyl)amino]-methyl}ethylcarbamate (2.39 g, 6.14 mmol) and triethylamine (941 μL, 6.75 mmol) in anhydrous THF (12 mL) at 0° C. under inert atmosphere. After stirring for 20 min, the reaction was poured into ice water and extracted twice with diethyl ether. The combined organic layers were washed twice with brine, dried over Na2SO4, and concentrated in vacuo. The resulting orange/brown oil was purified by silica gel chromatography (10% to 40% EtOAc/hexanes) to afford the title compound as a red-orange oil. 1H NMR (500 MHz, CDCl3) δ 7.40-7.21 (m, 6H), 7.16-6.96 (m, 3H), 5.20 (d, J=8.0 Hz, 1H), 5.01 (d, J=9.0 Hz, 1H), 4.75-4.66 (m, 1H), 4.59-4.48 (m, 2H), 4.39 (d, J=15.0 Hz, 1H), 4.04-3.92 (m, 2H), 3.87-3.28 (m, 4H), 1.43 (s, 9H). ES MS (M+1−100, for loss of BOC group)=409.4.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26]O)=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:13][CH2:12]1.CCN(CC)CC.CS(Cl)(=O)=O.[Na+].[I-].C([O-])([O-])=O.[Cs+].[Cs+].[NH:48]1[CH:52]=[N:51][N:50]=[N:49]1>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][N:48]3[CH:52]=[N:51][N:50]=[N:49]3)=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:13][CH2:12]1
Reactant: c1nnn[nH]1
Reactant: O=S(=O)(c1ccc(CO)cc1)C1CCN(CCc2ccc(F)cc2F)CC1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccc(Cn2cnnn2)cc1)C1CCN(CCc2ccc(F)cc2F)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-[2-(2,4-Difluorophenyl)ethyl]-4-(4-hydroxymethylphenylsulphonyl)piperidine (0.20 g, 0.51 mmol) was dissolved in anhydrous THF (10 ml) under nitrogen at 0° C. Et3N (0.14 ml, 1 mmol) and methanesulphonyl chloride (0.078 ml, 1 mmol) were added dropwise. The mixture was stirred at room temperature for 1 h, quenched with water and extracted into EtOAc. The organic extracts were combined, washed with water, dried (MgSO4) and solvent evaporated. The residue was dissolved in IPA (20 ml), and heated to reflux overnight with NaI (0.076 g), Cs2CO3 (0.197 g) and 1H-tetrazole (1.06 g, 15 mmol). The reaction mixture was cooled to room temperature and concentrated. The residue was partitioned between water and CH2Cl2 and the organic layer was washed with water, dried (MgSO4) and concentrated. Purification by column chromatography (SiO2; EtOAc:pet. ether 60-80° 1:1 to EtOAc:MeOH 99:1) gave the title compound, m.p. 168-169° C. (Found: C, 56.00; H, 4.91; N, 15.82. C21H23N5O2SF2 requires C, 56.36; H, 5.18; N, 15.63). δH (360 MHz, CDCl3) 1.64-1.77 (2H, m), 1.97-2.05 (4H, m), 2.48-2.53 (2H, m), 2.70-2.76 (2H, m), 2.86-2.95 (1H, m), 3.01-3.10 (2H, m), 5.71 (2H, s), 6.72-6.80 (2H, m), 7.08-7.15 (1H, m), 7.46 (2H, d, J 8 Hz), 7.91 (2H, d, J 8 Hz), 8.65 (1H, s).
Reaction SMILES: CCCCCC.Br[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:10][CH:9]=1.[CH2:21]([O:28][C@@H:29]1[C@@H:35]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@H:34]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C@@H:33]([CH2:52][O:53][CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[S:32][C:30]1([C:61]1[CH:66]=[CH:65][CH:64]=[C:63]([CH:67]=[O:68])[CH:62]=1)[OH:31])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:21]([O:28][C@@H:29]1[C@@H:35]([O:36][CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C@H:34]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C@@H:33]([CH2:52][O:53][CH2:54][C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)[S:32][C:30]1([C:61]1[CH:66]=[CH:65][CH:64]=[C:63]([CH:67]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:10][CH:9]=2)[OH:68])[CH:62]=1)[OH:31])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Brc1ccc(OC2CCOCC2)cc1
Reactant: O=Cc1cccc(C2(O)S[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC(c1ccc(OC2CCOCC2)cc1)c1cccc(C2(O)S[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75.3 %

Procedure:
2.6 M n-butylithium hexane solution (0.8 mL) was added to a mixture of 1-bromo-4-(4-tetrahydropyranyloxy)benzene (0.545 g, 2.12 mmol) and tetrahydrofuran (6 mL) at −78° C. After stirred for 1.5 hours, a tetrahydrofuran (8 mL) solution of 2,3,4,6-tetra-O-benzyl-1-C-(3-formylphenyl)-5-thio-D-glucopyranose (0.70 g, 1.06 mmol) was added and further stirred for three hours, and the reaction mixture was warmed to room temperature. After the reaction mixture was added with a saturated ammonium chloride aqueous solution and extracted with ethyl acetate, the organic phase was washed with brine and dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain 2,3,4,6-tetra-O-benzyl-1-C-[3-[(4-(4-tetrahydropyranyloxy)phenyl)(hydroxy)methyl]phenyl]-5-thio-D-glucopyranose (0.67 g, 76%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([O:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[C:12]([CH:15]=2)[C:13]#[N:14])[CH:5]=[CH:4][N:3]=1.O1CCOCC1.[CH3:29][O:30][CH2:31][CH2:32][CH2:33][N:34]1[CH:38]=[C:37]([NH2:39])[CH:36]=[N:35]1.C(N(CC)CC)C>C(O)C>[CH3:29][O:30][CH2:31][CH2:32][CH2:33][N:34]1[CH:38]=[C:37]([NH:39][C:2]2[N:7]=[C:6]([C:8]3[CH:9]=[CH:10][C:11]([O:16][CH:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[C:12]([CH:15]=3)[C:13]#[N:14])[CH:5]=[CH:4][N:3]=2)[CH:36]=[N:35]1
Reactant: N#Cc1cc(-c2ccnc(Cl)n2)ccc1OC1CCOCC1
Reactant: COCCCn1cc(N)cn1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: CCO
Product: COCCCn1cc(Nc2nccc(-c3ccc(OC4CCOCC4)c(C#N)c3)n2)cn1
Temperature: 100 °C
Reaction time: 48 h
Yield: 25.8 %

Procedure:
5-(2-Chloropyrimidin-4-yl)-2-(tetrahydropyran-4-yloxy)benzonitrile (200 mg) are dissolved in ethanol and dioxane in a 100 ml three-necked flask, and the 1-(3-methoxypropyl)-1H-pyrazol-4-ylamine (129 mg) prepared above and 0.8 ml of triethylamine are added. The yellow solution is stirred at 100° C. for two days. For work-up, the mixture is evaporated in a rotary evaporator and purified by chromatography, giving 71 mg of the desired product; HPLC-MS Rt. [min] 2.041; HPLC-MS [M+H] 435;
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[CH:16]=[C:15]([NH2:17])[C:14]([Cl:18])=[C:13]([Cl:19])[N:12]=1)=[O:10].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1COCC1>[NH2:17][C:15]1[CH:16]=[C:11]([C:9]2[O:10][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[N:8]=2)[N:12]=[C:13]([Cl:19])[C:14]=1[Cl:18]
Reactant: Nc1cc(C(=O)Nc2ccccc2O)nc(Cl)c1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Nc1cc(-c2nc3ccccc3o2)nc(Cl)c1Cl
Yield: 80.7 %

Procedure:
A solution of N-(2-hydroxyphenyl)-4-amino-5,6-dichloropyridine-2-carboxamide (1.80 g, 5.7 mmol) (obtained from N-(2-hydroxyphenyl)-2-(4,5,6-trichloro)pyridinecarboxamide via azide formation followed by sodium borohydride reduction) and p-toluenesulfonic acid (0.2 g) in toluene (50 mL) was refluxed overnight under nitrogen with a Dean-Stark trap. After cooling, the reaction mixture was diluted with ethyl acetate and THF, and the organic mixture washed with saturated aqueous sodium bicarbonate. The organic layer was dried, concentrated, and the residue triturated with petroleum ether/diethyl ether to provide 4-amino-2,3-dichloro-6-(2-benzoxazolyl)pyridine (1.30 g, 4.6 mmol). 1H NMR (DMSO-d6): δ 7.82 (d, 2H), 7.66 (s, 1H), 7.55-7.38 (m, 2H), 7.18 (br.s, 2H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:32][CH2:33][CH3:34])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:35](Cl)(=[O:39])[CH:36]([CH3:38])[CH3:37]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[N:12]=2)=[C:7]([O:32][CH2:33][CH3:34])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1
Reactant: CC(C)C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)C(C)C

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was reacted with isobutyryl chloride (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C33H37N2O2Cl2 [(M+H)+] 565.2383, observed 565.2384.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:28]([F:31])([F:30])[F:29])[CH:26]=2)[N:21]=[CH:20][CH:19]=1)[CH2:12][C:13]([O:15]CC)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-].Cl>CO.C1COCC1.O>[CH2:1]([O:8][C:9]([N:11]([C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:28]([F:31])([F:30])[F:29])[CH:26]=2)[N:21]=[CH:20][CH:19]=1)[CH2:12][C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CN(C(=O)OCc1ccccc1)c1ccnc2ccc(C(F)(F)F)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CN(C(=O)OCc1ccccc1)c1ccnc2ccc(C(F)(F)F)cc12

Procedure:
A solution of ethyl 2-(((benzyloxy)carbonyl)(6-(trifluoromethyl)quinolin-4-yl)amino)acetate (404 mg, 0.934 mmol, prepared in step E) in MeOH (15 mL) and THF (5 mL) and treated with a solution of LiOH (112 mg, 4.67 mol) in water (5 mL). After stirring at room temperature for xx hours, the pH was adjusted to ˜5 by the addition of aqueous HCl. After extraction with ethyl acetate, the organic layer was dried over Na2SO4 and concentrated in vacuo to yield the product.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[CH2:9])=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:19](Cl)([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:20]>C1C=CC=CC=1>[C:19]([O:1][CH2:2][CH2:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[CH2:9])=[CH:6][CH:5]=1)([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:20]
Reactant: CCOC(=O)C(=O)Cl
Reactant: C=Cc1ccc(CCO)cc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: C=Cc1ccc(CCOC(=O)C(=O)OCC)cc1
Temperature: 10 °C
Reaction time: 2 h

Procedure:
A 200 ml flask equipped with a stirrer, a thermometer and a dropping funnel was charged with 14.8 g (0.1 mol) of p-hydroxyethylstyrene, 150 ml of benzene and 10.1 g (0.1 mol) of triethylamine and cooled to 10° C. To the mixture was added dropwise with stirring 13.7 g (0.1 mol) of ethoxalyl chloride for one hour at 10° C. to precipitate a hydrochloride of triethylamine (white solid). After mixting at room temperature for 2 hours, 80 g of hexane was added to complete precipitation of the hydrochloride. The hydrochloride is removed by filteration and the resultant filtrate was condensed to obtain the aimed compound. The compound was identified by 1H NMR (360 Mz) and IR. ##STR7##
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12]2[CH:11]=[C:10]([C:13]([F:16])([F:15])[F:14])[CH:9]=[C:8]([C:17](O)=[O:18])[C:7]=2[CH:6]=[CH:5]1)[CH3:3].[NH2:20][CH2:21][C:22]1[C:23](=[O:30])[NH:24][C:25]([CH3:29])=[CH:26][C:27]=1[CH3:28].CN1CCOCC1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CS(C)=O>[CH3:28][C:27]1[CH:26]=[C:25]([CH3:29])[NH:24][C:23](=[O:30])[C:22]=1[CH2:21][NH:20][C:17]([C:8]1[C:7]2[CH:6]=[CH:5][N:4]([CH:2]([CH3:3])[CH3:1])[C:12]=2[CH:11]=[C:10]([C:13]([F:15])([F:16])[F:14])[CH:9]=1)=[O:18]
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: CC(C)n1ccc2c(C(=O)O)cc(C(F)(F)F)cc21
Agent: On1nnc2cccnc21
Solvent: CS(C)=O
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: Cc1cc(C)c(CNC(=O)c2cc(C(F)(F)F)cc3c2ccn3C(C)C)c(=O)[nH]1
Reaction time: 8 h
Yield: 65.4 %

Procedure:
To a solution of 1-(1-methylethyl)-6-(trifluoromethyl)-1H-indole-4-carboxylic acid (40 mg, 0.147 mmol) in dimethyl sulfoxide (1 mL) were added 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (41.7 mg, 0.221 mmol), N-methylmorpholine (0.065 mL, 0.590 mmol), 1-hydroxy-7-azabenzotriazole (40.1 mg, 0.295 mmol) and EDC (56.5 mg, 0.295 mmol), and the mixture was stirred overnight. The mixture was quenched with water (5 mL) and stirred for 10 min. The precipitate was collected by filtration and dried under high vacuum to give the title compound (39 mg, 63%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.47 (m, 6H), 2.13 (s, 3H), 2.23 (s, 3H), 4.36 (d, J=5.05 Hz, 2H), 4.99 (dt, J=13.20, 6.66 Hz, 1H), 5.89 (s, 1H), 6.98 (d, J=3.03 Hz, 1H), 7.68 (s, 1H), 7.86 (d, J=3.28 Hz, 1H), 8.08 (s, 1H), 8.45 (t, J=4.93 Hz, 1H), 11.56 (s, 1H). MS: (M+H)+=406.1.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([CH3:24])[C:8]=1[O:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)[NH2:5].[CH3:25][CH:26]([C:31](=O)[CH2:32][CH3:33])[C:27](OC)=[O:28].C1(C)C=CC(S(O)(=O)=O)=CC=1.O.C(=O)(O)[O-].[Na+]>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C>[CH2:32]([C:31]1[C:26]([CH3:25])=[C:27]([OH:28])[C:6]2[C:4](=[CH:3][C:2]([CH3:1])=[C:8]([O:9][CH2:10][CH2:11][CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:16][CH:15]=3)[C:7]=2[CH3:24])[N:5]=1)[CH3:33]
Reactant: Cc1cc(N)cc(C)c1OCCCOc1ccc(C(F)(F)F)cc1
Reactant: CCC(=O)C(C)C(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Solvent: O
Product: CCc1nc2cc(C)c(OCCCOc3ccc(C(F)(F)F)cc3)c(C)c2c(O)c1C
Yield: 91.6 %

Procedure:
A solution of 1.18 g of 3,5-dimethyl-4-(3-(4-trifluoromethylphenoxy)propoxy)aniline, 1.35 g of methyl 2-methyl-3-oxopentanoate, and 0.7 g of p-toluenesulfonic acid dissolved in 38 mL of xylene was heated under reflux for 7 hr. This reaction solution was cooled, and ethyl acetate and sodium bicarbonate water were added thereto, followed by separation. The ethyl acetate layer was washed with brine and was further concentrated under the reduced pressure to give 1.38 g of 2-ethyl-4-hydroxy-3,5,7-trimethyl-6-(3-(4-trifluoromethylphenoxy)propoxy)quinoline. Next, 1.38 g of the product thus obtained was added to 15 mL of dimethylacetamide, and 0.26 g of 60% sodium hydride and 0.6 g of methyl chloroformate were added thereto at room temperature. The reaction solution was stirred at room temperature for 2 hr, and ethyl acetate and distilled water were then added thereto. The organic layer was washed with brine and was concentrated under the reduced pressure. The crude product was purified by column chromatography on silica gel (BW300, manufactured by Fuji Sylysia Chemical Ltd., solvent: n-hexane/ethyl acetate) and was then recrystallized from n-hexane /ethyl acetate to give 1.13 g of 4-methoxycarbonyloxy-2-ethyl-3,5,7-trimethyl-6-(3-(4-trifluoromethylphenoxy)propoxy)quinoline (yield 72.2%).
Reaction SMILES: [ClH:1].[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])[C:9]([C:11]2[CH:12]=[C:13]3[N:19]=[C:18]([CH2:20][NH:21][C:22]4[CH:27]=[CH:26][C:25]([C:28](=[NH:30])[NH2:29])=[CH:24][CH:23]=4)[N:17]([CH3:31])[C:14]3=[N:15][CH:16]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C(OCC)(=O)C.C(O)C.N>>[ClH:1].[C:2]1([N:8]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])[C:9]([C:11]2[CH:12]=[C:13]3[N:19]=[C:18]([CH2:20][NH:21][C:22]4[CH:27]=[CH:26][C:25]([C:28](=[NH:29])[NH2:30])=[CH:24][CH:23]=4)[N:17]([CH3:31])[C:14]3=[N:15][CH:16]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCN(C(=O)c1cnc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Agent: Cl
Agent: N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cn1c(CNc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CCC(=O)O)c3ccccc3)cnc21
Yield: 80 %

Procedure:
Prepared analogously to Example 2 from 3-methyl-2-[N-(4-amidinophenyl)aminomethyl]imidazo[4,5-b]pyridin-6-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)amide hydrochloride and sodium hydroxide solution. Yield: 80% of theory, C25H25N7O3 (471.52); Rf value: 0.19 (silica gel; ethyl acetate/ethanol/ammonia=50:45:5); EKA mass spectrum: (M+H)+=472; (M+Na)+=494; (M+2Na)++=258.6.