Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C@H:3]2[CH2:7][CH:8]=[CH:9][CH2:10][C@@H:2]12.C(=O)([O-])[O-].[K+].[K+].[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O.C(OCC)(=O)C>[CH2:18]([N:5]1[C:1](=[O:11])[C@H:2]2[CH2:10][CH:9]=[CH:8][CH2:7][C@H:3]2[C:4]1=[O:6])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: ClCc1ccccc1
Reactant: O=C1NC(=O)[C@@H]2CC=CC[C@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1[C@H]2CC=CC[C@H]2C(=O)N1Cc1ccccc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 81.1 %

Procedure:
30.2 g of cis-1,2,3,6-tetrahydrophthalimide was dissolved in 200 ml of N,N-dimethylformamide. After adding 38.7 g of potassium carbonate and 30.4 g of benzyl chloride, the resulting mixture was stirred at 50° C. for 3 hours and further at room temperature overnight. Then the reaction mixture was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate. The organic layer was washed successively with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After filtering, the solvent was distilled off under reduced pressure. The crude crystals thus obtained were ground and washed with diisopropyl ether and n-hexane followed by filtration. Thus 39.1 g of the title compound was obtained as pale yellow crystals.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[C:14]1[CH:29]=[CH:28][C:17]2[C@:18]3([CH3:27])[C@@H:23]([CH2:24][CH2:25][C:16]=2[CH:15]=1)[NH:22][C:21](=[O:26])[CH2:20][CH2:19]3.[C:30](O)(C)(C)C.CC(C)([O-])C.[K+].CI>C(OCC)(=O)C>[CH3:30][N:22]1[C@H:23]2[C@@:18]([CH3:27])([C:17]3[CH:28]=[CH:29][C:14]([C:2]4[CH:3]=[CH:4][C:5]5[C:6]6[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=6)[CH2:12][C:13]=5[CH:1]=4)=[CH:15][C:16]=3[CH2:25][CH2:24]2)[CH2:19][CH2:20][C:21]1=[O:26]
Reactant: C[C@]12CCC(=O)N[C@@H]1CCc1cc(-c3ccc4c(c3)Cc3ccccc3-4)ccc12
Reactant: CC(C)(C)O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc5c(c4)Cc4ccccc4-5)cc3CC[C@@H]12
Temperature: 25 °C
Reaction time: 4 h
Yield: 82 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-8-(2-fluorenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (31 mg, 0.08 mmol), 0.2 mL of t-butanol, and potassium t-butoxide (27 mg, 0.24 mmol). Methyl iodide (0.015 mL, 0.24 mmol) was added and the mixture was stirred at room temperature for 4 h. The mixture was diluted with ethyl acetate, and purified by silica gel chromatography (ethyl acetate eluent) to give 26 mg (82%) of the title compound as an off-white solid. mp 175° (decomp). FDMS: m/e=393.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13].[C:14]1(=O)[O:19][C:17](=[O:18])[CH2:16][CH2:15]1.Cl>C1COCC1.O>[Cl:6][C:7]1[C:8]([Cl:13])=[CH:9][CH:10]=[CH:11][C:12]=1[CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: Clc1ccccc1Cl
Reactant: O=C1CCC(=O)O1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCCc1cccc(Cl)c1Cl
Reaction time: 0.5 h

Procedure:
In a 100 ml three necked RB flask equipped with a nitrogen gas inlet and an additional funnel, was taken 4 ml of n-butyl lithium (4 ml, 1.8 M in hexanes). Then 10 ml of dry THF was added and the reaction mixture was kept in −80° C. for 0.5 h. A solution of orthodichlorobenzene (0.01 mol, 1.47 g) in 10 ml THF was added in drops by the additional funnel to the n-butyl lithium solution for the period of 10 minutes with keeping the temperature below −78° C. The mixture was stirred for half an hour to form a pale yellow color. Then a solution of succinic anhydride 1 g (0.01 mol) in 10 ml THF was added slowly for the period of 15 minutes. As the addition continued the reaction mixture turned to yellow color. After one hour water 20 ml was added to quench the reaction and acidified with 5 N HCl. It was then extracted with DCM. The organic layer was dried and evaporated to give the required product as oil which was recrystallized from toluene. LCMS analysis revealed the formation of the product. m/e: 246.98
Reaction SMILES: [CH:1]([NH:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]([NH:20][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])[CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:2].[Cl:26][C:27]1[CH:28]=[C:29]([N:34]=C=O)[CH:30]=[C:31]([Cl:33])[CH:32]=1>C1COCC1.C(Cl)Cl>[Cl:26][C:27]1[CH:28]=[C:29]([CH:30]=[C:31]([Cl:33])[CH:32]=1)[NH:34][C:1]([NH:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]([NH:20][C:21](=[O:25])[CH:22]([CH3:23])[CH3:24])[CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:2]
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCNC=O)CC2)c1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCNC(=O)Nc3cc(Cl)cc(Cl)c3)CC2)c1

Procedure:
Prepared by Procedure Q2 (THF/DCM, 1:3) and Scheme AT using N-(3-{1-[4-(formylamino)butyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 3,5-dichlorophenyl isocyanate: ESMS m/e: 505.0 (M+H)+.
Reaction SMILES: C(Cl)Cl.[Cl:4][C:5]1[CH:6]=[C:7]([NH:20][C:21]2[C:26]3[C:27]4[CH2:35][CH2:34][C:33]5[N:32]([CH2:36][CH2:37]O)[N:31]=[CH:30][C:29]=5[C:28]=4[S:39][C:25]=3[N:24]=[CH:23][N:22]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1.S(Br)([Br:42])=O>O>[Br:42][CH2:37][CH2:36][N:32]1[C:33]2[CH2:34][CH2:35][C:27]3[C:26]4[C:25](=[N:24][CH:23]=[N:22][C:21]=4[NH:20][C:7]4[CH:8]=[CH:9][C:10]([O:11][CH2:12][C:13]5[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=5)=[C:5]([Cl:4])[CH:6]=4)[S:39][C:28]=3[C:29]=2[CH:30]=[N:31]1
Reactant: O=S(Br)Br
Reactant: OCCn1ncc2c1CCc1c-2sc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Solvent: O
Solvent: ClCCl
Product: Fc1cccc(COc2ccc(Nc3ncnc4sc5c(c34)CCc3c-5cnn3CCBr)cc2Cl)c1
Temperature: 25 °C
Yield: 61.5 %

Procedure:
To 10 mL CH2Cl2 cooled to 0° C. was added 2-[6-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-4,5-dihydro-3H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-3-yl]ethanol (295 mg, 0.57 mmol) followed by thionyl bromide (0.11 mL, 1.41 mmol), and the contents allowed to stir with warming to rt. After 4 h stirring at rt, the contents were diluted with H2O (10 mL). The layers were separated and the aqueous layer extracted with CH2Cl2 (3×10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was triturated from methanol to afford the final product (205 mg, 62%) as an off-white solid. 1H-NMR (DMSO-d6) δ 3.09 (t, 2H), 3.39 (t, 2H), 3.85 (m, 2H), 4.52 (m, 2H), 5.24 (s, 2H), 7.14-7.34 (m, 4H), 7.40-7.53 (m, 2H), 7.75 (s, 1H), 7.79 (d, 1H), 8.35 (s, 1H), 8.40 (s, 1H); LCMS RT=3.82 min; [M+H]+=584.0, 586.0.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1.[CH3:20]O>>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:20])[CH:5]=[CH:4][C:3]=1[C:9](=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1
Reactant: COc1ccc(CC(=O)c2ccc(O)cc2O)cc1
Reactant: CO
Product: COc1ccc(CC(=O)c2ccc(OC)cc2O)cc1
Yield: 81 %

Procedure:
Using the previous procedure and starting from 1-(2,4-dihydroxyphenyl)-2-(4-methoxyphenyl)ethanone (8.0 g, 11.0 mmol) and methanol (1.32 mL, 32.55 mmol), 6.8.5 g (81%) of the title compound was obtained as a white solid: mp 101-102° C. (lit. 104° C.); IR (KBr) 1637, 1611, 1513, 1459, 1346. 1301, 1237, 1174, 1148, 1026 797, 787, 626, 522 cm−1; 1H NMR (400 MHz, CDCl3) δ 12.72 (br s, 1H), 7.73 (d, J=8.8 Hz, 1H), 7.17 (d, J=8.6 Hz. 2H), 6.86 (d, J=8.6 Hz, 2H), 6.40-6.44 (m, 2H), 4.13 (s, 2H), 3.81 (s, 3H), 3.77 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 202.73, 166.55, 166.27, 159.07, 132.42, 130.78, 126.73, 114.61, 113.53, 108.21, 101.42, 55.99, 55.67, 44.37.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:23][C:24]1[CH:33]=[C:32]2[C:27]([CH:28]=[CH:29][C:30]([CH3:34])=[N:31]2)=[CH:26][CH:25]=1>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)[N:5]=[CH:4][N:3]=[C:2]2[O:23][C:24]1[CH:33]=[C:32]2[C:27]([CH:28]=[CH:29][C:30]([CH3:34])=[N:31]2)=[CH:26][CH:25]=1
Reactant: Cc1ccc2ccc(O)cc2n1
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(C)CC1
Product: COc1cc2c(Oc3ccc4ccc(C)nc4c3)ncnc2cc1OCC1CCN(C)CC1
Yield: 62.4 %

Procedure:
Using an analogous procedure to that described in Example 42, 4-chloro-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (100 mg, 0.31 mmol), (prepared as described for the starting material in Example 10), was reacted with 7-hydroxy-2-methylquinoline (54 mg, 0.34 mmol), (J. Med. Chem. 1998, 41, 4062), to give 6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)-4-(2-methylquinolin-7-yloxy)quinazoline (86 mg, 63%).
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([NH2:12])=[N:9][C:8]=2[C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19](Cl)(=[O:21])[CH3:20].O>CN(C)C(=O)C>[C:1]1([C:7]2[S:11][C:10]([NH:12][C:19](=[O:21])[CH3:20])=[N:9][C:8]=2[C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)Cl
Reactant: Nc1nc(-c2cccnc2)c(-c2ccccc2)s1
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(=O)Nc1nc(-c2cccnc2)c(-c2ccccc2)s1
Temperature: 80 °C
Reaction time: 3 h
Yield: 58.5 %

Procedure:
To a solution of [5-phenyl-4-(3-pyridyl)-1,3-thiazol-2-yl]amine (1.10 g, 4.34 mmol) in N,N-dimethylacetamide (20 mL) was added acetyl chloride (680 mg, 8.68 mmol) and stirred at 80° C. for 3 h. Water was added to the reaction mixture and extracted with ethyl acetate twice. The combined organic phases were washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from chloroform-ethyl ether to give the title compound (750 mg, yield 59%).
Reaction SMILES: [CH:1]1([C:4]2[CH:24]=[CH:23][C:7]([CH2:8][NH:9][CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][C:15](F)=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[CH3:25]C1(C2C=CC(C=O)=CC=2)CC1.FC(F)(F)C1C=C(CCN)C=CC=1.[BH4-].[Na+]>>[CH3:25][C:1]1([C:4]2[CH:24]=[CH:23][C:7]([CH2:8][NH:9][CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: Fc1ccc(CCNCc2ccc(C3CC3)cc2)cc1C(F)(F)F
Reactant: CC1(c2ccc(C=O)cc2)CC1
Agent: NCCc1cccc(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Product: CC1(c2ccc(CNCCc3cccc(C(F)(F)F)c3)cc2)CC1
Yield: 62 %

Procedure:
The title compound was synthesized in analogy to (4-cyclopropylbenzyl)-[2-(4-fluoro-3-trifluoromethylphenyl)-ethyl]-amine (described in example S53) using 4-(1-methyl-cyclo-propyl)-benzaldehyde (150 mg, 0.94 mmol), 2-(3-trifluoromethylphenyl)-ethylamine (177 mg, 0.94 mmol) and sodium borohydride (53 mg, 1.40 mmol). The isolated residue was purified by flash column chromatography (2%-5% MeOH in EtOAc) to give the desired product (195 mg, 62%) as a colorless oil. MS (ISP) 334.3 (M+H)+.
Reaction SMILES: [C:1]([Cl:6])(=O)[C:2]([Cl:4])=[O:3].ClC(=[CH:12][C:13]1[CH:18]=[C:17]([C:19]2[C:23]([Cl:24])=[C:22]([O:25][CH:26]([F:28])[F:27])[N:21]([CH3:29])[N:20]=2)[C:16]([Cl:30])=[CH:15][C:14]=1[Cl:31])C(O)=O>CN(C)C=O.C1(C)C=CC=CC=1>[Cl:6][C:1](=[CH:12][C:13]1[CH:18]=[C:17]([C:19]2[C:23]([Cl:24])=[C:22]([O:25][CH:26]([F:27])[F:28])[N:21]([CH3:29])[N:20]=2)[C:16]([Cl:30])=[CH:15][C:14]=1[Cl:31])[C:2]([Cl:4])=[O:3]
Reactant: Cn1nc(-c2cc(C=C(Cl)C(=O)O)c(Cl)cc2Cl)c(Cl)c1OC(F)F
Reactant: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cn1nc(-c2cc(C=C(Cl)C(=O)Cl)c(Cl)cc2Cl)c(Cl)c1OC(F)F

Procedure:
3 drops of dimethylformamide and then 11.1 g (87 mmol) of oxalyl chloride were added dropwise to a solution of 12.5 g (29 mmol) of 2-chloro-3-(2,4-dichloro-5-(4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazol-3-yl)phenyl)propenoic acid in 300 ml of toluene. The reaction mixture was stirred at reflux temperature for 5 hours and then concentrated. Yield: quantitative.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH2:10]([O:12][C:13]([N:15]=[C:16]=[O:17])=[O:14])C.[Si]([O:25][C:26]1[CH:31]=[C:30]([O:32][Si](C(C)(C)C)(C)C)[CH:29]=[CH:28][C:27]=1[C@H:40]1[CH2:45][CH2:44][C@H:43]([OH:46])[CH2:42][CH2:41]1)(C(C)(C)C)(C)C>CN(C)C=O>[C:16]([NH:15][C:13]([O:12][CH3:10])=[O:14])([O:46][C@H:43]1[CH2:42][CH2:41][C@H:40]([C:27]2[CH:28]=[CH:29][C:30]([OH:32])=[CH:31][C:26]=2[OH:25])[CH2:45][CH2:44]1)=[O:17]
Reactant: CCOC(=O)N=C=O
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@H](O)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)NC(=O)O[C@H]1CC[C@H](c2ccc(O)cc2O)CC1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
N,N-Diisopropylethylamine (497 μl) and ethylisocyanatoformate (177 μl) were added to a stirred solution of trans-4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexanol (250 mg) in anhydrous dimethylformamide (2 ml). After 120 hr at 50° C., the reaction mixture was partitioned between ethyl acetate (50 ml) and water (50 ml). The aqueous layer was extracted with ethyl acetate (2×50 ml). The combined organic extracts were washed with brine (50 ml), dried over magnesium sulfate and evaporated in vacuo. The residue was dissolved in methanol (10 ml) and was stirred with fluoride resin (300 mg) for 16 hr at room temperature. The suspension was filtered through a pad of celite, which was washed well with methanol. The combined filtrates were concentrated in vacuo and the residue was purified using flash column chromatography (SiO2, ethyl acetate/petrol, 1:3 v/v) and then preparative HPLC to give the title compound (4 mg, 2%) as a pale yellow gum. δH (CD3OD) 1.20-1.40 (4H, m), 1.55 (3H, t), 1.80-1.90 (2H, m), 2.00-2.18 (2H, m), 2.72-2.82 (1H, m), 4.20 (2H, q), 6.20-6.25 (2H, m), 6.84 (1H, d); m/z (ES−) 322 (M−H−).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[C:9](=[O:14])[CH2:8][C:7]=2[CH:15]=1)#[N:2].CC(C)([O-])C.[K+].CN(C)C=O.[C:27]1([N:33]=[C:34]=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(O)(=O)C>[C:27]1([NH:33][C:34]([C:8]2[C:7]3[CH:15]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=3[O:11][C:10]([CH3:13])([CH3:12])[C:9]=2[OH:14])=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C=Nc1ccccc1
Reactant: CC1(C)Oc2ccc(C#N)cc2CC1=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC1(C)Oc2ccc(C#N)cc2C(C(=O)Nc2ccccc2)=C1O
Temperature: 0 °C
Yield: 21.4 %

Procedure:
To a mixture of 0.5 g of 6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-one, 0.39 g of potassium t-butoxide, and 5 ml of dried N,N-dimethylformamide was added dropwise a mixture of 0.42 g of phenyl isocyanate and 1.5 ml of dried N,N-dimethylformamide while stirring under cooling with ice. After stirring for 4 hours under ice-cooling, ice-water was added thereto, and the mixture was made acidic with acetic acid and extracted with diethyl ether. The ether layer was washed with water and dried over sodium sulfate. Diethyl ether was removed by distillation, and the residue was purified by silica gel column chromatography (developing solution: CH2Cl2) to obtain 0.17 g of N-phenyl-6-cyano-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-carboxamide represented by formula shown below.
Reaction SMILES: Br[CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[SH:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1>>[CH2:6]([O:5][C:3](=[O:4])[CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=1)[S:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[CH3:7]
Reactant: Oc1ccc(S)cc1
Reactant: CCOC(=O)C(Br)c1cccc(Cl)c1
Product: CCOC(=O)C(Sc1ccc(O)cc1)c1cccc(Cl)c1
Yield: 82 %

Procedure:
Ethyl(3-chlorophenyl)[(4-hydroxyphenyl)sulfanyl]acetate was prepared according to the general method as outlined in example 1 (step 1), starting from ethyl bromo(3-chlorophenyl)acetate (6.16 g, 16.5 mmol) and 4-mercaptophenol (2.08 g, 16.5 mmol); 4.36 g clear oil. Yield 82%; MS: 321 (M−H)−
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][C:40](=[O:48])[NH:41][C:42]([C:45](O)=[O:46])([CH3:44])[CH3:43])=[CH:33][C:32]=2[CH3:49])=[C:28]([CH:50]([CH3:52])[CH3:51])[NH:27][N:26]=1)(=O)C.[CH3:53][N:54]1[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]1.NC(C)(C)C(N)=O>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][C:40](=[O:48])[NH:41][C:42]([C:45]([N:57]4[CH2:58][CH2:59][N:54]([CH3:53])[CH2:55][CH2:56]4)=[O:46])([CH3:43])[CH3:44])=[CH:33][C:32]=3[CH3:49])=[C:28]([CH:50]([CH3:51])[CH3:52])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCC(=O)NC(C)(C)C(=O)O)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CN1CCNCC1
Agent: CC(C)(N)C(N)=O
Product: Cc1cc(OCCC(=O)NC(C)(C)C(=O)N2CCN(C)CC2)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C

Procedure:
The title compound was prepared in a similar manner to that described in Example 78 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{2-[1-carboxy-1-(methyl)ethyl-carbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole and 1-methylpiperazine instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-carboxyethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole and 2-amino-2-methylpropionamide, respectively.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]=[C:9]([C:12]([NH2:14])=O)[O:8][C:7]=2[CH:15]=1.P(Cl)(Cl)(Cl)=O.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]=[C:9]([C:12]#[N:14])[O:8][C:7]=2[CH:15]=1
Reactant: COc1ccc2c(c1)OC(C(N)=O)=CO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc2c(c1)OC(C#N)=CO2

Procedure:
1.76 g (8.52 mmol) of the amide obtained in Step A and 4.62 g (30 mmol) of phosphorus oxychloride are dissolved in 40 ml of anhydrous pyridine. The reaction medium is then heated at reflux for 1 hour under an inert atmosphere; the solvent is then evaporated in vacuo. The residue obtained is slowly hydrolysed with a saturated solution of sodium hydrogen carbonate; the aqueous phase is then extracted with dichloromethane. The organic phase, dried over magnesium sulphate and then filtered, is concentrated in vacuo. The title nitrile is obtained pure in the form of a white solid after passage over a silica column (eluant:AcOEt/PE:10/60).
Reaction SMILES: O[N:2]=[C:3]([C:11](=O)[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>C(#N)C>[F:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]2[NH:25][C:11]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)=[C:3]([C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[N:2]=2)=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)C(=NO)C(=O)c1ccncc1
Reactant: NCc1ccc(F)cc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)c1nc(-c2ccc(F)cc2)[nH]c1-c1ccncc1

Procedure:
tert-Butyl 2-hydroxyimino-3-oxo-3-(4-pyridyl)propionate and 4-fluorobenzylamine were dissolved in acetonitrile (80 ml). The mixture was reacted and treated in the same manner as in Starting Material Synthetic Example 5 to give tert-butyl 2-(4-fluorophenyl)-5-(4-pyridyl)imidazole-4-carboxylate.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]([CH2:14][O:15]CC1C=CC=CC=1)([OH:13])[CH2:4][O:5]CC1C=CC=CC=1.C(O)C>[Pd].C1(C)C=CC=CC=1>[F:1][C:2]([F:24])([F:23])[C:3]([OH:13])([CH2:14][OH:15])[CH2:4][OH:5]
Reactant: OC(COCc1ccccc1)(COCc1ccccc1)C(F)(F)F
Agent: [Pd]
Solvent: CCO
Solvent: Cc1ccccc1
Product: OCC(O)(CO)C(F)(F)F
Temperature: 50 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
1,1,1-Trifluoro-3-[(benzyl)oxy]-2-{[(benzyl)oxy]methyl}-2-propanol (1.3 kg, 3.82 mol, 1.0 eq.) was placed in a 10 L flange flask equipped with a overhead stirrer, followed by ethanol (4.5 L). 10% palladium on carbon (27 g) was added under Argon atmosphere. The reaction was then subjected to hydrogenolysis at atmospheric pressure (6 balloons) and stirred overnight at 50° C. (the balloons were topped up repeatably during the day). 1H NMR showed completion of reaction had been reached after 1 week, required additional 10% palladium on carbon (4 g). The reaction mixture was filtered through a pad of celite and washed with ethanol (2.5 L). The filtrate was concentrated under reduced pressure to give an oil. This was placed under high vacuum overnight to obtain a solid material. Toluene (1.5 L) was added and the mixture heated until the solid dissolved (˜60° C.), 2 layers were observed. The mixture was stirred using a magnetic stirrer and cooled using an ice-water bath, where a solid precipitated. The solid was broken up and stirred for a further 30 minutes, then isolated by filtration. The solid was washed with toluene (250 ml) and petroleum ether (250 ml). The solid was dried under high vacuum overnight to yield desired product (465 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(N(CC)C(C)C)(C)C.Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]1[CH2:11][CH2:12][N:13]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:14][CH2:15]1
Reactant: COc1ccc(C2CCNCC2)c(F)c1
Reactant: CCOC(=O)CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCC(c2ccc(OC)cc2F)CC1

Procedure:
To a stirred solution of 4-(2-fluoro-4-methoxyphenyl)piperidine (40 mg; 0.19 mmol) in DMF (1 mL) under an atmosphere of N2 was added N,N-diisopropylethylamine (33 μL; 0.19 mmol), followed by ethyl bromoacetate (21 μL; 0.19 mmol). The resultant solution was stirred at room temperature for 2.5 h. The reaction was partitioned between EtOAc (10 mL) and H2O (10 mL). The aqueous layer was extracted with EtOAc (3×10 mL) and the combined extracts were washed with brine (10 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0-25% EtOAc/hexanes gradient) to afford ethyl [4-(2-fluoro-4-methoxyphenyl)piperidin-1-yl]acetate as a colorless oil. LCMS=295.9 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.14 (t, J=8.7 Hz, 1 H), 6.65 (dd, J=8.5, 2.5 Hz, 1 H), 6.58 (dd, J=12.43, 2.5 Hz, 1 H), 4.20 (q, J=7.1 Hz, 2 H), 3.77 (s, 3 H), 3.26 (s, 2H), 3.06 (d, J=11.4 Hz, 2 H), 2.80 (tt, J=12.1, 3.7 Hz, 1 H), 2.32 (t, J=11.2 Hz, 2 H), 1.87 (qd, J=12.3, 3.3 Hz, 2 H), 1.78 (d, J=12.1 Hz, 2 H), 1.29 (t, J=7.1 Hz, 3 H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[C:6]([O:10][C:11]([N:13]1[CH2:17][CH2:16][CH2:15][C@H:14]1[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]2[CH:32]=[CH:31][C:30](I)=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)=[O:12])([CH3:9])([CH3:8])[CH3:7]>>[C:6]([O:10][C:11]([N:13]1[CH2:17][CH2:16][CH2:15][C@H:14]1[CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([C:2]3[S:1][CH:5]=[CH:4][N:3]=3)=[CH:31][CH:32]=2)=[CH:24][CH:25]=1)=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: c1cscn1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccc(Cc2ccc(I)cc2)cc1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccc(Cc2ccc(-c3nccs3)cc2)cc1
Yield: 55.5 %

Procedure:
The title compound (200 mg, 86%) was prepared from thiazole (0.28 g, 3.2 mmol) and (S)-2-[4-(4-iodo-benzyl)-phenoxymethyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.4 g, 0.8 mmol) using the procedure of Example 146, step 1; 1HNMR (400 MHz, CDCl3) δ 7.87 (d, J=8.4 Hz, 2H), 7.84 (d, J=3.2 Hz, 1H), 7.30 (d, J=3.6 Hz, 1H), 7.25 (d, J=8.4 Hz, 2H), 7.10 (d, J=8 Hz, 2H), 6.86 (br d, J=7.2 Hz, 2H), 4.10 (br, 2H), 3.96 (s, 2H), 3.9-3.75 (br, 2H), 3.40 (br, 2H), 2.03-1.84 (br, 4H), 1.46 (s, 9H); MS (ESI+) 451 (M+1, 100).