Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:30])[C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C@@H:14]([CH3:31])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:38]([O:40][C:41](=[O:47])[C:42]([CH3:46])([CH3:45])[CH2:43]Cl)[CH3:39]>CN(C=O)C>[CH2:38]([O:40][C:41](=[O:47])[C:42]([CH3:46])([CH3:45])[CH2:43][O:29][C:26]1[CH:25]=[CH:24][C:23]([C:22]([N:15]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@H:12]([N:8]([C:9](=[O:11])[CH3:10])[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH2:13][C@@H:14]2[CH3:31])=[O:30])=[CH:28][CH:27]=1)[CH3:39]
Reactant: CCOC(=O)C(C)(C)CCl
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(O)cc2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)COc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Temperature: 90 °C
Yield: 31.2 %

Procedure:
(2S,4R)-N-(4-Chloro-phenyl)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide (0.32 g, 0.74 mmol) was dissolved in 10 ml DMF at room temperature and K2CO3 (0.51 g, 3.7 mmol) was added. 3-Chloro-2,2-dimethyl-propionic acid ethyl ester (0.25 g, 1.52 mmol) was added and the reaction was allowed to heat to 90° C. for 6 days. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water, then extracted three times with ethyl acetate, dried over MgSO4, filtered and concentrated down. The crude residue was purified by silica gel chromatography (60% EtOAc/40% Hexane) to afford the (2S,4R)-3-(4-{4-[acetyl(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxy)-2,2-dimethyl-propionic acid ethyl ester (0.13 g, 32%).
Reaction SMILES: Br.[CH3:2][N:3]([CH3:25])[CH2:4][CH2:5][CH2:6][C:7]1([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[C:11]2[CH:12]=[CH:13][C:14]([C:16]#[N:17])=[CH:15][C:10]=2[CH2:9][O:8]1.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([NH:33][C:16]([C:14]1[CH:13]=[CH:12][C:11]2[C:7]([CH2:6][CH2:5][CH2:4][N:3]([CH3:25])[CH3:2])([C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)[O:8][CH2:9][C:10]=2[CH:15]=1)=[NH:17])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CN(C)CCCC1(c2ccc(F)cc2)OCc2cc(C#N)ccc21
Reactant: NCc1ccccc1
Agent: Br
Product: CN(C)CCCC1(c2ccc(F)cc2)OCc2cc(C(=N)NCc3ccccc3)ccc21
Temperature: 80 °C
Yield: 19 %

Procedure:
Using 250 mg of 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carbonitrile hydrobromide (citalopram HBr) and benzylamine (1.2 equiv) gave, after heating at 80° C. for 14 h, title product (72 mg, 19% yield) as a white solid.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[N:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:12]=2[C:21]([O:23]C)=[O:22])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[C:1]1([S:7]([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[N:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:12]=2[C:21]([OH:23])=[O:22])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccccc2)ccc2ncccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1c(NS(=O)(=O)c2ccccc2)ccc2ncccc12
Temperature: 70 °C
Yield: 14.5 %

Procedure:
A solution of Example 96C (0.073 g, 0.21 mmol) in methanol (4 mL) was treated with 2 mL conc. NaOH and heated to 70° C. for 18 hours. The mixture was concentrated, diluted with water, acidified to pH 5 with 1M HCl, and extracted with dichloromethane. The extract was dried (MgSO4), filtered, and concentrated to provide the desired product (0.010 g). MS (ESI(+)) m/e 329 (M+H)+; (ESI(−)) m/e 327 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 10.01 (dd, 1H), 8.97 (m, 1H), 8.30 (d, 1H), 7.92 (d, 1H), 7.74 (m, 5H), 7.54 (m, 1H).
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]([CH2:17][CH2:18][C:19]#[N:20])[CH2:6][CH2:7][N:8]([CH2:13][CH2:14][C:15]#[N:16])[CH2:9][CH2:10][C:11]#[N:12])#[N:2].[H][H]>CO.N.[Ni]>[NH2:12][CH2:11][CH2:10][CH2:9][N:8]([CH2:13][CH2:14][CH2:15][NH2:16])[CH2:7][CH2:6][N:5]([CH2:17][CH2:18][CH2:19][NH2:20])[CH2:4][CH2:3][CH2:1][NH2:2]
Reactant: [H][H]
Reactant: N#CCCN(CCC#N)CCN(CCC#N)CCC#N
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCCCN(CCCN)CCN(CCCN)CCCN

Procedure:
Preparation of CH3 (CH2)6C(O)N CH2 (CHOH)4CH2OH!--(CH2)3 !2--N(CH2)2N-- (CH2)3 -- CH2 (CHOH)4CH2OH!NC(O)(CH2 6CH3 !2One mole of ethylenediamine (60g) is added to 250 g (4.7 moles) acrylonitrile and heated to 100° C. for 2 hrs. Excess acrylonitrile is vacuum stripped to give about 200 g tetrakis (2-cyanoethyl)ethylenediamine. The nitrile is dissolved in 2 l dry methanol saturated with ammonia. It is hydrogenated in the presence of 20 Raney nickel at 100°-120° C. for 3 hrs under 1000-1500 psi hydrogen. The sample is decanted, filtered and stripped under vacuum to give about 200 g tetrakis(3-aminopropyl)ethylenediamine. The whole sample (200 g, 0.7 mole) is added to 5040g 10% aqueous glucose (2.8 mole) and reduced with hydrogen at 1500 psi in the presence of 50 g Raney nickel. The sample is decanted, filtered and stripped to give about 600 g (0.63 mole) tetrakis(glucitylaminopropyl)ethylenediamine. The latter is stripped dry and melted in 200 g propylene glycol. Methyl octanoate (398 g, 2.5 mole) is added along with 0.1 mole 25% sodium methoxide/methanol. The sample is stirred at 85° C. for 3 hrs under 0.5 arm vacuum to give the product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9](OC)(=[O:12])[CH:10]=[CH2:11].BrC1C=CC(OC(C)C(O)=O)=CC=1>CO.S(=O)(=O)(O)O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:8][CH2:11][CH2:10][C:9]2=[O:12]
Reactant: C=CC(=O)OC
Reactant: Oc1ccc(Br)cc1
Agent: CC(Oc1ccc(Br)cc1)C(=O)O
Agent: O=S(=O)(O)O
Solvent: CO
Product: O=C1CCOc2ccc(Br)cc21

Procedure:
The title compound was prepared by the method of Canalini et al.2 by the reaction of 4-bromophenol (40 g, 0.23 mole) and methyl acrylate (100 ml) in the presence of Triton B (6 ml of a 40% solution in methanol); followed by dilute acid hydrolysis of the resulting ester and cyclisation of the (4-bromophenoxy)propionic acid in concentrated sulphuric acid. The product was recrystallised from petroleum ether (60°-80° C.) to give a white crystalline solid (6.80 g, 13%). M.p. 78°-80° C.
Reaction SMILES: C([Li])(CC)C.CN(C)CCN(C)CCN(C)C.[C:18]([Si:22]([O:25][CH2:26][C:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[F:36])([CH3:29])[CH3:28])([CH3:24])[CH3:23])([CH3:21])([CH3:20])[CH3:19].CN([CH:40]=[O:41])C>O1CCCC1>[Si:22]([O:25][CH2:26][C:27]([C:30]1[C:31]([F:36])=[C:32]([CH:33]=[CH:34][CH:35]=1)[CH:40]=[O:41])([CH3:29])[CH3:28])([C:18]([CH3:19])([CH3:20])[CH3:21])([CH3:23])[CH3:24]
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)c1ccccc1F
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)c1cccc(C=O)c1F
Temperature: -78 °C
Reaction time: 2 h

Procedure:
sec-Butyllithium (1.4M in cyclohexane, 3.54 mL) was added to dry tetrahydrofuran (10 mL) under nitrogen and the solution cooled to −78° C. N1-(2-(dimethylamino)ethyl)-N1,N2,N2-trimethylethane-1,2-diamine (0.859 g) was added slowly dropwise. A solution of tert-butyl(2-(2-fluorophenyl)-2-methylpropoxy)dimethylsilane (example 90, step e) (1.4 g) in dry tetrahydrofuran (3 mL) was then added dropwise over 5 minutes. The reaction mixture was stirred for 2 hours at −78° C. DMF (2.69 mL) was added dropwise over 5 minutes and the mixture stirred at −78° C. for 1 hour followed by room temperature for 45 minutes. The reaction mixture was quenched by addition of water. Ethyl acetate (200 mL) was added and the organic washed three times with water followed by twice with 2M HCl and twice with water, then brine and dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography, elution gradient 1 to 5% ethyl acetate in isohexane. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.98 g.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[N:4]=1.[CH3:12][C:13](OC(C)=O)=[O:14]>CN(C1C=CN=CC=1)C>[C:13]([N:7]1[C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[N:4]=[C:3]1[CH2:2][Cl:1])(=[O:14])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: ClCc1nc2ccccc2[nH]1
Agent: CN(C)c1ccncc1
Product: CC(=O)n1c(CCl)nc2ccccc21
Yield: 57 %

Procedure:
2-(Chloromethyl)-1H-benzimidazole (3.32 g, 0.02 mol) and DMAP (0.2 g) in Ac2O (50 ml) were refluxed for 8 h. The excess Ac2O was evaporated under vacuum and the residue was purified by column chromatography (silica, EtOAc:hexanes 2:1, first fraction) to obtain 2.37 g of product 7 (57%)
Reaction SMILES: [C:1]([CH:4]1[CH2:8][CH:7]([CH2:9][CH2:10][CH2:11][CH3:12])[O:6][C:5]1=[O:13])(=O)[CH3:2].[OH-].[Na+].C(=O)[C:17]1[CH:22]=[CH:21]C=[CH:19][CH:18]=1>>[C:2]1([CH:1]=[C:4]2[CH2:8][CH:7]([CH2:9][CH2:10][CH2:11][CH3:12])[O:6][C:5]2=[O:13])[CH:21]=[CH:22][CH:17]=[CH:18][CH:19]=1
Reactant: O=Cc1ccccc1
Reactant: CCCCC1CC(C(C)=O)C(=O)O1
Agent: [Na+]
Agent: [OH-]
Product: CCCCC1CC(=Cc2ccccc2)C(=O)O1

Procedure:
3-Phenylmethylene-5-butyldihydro-2(3H)-furanone was prepared by reacting 3-acetyl-5-butyldihydro-2(3H)-furanone with sodium hydroxide and benzaldehyde in accordance with the procedure described in Example I. The crude product (64.5% yield) was recovered by distillation of the reaction mixture at 25°-147° C. (0.04 mm/Hg) to remove light ends. The structure was confirmed by proton nuclear magnetic resonance spectroscopy.
Reaction SMILES: [CH3:1][Mg]Br.[CH:4]([N:17]1[CH2:20][C:19](=[O:21])[CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C1COCC1>[CH:4]([N:17]1[CH2:20][C:19]([CH3:1])([OH:21])[CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: C[Mg]Br
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: C1CCOC1
Product: CC1(O)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 0 °C
Yield: 81.2 %

Procedure:
To a solution of methylmagnesium bromide (263 mL, 790 mmol) in anhydrous THF (800 mL) was added a solution of 1-benzhydrylazetidin-3-one (75 g, 316 mmol) in THF (300 mL) rapidly with vigorous stirring at 0° C. The reaction mixture was stirred for 10 min, then allowed to warm to 25° C. and stirred for 2 h. The reaction mixture was quenched by the addition of saturated aqueous ammonium chloride (1 L), diluted with water (1 L) and extracted with EtOAc (3×1 L). The combined organic phase was washed with brine (0.5 L), dried over anhydrous Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was purified by column chromatography on silica gel (eluting with 10-20% EtOAc in petroleum ether) to give 1-benzhydryl-3-methylazetidin-3-ol (65 g, 81%) as a white solid. 1H NMR (CDCl3, 400 MHz): δ 7.42 (m, 4H), 7.31 (m, 4H), 7.22 (m, 2H), 4.36 (s, 1H), 3.20 (m, 2H), 2.99 (m, 2H), 1.53 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:15][C:16]1[S:17][C:18]2[CH:24]=[C:23]([NH:25][C:26]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([C:36]([F:39])([F:38])[F:37])[CH:30]=3)=[O:27])[CH:22]=[CH:21][C:19]=2[N:20]=1>>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([NH:28][C:26]([NH:25][C:23]2[CH:22]=[CH:21][C:19]3[N:20]=[C:16]([NH:15][C:2]4[C:11]5[C:6](=[CH:7][C:8]([OH:14])=[C:9]([O:12][CH3:13])[CH:10]=5)[N:5]=[CH:4][N:3]=4)[S:17][C:18]=3[CH:24]=2)=[O:27])=[CH:30][C:31]=1[C:36]([F:38])([F:37])[F:39]
Reactant: Nc1nc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2s1
Reactant: COc1cc2c(Cl)ncnc2cc1O
Product: COc1cc2c(Nc3nc4ccc(NC(=O)Nc5ccc(Cl)c(C(F)(F)F)c5)cc4s3)ncnc2cc1O

Procedure:
1-(4-Chloro-3-trifluoromethyl-phenyl)-3-[2-(7-hydroxy-6-methoxy-quinazolin-4-ylamino)-benzothiazol-6-yl]-urea was prepared according to GP 1 starting from 4-Chloro-6-methoxy-quinazolin-7-ol and intermediate 3.
Reaction SMILES: [N:1]([C@@H:4]1[C:21]2[C@:16]([CH3:24])([CH:17]3[CH2:23][C@@H:18]3[C:19](=[O:22])[CH:20]=2)[C@@H:15]2[C@H:6]([C@H:7]3[C@@:11]([CH2:13][CH2:14]2)([CH3:12])[C:10](=[O:25])[CH2:9][CH2:8]3)[CH2:5]1)=[N+]=[N-].C(S)CCS.C(N(CC)CC)C>CO>[NH2:1][C@@H:4]1[C:21]2[C@:16]([CH3:24])([CH:17]3[CH2:23][C@@H:18]3[C:19](=[O:22])[CH:20]=2)[C@@H:15]2[C@H:6]([C@H:7]3[C@@:11]([CH2:13][CH2:14]2)([CH3:12])[C:10](=[O:25])[CH2:9][CH2:8]3)[CH2:5]1
Reactant: C[C@]12CC[C@H]3[C@@H](C[C@H](N=[N+]=[N-])C4=CC(=O)[C@H]5CC5[C@@]43C)[C@@H]1CCC2=O
Agent: SCCCS
Solvent: CCN(CC)CC
Solvent: CO
Product: C[C@]12CC[C@H]3[C@@H](C[C@H](N)C4=CC(=O)[C@H]5CC5[C@@]43C)[C@@H]1CCC2=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 63.8 %

Procedure:
A mixture of 6α-azido-1,2β-methylenandrost-4-ene-3,17-dione (1695 mg, 5 mmol), 1,3-propanedithiol (0.25 ml, 2.5 mmol), triethylamine (0.35 ml, 2.5 mmol) and methanol (2.5 ml) is stirred for 6 hours at room temperature. Then the reaction mixture is evaporated in vacuo to dryness. The residue is taken up in ether, the etheral solution washed with water, dried and evaporated in vacuo. Column chromatography of the residue over silica gel affords the pure 6α-amino-1,2β-methylenandrost-4-ene-3,17-dione (1000 mg, 64%).
Reaction SMILES: [CH2:1]([O:4][CH:5]1[NH:9][C:8](=[O:10])[CH2:7][CH2:6]1)[CH2:2][CH3:3].[OH-].[K+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCCC1>[CH2:13]([N:9]1[CH:5]([O:4][CH2:1][CH2:2][CH3:3])[CH2:6][CH2:7][C:8]1=[O:10])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCCOC1CCC(=O)N1
Reactant: BrCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCOC1CCC(=O)N1Cc1ccccc1
Reaction time: 1 h
Yield: 61.4 %

Procedure:
To a mixture of 4 g of 5-(n-propyloxy)-pyrrolidin-2-one, 0.4 g of n-tetrabutylammonium bromide and 2.34 g of potassium hydroxide hydrated to 85% in 70 cm3 of tetrahydrofuran, there is added a solution of 4.78 g of benzyl bromide in 25 cm3 of tetrahydrofuran, operating at between 20° C. and 30° C. After agitating for 1 hour, filtering and then evaporating under reduced pressure, the residue is chromatographed on silica, (eluent: ethyl acetate--n-hexane, 1--1). 4 g of the expected product is obtained.
Reaction SMILES: [CH2:1]([C:3]1(CCC)[C:7]2[C:8]([CH3:23])=[CH:9][C:10]([CH3:22])=[C:11]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=3)[C:6]=2[O:5][CH2:4]1)[CH3:2].C([SiH](CC)CC)C.O>FC(F)(F)C(O)=O>[CH2:1]([CH:3]1[C:7]2[C:8]([CH3:23])=[CH:9][C:10]([CH3:22])=[C:11]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([CH:19]([CH3:20])[CH3:21])=[CH:17][CH:18]=3)[C:6]=2[O:5][CH2:4]1)[CH3:2]
Reactant: CCCC1(CC)COc2c(Cc3ccc(C(C)C)cc3)c(C)cc(C)c21
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCC1COc2c(Cc3ccc(C(C)C)cc3)c(C)cc(C)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a mixed solution of 3-ethyl-7-(4-isopropylbenzyl)-4,6-dimethyl-3-propyl-1-benzofuran obtained in Reference Example 183 (941 mg, 2.94 mmol) in trifluoroacetic acid (5 mL) was added dropwise triethylsilane (0.94 mL, 5.87 mmol), and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, which was extracted with ethyl acetate, and then the organic layer was washed with a saturated sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4) to obtain 940 mg (yield 99%) of the title compound. Oily matter.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[N:7]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])[C:6]2[CH:13]=[C:14]([N:18]3[C:23](=[O:24])[CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[N:20]([CH3:29])[C:19]3=[O:30])[C:15]([F:17])=[CH:16][C:5]=2[N:4]=1.S(=O)(=O)(O)O.[CH3:38][CH:39](O)[CH3:40]>>[F:32][C:2]([F:1])([F:31])[C:3]1[N:7]([CH:8]([CH3:12])[C:9]([O:11][CH:39]([CH3:40])[CH3:38])=[O:10])[C:6]2[CH:13]=[C:14]([N:18]3[C:23](=[O:24])[CH:22]=[C:21]([C:25]([F:27])([F:26])[F:28])[N:20]([CH3:29])[C:19]3=[O:30])[C:15]([F:17])=[CH:16][C:5]=2[N:4]=1
Reactant: CC(C)O
Reactant: CC(C(=O)O)n1c(C(F)(F)F)nc2cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc21
Agent: O=S(=O)(O)O
Product: CC(C)OC(=O)C(C)n1c(C(F)(F)F)nc2cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc21

Procedure:
A stirred mixture of 0.7 gram (0.002 mole) of 2-[2-trifluoromethyl-5-fluoro-6-(1-methyl-6-trifluoromethyluracil-3-yl)benzimidazol-1-yl]propanoic acid, 0.1 mL of concentrated sulfuric acid, and 1.0 gram of molecular sieves (synthetic zeolites, 4 to 8 mesh, pore size 4 angstroms) in 1-methylethanol was heated at reflux for about 18 hours. After this time, the reaction mixture was cooled and concentrated under reduced pressure to a residue. The residue was dissolved in ethyl acetate and washed with an aqueous solution saturated with sodium bicarbonate and then with an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil, which was triturated with petroleum ether, yielding solid 1-methylethyl 2-[2-trifluoromethyl-5-fluoro-6-(1-methyl-6-trifluoromethyluracil-3-yl)benzimidazol-1-yl]propanoate, mp 133°-135° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Br-].C([P+](CCCC)(CCCC)[CH2:7][C:8]1[C:9]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[N:10][C:11]([N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])=[N:12][C:13]=1[CH:14]([CH3:16])[CH3:15])CCC.[CH:38]([C@H:40]1[O:45][C:44]([CH3:47])([CH3:46])[O:43][C@@H:42]([CH2:48][C:49]([N:51]([O:53][CH3:54])[CH3:52])=[O:50])[CH2:41]1)=O.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C.CCCCCC>[CH3:22][N:17]([C:11]1[N:10]=[C:9]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:8](/[CH:7]=[CH:38]/[C@H:40]2[O:45][C:44]([CH3:46])([CH3:47])[O:43][C@@H:42]([CH2:48][C:49]([N:51]([O:53][CH3:54])[CH3:52])=[O:50])[CH2:41]2)=[C:13]([CH:14]([CH3:16])[CH3:15])[N:12]=1)[S:18]([CH3:21])(=[O:20])=[O:19]
Reactant: CON(C)C(=O)C[C@H]1C[C@@H](C=O)OC(C)(C)O1
Reactant: CCCC[P+](CCCC)(CCCC)Cc1c(-c2ccc(F)cc2)nc(N(C)S(C)(=O)=O)nc1C(C)C
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: O
Product: CON(C)C(=O)C[C@H]1C[C@@H](/C=C/c2c(-c3ccc(F)cc3)nc(N(C)S(C)(=O)=O)nc2C(C)C)OC(C)(C)O1
Reaction time: 6 h
Yield: 76.4 %

Procedure:
Tributyl[2-(N-methyl-N-methanesulfonylamino)-4-(4-fluorophenyl)-6-isopropyl-pyrimidin-5-ylmethyl]phosphonium bromide (13.9 g), 2-[(4R,6S)-6-formyl-2,2-dimethyl-[1,3]dioxan-4-yl]-N-methoxy-N-methyl-acetamide (5.0 g), dimethylformamide (100.0 mL), and potassium carbonate (8.5 g) were added to a reactor. The reaction mixture was stirred at 70˜75° C. for 6 hours. The reaction was monitored with thin layer chromatography (ethyl acetate/n-hexane=1:3). The reaction mixture was cooled to 20˜30° C. Water (60.0 mL) was added to the reaction mixture under stirring. The separated organic layer was washed with water (60.0 mL) and 2% sodium chloride solution (50.0 mL). The organic layer was concentrated under reduced pressure to remove the solvent and then isopropanol (50.0 mL) was added thereto. The reaction mixture was stirred at 0˜5° C. for over 1 hour and then filtered under reduced pressure. The resulting white solid was dried under vacuum to obtain E-(6-{2-[2-(N-methyl-N-methanesulfonylamino)-4-(4-fluorophenyl)-6-isopropyl-pyrimidin-5-yl]vinyl}-[(4R,6S)-2,2-dimethyl-[1,3]dioxan-4-yl])-N-methoxy-N-methyl-acetamide (8.8 g, yield 76%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([OH:17])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22].Cl[C:39]1[N:44]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:42]=[CH:41][N:40]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([O:17][C:39]3[N:44]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:42]=[CH:41][N:40]=3)[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22]
Reactant: FC(F)(F)c1ccnc(Cl)n1
Reactant: COc1cc2c(cc1O)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NC1CCc3ccccc31)CC2
Product: COc1ccc(CC2c3cc(Oc4nccc(C(F)(F)F)n4)c(OC)cc3CCN2CC(=O)NC2CCc3ccccc32)cc1OC

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide with 2-chloro-4-trifluoromethyl-pyrimidine
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2([CH2:14][C:15]([OH:17])=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[N+:20]([O-])([OH:22])=[O:21]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2([CH2:14][C:15]([OH:17])=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:7])=[CH:18][C:19]=1[N+:20]([O-:22])=[O:21]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)CC1(C(=O)c2ccc(Cl)cc2)CCCCC1
Product: O=C(O)CC1(C(=O)c2ccc(Cl)c([N+](=O)[O-])c2)CCCCC1

Procedure:
Prepared analogously to Example 189b from [1-(4-chloro-benzoyl)-cyclohexyl]-acetic acid and fuming nitric acid.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:10]([C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Cl)=[CH:14][CH:13]=1)[CH3:11]>C1(C)C=CC=CC=1>[CH2:10]([C:12]1[CH:19]=[CH:18][C:15]([CH2:16][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[OH:9])=[CH:14][CH:13]=1)[CH3:11]
Reactant: CCc1ccc(CCl)cc1
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCc1ccc(Cc2ccccc2O)cc1
Reaction time: 0.17 h
Yield: 61.2 %

Procedure:
A 60% dispersion of NaH/mineral oil (144 mg, 3.6 mmol) under Ar was added dropwise to a stirred solution of phenol (284 mg, 3 mmol) in PhMe (15 mL). After 10 min, p-ethylbenzyl chloride (1.23 g, 5.3 mmol) in PhMe (2 mL) was added prior to heating the reaction for 6 hr at 80°. After cooling, the volatiles were removed using a rotary evaporator and the residue dissolved in 15 mL of MeOH. The MeOH solution was extracted 4× with hexane prior to concentration. The resulting residue was dissolved in 1:1 EtOAc/H2O (100 mL), the pH adjusted to 5 and the two phases separated. After drying over Na2SO4 and removal of the EtOAc, 390 mg of crude title 2-(4′-ethylbenzyl)phenol was obtained. Prep HPLC yielded 275 mg of clean 2-(4′-ethylbenzyl)phenol.
Reaction SMILES: C(OC(OC(C)(C)C)N(C)C)(C)(C)C.[Br:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)[C:17]=1[C:34]([OH:36])=[O:35].[C:37]1(C)[CH:42]=CC=[CH:39][CH:38]=1>>[Br:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)[C:17]=1[C:34]([O:36][CH:37]([CH2:38][CH3:39])[CH3:42])=[O:35]
Reactant: Cc1ccccc1
Reactant: O=C(O)c1c(Br)c2ccccc2n1Cc1ccc(Cl)c(Cl)c1
Agent: CN(C)C(OC(C)(C)C)OC(C)(C)C
Product: CCC(C)OC(=O)c1c(Br)c2ccccc2n1Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N,N-dimethylformamide di-t-butyl acetal (19.90 ml) was added dropwise to a suspension of 3-bromo-N-(3,4-dichlorobenzyl)indole-2-carboxylic acid (8.31 g) in toluene (150 ml), under an atmosphere of argon, and stirred at ambient temperature for 2 hours. The reaction was cooled, filtered, and washed with brine (100 ml), saturated NaHCO3 (aq.) (100 ml), and brine (100 ml), dried (MgSO4) and concentrated in vacuo to afford the product as a clear oil that crystallised upon standing (7.65 g, 81%); NMR d (CD3SOCD3) 1.49 (s, 9H), 5.76 (s, 2H), 6.86 (m, 1H), 7.24 (t, 1H), 7.35-7.68 (m, 5H); M/z (+) 456 (MH−), 400.