Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([C:18]2[O:19][C:20]([C:23]3[N:28]=[CH:27][C:26]([C:29]([O:31]C)=[O:30])=[CH:25][CH:24]=3)=[CH:21][N:22]=2)=[O:17])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-].Cl>C1COCC1.O.CCOC(C)=O>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][C:16]([C:18]2[O:19][C:20]([C:23]3[N:28]=[CH:27][C:26]([C:29]([OH:31])=[O:30])=[CH:25][CH:24]=3)=[CH:21][N:22]=2)=[O:17])=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(-c2cnc(C(=O)CCc3ccc(Oc4ccccc4)cc3)o2)nc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(-c2cnc(C(=O)CCc3ccc(Oc4ccccc4)cc3)o2)nc1
Yield: 57.5 %

Procedure:
Methyl 6-(2-(3-(4-phenoxyphenyl)propanoyl)oxazol-5-yl)pyridine-3-carboxylate (57 mg, 0.13 mmol) was dissolved in THF/H2O (3:2, 7.5 mL) and LiOH (10 mg, 0.40 mmol) was added. The reaction solution was stirred at room temperature under an atmosphere of Ar for 2 h before the addition of 1 N HCl to adjust the solution to an acidic pH to quench the reaction. The reaction solution was diluted with EtOAc and the organic and aqueous layers were separated. The aqueous layer was extracted with EtOAc (3×). The organic phases were combined and washed with saturated aqueous NaCl, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 1% AcOH/EtOAc) to provide 6-(2-(3-(4-phenoxyphenyl)propanoyl)oxazol-5-yl)pyridine-3-carboxylic acid as a light tan solid (31 mg, 56%): 1H NMR (THF-d8, 600 MHz) δ 9.18 (s, 1H), 8.41 (dd, 1H, J=8.4, 1.8 Hz), 7.98 (s, 1H), 7.97 (d, 1H, J=8.4 Hz), 7.30-7.25 (m, 4H), 7.03 (t, 1H, J=7.8 Hz), 6.94 (d, 2H, J=7.8 Hz), 6.91 (d, 2H, J=8.4 Hz), 3.42 (t, 2H, J=7.8 Hz), 3.04 (t, 2H, J=7.8 Hz); 13C NMR (CDCl3, 150 MHz) δ 187.3, 166.2, 159.7, 158.9, 156.7, 153.7, 152.4, 150.5, 139.4, 137.1, 130.7, 130.6, 129.3, 127.6, 123.8, 120.3, 120.0, 119.4, 41.7, 29.8; HR ESI-TOF m/z 415.1284 (M+H+, C24H18N2O5, requires 415.1288).
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:23][CH:22]=[C:21]([C:24]([OH:26])=O)[CH:20]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.Cl.Cl.[CH3:60][N:61]([CH3:77])[CH:62]1[CH2:66][CH2:65][N:64]([CH2:67][C:68]2[CH:73]=[CH:72][C:71]([CH2:74][NH:75][CH3:76])=[CH:70][CH:69]=2)[CH2:63]1>C(Cl)Cl>[CH:1]1([N:4]([CH2:18][C:19]2[O:23][CH:22]=[C:21]([C:24]([N:75]([CH2:74][C:71]3[CH:70]=[CH:69][C:68]([CH2:67][N:64]4[CH2:65][CH2:66][CH:62]([N:61]([CH3:60])[CH3:77])[CH2:63]4)=[CH:73][CH:72]=3)[CH3:76])=[O:26])[CH:20]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:2][CH2:3]1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2cc(C(=O)O)co2)C2CC2)c(C)c1
Reactant: CNCc1ccc(CN2CCC(N(C)C)C2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N(Cc2cc(C(=O)N(C)Cc3ccc(CN4CCC(N(C)C)C4)cc3)co2)C2CC2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BH using 5-({cyclopropyl[(4-methoxy-2,6-dimethylphenyl)sulfonyl]amino}methyl)furan-3-carboxylic acid (40 mg, 0.105 mmol), EDCI (29 mg, 0.15 mmol), HOBt (22 mg, 0.16 mmol), DIPEA (0.04 mL, 0.22 mmol), N,N-dimethyl-1-{4-[(methylamino)methyl]benzyl}pyrrolidin-3-amine trihydrochloride (34 mg, 0.13 mmol) and DCM (10 mL).
Reaction SMILES: I[C:2]1[C:10]2[C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[N:8][C:7]([CH3:17])=[N:6][C:5]=2[N:4]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:3]=1.[C:26]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)#[N:27].C(=O)([O-])[O-].[K+].[K+]>C(O)C.O.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>[CH3:17][C:7]1[N:8]=[C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:10]2[C:2]([C:32]3[CH:33]=[C:28]([CH:29]=[CH:30][CH:31]=3)[C:26]#[N:27])=[CH:3][N:4]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:5]=2[N:6]=1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: Cc1nc(N2CCOCC2)c2c(I)cn(COCC[Si](C)(C)C)c2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Cc1nc(N2CCOCC2)c2c(-c3cccc(C#N)c3)cn(COCC[Si](C)(C)C)c2n1
Temperature: 90 °C

Procedure:
To a solution of 5-iodo-2-methyl-4-(morpholin-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (C24) (100 mg, 0.21 mmol), (3-cyanophenyl)boronic acid (62 mg, 0.42 mmol) and potassium carbonate (100 mg, 0.72 mmol) in a mixture of ethanol and water (4:1, 5 mL) was added dichlorobis(triphenylphosphine)palladium (15 mg, 21 μmol). The reaction mixture was degassed and purged with nitrogen; this procedure was carried out a total of three times. After the reaction mixture had heated at 90° C. for 3 hours, it was allowed to cool and concentrated in vacuo. Purification via preparative thin layer chromatography (Eluent: 1:1 petroleum ether/ethyl acetate) provided the product as a yellow oil. Yield: 52 mg, 0.12 mmol, 57%. LCMS m/z 451.3 [M+H+].
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH:12]=[CH:11][C:10]=1[CH:23]1[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:30]([NH2:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C[N+](C)(C)C.[OH-].[Na+]>ClCCCl>[CH2:30]([NH:37][C@H:26]1[CH2:27][CH2:28][C@@H:23]([C:10]2[CH:11]=[CH:12][C:13]([O:15][Si:16]([C:19]([CH3:21])([CH3:22])[CH3:20])([CH3:17])[CH3:18])=[CH:14][C:9]=2[O:8][Si:1]([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:2])[CH3:3])[CH2:24][CH2:25]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C2CCC(=O)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C[N+](C)(C)C
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@@H](NCc3ccccc3)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Reaction time: 2.5 h

Procedure:
To a round bottomed flask equipped with magnetic stirrer was loaded 4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexanone (3.20 g, 7.36 mmol). Anhydrous 1,2-dichloroethane (85 ml) was added, and to the stirred solution was added benzylamine (0.97 ml, 8.83 mmol) as a solution in 1,2-dichloroethane (20 ml). Activated powdered 4 Å molecular sieves (5.80 g) were added and the reaction mixture stirred vigorously for 2.5 hr. Tetramethylammoniumtriacetoxyborohydride (2.90 g, 11.0 mmol) was added in one portion and the reaction mixture stirred for 64 hr at room temperature. Aqueous sodium hydroxide solution (30 ml, 0.4M) was added and vigorous stirring was continued for 0.5 hr. The reaction mixture was then filtered through celite, washing with dichloromethane (100 ml). The layers were separated and the aqueous layer was extracted with dichloromethane (2×50 ml). The combined organic phases were washed with brine (100 ml), dried over magnesium sulfate, filtered and concentrated in vacuo affording the crude product. Purification via flash column chromatography (SiO2, ethyl acetate/petroleum ether, gradient elution using 1:9, 1:4, then 3:7 v/v) furnished the title product (2.69 g, 70%) as a pale yellow oil. δH(CDCl3) 0.01 (6H, s), 0.05 (6H, s), 0.77 (9H, s), 0.83 (9H, s), 1.31 (1H, br), 1.39 (4H, m), 1.52 (2H, m), 1.70 (2H, m), 2.69 (1H, m), 2.75 (1H, m), 6.10 (1H, d), 6.23 (1H, dd), 6.84 (1H, d), 7.15 (5H, m).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([CH:7]=O)[C:4]([CH:9]=[O:10])=[CH:3][CH:2]=1.[C:11]([C:16]1[CH:21]=[CH:20][C:19]([N:22]=C=O)=[CH:18][CH:17]=1)([O:13][CH2:14][CH3:15])=[O:12]>>[O:10]=[C:9]1[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[CH2:7][N:22]1[C:19]1[CH:18]=[CH:17][C:16]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1ccc(N=C=O)cc1
Reactant: O=Cc1ccccc1C=O
Product: CCOC(=O)c1ccc(N2Cc3ccccc3C2=O)cc1
Temperature: 170 °C

Procedure:
A mixture of o-phthalicdicarboxaldehyde (17.54 g, 0.131 mol) and p-carbethoxyphenylisocyanate (25.0 g, 0.131 mol) is heated in an oil bath at 170° C. for 4.0 hours under nitrogen atmosphere. The hot melt is then slowly poured into CHC13 (300 ml). The solution is then evaporated to dryness when a solid residue is obtained. The crude 4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)benzoic acid, ethyl ester is triturated with isopropyl ether and then recrystallized from CH2Cl2 - isopropyl ether (1:1, 300 ml) to give white solid. Yield 5.07 g (13.8%); mp 182°-184° C.
Reaction SMILES: [Cl:1](O)(=O)(=O)=O.[S:6]1[CH:10]=[CH:9][N:8]2[CH2:11][CH:12]([C:14]3[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=3)[NH:17]C(=O)C)[N:13]=[C:7]12.[ClH:24]>>[ClH:1].[ClH:24].[NH2:17][C:16]1[CH:15]=[C:14]([CH:12]2[CH2:11][N:8]3[C:7]([S:6][CH:10]=[CH:9]3)=[N:13]2)[CH:23]=[CH:22][CH:21]=1
Reactant: CC(=O)Nc1cccc(C2CN3C=CSC3=N2)c1
Reactant: [O-][Cl+3]([O-])([O-])O
Agent: Cl
Product: Nc1cccc(C2CN3C=CSC3=N2)c1

Procedure:
A 2.80 g. (00078 mole) portion of 3'-(5,6-dihydroimidazo[2,1-b]thiazol-6-yl)acetanilide perchlorate (Example 7) is converted to the free base and then dissolved in 15 ml. of 6N hydrochloric acid. The solution is stirred at reflux for 1.6 hours and then evaporated at reduced pressure. The residue is azeotroped with 2-propanol and crystallized from 95% ethanol/2-propanol to give 1.69 g. (75%) of crystalline product, melting point 242°-244° C. Anal. Calcd, for C11H13Cl2N3S: C, 45.54; H, 4.52; Cl, 24.43; N, 14.48; S. 11.05. Found: C, 45.39; H, 4.66; Cl, 24.26; N, 12.27; S, 10.83.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:12]O)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][O:10][CH3:11].N1C=CC=CC=1.S(Cl)([Cl:22])=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:12][Cl:22])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][O:10][CH3:11]
Reactant: COCOc1ccc(CO)cc1Br
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COCOc1ccc(CCl)cc1Br
Reaction time: 1 h

Procedure:
(3-Bromo-4-methoxymethoxy-phenyl)-methanol (250 mg) was dissolved in DCM (20 mL), pyridine (0.15 mL) was added followed by thionyl chloride (0.15 mL), and the mixture was stirred for 1 hour. The mixture was partitioned with water and ethyl acetate. The solvent removal gave 2-bromo-4-chloromethyl-1-methoxymethoxy-benzene as a clear oil, which was used directly in next step. The oil was dissolved in acetone, and sodium iodide (300 mg) was added. The mixture was stirred overnight and a yellow precipitate was formed. Extraction with ethyl acetate and water gave 2-iodo-4-chloromethyl-1-methoxymethoxy-benzene as a brown oil that turned into solid after standing. 1HNMR (CDCl3, 300 MHz): 7.58 (d, J=2.0 Hz, 1H), 7.25 (dd, J=2.0, 8.5 Hz, 1H), 7.07 (d, J=8.5 Hz, 1H), 5.25 (s, 2H), 4.39(s, 2H), 3.51 (s, 3H) ppm. The iodide (170 mg) and trimethylphosphate (0.1 mL) were mixed and stirred at 120° C. for 1 hour. After cooling to room temperature, the reaction mixture was directly applied to silica gel column eluting with 5% MeOH in DCM to yield 150 mg of the corresponding phosphonate.
Reaction SMILES: CO.[OH-].[K+].[Br:5][C:6]([Br:26])=[C:7]([C:17]1[CH:22]=[CH:21][C:20]([O:23]C#N)=[CH:19][CH:18]=1)[C:8]1[CH:13]=[CH:12][C:11]([O:14]C#N)=[CH:10][CH:9]=1.Cl>O>[Br:5][C:6]([Br:26])=[C:7]([C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[C:8]1[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=1
Reactant: N#COc1ccc(C(=C(Br)Br)c2ccc(OC#N)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Oc1ccc(C(=C(Br)Br)c2ccc(O)cc2)cc1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
A 4-necked 5-liter flask, equipped with a mechanical stirrer, a thermometer, and a condenser, is charged with methanol (800 g). Potassium hydroxide (440 g) is added in portions to the methanol solution. After the addition, the solution is cooled to 20° C. To this stirring solution, 1,1,1-tribromo-2,2-(4-hydroxyphenyl)ethane (420 g) is added in portions. The reaction temperature is kept below 40° C. After the addition, the temperature is raised to 50° C. and kept for 2 hours. The reaction mixture is cooled to room temperature and neutralized with 25% HCl solution. After the neutralization, the mixture is heated to reflux and water is added. The mixture is allowed to cool to the room temperature. The precipitates formed are filtered and dried to afford 1,1-dibromo-2,2-bis(4-hydroxyphenyl)ethene.
Reaction SMILES: Cl[S:2]([N:5]=C=O)(=[O:4])=[O:3].C(O)=O.[NH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Br:22])[CH:18]=2)[CH:13]=1.C(OCC)(=O)C>C1C=CC=CC=1>[Br:22][C:17]1[CH:16]=[CH:15][C:14]2[C:19](=[CH:20][CH:21]=[C:12]([NH:11][S:2](=[O:4])(=[O:3])[NH2:5])[CH:13]=2)[CH:18]=1
Reactant: Nc1ccc2cc(Br)ccc2c1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: O=CO
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: NS(=O)(=O)Nc1ccc2cc(Br)ccc2c1
Temperature: 25 °C
Reaction time: 19.5 h

Procedure:
A solution of chlorosulfonyl isocyanate (870 μl, WAKO) in benzene (10 ml) was added dropwise with formic acid (377 μl, WAKO) under ice cooling, warmed to room temperature, stirred and for 19.5 hours, then warmed to 40° C., and further stirred for 4 hours. The reaction mixture was added dropwise with a solution of 2-amino-6-bromonaphthalene (443 mg) in benzene (5 ml) under ice cooling, warmed to room temperature, and stirred 21.5 hours. The reaction mixture was filtered to obtain solid, and the solid was added with ethyl acetate, mixed and filtered again. The solvent of the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography (Quad, hexane:ethyl acetate=2:1) to obtain the title compound (Intermediate 66, 158 mg).
Reaction SMILES: [H-].[Na+].[OH:3][C@@H:4]([CH2:9][O:10][C@H:11]([CH3:15])[CH2:12][O:13][CH3:14])[C:5]([O:7][CH3:8])=[O:6].Cl[C:17]1[N:22]=[CH:21][N:20]=[C:19]2[N:23]([C:26]3[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][N:27]=3)[N:24]=[CH:25][C:18]=12>C1COCC1.C(OCC)(=O)C>[Cl:32][C:31]1[C:26]([N:23]2[C:19]3=[N:20][CH:21]=[N:22][C:17]([O:3][C@@H:4]([CH2:9][O:10][C@H:11]([CH3:15])[CH2:12][O:13][CH3:14])[C:5]([O:7][CH3:8])=[O:6])=[C:18]3[CH:25]=[N:24]2)=[N:27][CH:28]=[CH:29][CH:30]=1
Reactant: COC[C@@H](C)OC[C@H](O)C(=O)OC
Reactant: Clc1cccnc1-n1ncc2c(Cl)ncnc21
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC[C@@H](C)OC[C@H](Oc1ncnc2c1cnn2-c1ncccc1Cl)C(=O)OC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 55.8 %

Procedure:
Sodium hydride (62.4 mg, 1.56 mmol) was to (S)-methyl 2-hydroxy-3-((R)-1-methoxypropan-2-yloxy)propanoate (Intermediate Y6) (200 mg, 1.04 mmol) in anhydrous THF (5 mL) at 0° C. under nitrogen. The resulting mixture was stirred for 10 minutes at 0° C. and then 4-chloro-1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate B15) (360 mg, 1.35 mmol) was added and the reaction was allowed to warm up to room temperature and stirred for 1 hour. The reaction mixture was diluted with ethyl acetate (20 mL), and washed sequentially with water (10 mL) and saturated brine (5 mL). The organic layer was dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 0-100% ethyl acetate in isohexane to afford the product (245 mg, 55.8%). 1H NMR (400 MHz, CDCl3) δ 1.19 (d, 3H), 3.33-3.48 (m, 5H), 3.74-3.82 (m, 4H), 4.13-4.18 (m, 2H), 5.81-5.86 (m, 1H), 7.43-7.48 (m, 1H), 7.98-8.02 (m, 1H), 8.39-8.41 (m, 1H), 8.58 (s, 1H), 8.60-8.63 (m, 1H); m/z (ESI+) (M+H)+=422.36; HPLC tR=1.93 min.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][C:17]1([CH3:23])[CH2:21][O:20][C:19](=[O:22])[NH:18]1)C1C=CC=CC=1>C(O)C.[C].[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][C:17]1([CH3:23])[CH2:21][O:20][C:19](=[O:22])[NH:18]1
Reactant: CC1(CCc2ccccc2OCc2ccccc2)COC(=O)N1
Agent: [Pd]
Solvent: CCO
Product: CC1(CCc2ccccc2O)COC(=O)N1
Reaction time: 6 h
Yield: 61.2 %

Procedure:
To a solution of 4-(2-(2-benzyloxyphenyl)ethyl)-4-methyl-2-oxazolidinone (4.60 g) in ethanol (200 ml), 10% palladium-carbon (0.60 g) was added and the mixture was subjected to catalytic reduction at room temperature for 6 hours. Catalyst was filtered off form the reaction solution and the solvent was distilled away under reduced pressure. The residue was crystallized from ether-isopropyl ether to give the subject compound (2.0 g).
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.Br[CH:11]([CH3:14])[CH2:12][OH:13]>C(O)(C)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH:11]([CH3:14])[CH2:12][OH:13])=[CH:5][CH:4]=1
Reactant: CC(Br)CO
Reactant: Oc1ccc(Cl)cc1
Agent: [Na]
Solvent: CC(C)O
Product: CC(CO)Oc1ccc(Cl)cc1
Reaction time: 20 h

Procedure:
2.3 g. of sodium are dissolved in 170 ml. of absolute isopropanol, 12.85 g. of p-chlorophenol are introduced, 13.9 g. of 2-bromo-propanol are added dropwise and the mixture is boiled for 20 hours. The mixture is evaporated and worked up using water and ether to give 2-(4-chlorophenoxy)-propanol.
Reaction SMILES: F[B-](F)(F)F.[CH3:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:17]=[C:16]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:27]=2[CH3:33])[O+]=1.[PH3:34]>C(O)CCC>[CH3:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:17]=[C:16]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:27]=2[CH3:33])[P:34]=1
Reactant: Cc1ccc(-c2cc(-c3ccccc3)cc(-c3ccc(C)cc3C)[o+]2)c(C)c1
Reactant: P
Agent: F[B-](F)(F)F
Solvent: CCCCO
Product: Cc1ccc(-c2cc(-c3ccccc3)cc(-c3ccc(C)cc3C)p2)c(C)c1

Procedure:
20 g (44 mmol) of 2,6-bis(2,4-dimethylphenyl)-4-phenylpyrylium tetrafluoroborate in 150 ml of n-butanol were used as starting material. The autoclave product obtained after the reaction with PH3 was evaporated to half its volume under reduced pressure. The solid which precipitated was filtered off with suction, washed with n-butanol and subsequently dissolved in toluene. The toluene solution was then washed with water until the aqueous phase was neutral. After removal of the solvent and washing with a little n-pentane, the residue was dissolved in 250 ml of diethyl ether/methanol (3:2). The solution obtained was evaporated under reduced pressure at about 30° C. until a solid precipitated. The solid was filtered off with suction, washed with a little methanol and n-pentane and subsequently dried in a high vacuum. Yield: 8.9 g (53%) of white solid.
Reaction SMILES: [CH3:1][C:2]([NH:4][C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7](Cl)[C:6]=1[Cl:15])=[O:3].[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[OH:24].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][C:2]([NH:4][C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([O:24][C:18]2[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:17]=2[Cl:16])[C:6]=1[Cl:15])=[O:3]
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: CC(=O)Nc1c([N+](=O)[O-])ccc(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(=O)Nc1c([N+](=O)[O-])ccc(Oc2ccc(Cl)cc2Cl)c1Cl
Temperature: 0 °C

Procedure:
A mixture of N-methylcarbonyl 2,3-dichloro-6-nitroaniline (0.90 g, 3.6 mmol), 2,4-dichloro-phenol (0.59 g, 3.6 mmol) and potassium carbonate (1.0 g, 7.2 mmol), in 20 ml of DMSO, is stirred at 90° for 3 hours. The reaction is then cooled and poured onto about 60 g of ice. A yellow solid is collected by filtration to give N-methylcarbonyl 2-chloro-3-(2,4-dichloro-phenoxy)-6-nitroaniline.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][C:10]#[N:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>CN(C)C=O.C(OCC)(=O)C.O>[C:10]([CH:9]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])#[N:11]
Reactant: N#CCc1ccccc1
Reactant: CCOC(=O)CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)CCCC(C#N)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.4 %

Procedure:
5 g of sodium hydride (as a 55% w/w dispersion in mineral oil) were added slowly to a solution of 11.7 g of phenylacetonitrile and 19.5 g of ethyl 4-bromobutyrate in 150 ml of dimethylformamide, and the reaction mixture was stirred for 4 hours at room temperature. It was then dissolved in ethyl acetate and water. The ethyl acetate layer was separated, washed with an aqueous solution of potassium bisulfate and then with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The oily residue was subjected to silica gel column chromatography using a 1:4 by volume mixture of ethyl acetate and cyclohexane as eluent, to give 13.5 g of the title compound as a colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:19])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[C:17]#[N:18].[NH2:20][C:21]1[CH:22]=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2>>[C:17]([C:10]1[CH:11]=[C:12]([C:14]([NH:20][C:21]2[CH:22]=[N:23][C:24]3[C:29]([CH:30]=2)=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:16])[S:13][C:9]=1[S:8][C:7]1[C:6]([Cl:19])=[CH:5][N:4]=[CH:3][C:2]=1[Cl:1])#[N:18]
Reactant: N#Cc1cc(C(=O)O)sc1Sc1c(Cl)cncc1Cl
Reactant: Nc1cnc2ccccc2c1
Product: N#Cc1cc(C(=O)Nc2cnc3ccccc3c2)sc1Sc1c(Cl)cncc1Cl

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-cyano-thiophene-2-carboxylic acid (47 mg, 0.14 mmol) from step C of example 203 and 3-amino-quinoline (40 mg, 0.15 mmol). The crude material was purified by reverse phase HPLC and the title compound was obtained as a yellow solid (14.9 mg, 23% yield). MS m/z: 456.98, 458.97 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=[O:6].[H-].[Na+].C(OCC)(=O)C>CN(C=O)C.C1COCC1>[N:10]1[CH:11]=[CH:12][CH:13]=[C:8]([N:7]2[CH2:2][CH2:3][NH:4][C:5]2=[O:6])[CH:9]=1
Reactant: O=C(NCCCl)Nc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1NCCN1c1cccnc1
Temperature: 25 °C
Yield: 98.1 %

Procedure:
1-(2-Chloro-ethyl)-3-pyridin-3-yl-urea (I-1a: 1000 mg, 5.0 mmol) in dry DMF (10 mL) was added to a stirred solution of sodium hydride (216 mg, 9.0 mmol) in THF (10 mL) at 0° C. The reaction temperature was maintained at room temperature for 30 minutes. The reaction was monitored by TLC (100% ethyl acetate). The reaction mixture was quenched with MeOH (5 mL) at 0° C. The reaction mixture was concentrated under reduced pressure and partitioned between ice water and chloroform. The organic layer was dried over Na2SO4, and concentrated under reduced pressure to afford 800 mg (97% yield) of 1-pyridin-3-yl-imidazolidin-2-one.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12].[OH-].[K+].O.[CH2:17]([OH:20])[CH2:18][CH3:19]>>[CH2:17]([O:20][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH2:18][CH3:19]
Reactant: CCCO
Reactant: O=C(O)CCCCCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCCOCCCCCCCCCC(=O)O
Temperature: 102 °C
Reaction time: 18 h

Procedure:
10-bromodecanoic acid (1g, 3.98 mmol) was added to a solution of potassium hydroxide (0.893g, 15.9 mmol) in n-propanol (30 mL) and stirred at 102° C. for 18 hrs. The reaction was allowed to cool to room temperature after the addition of 20 mL water. After acidification to pH=1 and extraction into ethyl acetate, the organic phase was dried over sodium sulfate and solvent removed at reduced pressure to yield a yellow oil. The product was purified by silica column chromatography in 2% diethyl ether/methylene chloride/0.2% formic acid, and then in 7% ethyl acetate/hexane/0.3% formic acid. Recrystallization from hexane at -20° C. yielded 10-(propoxy)decanoic acid (74 mg, 12%: mp <30° C.; 1H NMR (300 MHz, CDC13) δ 0.91 (t, 3H, J=7.5, CH3), 1.18-1.40 (br, 10H, methylene envelope), 1.48-1.67 (bm, 6 H, CH3CH2CH2OCH2CH2, CH2CH2COOH), 2.33 (t, 2H, J=7.4, CH2COOH), 3.31-3.45 (bm, 4H, CH2OCH2), 10.37 (br, 1H COOH); 13C NMR (75.4 MHz, CDC13) 10.67, 22.94, 24.72, 26.19, 29.09, 29.22, 29.41, 29.74, 34.11, 70.88, 72.53, 179.69; m/z 231 (M+H).