Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=1.[C:16](=[O:18])=[O:17]>>[CH:13]1([C:9]2[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=2)[C:16]([OH:18])=[O:17])[CH2:15][CH2:14]1
Reactant: O=C=O
Reactant: Brc1cccc(C2CC2)c1
Agent: [Li]CCCC
Product: O=C(O)c1cccc(C2CC2)c1
Reaction time: 1 h

Procedure:
1.0 M Diethyl zinc in hexanes (27.3 ml, 27.3 mmol) was added to a solution of 2,4,6-trichlorophenol (5.4 g, 27.3 mmol) in dichloromethane (100 ml) at −40° C. After stirring for 15 minutes, diiodo-methane (2.2 mL, 27.3 mmol) was added at −40° C. and stirred for an additional 15 minutes. 1-Bromo-3-vinyl-benzene (2.5 g, 13.7 mmol) was then added to the reaction mixture, allowed to warm to room temperature, and left stirring overnight. The reaction mixture was diluted with dichloromethane, washed with 1N HCl (2×), saturated sodium bicarbonate (2×), saturated sodium sulfite, 1N sodium hydroxide, and saturated brine, dried over magnesium sulfate, filtered and concentrated. GC-MS revealed that the reaction mixture contained 1-Bromo-3-cyclopropyl-benzene and 1-bromo-3-vinyl-benzene. To remove the bromo-3-vinyl-benzene, the crude mixture was reacted with potassium permanganate. A solution of potassium permanganate/water (1.5 g/20 mL) was added drop-wise to a solution of the crude mixture (˜3.5 g) in THF (40 mL) at 0° C. and then allowed to warm to room temperature. After 1 hour, the reaction was diluted with diethyl ether, washed with water and saturated brine, dried over anhydrous sodium sulfate filtered and concentrated. Purication by flash column chromatography eluted with 100 hexanes afforded 1-bromo-3-cyclopropyl-benzene (2.20 g, 81%). 1.6 M n-Butyllithium in hexanes (3.2 mL, 5.1 mmol) was added drop-wise to a solution of 1-bromo-3-cyclopropyl-benzene at −78° C. and stirred for 1 hour. This reaction mixture was then transferred via canula to a 250 mL round bottom flask equipped with a stirrer bar approximately ¼ full of solid carbon dioxide and stirred and for 1 hour. The reaction mixture was concentrated and then the residue was diluted with water. The aqueous layer was washed with dichloromethane (3×), acidified with 1 N HCl to pH˜2, and extracted with ethyl acetate. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford 3-cyclopropyl-benzoic (356 mg, 43%, white solid). 1H NMR (DMSO), δ (ppm): 12.90 (bs, 1H), 7.71 (d, 1H), 7.64 (s, 1H), 7.34 (m, 2H), 2.01 (m, 1H), 0.99 (m, 2H), 0.70 (m, 2H).
Reaction SMILES: [C:1]([C:3]1([C:13]2[N:18]=[CH:17][C:16]([NH:19][C:20]([C:22]3[CH:23]=[N:24][N:25]([C:27]4[CH:32]=[CH:31][C:30]([CH:33]([CH3:35])[CH3:34])=[CH:29][CH:28]=4)[CH:26]=3)=[O:21])=[CH:15][CH:14]=2)[CH2:12][CH2:11][C:6]2(OCC[O:7]2)[CH2:5][CH2:4]1)#[N:2].O.Cl.C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C>[C:1]([C:3]1([C:13]2[N:18]=[CH:17][C:16]([NH:19][C:20]([C:22]3[CH:23]=[N:24][N:25]([C:27]4[CH:28]=[CH:29][C:30]([CH:33]([CH3:35])[CH3:34])=[CH:31][CH:32]=4)[CH:26]=3)=[O:21])=[CH:15][CH:14]=2)[CH2:12][CH2:11][C:6](=[O:7])[CH2:5][CH2:4]1)#[N:2]
Reactant: CC(C)c1ccc(-n2cc(C(=O)Nc3ccc(C4(C#N)CCC5(CC4)OCCO5)nc3)cn2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)c1ccc(-n2cc(C(=O)Nc3ccc(C4(C#N)CCC(=O)CC4)nc3)cn2)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 101 %

Procedure:
A solution of N-[6-(8-cyano-1,4-dioxaspiro[4.5]dec-8-yl)pyridin-3-yl]-1-(4-isopropylphenyl)-1H-pyrazole-4-carboxamide (236 mg) in a mixture of acetic acid (5 ml), water (1 ml) and 1N hydrochloric acid aqueous solution (1 ml) was stirred at 100° C. for two hours. After completion of the reaction, a saturated aqueous solution of potassium carbonate was added and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified with column chromatography to give the titled compound (216 mg).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([CH:7]([CH3:13])[C:8]([O:10]CC)=O)[C:3]1=[O:14].[CH3:15][C@H:16]1[CH2:21][CH2:20][CH2:19][C@@H:18]([CH3:22])[N:17]1[CH2:23][CH2:24][NH2:25]>>[CH3:15][C@H:16]1[CH2:21][CH2:20][CH2:19][C@@H:18]([CH3:22])[N:17]1[CH2:23][CH2:24][NH:25][C:8](=[O:10])[CH:7]([N:4]1[CH2:5][CH2:6][CH:2]([OH:1])[C:3]1=[O:14])[CH3:13]
Reactant: C[C@@H]1CCC[C@H](C)N1CCN
Reactant: CCOC(=O)C(C)N1CCC(O)C1=O
Product: CC(C(=O)NCCN1[C@H](C)CCC[C@@H]1C)N1CCC(O)C1=O

Procedure:
1.5 g of ethyl (R/S)-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)propionate are left to stand at room temperature for 24 hours with 2.45 g of cis-2-(2,6-dimethyl-1-piperidinyl)ethylamine. Thereafter, the excess cis-2-(2,6-dimethyl-1-piperidinyl)ethylamine is distilled off in a high vacuum and the residue (3.5 g) is chromatographed on 30 g of silica gel (granular size 0.2-0.5 mm). The (R/S)-cis-N-[2-(2,6-dimethyl-1-piperidinyl)ethyl]-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)propionamide which is eluted with methanol has a melting point of 129°-130° after recrystallization from ethyl acetate.
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:8]=[N:9][C:10]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:11][CH:12]=1)(=O)=O.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>CN(C=O)C.O>[O:24]1[CH2:25][CH2:26][N:21]([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:15])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[N:9][CH:8]=2)[CH2:22][CH2:23]1
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)Nc1ccc(COS(C)(=O)=O)cn1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(CN2CCOCC2)cn1
Temperature: 80 °C
Reaction time: 4 h
Yield: 95.4 %

Procedure:
A mixture containing (6-(tert-butoxycarbonylamino)pyridin-3-yl)methyl methanesulfonate (102; 1.21 g, 5.0 mmol), morpholine (48; 1.31 g, 15.0 mmol), K2CO3 (2.10 g, 15.0 mmol) and NaI (0.12 g, 0.75 mmol) in DMF (30 mL) was stirred at 80° C. for 4 h. Upon cooling to room temperature, water (30 mL) was added and the mixture was extracted with ethyl acetate (3×30 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The resulting residue was purified by chromatography (petroleum ether:ethyl acetate=10:1 to 1:1) to afford tert-butyl 5-(morpholinomethyl)pyridin-2-ylcarbamate 107 (1.40 g, 95%).
Reaction SMILES: Br[CH2:2][C:3]([CH2:8][CH3:9])([CH2:6][CH3:7])[CH2:4][OH:5].[S-:10][C:11]#[N:12].[K+].CN(C)C=O.C(OCC)C>O>[OH:5][CH2:4][C:3]([CH2:8][CH3:9])([CH2:6][CH3:7])[CH2:2][S:10][C:11]#[N:12]
Reactant: N#C[S-]
Reactant: CCC(CC)(CO)CBr
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: CCC(CC)(CO)CSC#N
Temperature: 130 °C
Reaction time: 7 h
Yield: 98.6 %

Procedure:
A mixture of 3-bromo-2,2-diethyl-1-propanol (23.3 g), potassium thiocyanate (17.5 g) and dimethylformamide (80 ml) was stirred for 7 hours at 130° C. The reaction solution was cooled to room temperature, to which a mixture of diethyl ether (50 ml) and water (100 ml) were added. The ethernal layer was collected. The aqueous layer was extracted with 80 ml of diethyl ether. The combined ethernal layers were washed with a saturated saline, dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was distilled under reduced pressure to obtain 3-hydroxy-2,2-diethyl-1-propylthiocyanate (20.4 g) as oil.
Reaction SMILES: [NH:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)C(C)=O.[OH-].[K+].[C:14](=[O:16])=[O:15]>>[NH2:1][C:5]1[CH:6]=[C:7]([C:14]([OH:16])=[O:15])[C:8]([OH:11])=[CH:9][CH:10]=1
Reactant: O=C=O
Reactant: CC(=O)Nc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Product: Nc1ccc(O)c(C(=O)O)c1
Temperature: 210 °C
Yield: 92 %

Procedure:
p-Acetaminophenol 15 g, potassium hydroxide 37.5 g, and diatomite 90 g were added into a 500 ml autoclave, and CO2 was introduced to perform a carboxylation reaction under a reaction pressure of 5.0 MPa and heated to 210° C., maintained for 1 hour, then the reaction was terminated, cooled to 80° C., and 1500 ml distilled water was added to dissolve potassium 5-aminosalicylate. After decolorization, the aqueous phase was acidified with 20˜30% sulfuric acid until pH=4, cooled and then filtered to obtain the product of 5-aminosalicylic acid, the content is 96% and the yield is 92%.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[O:22])[NH:12][C:13]1[S:14][CH:15]=[C:16]([S:18]([CH3:21])(=[O:20])=[O:19])[N:17]=1)(=O)C>Cl>[OH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([NH:12][C:13]1[S:14][CH:15]=[C:16]([S:18]([CH3:21])(=[O:20])=[O:19])[N:17]=1)=[O:22]
Reactant: CC(=O)Oc1ccccc1C(=O)Nc1nc(S(C)(=O)=O)cs1
Agent: Cl
Product: CS(=O)(=O)c1csc(NC(=O)c2ccccc2O)n1

Procedure:
2-{[4-(methylsulfonyl)-1,3-thiazol-2-yl]carbamoyl}phenyl acetate (62, 118.2 mg, 0.3473 mmol) was suspended in conc. hydrochloric acid (2.0 mL) and stirred rapidly. The slurry become homogenous momentarily, and then re-precipitates. The suspension was stirred rapidly at 50° C. for 16 hours before cooling, and filtering on a fine fritted funnel. The solids were washed with water (ca. 5 mL), and dried in vacuo to give 60 as a colorless powder.
Reaction SMILES: Cl.Cl[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][N:15]=2)=[N:5][N:4]=1.[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1.C([O-])(O)=O.[Na+]>ClCCl.CO>[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][C:3]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]([CH2:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][N:15]=3)=[N:5][N:4]=2)=[CH:23][CH:22]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: Clc1nnc(Cc2ccncn2)c2ccccc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Clc1ccc(Nc2nnc(Cc3ccncn3)c3ccccc23)cc1

Procedure:
A mixture of 100 mg (0.45 mmol) 1-chloro-4-(4-pyrimidinylmethyl)phthalazine hydrochloride and 149 mg (1.17 mmol) 4-chloroaniline is heated for 1.5 h to 100° C. The reaction mixture is distributed between dichloromethane/CH3OH, 19:1 and sat. NaHCO3 solution. The organic phase is separated off, washed with water and brine, dried (Na2SO4), and concentrated by evaporation. Chromatography (SiO2; ethyl acetate/CH3OH, 19:1) and crystallization from ethyl acetate/ether yield the title compound: m.p.: 174-176° C.; FAB MS (M+H)+=348. The starting material is prepared as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:14])[C:10]=1[O:11][CH2:12][CH3:13])[C:5]([OH:7])=O.[NH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([Cl:26])[CH:17]=1>>[Cl:14][C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([Cl:1])[C:10]=1[O:11][CH2:12][CH3:13])[C:5]([NH:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([Cl:26])[CH:17]=1)=[O:7]
Reactant: CCOc1c(Cl)cc(C(=O)O)cc1Cl
Reactant: COC(=O)c1ccc(N)cc1Cl
Product: CCOc1c(Cl)cc(C(=O)Nc2ccc(C(=O)OC)c(Cl)c2)cc1Cl
Yield: 39 %

Procedure:
Methyl 4-(3,5-dichloro-4-ethoxybenzamido)-2-chlorobenzoate (AAA-017) (175 mg, 39%) was prepared in essentially the same manner as in Step (iii) for AAA-001, except that 3,5-dichloro-4-ethoxybenzoic acid was used instead of 3,5-dichloro-4-(cyclopentyloxy)benzoic acid and methyl 4-amino-2-chlorobenzoate was used instead of methyl 4-aminobenzoate: m/z 402 (M−H)− (ES−). 1H NMR (400 MHz, CDCl3) δ: 7.93 (2H, d), 7.85 (1H, s), 7.83 (1H, d), 7.80 (2H, s), 4.18 (2H, q), 3.93 (3H, s), 1.49 (3H, t).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:5])[CH2:3][OH:4].[Cl:6][C:7]1[CH:12]=[C:11]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=3F)[N:17]=[CH:16][N:15]=2)[CH:10]=[CH:9][C:8]=1[OH:25]>>[NH2:1][C@@H:2]([CH3:5])[CH2:3][O:4][C:22]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:23]=1[C:14]([NH:13][C:11]1[CH:10]=[CH:9][C:8]([OH:25])=[C:7]([Cl:6])[CH:12]=1)=[N:15][CH:16]=[N:17]2
Reactant: Oc1ccc(Nc2ncnc3cccc(F)c23)cc1Cl
Reactant: C[C@H](N)CO
Product: C[C@H](N)COc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12
Yield: 54 %

Procedure:
The procedure described in Example 3 (preparation of starting materials) was repeated using (2S)-2-aminopropan-1-ol and 2-chloro-4-[(5-fluoroquinazolin-4-yl)amino]phenol (obtained as described in Example 4.5, preparation of starting materials) to give 4-[(5-{[(2S)-2-aminopropyl]oxy}quinazolin-4-yl)amino]-2-chlorophenol in 54% yield; NMR spectrum (DMSO-d6); 1.30 (d, 3H), 3.30 (bs, 2H), 3.80 (m, 1H), 4.40 (m, 2H), 7.00 (d, 1H), 7.20 (d, 1H), 7.30 (d, 1H), 7.50 (dd, 1H), 7.70 (t, 1H), 8.00 (d, 1H), 8.45 (s, 1H); Mass spectrum MH+ 345.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:29](=[O:30])[C:28]3[CH:32]=[CH:33][C:25]([Cl:24])=[CH:26][CH:27]=3)=[CH:19][CH:20]=2)[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1[C@@H](CCc2ccc(N)cc2)COC1(C)C
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@@H](CCc2ccc(NC(=O)c3ccc(Cl)cc3)cc2)COC1(C)C
Temperature: 50 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
To a stirred solution of (S)-4-[2-(4-amino-phenyl)-ethyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (20) in THF (4 ml) were added 4-chlorobenzoic acid (147 mg), N-methylmorpholine (0.27 ml) and TBTU (401 mg). The reaction mixture was heated to 50° C. and stirred for 16 h. The reaction mixture was then concentrated in vacuo and the residue was purified by flash column chromatography (SiO2; gradient: EtOAc/heptane) to afford (S)-4-{2-[4-(4-chloro-benzoylamino)-phenyl]-ethyl}-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester as a white solid (254 mg, 89%). MS (ISP): 478.3 ([{37Cl}M+NH4]+), 476.3 ([{35Cl}M+NH4]+), 405.4 ([{37Cl}M+H—C4H8]+), 403.2 ([{35Cl}M+H—C4H8]+).
Reaction SMILES: Br[CH:2]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=O.[CH2:22]([NH:28][C:29]([NH2:31])=[S:30])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>C(O)C>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:31]=[C:29]([NH:28][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[S:30][C:2]=2[C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(C(Br)C(=O)c2ccc(F)cc2)cc1
Reactant: CCCCCCNC(N)=S
Solvent: CCO
Product: CCCCCCNc1nc(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)s1
Temperature: 25 °C
Yield: 71.9 %

Procedure:
To a solution of 2-bromo-1-(4-fluorophenyl)-2-(4-methylsulfonylphenyl)ethanone (Example 26, Step 2) (0.503 g, 1.35 mmol) in ethanol (10 mL) in a 25 mL round bottom flask was added N-hexylthiourea (0.239, 1.49 mmol). The solution was heated to reflux for 14 hours and the reaction was cooled to room temperature. The resulting suspension was concentrated in vacuo, suspended in methylene chloride (100 mL) and washed with NaHCO3 saturated solution (3×10 mL), dried over sodium sulfate, filtered and concentrated yielding 4-(4-fluorophenyl)-2-n-hexylamino-5-(4-methylsulfonylphenyl)thiazole (0.420 g, 72%) as a white powder: mp 161°-162° C., 1HNMR (DMSO d6) 400 mHz 7.95 (t, J=5.38 Hz, 1 H), 7.77 (d, J=8.79 Hz, 2 H), 7.44-7.36 (m, 4 H), 7.15 (t, J=9.28, 2 H), 3.24 (q , J=5.86, 2H), 3.18 (s, 3 H), 1.61-1.52 (m, 2 H), 1.38-1.20 (m, 6 H), 0.85 (t, J=6.84 Hz, 3 H); MS
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@@H:4]([O:14][CH2:15][CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[Cl:13].[C:18]([C:22]1[O:23][C:24]([CH3:29])=[C:25]([CH2:27]Cl)[N:26]=1)([CH3:21])([CH3:20])[CH3:19].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[CH3:1][O:2][C:3](=[O:17])[C@@H:4]([O:14][CH2:15][CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:27][C:25]2[N:26]=[C:22]([C:18]([CH3:21])([CH3:20])[CH3:19])[O:23][C:24]=2[CH3:29])=[CH:8][C:7]=1[Cl:13]
Reactant: CCO[C@@H](Cc1ccc(O)cc1Cl)C(=O)OC
Reactant: Cc1oc(C(C)(C)C)nc1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Product: CCO[C@@H](Cc1ccc(OCc2nc(C(C)(C)C)oc2C)cc1Cl)C(=O)OC

Procedure:
In analogy to the procedure described in example 46 c], (2S)-3-(2-chloro-4-hydroxy-phenyl)-2-ethoxy-propionic acid methyl ester was reacted with 2-tert-butyl-4-chloromethyl-5-methyl-oxazole (example 1, step b]) in the presence of cesium carbonate and potassium iodide to yield (S)-3-[4-(2-tert-butyl-5-methyl-oxazol-4-ylmethoxy)-2-chloro-phenyl]-2-ethoxy-propionic acid methyl ester as colorless liquid.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:8]([C:11]1[CH:12]=[CH:13][C:14](Cl)=[N:15][CH:16]=1)([O-:10])=[O:9].C(OCC)C>[OH-].[Na+].C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[N+:8]([C:11]1[CH:12]=[CH:13][C:14]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:15][CH:16]=1)([O-:10])=[O:9]
Reactant: Oc1ccccc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: O=[N+]([O-])c1ccc(Oc2ccccc2)nc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 48.7 %

Procedure:
Phenol (0.9 g, 9.5 mmol) was dissolved in sodium hydroxide (50% solution, 12 mL). 5-Nitro-2-chloropyridine (1.5 g, 9.5 mmol) in toluene (15 mL) was added followed by addition of tetrabutylammonium bromide (0.3 g, 0.95 mmol). The reaction mixture was stirred for 16 hours at 20° C. and 5 hours at 80° C. where after it was cooled to room temperature and diethyl ether (100 mL) added. The organic phase was washed with water (5×50 mL), dried (MgSO4), and concentrated in vacuo to give 1.0 g of 5-nitro-2-phenoxypyridine.
Reaction SMILES: [C:1]12[C:12]([O:13][CH:14]3[CH2:19][CH2:18][CH:17]([NH:20]C(=O)OCCCC)[CH2:16][CH2:15]3)=[CH:11][CH:10]=[CH:9][C:8]=1[S:7][C:6]1[CH2:5][CH2:4][CH2:3][C:2]2=1.Cl.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[C:1]12[C:12]([O:13][CH:14]3[CH2:19][CH2:18][CH:17]([NH2:20])[CH2:16][CH2:15]3)=[CH:11][CH:10]=[CH:9][C:8]=1[S:7][C:6]1[CH2:5][CH2:4][CH2:3][C:2]2=1
Reactant: CCCCOC(=O)NC1CCC(Oc2cccc3sc4c(c23)CCC4)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: NC1CCC(Oc2cccc3sc4c(c23)CCC4)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
Into a 50-mL round-bottom flask placed ten-butyl N-(4-[7-thiatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yloxy]cyclohexyl)carbamate (200 mg, 0.52 mmol, 1.00 equiv) in 16 mL of dichloromethane was added hydrochloric acid (0.5 mL) at 0° C. The resulting solution was stirred for 2 h at room temperature. Then the pH value was adjusted to 8-9 with saturated aqueous sodium carbonate and extracted with 3×50 mL of ethyl acetate and the organic layers combined. The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give the resulted 4-[7-thiatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yloxy]cyclohexan-1-amine (140 mg, 90% purity) as a white solid which was used for next step without further purification. MS (ES, m/z): 290 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH2:18][CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:31]([Si:34](OS(C(F)(F)F)(=O)=O)([CH:38]([CH3:40])[CH3:39])[CH:35]([CH3:37])[CH3:36])([CH3:33])[CH3:32].C([O-])(O)=O.[Na+]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([Si:34]([CH:38]([CH3:40])[CH3:39])([CH:35]([CH3:37])[CH3:36])[CH:31]([CH3:33])[CH3:32])[CH:13]=[C:12]2[CH2:18][CH2:19][N:20]1[C:21](=[O:30])[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:28]1=[O:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1CCc1c[nH]c2ccc(OCc3ccccc3)cc12
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(CCN2C(=O)c3ccccc3C2=O)c2cc(OCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Combine a mixture of an oil dispersion of KH (40%, 1 g) in 30 mL anhydrous THF and a suspension of 2-(2-(5-benzyloxy-1H-indol-3-yl)ethyl)isoindole-1,3-dione (1.2 g, 3 mmol) in 30 mL THF portionwise. Stir for 1 hour at ambient temperature, cooled to 0° C., add triisopropylsilyltrifluoromethanesulfonate (1.85 g, 6 mmol) and stir an additional 1 hour at ambient temperature. Pour the reaction into a rapidly stirring solution of saturated NaHCO3 and extract with 2×50 mL EtOAc. Combine the organic layer, dry over MgSO4 and concentrate to dryness and chromatograph on silica gel eluting with 1% MeOH in CHCl3 to give 2-(2-(5-benzyloxy-1-triisopropylsilanyl-1H-indol-3-yl)ethyl)isoindole-1,3-dione as an oil.
Reaction SMILES: [O-2].[Mg+2:2].[C:3]([OH:15])(=[O:14])[CH2:4][C:5]([CH2:10][C:11]([OH:13])=[O:12])([C:7]([OH:9])=[O:8])[OH:6]>C(O)C>[C:3]([O-:15])(=[O:14])[CH2:4][C:5]([CH2:10][C:11]([O-:13])=[O:12])([C:7]([O-:9])=[O:8])[OH:6].[Mg+2:2].[C:3]([O-:15])(=[O:14])[CH2:4][C:5]([CH2:10][C:11]([O-:13])=[O:12])([C:7]([O-:9])=[O:8])[OH:6].[Mg+2:2].[Mg+2:2]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Mg+2]
Agent: [O-2]
Solvent: CCO
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Reaction time: 2 h
Yield: 97 %

Procedure:
9.4 grams (0.24 Mole) of magnesium oxide and 30 grams (0.16 Mole) of citric acid were placed into a beaker provided with a reflux condenser. 80 ml ethanol was added and the mixture was stirred and boiled at atmospheric pressure for 2 hours. The reaction mixture was cooled and thereafter filtered yielding 35 grams of magnesium citrate having the physical characteristic of a fine white powder.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[N:10](CC=C)[C:9]=2[C:8](=[O:18])[NH:7][C:6]1=[O:19])[CH2:2][CH2:3][CH3:4].[C:20]1([CH2:26][C:27]2[N:31]=[C:30]([CH2:32][CH2:33][CH2:34]O)[O:29][N:28]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1.N1CCOCC1>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:18])[N:7]([CH2:34][CH2:33][CH2:32][C:30]2[O:29][N:28]=[C:27]([CH2:26][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:31]=2)[C:6]1=[O:19])[CH2:2][CH2:3][CH3:4]
Reactant: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCCC
Reactant: OCCCc1nc(Cc2ccccc2)no1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: CCCCn1c(=O)n(CCCc2nc(Cc3ccccc3)no2)c(=O)c2[nH]c(Cl)nc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 23.2 %

Procedure:
A solution of 3-butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (205 mg, 0.73 mmol) in anhydrous THF (4 ml) was treated with 3-[3-(phenylmethyl)-1,2,4-oxadiazol-5-yl]-1-propanol (190 mg, 0.87 mmol) and PPh3 (247 mg, 0.94 mmol). DBAD (217 mg, 0.94 mmol) was added in one portion and the mixture was stirred at rt under nitrogen for 18 h. The mixture was degassed by high vacuum then Pd(PPh3)4 (84 mg, 0.073 mmol) and morpholine (636 μl, 7.3 mmol) were added. The mixture was stirred at rt under nitrogen for 3 h. The mixture was partitioned between EtOAc and 2M HCl (aq) and the organic layer separated, washed with brine, dried (MgSO4) and concentrated. The crude material was purified by an aminopropyl column using MeOH to load the compound onto the column and wash through the impurities, then with 2-4% AcOH/MeOH gradient to remove the compound from the column. Further purification was effected by MDAP to give the title compound as a white solid (75 mg, 23%).