Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:22])[N:13]([C:15]3[N:20]=[CH:19][NH:18][C:17](=[O:21])[CH:16]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1.CI.[C:25](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:22])[N:13]([C:15]3[N:20]=[CH:19][N:18]([CH3:25])[C:17](=[O:21])[CH:16]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)cn1-c1cc(=O)[nH]cn1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1-c1cc(=O)n(C)cn1
Temperature: 25 °C
Yield: 11.2 %

Procedure:
To a solution of 50.0 mg (0.160 mmol) of 6-[4-(2-chloro-pyridin-4-ylethynyl)-2-methyl-imidazol-1-yl]-3H-pyrimidin-4-one and 0.020 ml (45.5 mg, 0.321 mmol) of methyl iodide in 10 ml of acetone were added 44 mg (0.321 mmol) of potassium carbonate. The suspension was stirred for 48 at room temperature. The suspension was filtered and the salts were washed with acetone. The filtrate was concentrated in vaccuo. The residue was dissolved in ethyl acetate/methanol, 1 g of silicagel was added and the suspension was concentrated in vaccuo. The silicagel containing adsorbed product was loaded onto a flash chromatography column and eluted with a 90:10 mixture of ethyl acetate and methanol. One obtains 6 mg (0.018 mmol, 11.5%) of the title compound as a crystalline light yellow solid, MS: 326.2, 328.2 (M+H+) separated from the undesired O-alkylation product.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][C:6]2[C:9]3[C:14]([NH:15][C:16]4[CH:25]=[CH:24][C:19]5[NH:20][C:21](=[O:23])[S:22][C:18]=5[CH:17]=4)=[N:13][CH:12]=[N:11][C:10]=3[S:26][C:5]=2[CH2:4]1.[OH:27][C:28]([CH3:33])([CH3:32])[C:29](O)=[O:30]>>[OH:27][C:28]([CH3:33])([CH3:32])[C:29]([NH:1][CH2:2][CH:3]1[CH2:8][CH2:7][C:6]2[C:9]3[C:14]([NH:15][C:16]4[CH:25]=[CH:24][C:19]5[NH:20][C:21](=[O:23])[S:22][C:18]=5[CH:17]=4)=[N:13][CH:12]=[N:11][C:10]=3[S:26][C:5]=2[CH2:4]1)=[O:30]
Reactant: NCC1CCc2c(sc3ncnc(Nc4ccc5[nH]c(=O)sc5c4)c23)C1
Reactant: CC(C)(O)C(=O)O
Product: CC(C)(O)C(=O)NCC1CCc2c(sc3ncnc(Nc4ccc5[nH]c(=O)sc5c4)c23)C1

Procedure:
10 mg (130 μmol) (RS)-6-{[7-(aminomethyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-yl]amino}-1,3-benzothiazol-2(3H)-one (prepared according to example 20) were transformed in analogy to example 23 using 2-hydroxy-2-methylpropanoic acid to give after working up and purification 23.8 mg (38%) of the title compound.
Reaction SMILES: [CH3:1][C@@H:2]1[C@@H:41]([OH:42])[C@@H:40]([CH3:43])[C@H:39]([CH3:44])[O:38][C:36](=[O:37])[CH2:35][C@H:34]([OH:45])[CH2:33][C@H:32]([OH:46])[CH2:31][CH2:30][C@@H:29]([OH:47])[C@H:28]([OH:48])[CH2:27][C@H:26]([OH:49])[CH2:25][C@@:23]2([OH:50])[O:24][C@H:19]([C@H:20]([C:52]([OH:54])=[O:53])[C@@H:21]([OH:51])[CH2:22]2)[CH2:18][C@@H:17]([O:55][C@@H:56]2[O:61][C@H:60]([CH3:62])[C@@H:59]([OH:63])[C@H:58]([NH2:64])[C@@H:57]2[OH:65])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=[CH:3]1.[Cl-].[Cl-].[Ca+2:68].Cl.[C:70]([OH:77])(=[O:76])[CH2:71][CH2:72][C:73]([OH:75])=[O:74].[NH4+].[OH-]>CO>[CH3:1][C@@H:2]1[C@@H:41]([OH:42])[C@@H:40]([CH3:43])[C@H:39]([CH3:44])[O:38][C:36](=[O:37])[CH2:35][C@H:34]([OH:45])[CH2:33][C@H:32]([OH:46])[CH2:31][CH2:30][C@@H:29]([OH:47])[C@H:28]([OH:48])[CH2:27][C@H:26]([OH:49])[CH2:25][C@@:23]2([OH:50])[O:24][C@H:19]([C@H:20]([C:52]([OH:54])=[O:53])[C@@H:21]([OH:51])[CH2:22]2)[CH2:18][C@@H:17]([O:55][C@@H:56]2[O:61][C@H:60]([CH3:62])[C@@H:59]([OH:63])[C@H:58]([NH2:64])[C@@H:57]2[OH:65])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=[CH:3]1.[Ca:68].[C:70]([OH:77])(=[O:76])[CH2:71][CH2:72][C:73]([OH:75])=[O:74]
Reactant: [Ca+2]
Agent: C[C@@H]1[C@H](O)[C@@H](C)/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](O[C@@H]2O[C@H](C)[C@@H](O)[C@H](N)[C@@H]2O)C[C@@H]2O[C@](O)(C[C@@H](O)C[C@@H](O)[C@H](O)CC[C@@H](O)C[C@@H](O)CC(=O)O[C@H]1C)C[C@H](O)[C@H]2C(=O)O
Agent: C[C@@H]1[C@H](O)[C@@H](C)C=CC=CC=CC=CC=CC=CC=C[C@H](O[C@@H]2O[C@H](C)[C@@H](O)[C@H](N)[C@@H]2O)C[C@@H]2O[C@](O)(C[C@@H](O)C[C@@H](O)[C@H](O)CC[C@@H](O)C[C@@H](O)CC(=O)O[C@H]1C)C[C@H](O)[C@H]2C(=O)O
Agent: Cl
Solvent: CO
Product: [Ca]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10.66 g amphotericin B (938γ/mg of activity-equivalent to 10 g of chemical activity) suspended in 2.5 liters of anhydrous methanol containing 11.1 ml of 5% CaCl2 in methanol (equivalent to 200 mg Ca ion) is solubilized by means of 1.8 ml of 5.8 N HCl (pH 3.9). To the resulting solution are added 100 ml of methanol containing 10 g of reagent grade succinic acid to form a mixture of pH 3.2. The pH of the mixture is adjusted to about 7 by the addition of 7.7 ml concentrated NH4OH. The mixture is then heated to 45°-50° C. and slurried for 1 hour and thereafter is cooled to room temperature, filtered and the wet cake dried overnight under vacuum at 45° C. to yield 9.1 g of crystalline complex.
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[C:10]([N:29]1[CH:33]=[C:32]([CH:34]=[O:35])[N:31]=[CH:30]1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl>O1CCCC1.[Cl-].C[SiH](C)C.[Zn]>[OH:35][CH:34]([C:32]1[N:31]=[CH:30][N:29]([C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:33]=1)[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: C[SiH](C)C
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.6 %

Procedure:
2.15 ml (14.5 mmol) of tert-butyl bromoacetate are added dropwise to a solution of 1 g (15.3 mmol) of zinc 20 mesh in 20 ml of tetrahydrofuran, stirred for 15 min with a few drops of trimethylsilane chloride. After stirring for 15 minutes at ambient temperature, the temperature of the mixture is kept at 50° C. for 1 hour. After a return to ambient temperature, a solution containing 1.2 g (3.6 mmol) of 1-trityl-1H-imidazole-4-carbaldehyde in 10 ml of THF is added. The reaction medium is stirred for 6 h at ambient temperature, and then treated with a 1N aqueous solution of hydrochloric acid and extracted with ethyl acetate. The organic phase is washed successively with a saturated aqueous solution of sodium hydrogen carbonate and then with water. After drying over magnesium sulphate and filtration, the solvent is evaporated off. The residue obtained is precipitated from diisopropyl ether and filtered off. 1.4 g of tert-butyl 3-hydroxy-3-(1-trityl-1H-imidazol-4-yl)propanoate are obtained in the form of a white powder with a yield of 84%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[CH:22])=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:23].Cl[C:25]1[S:26][C:27]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:28][N:29]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:15])([F:17])[F:16])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[C:22][C:25]4[S:26][C:27]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:28][N:29]=4)=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:23]
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)c(C)c3)nc12
Reactant: NS(=O)(=O)c1cnc(Cl)s1
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C#Cc4ncc(S(N)(=O)=O)s4)c3n2)ccc1Cl

Procedure:
The title compound was prepared from 5-(4-chloro-3-methyl-phenyl)-3-ethynyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (example C.1) (336 mg, 1.0 mmol) and 2-chloro-thiazole-5-sulfonamide (199 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (209 mg, 42%). MS (ISN) 496.0 [(M−H)−]; mp 123° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH2:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[C:13]([C:16]1[CH:17]=[C:18]([CH:29]=[CH:30][CH:31]=1)[O:19][C:20]1[N:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](O)=[O:23])(=[O:15])[CH3:14].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=N)C.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[C:13]([C:16]1[CH:17]=[C:18]([CH:29]=[CH:30][CH:31]=1)[O:19][C:20]1[N:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([S:9](=[O:10])(=[O:11])[NH2:12])=[CH:7][CH:8]=1)=[O:23])(=[O:15])[CH3:14]
Reactant: NCc1ccc(S(N)(=O)=O)cc1
Reactant: CC(=O)c1cccc(Oc2ncccc2C(=O)O)c1
Agent: CCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)c1cccc(Oc2ncccc2C(=O)NCc2ccc(S(N)(=O)=O)cc2)c1
Temperature: 25 °C

Procedure:
A solution of 4-Aminomethyl-benzenesulfonamide (0.248 grams, 1.11 mmole), 2-(3-Acetyl-phenoxy)-nicotinic acid (0.300 grams, 1.167 mmole), 1-hydroxybenzotriazole hydrate (0.165 grams, 1.22 mmole) and 1-(3-dimethylamino)-propyl)-3-ethylcarbodiimide hydrochloride (0.256 grams, 1.33 mmole) in dimethylformamide (15 ml) was stirred for 10 minutes. To the stirring solution was added triethyl amine (0.280 grams, 2.78 mmole) and stirred over night at room temperature. The mixture was diluted with ethyl acetate and washed with water and brine, dried over MgSO4, filtered and concentrated to give a solid. Recrystalization from ethyl acetate/hexane gave a solid. (0.280 g); M.P.162-164° C.; MS (m/e) 425 (M+).
Reaction SMILES: [CH3:1]N(C=O)C.[Br:6][C:7]1[C:8](=[O:15])[NH:9][C:10]([CH3:14])=[C:11]([Br:13])[CH:12]=1.CI.C([O-])([O-])=O.[K+].[K+]>O>[Br:6][C:7]1[C:8](=[O:15])[N:9]([CH3:1])[C:10]([CH3:14])=[C:11]([Br:13])[CH:12]=1
Reactant: CN(C)C=O
Reactant: Cc1[nH]c(=O)c(Br)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: Cc1c(Br)cc(Br)c(=O)n1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 78 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with DMF (50 mL), 327c (10.0 g, 37.5 mmol), CH3I (5.3 g, 37.5 mmol), and K2CO3 (7.8 g, 56.2 mmol). The mixture was stirred at room temperature for 5 h. Water (100 mL) was added and the resulting white solid was collected to afford 327d (8.2 g, 78%) as a white solid. MS-ESI: [M+H]+ 280.
Reaction SMILES: [ClH:1].[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH:10]1[NH:16][C:15](=[NH:17])[CH2:14][CH2:13][CH2:12][CH2:11]1.C(O)C.[H][H]>Cl.[Pt]=O>[ClH:1].[ClH:1].[NH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][CH2:9][CH:10]1[NH:16][C:15](=[NH:17])[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: [H][H]
Reactant: N=C1CCCCC(CCc2ccccn2)N1
Agent: O=[Pt]
Agent: Cl
Solvent: CCO
Product: N=C1CCCCC(CCC2CCCCN2)N1
Yield: 109.4 %

Procedure:
The product of Example 290 (138 mg, 0.5 mmol), platinum oxide (100 mg), conc HCl (0.5 mL) and ethanol (30 mL) were shaken on a Parr hydrogenator at 55 psi of hydrogen overnight. Filtration and concentration in vacuo gave a colorless oil. The oil was purified by C-18 reverse phase chromatography eluting with a CH3CN/H2O (0.05% TFA) gradient to give a white solid. The solid was dissolved in 1N HCl and lyophilized to afford the title product as a colorless foam (81 mg, 55% yield).
Reaction SMILES: CON(C)[C:4]([C@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:5].[CH2:19]([O:26][C:27]1[CH:32]=[CH:31][C:30]([Mg]Br)=[CH:29][CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[CH2:19]([O:26][C:27]1[CH:32]=[CH:31][C:30]([C:4]([C@H:6]2[CH2:10][CH2:9][CH2:8][N:7]2[C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])=[O:5])=[CH:29][CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Br[Mg]c1ccc(OCc2ccccc2)cc1
Reactant: CON(C)C(=O)[C@H]1CCCN1C(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 65 °C
Yield: 50.4 %

Procedure:
To (R)-tert-butyl 2-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate (716 mg, 2.77 mmol) in THF (27.700 mL) at 0° C. was added (4-(benzyloxy)phenyl)magnesium bromide (8.32 mL, 16.63 mmol) dropwise. After complete addition, the solution was heated to 65° C. for 1 h. The reaction was cooled to 0° C., quench carefully with 1N HCl and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (5%→60% ethyl acetate in hexanes) to afford (R)-tert-butyl 2-(4-(benzyloxy)benzoyl)pyrrolidine-1-carboxylate (533 mg, 1.397 mmol, 50.4% yield) as an amorphous yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.87-8.00 (m, 2H), 7.29-7.47 (m, 5H), 6.95-7.07 (m, 2H), 5.13-5.31 (m, 1H), 5.10-5.13 (m, J=3.78 Hz, 2H), 3.40-3.73 (m, 2H), 2.19-2.35 (m, 1H), 1.82-1.98 (m, 3H), 1.21-1.30 (m, 9H); LRMS (ESI) m/e 282.17 [(M-Boc+H)+, calcd for C18H20NO2 282.15]; m/e 404.11 [(M+Na)+, calcd for C23H27NNaO4 404.18].
Reaction SMILES: [CH2:1]([C:8]1[N:13]=[C:12]([N:14]([CH2:21][CH3:22])[CH2:15][C:16]2[NH:17][CH:18]=[N:19][CH:20]=2)[CH:11]=[C:10](Cl)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])=O.[NH4+]>CO.[Pd]>[CH2:1]([C:8]1[N:13]=[C:12]([N:14]([CH2:21][CH3:22])[CH2:15][C:16]2[NH:17][CH:18]=[N:19][CH:20]=2)[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(Cc1cnc[nH]1)c1cc(Cl)nc(Cc2ccccc2)n1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCN(Cc1cnc[nH]1)c1ccnc(Cc2ccccc2)n1

Procedure:
(2-Benzyl-6-chloro-pyrimidin-4-yl)-ethyl-(3H-imidazol-4-ylmethyl)-amine (0.164 g, 0.5 mmol) was dissolved in methanol (3 ml), ammonium formate (0.315 g, 0.5 mmol) and palladium on charcoal (0.164 g, 10% Pd) was added and the mixture was refluxed for one hour. After cooling the catalyst was filtered off and the solvent was evaporated. The residue was purified by flash chromatography (column: Isolute® Flash-NH2 from Separtis; eluent: ethyl acetate/methanol=95:5) to yield a white solid, (0.03 g, 21%); MS (ISP): 294.4 ((M+H)+.).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([C:16]3[C:17](=[O:25])[N:18]([CH3:24])[C:19]([S:22][CH3:23])=[N:20][CH:21]=3)=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1.[CH3:26][N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1.C([O-])([O-])=O.[K+].[K+]>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.O1CCOCC1.O>[CH3:24][N:18]1[C:17](=[O:25])[C:16]([C:12]2[CH:11]=[CH:10][C:9]([O:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:30]4[CH:29]=[N:28][N:27]([CH3:26])[CH:31]=4)[CH:7]=3)=[C:14]([CH3:15])[N:13]=2)=[CH:21][N:20]=[C:19]1[S:22][CH3:23]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CSc1ncc(-c2ccc(Oc3ccnc(Cl)c3)c(C)n2)c(=O)n1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CSc1ncc(-c2ccc(Oc3ccnc(-c4cnn(C)c4)c3)c(C)n2)c(=O)n1C
Temperature: 90 °C
Yield: 34.3 %

Procedure:
A mixture of 5-(5-((2-chloropyridin-4-yl)oxy)-6-methylpyridin-2-yl)-3-methyl-2-(methylthio)pyrimidin-4(3H)-one (0.52 g, 0.97 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.22 g, 1.07 mmol), and K2CO3 (0.40 g, 2.9 mmol) in 5:1 dioxane/water (6 mL) was sparged with Ar, treated with Pd(PPh3)4 (0.12 g, 0.10 mmol), sparged again with Ar and heated at 90° C. overnight. The solids were removed via filtration, the filtrate treated with satd. NaHCO3, extracted with EtOAc (3×) and the combined organics were dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford 3-methyl-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-(methylthio)pyrimidin-4(3H)-one (140 mg, 34%). MS (ESI) m/z: 421.1 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11]CC)=[O:10])=[CH:4][CH:3]=1.[CH2:14](Br)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>O.CN(C)C=O>[CH2:25]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14]
Reactant: CCOC(=O)Cc1ccc(O)cc1
Reactant: CCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCOc1ccc(CC(=O)O)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 62.4 %

Procedure:
To a dimethylformamide (DMF, 100 ml) solution of ethyl 4-hydroxyphenylacetate (18 g, 0.1 mol.) and dodecyl bromide (25 g, 0.1 mol.) was added potassium carbonate (15 g, 0.1 mol.). The mixture was stirred at 100° C. for one hour. To the reaction solution, after cooling, was added water (200 ml) and the mixture was subjected to extraction with isopropyl ether (IPE). The organic layer was washed with water, dried and concentrated under reduced pressure. The concentrate was dissolved in a mixture of methanol (100 ml) and tetrahydrofuran (THF, 100 ml). To the solution was added aqueous sodium hydroxide (10 g, 0.25 mol.), and the mixture was stirred at 50° C. The reaction solution was concentrated under reduced pressure, whose pH was adjusted to 4, followed by extraction with ethyl acetate. The organic layer was washed with water, dried and concentrated under reduced pressure to leave crude crystals. Recrystallization from hexane-IPE gave 4-dodecyloxyphenylacetic acid (1-e, 20 g, 63%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([F:12])=[CH:7]2.[Cl-].C([O:18][C:19](=[O:22])[CH2:20][Zn+])(C)(C)C.[OH-].[Na+].CO>O1CCOCC1>[F:12][C:8]1[CH:9]=[N:10][C:11]2[C:6]([CH:7]=1)=[CH:5][CH:4]=[CH:3][C:2]=2[CH2:20][C:19]([OH:22])=[O:18]
Reactant: CC(C)(C)OC(=O)C[Zn+]
Reactant: Fc1cnc2c(Br)cccc2c1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: O=C(O)Cc1cccc2cc(F)cnc12

Procedure:
The title compound was prepared from 8-bromo-3-fluoroquinoline (568 mg, 2.51 mmol) and 0.5 M (2-Tert-butoxy-2-oxoethyl)zinc(II) chloride according to Protocol P, accept that the ester was converted to the acid using NaOH and MeOH in dioxane. Method [7] retention time 2.39 min by HPLC (M+=206).
Reaction SMILES: [C:1]1([C:7]([NH:9][C:10]2[S:11][C:12]([C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])=[C:13]([CH3:22])[C:14]=2[C:15]([O:17]C(C)(C)C)=[O:16])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:26]([O:25][C:23]([C:12]1[S:11][C:10]([NH:9][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:8])=[C:14]([C:15]([OH:17])=[O:16])[C:13]=1[CH3:22])=[O:24])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Cc1c(C(=O)OCc2ccccc2)sc(NC(=O)c2ccccc2)c1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(C(=O)OCc2ccccc2)sc(NC(=O)c2ccccc2)c1C(=O)O
Reaction time: 19 h
Yield: 94.6 %

Procedure:
To a solution of the compound prepared in Example 8 (1.33 g, 2.94 mmol) in DCM (20 ml). was added TFA (20 ml) dropwise. After 19 hours, the reaction was concentrated under reduced pressure, and partitioned between CHCl3 and H2O. The aqueous phase basified with sat. NaHCO3, and the layers were separated. The aqueous phase was extracted with CHCl3. The combined organic layers were washed with H2O, dried over MgSO4 and concentrated under reduced pressure to yield 1.10 g (95%) of a tan solid. 1H-NMR (CDCl3) 2.76 (s, 3H) 5.23 (s, 2H), 7.20-7.60 (m, 8H), 7.93 (d, 2H, J=8.0 Hz)
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][CH:3]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].[OH-].[K+].[CH2:23](Cl)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CC(C)=O>[CH2:23]([O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][CH:3]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: ClCc1ccccc1
Reactant: Oc1ccc(O)c2ccccc12
Agent: O=S([O-])S(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Product: Oc1ccc(OCc2ccccc2)c2ccccc12

Procedure:
23.7 g. (0.147 mole) 1,4-Dihydroxynaphthalene (purified by shaking an ethereal solution thereof with sodium dithionite solution) are dissolved in 200 ml. acetone. After adding 20.3 g. (0.147 mole) of pulverised potassium hydroxide and heating to reflux temperature, 18.6 g. (16.9 ml.) benzyl chloride are added dropwise thereto in the course of 60 minutes. The reaction mixture is thereafter heated under reflux for 4 hours while stirring, evaporated and the residue is mixed with 100 ml. water and extracted with diethyl ether. The ethereal solution is dried with anhydrous magnesium sulphate, filtered and evaporated. The tar-like residue is extracted with cyclohexane. The combined extracts are cooled, considerable amounts of a tarry product thereby first separating out. Thereafter, the pure compound crystallises out. It is washed with cyclohexane and dried. Yield 4.3 g. (11.9% of theory); m.p. 118°-119° C.
Reaction SMILES: [BH4-].[Na+].[C:3]([N:10]1[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH:11]1[CH3:17])([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]>CCO>[C:3]([N:10]1[CH2:15][CH2:14][C@@H:13]([OH:16])[CH2:12][C@@H:11]1[CH3:17])([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: CC1CC(=O)CCN1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: C[C@H]1C[C@H](O)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
213 mg (5.6 mmol) of NaBH4 were added portionwise at 0° C. to a solution of 1.0 g (4.7 mmol) 1-Boc-2-methyl-piperidin-4-on in 10 mL EtOH. The mixture was stirred at room temperature for another 2 h. The solvent was removed by distillation and the remainder was dissolved in water and ethyl acetate. The aqueous layer was extracted twice with ethyl acetated and the combined organic layers were dried over Na2SO4. After filtration the solvent was removed by distillation and the crude product was purified by column chromatography n-heptane/ethyl acetate (1/1) to yield 367 mg (36%) of the cis-isomer 25 and 205 mg (20%) of the trans-isomer 26 in addition to 97 mg (10%) mixture of both isomers.
Reaction SMILES: CC#N.[F:4][C:5]([F:10])([F:9])[CH:6]1[O:8][CH2:7]1.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3].[O:36]([C:43]1[CH:44]=[C:45]([CH2:49][C:50]([NH:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([C:64]3[CH:68]=[CH:67][O:66][CH:65]=3)[CH:59]=2)(O)C(F)(F)F)C=C[CH:48]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(OCC)C.CCO>[O:36]([C:43]1[CH:48]=[C:50]([N:56]([CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([C:64]3[CH:68]=[CH:67][O:66][CH:65]=3)[CH:59]=2)[CH2:7][CH:6]([OH:8])[C:5]([F:10])([F:9])[F:4])[CH:49]=[CH:45][CH:44]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: OC(Cc1cccc(Oc2ccccc2)c1)(NCc1cccc(-c2ccoc2)c1)C(F)(F)F
Reactant: FC(F)(F)C1CO1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CCOCC
Solvent: CC#N
Solvent: CCO
Product: OC(CN(Cc1cccc(-c2ccoc2)c1)c1cccc(Oc2ccccc2)c1)C(F)(F)F
Reaction time: 18 h

Procedure:
To a CH3CN (2 mL) solution of amine (0.20 g, 0.58 mmol) from EX-601B was added 1,1,1-trifluoro-2,3-epoxypropane (0.10 mL, 1.2 mmol) and Yb(OTf)3 (0.035 g, 0.056 mmol). The cloudy solution was stiffed in a sealed flask at 40° C. After 18 h, additional 1,1,1-trifluoro-2,3-epoxypropane (0.20 mL, 2.4 mmol) and Yb(OTf)3 (0.035 g, 0.056 mmol) were added, and the mixture was heated an additional 4 h. diluted with diethyl ether and washed with water and brine. The organic layer was dried (MgSO4) and evaporated to an oil. Purification by flash chromatography on silica gel eluting with 10% ethyl acetate in hexane gave an oil which was dissolved in EtOH, stripped and dried in vacuo to give 0.14 g (53%) of the desired 3[(3-phenoxyphenyl) [[(3-(3-furanyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a colorless oil, >99% pure by HPLC analysis. Anal. calcd. for C26H22NO3F3.0.3 EtOH: