Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:12]([NH:14][C:15]2[O:16][C:17]([C:20]3[O:21][CH:22]=[CH:23][CH:24]=3)=[N:18][N:19]=2)=[O:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH2:25]([C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=2)=[CH:29][CH:28]=1)[CH3:26]>>[CH2:25]([C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][C:36]([C:2]3[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]([NH:14][C:15]4[O:16][C:17]([C:20]5[O:21][CH:22]=[CH:23][CH:24]=5)=[N:18][N:19]=4)=[O:13])[CH:3]=3)=[CH:35][CH:34]=2)=[CH:29][CH:28]=1)[CH3:26]
Reactant: O=C(Nc1nnc(-c2ccco2)o1)c1cc(Br)cc(C(F)(F)F)c1
Reactant: CCc1ccc(-c2ccc(B(O)O)cc2)cc1
Product: CCc1ccc(-c2ccc(-c3cc(C(=O)Nc4nnc(-c5ccco5)o4)cc(C(F)(F)F)c3)cc2)cc1

Procedure:
The title compound was synthesized in accordance with the synthesis method of compound Ia-50, using 3-bromo-N-[5-(2-furyl)-1,3,4-oxadiazol-2-yl]-5-trifluoromethylbenzenecarboxamide prepared in Reference Example 39 instead of compound Ia-50 and using commercially available 4′-ethyl-4-biphenylboronic acid instead of 1-methyl-5-indoleboronic acid pinacol ester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:35][C:36](=[O:42])[C:37](OCC)=[O:38])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[C:20]([O:33][CH3:34])[CH:19]=3)[S:17][C:10]=12.[CH3:43][O:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[CH2:51][CH2:52][NH2:53]>>[F:1][C:2]1[CH:3]=[C:4]([NH:35][C:36](=[O:42])[C:37]([NH:53][CH2:52][CH2:51][C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=2[O:44][CH3:43])=[O:38])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[C:20]([O:33][CH3:34])[CH:19]=3)[S:17][C:10]=12
Reactant: COc1ccccc1CCN
Reactant: CCOC(=O)C(=O)Nc1ccc(Oc2ccnc3cc(-c4ccc(OCCN5CCOCC5)c(OC)c4)sc23)c(F)c1
Product: COc1ccccc1CCNC(=O)C(=O)Nc1ccc(Oc2ccnc3cc(-c4ccc(OCCN5CCOCC5)c(OC)c4)sc23)c(F)c1
Temperature: 25 °C
Yield: 57.1 %

Procedure:
Amino ester 140 (80 mg, 0.13 mmol) and 2-(2-methoxyphenyl)ethanamine (0.2 mL, 1.34 mmol) were mixed together and stirred at room temperature until completion of the reaction. The mixture was quenched with a saturated aqueous solution of ammonium chloride and extracted three times with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered and evaporated. The crude product was purified by flash chromatography (eluent: 3% MeOH/97% DCM to 5% MeOH/95% DCM). This solid product was then triturated with ethyl acetate to afford pure title compound 136 as a white solid (52 mg, 57% yield). 1H NMR (DMSO-d6) δ (ppm): 11.03 (s, 1H), 9.04 (t, J=5.9 Hz, 1H), 8.48 (d, J=5.5 Hz, 1H), 8.05-8.01 (m, 2H), 7.82 (d, J=9.0 Hz, 1H), 7.53 (t, J=9.1 Hz, 1H), 7.47 (d, J=2.2 Hz, 1H), 7.38 (dd, J=2.2 and 8.2 Hz, 1H), 7.21 (td, J=1.8 and 7.8 Hz, 1H), 7.14 (dd, J=1.8 and 7.4 Hz, 1H), 7.11 (d, J=8.6 Hz, 1H), 6.97 (d, J=7.4 Hz, 1H), 6.88 (td, J=1.0 and 7.3 Hz, 1H), 6.60 (d, J=5.5 Hz, 1H), 4.14 (t, J=6.0 Hz, 2H), 3.89 (s, 3H), 3.80 (s, 3H), 3.59-3.57 (m, 4H), 3.46-3.41 (m, 2H), 2.83 (t, J=7.0 Hz, 2H), 2.73-2.70 (m, 2H), one peak (4H) did not show, it was probably under H2O or DMSO. MS (m/z): 701.1 (M+H).
Reaction SMILES: [SH:1][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[C:7]([OH:14])(=[O:13])/[CH:8]=[CH:9]/[CH2:10][CH2:11][CH3:12].C(N(CC)CC)C>O1CCCC1>[S:3]1[CH:4]=[CH:5][CH:6]=[C:2]1[S:1][CH:9]([CH2:10][CH2:11][CH3:12])[CH2:8][C:7]([OH:14])=[O:13]
Reactant: Sc1cccs1
Reactant: CCC/C=C/C(=O)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCC(CC(=O)O)Sc1cccs1

Procedure:
A solution of 2-mercaptothiophene (51.1 g, 0.44 mol), trans-2-hexenoic acid (1) (49.1 g, 0.43 mol), triethylamine (29.3 g, 0.29 mol) in tetrahydrofuran (490 ml) was stirred and refluxed under nitrogen for 21 hours. The mixture was concentrated in vacuo and the residue was distributed between ethyl acetate (500 ml) and 3N hydrochloric acid (200 ml), the aqueous layer was separated and extracted with ethyl acetate (200 ml), the combined ethyl acetate extracts were washed with 3N hydrochloric acid, twice with water and dried over sodium sulfate. The solvent was evaporated in vacuo to yield pale yellow oily product weighing 99 g (100%), which was >96% pure by HPLC.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:5]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:25][CH2:26][CH3:27].O>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:25][CH2:26][CH3:27])[CH2:14][CH2:13]2)[CH:5]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:7]=1
Reactant: CCCI
Reactant: CS(=O)(=O)c1cc(F)cc(C2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCCN1CCC(c2cc(F)cc(S(C)(=O)=O)c2)CC1
Temperature: 150 °C
Yield: 46.5 %

Procedure:
To a solution of 4-[3-fluoro-5-(methylsulfonyl)phenyl]piperidine (0.5 g, 1.94 mmol) in acetonitrile (5 ml) was added potassium carbonate (0.53 g, 3.83 mmol) and 1-iodopropane (0.189 ml, 1.94 mmol) and the mixture was heated with microwave irradiation for 20 min at 150° C. The mixture was cooled to ambient temperature and water (50 ml) was added. The aqueous residue was extracted with ethylacetate (3×50 ml) and the combined organic phases was dried, concentrated, and purified by flash column chromatography (ethylacetate/methanol, 1:1) to give the title compound (0.27 g, 46%). The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 187-189° C. MS m/z (relative intensity, 70 eV) 299 (M+, 3), 271 (15), 270 (bp), 147 (5) 133 (5).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.Cl[C:24]1[CH:29]=[CH:28][C:27]2=[N:30][N:31]=[C:32]([C:33]([F:36])([F:35])[F:34])[N:26]2[N:25]=1>C(O)C>[F:35][C:33]([F:34])([F:36])[C:32]1[N:26]2[N:25]=[C:24]([N:4]3[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]3)[CH:29]=[CH:28][C:27]2=[N:30][N:31]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Temperature: 70 °C
Yield: 90.7 %

Procedure:
A mixture of tert-butyl piperazine-1-carboxylate (8.29 g, 44.5 mmol) and ethanol (90 mL) was added to a mixture of DIPEA (9.16 mL, 52.6 mmol) and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[3,4-f]pyridazine (obtained as described in Monatsh. Chem. (1972) 103(6), 1591-603) (9.0 g, 40.4 mmol) in ethanol (90 mL). The mixture was heated at 70° C. for 11 hours and then allowed to cool to ambient temperature to give a precipitate. The is precipitate was collected by filtration, washed with chilled ethanol and then with water, and dried under vacuum to afford tert-butyl 4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazine-1-carboxylate (13.64 g, 90.6%) as a white solid that was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][CH2:12][C:13]1[O:14][C:15]([CH2:21][OH:22])=[C:16]([OH:20])[C:17](=[O:19])[CH:18]=1)(=[O:10])=[O:9].[CH2:23](OC1C(=O)C=C(CNS(C2C=CC=CC=2)(=O)=O)OC=1CO)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([O:20][C:16]1[C:17](=[O:19])[CH:18]=[C:13]([CH2:12][NH:11][S:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])(=[O:9])=[O:10])[O:14][C:15]=1[CH2:21][OH:22])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=c1cc(CNS(=O)(=O)c2ccccc2Cl)oc(CO)c1O
Reactant: O=c1cc(CNS(=O)(=O)c2ccccc2)oc(CO)c1OCc1ccccc1
Product: O=c1cc(CNS(=O)(=O)c2ccccc2Cl)oc(CO)c1OCc1ccccc1
Yield: 35 %

Procedure:
N-(5-Benzyloxy-6-hydroxymethyl-4-oxo-4H-pyran-2-ylmethyl)-2-chloro-benzenesulfonamide (10-03) (3.5 g, 35.0%) was synthesized as a white solid from 2-chloro-N-(5-hydroxy-6-hydroxymethyl-4-oxo-4H-pyran-2-ylmethyl)-benzenesulfonamide (9-03) (8.0 g, 23.18 mmol) following the procedure described for N-(5-benzyloxy-6-hydroxymethyl-4-oxo-4H-pyran-2-ylmethyl)-benzenesulfonamide (10-01).
Reaction SMILES: C([O:3][C:4](=[O:19])[CH2:5][C:6]([OH:18])([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:7][CH2:8][CH3:9])C.[OH-].[Na+]>CO>[OH:18][C:6]([CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)([CH2:7][CH2:8][CH3:9])[CH2:5][C:4]([OH:19])=[O:3]
Reactant: CCCC(O)(CCc1ccccc1)CC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(O)(CCc1ccccc1)CC(=O)O
Reaction time: 8 h

Procedure:
Ethyl-3-hydroxy-3-(2-phenylethyl)hexanoate (II, EXAMPLE 1,200 mmol) is dissolved in methanol (423 ml) and 2M sodium hydroxide (150 ml, 300 mmol) is added. The reaction mixture is stirred at 20-25° overnight. Methanol is removed and the remaining aqueous mixture is acidified with hydrochloric acid (4 M). The desired product is extracted into methyl t-butyl ether and dried over magnesium sulfate. The product is concentrated to give the title compound, TLC Rf =0.10 (ethyl acetate/hexane, 30/70); NMR (CDCl3) 7.43-7.13, 2.77-2.62, 2.06, 1.87-1.76, 1.63-1.57, 1.45-1.31 and 0.93 δ; CMR (CDCl3) 176.9, 141.9, 128.4, 128.3, 125.9, 73.4, 42.7, 41.4, 40.9, 31.9, 17.0 and 14.5 δ; MS (CI, ammonia) m/z (relative intensity) 254 (100), 236 (28), 218 (3), 194 (3), 159 (5).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:40]C)=[N:4][CH:5]=[C:6]([Cl:39])[C:7]=1[CH2:8][CH2:9][N:10]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:11]([C:13]1[CH:14]=[N:15][N:16]([C@H:22]2[CH2:27][CH2:26][C@H:25]([C:28]([O:30]CC)=[O:29])[C@H:24]([CH3:33])[CH2:23]2)[C:17]=1[C:18]([F:21])([F:20])[F:19])=[O:12].Cl>>[Cl:1][C:2]1[C:3](=[O:40])[NH:4][CH:5]=[C:6]([Cl:39])[C:7]=1[CH2:8][CH2:9][N:10]([CH2:34][C:35]([CH3:37])([CH3:36])[CH3:38])[C:11]([C:13]1[CH:14]=[N:15][N:16]([C@H:22]2[CH2:27][CH2:26][C@H:25]([C:28]([OH:30])=[O:29])[C@H:24]([CH3:33])[CH2:23]2)[C:17]=1[C:18]([F:21])([F:20])[F:19])=[O:12]
Reactant: CCOC(=O)[C@H]1CC[C@H](n2ncc(C(=O)N(CCc3c(Cl)cnc(OC)c3Cl)CC(C)(C)C)c2C(F)(F)F)C[C@H]1C
Agent: Cl
Product: C[C@@H]1C[C@@H](n2ncc(C(=O)N(CCc3c(Cl)c[nH]c(=O)c3Cl)CC(C)(C)C)c2C(F)(F)F)CC[C@@H]1C(=O)O
Temperature: 120 °C
Yield: 56 %

Procedure:
(1S,2R,4S)-ethyl 4-(4-((2-(3,5-dichloro-2-methoxypyridin-4-yl)ethyl)(neopentyl)carbamoyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylcyclohexanecarboxylate (109 mg, 0.175 mmol) was treated with aqueous hydrochloric acid (5.0 N, 3.00 mL, 15.00 mmol) and hydrochloric acid (4.0 N in 1,4-dioxane, 3.00 mL, 12.00 mmol), fitted with a reflux condenser and heated to 120° C. for 3 h. The reaction mixture was concentrated to dryness under reduced pressure (rotary evaporator) and the crude residue was purified on a Gilson (Gemini™ Phenomenex; 30×150 mm, 5 u, using a gradient of 10-95% 0.1% TFA/CH3CN in 0.1% TFA/water), concentrated in a genevac overnight affording (1S,2R,4S)-4-(4-((2-(3,5-dichloro-2-oxo-1,2-dihydropyridin-4-yl)ethyl)(neopentyl)carbamoyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylcyclohexanecarboxylic acid (57 mg, 0.098 mmol, 56% yield) as a white amorphous solid. MS (ESI) 579.0, 581.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH:7]=O)[CH3:2].[C:14]([S@:18]([NH2:20])=[O:19])([CH3:17])([CH3:16])[CH3:15].[Na+].[Cl-]>C1COCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])/[CH:7]=[N:20]/[S:18]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:19])[CH3:2]
Reactant: CCOc1cc(C=O)ccc1OC
Reactant: CC(C)(C)[S@](N)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1cc(/C=N/S(=O)C(C)(C)C)ccc1OC
Temperature: 66 °C

Procedure:
In the first step, a reaction flask was charged with 3-ethoxy-4-methoxybenzaldehyde (2.0 g, 11 mmol), (R)-tert-butylsulfinamide (Ellman's auxiliary) (1.5 g, 12.2 mmol, 1.1 equiv) and THF (20 vol) then treated with Ti(OEt)4 (4.6 mL, 22 mmol, 2.0 equiv, ˜20% Ti). The reaction was heated for ˜6 h at 65-67° C. then cooled to 20-25° C. and added to 2% aqueous NaCl (20 vol). The slurry was filtered and the white precipitate (titanium salts) was washed with EtOAc. The organic portion was dried with MgSO4 and concentrated to afford (E)-N-(3-ethoxy-4-methoxybenzylidene)-2-methylpropane-2-sulfinamide (Compound E).
Reaction SMILES: [Si:1]([O:8][CH:9]([C:22]1[O:23][CH:24]=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li]C(C)(C)C.[Br:32]Br>C1COCC1.CCOC(C)=O>[Br:32][C:24]1[O:23][C:22]([CH:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:26][CH:25]=1
Reactant: CC(C)(C)[Si](C)(C)OC(CCCCCCc1ccccc1)c1ncco1
Reactant: BrBr
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OC(CCCCCCc1ccccc1)c1ncc(Br)o1
Temperature: -78 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
2-(1-(tert-Butyldimethylsilyloxy)-7-phenylheptyl)oxazole (201 mg, 0.554 mmol) was dissolved in anhydrous THF (5 mL), cooled to −78° C. and t-BuLi (1.7 M in pentane, 1.3 equiv) was added dropwise under Ar. The reaction mixture was stirred for 2 h at −40° C., cooled to −78° C. and bromine (3 equiv) was added dropwise. The reaction mixture was warmed to room temperature, diluted with EtOAc, washed with saturated Na2S2O3, washed with saturated aqueous NaCl and dried over Na2SO4. Evaporation in vacuo yielded the crude aryl bromide, which was purified by flash chromatography (0-1.5% EtOAc/hexanes) to afford the title compound as a clear oil (218 mg, 90%): 1H NMR (CDCl3, 600 MHz) 7.28-7.26 (m, 2H), 7.17-7.16 (m, 3H), 6.92 (s, 1H), 4.74 (t, 1H, J=7.2 Hz), 2.59 (t, 2H, J=7.8 Hz), 1.90-1.79 (m, 2H), 1.60-1.59 (m, 2H), 1.53-1.34 (m, 6H), 0.88 (s, 9H), 0.07 (s, 3H), −0.02 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ 167.8, 143.6, 129.3, 129.1, 127.7, 126.5, 122.1, 69.5, 37.0, 36.8, 32.3, 30.0, 26.6, 26.6, 25.9, 19.1, −4.1, −4.3.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[N+:17]([O-])=O)=[O:5])[CH3:2].[F:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][NH2:25]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:25][CH2:24][C:23]1[CH:26]=[CH:27][CH:28]=[C:21]([F:20])[CH:22]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c([N+](=O)[O-])cccc2c1Cl
Reactant: NCc1cccc(F)c1
Product: CCOC(=O)c1cnc2c(N)cccc2c1NCc1cccc(F)c1
Yield: 90 %

Procedure:
The compound prepared in Example 3 was reacted with 3-fluoro-benzylamine according to the method as described in Example 4 and the obtained compound was treated as described in Example 14 to prepare the title compound (yield 90%).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([NH2:14])[CH:5]=[CH:4][C:3]1=2.[CH2:16]([O:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](O)=[O:30])=[CH:24][CH:23]=1)=[O:21])[CH:17]=[CH2:18]>>[CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([NH:14][C:29]([CH2:28][C:25]3[CH:26]=[CH:27][C:22]([C:20]([O:19][CH2:16][CH:17]=[CH2:18])=[O:21])=[CH:23][CH:24]=3)=[O:30])[CH:5]=[CH:4][C:3]1=2
Reactant: C=CCOC(=O)c1ccc(CC(=O)O)cc1
Reactant: CC1(C)CCC(C)(C)c2cc(N)ccc21
Product: C=CCOC(=O)c1ccc(CC(=O)Nc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1

Procedure:
In a manner similar to Example 4(c), by reaction of 2 g (10 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylamine with 2.2 g (10 mmol) of 4-(allyloxycarbonyl)phenylacetic acid, 3.7 g (92%) of the expected ester, melting point 49°-50° C., are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13](O)=[O:14])[N:10]=[CH:9]2)=[CH:4][CH:3]=1.O1CCCC1.B.CO>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[C:11]([CH2:13][OH:14])[N:10]=[CH:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)cn1
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: OCc1cn(-c2ccc(F)cc2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(4-Fluoro-phenyl)-1H-imidazole-4-carboxylic acid (18 g, 87 mmol) was dissolved in 90 mL dry THF. Borane tetrahydrofuran complex (174 mL, 1M in THF, 174 mmol) was added dropwise. The reaction was refluxed for 2 h and stirred at room temperature overnight. The reaction mixture was cooled to 0° C. and 100 mL methanol were added dropwise. The solvents were evaporated. The residue was taken up in 100 mL 2N HCl and refluxed for 2 h. The reaction mixture was then cooled to 0° C. and 120 mL 2N sodium hydroxide solution were added dropwise. The solid material was filtered off and dried at 50° C. and 15 mbar. The desired compound was obtained as a white solid (13 g, 78%), MS: m/e=193.2 (M+H)+.
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][C:12](Br)=[N:11][C:10]=1[C:15]([NH:17][C:18]1[CH:19]=[N:20][N:21]([CH3:40])[C:22]=1[N:23]1[CH2:29][C:28]([F:31])([F:30])[CH2:27][CH:26]([NH:32]C(=O)OC(C)(C)C)[CH2:25][CH2:24]1)=[O:16])=O)(C)(C)C.[F:41][C:42]1[CH:43]=[N:44][CH:45]=[C:46]([F:61])[C:47]=1[Sn](CCCC)(CCCC)CCCC>>[NH2:8][C:9]1[S:13][C:12]([C:47]2[C:46]([F:61])=[CH:45][N:44]=[CH:43][C:42]=2[F:41])=[N:11][C:10]=1[C:15]([NH:17][C:18]1[CH:19]=[N:20][N:21]([CH3:40])[C:22]=1[N:23]1[CH2:24][CH2:25][CH:26]([NH2:32])[CH2:27][C:28]([F:30])([F:31])[CH2:29]1)=[O:16]
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1N1CCC(NC(=O)OC(C)(C)C)CC(F)(F)C1
Reactant: CCCC[Sn](CCCC)(CCCC)c1c(F)cncc1F
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cncc3F)sc2N)c1N1CCC(N)CC(F)(F)C1
Yield: 43 %

Procedure:
Following the procedure for Example 422 starting from tert-butyl 1-(4-(5-(tert-butoxycarbonyl-amino)-2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-6,6-difluoroazepan-4-ylcarbamate and 3,5-difluoro-4-(tributylstannyl)pyridine gave 438 as a white solid (68 mg, 43% over two steps). 1H NMR (400 MHz, d6-DMSO) δ 8.83 (s, 1H), 8.67 (s, 2H), 7.78 (s, 2H), 7.61-7.56 (m, 1H), 3.79-3.56 (m, 4H), 3.46-3.33 (m, 1H), 3.37-3.16 (m, 2H), 3.16-3.06 (m, 1H), 2.35-2.08 (m, 2H), 1.91-1.78 (m, 1H), 1.81-1.60 (m, 3H). LCMS (ES+) m/z 485 (M+1)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.[H-].[Na+].[Cl:11][CH2:12][CH2:13][CH2:14]I.[Na+].[Cl-]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH2:14][CH2:13][CH2:12][Cl:11])[CH:3]=1
Reactant: ClCCCI
Reactant: Oc1cncc(Br)c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: ClCCCOc1cncc(Br)c1
Temperature: 25 °C
Yield: 148.8 %

Procedure:
Under a nitrogen atmosphere, a solution of 5-bromo-3-hydroxypyridine (1.90 g, 10.92 mmol) in DMF (10 mL) was slowly added over 10 min to a cold (0-5° C.), stirring slurry of sodium hydride (0.52 g of an 80% dispersion in mineral oil, 17.47 mmol) in DMF (14 mL). The mixture was allowed to warm to ambient temperature and further stirred for 1H. To this slurry was added dropwise over 5 min 1-choro-3-iodopropane (2.68 g, 13.10 mmol), and the resulting dark-brown mixture was stirred at ambient temperature for 48 h. Cold water (30 mL) was carefully added, followed by saturated NaCl solution (20 mL). The resulting mixture was extracted with ether (5×25 mL). The combined ether extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation producing a dark-brown oil (4.07 g). The product was used in the next step without further purification. EI-MS: m/z (relative intensity) 251 (M+, 31.89%), 249 (M+, 23.99%), 175 (65.68%), 173 (67.42%), 94 (37.06%), 41 (100.00%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[CH2:12]([N:19]=[C:20]=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([NH:19][C:20]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1cccc2cnccc12
Reactant: O=C=NCc1ccccc1
Product: O=C(NCc1ccccc1)Nc1cccc2cnccc12

Procedure:
Prepared from 5-aminoisoquinoline and benzyl isocyanate according to the procedure of Description 61. m/z (ES+) 278 (M+H)+.
Reaction SMILES: [O:1]([CH2:8][CH2:9]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[O:1]([CH2:8][CH2:9][N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCCOc1ccccc1
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: c1ccc(OCCN2CCCCC2)cc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 96.4 %

Procedure:
A mixture of 20 g of 2-phenoxyethyl bromide thus obtained, 7.92 g of piperidine and 12.86 g of potassium carbonate was added into 100 ml of ethyl alcohol and stirred for 6 hours at 100° C. The mixture obtained was filtered and condensed under reduced pressure to give 18.4 g of 1-(2-phenoxyethyl)piperidine having a boiling point of 111° C. to 112° C. at 7 mmHg in a yield of 90%.
Reaction SMILES: COC(=O)[C@@H](N[C:19]([C:21]1[CH:22]=[C:23]([C:28]2[CH:33]=[CH:32][C:31](F)=C(Cl)C=2)[CH:24]=[CH:25][C:26]=1[OH:27])=[O:20])CC1C=CC(C2C=CC=CC=2)=CC=1.[CH3:37][O:38][C:39](=[O:50])[C@@H:40]([NH2:49])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([Br:48])=[CH:44][CH:43]=1>>[CH3:37][O:38][C:39](=[O:50])[C@@:40]([NH2:49])([C:19]([C:21]1[C:26]([OH:27])=[CH:25][C:24]2[C:23](=[CH:28][CH:33]=[CH:32][CH:31]=2)[CH:22]=1)=[O:20])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([Br:48])=[CH:44][CH:43]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(Br)cc1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(-c2ccc(F)c(Cl)c2)ccc1O
Product: COC(=O)[C@](N)(Cc1ccc(Br)cc1)C(=O)c1cc2ccccc2cc1O

Procedure:
1.0 g (2.5 mmol) of resin-bound naphthoic acid obtained in Example 1 was reacted with 1.95 g (7.5 mmol) of (2S)-Amino-3-(4-bromophenyl)-propionic acid methyl ester as described in the general procedure A to give resin-bound 2-(S)-(3-Hydroxy-naphthalene-2-carbonyl)-amino-3-(4-bromophenyl)-propionic acid methyl ester.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[O:7][C:8]=1[CH:9]([CH3:12])[CH2:10][OH:11])([CH3:3])[CH3:2].[CH3:23][O:24][C:25](=[O:35])[CH2:26][C:27]1[CH:32]=[CH:31][C:30](O)=[CH:29][C:28]=1[CH3:34].C1(C)C=CC=CC=1.C(P(CCCC)CCCC)CCC>CCOCC>[CH3:23][O:24][C:25](=[O:35])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:11][CH2:10][CH:9]([C:8]2[O:7][C:6]([C:13]3[CH:14]=[CH:15][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:17][CH:18]=3)=[N:5][C:4]=2[CH:1]([CH3:2])[CH3:3])[CH3:12])=[CH:29][C:28]=1[CH3:34]
Reactant: COC(=O)Cc1ccc(O)cc1C
Reactant: CC(C)c1nc(-c2ccc(C(F)(F)F)cc2)oc1C(C)CO
Agent: CCCCP(CCCC)CCCC
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COC(=O)Cc1ccc(OCC(C)c2oc(-c3ccc(C(F)(F)F)cc3)nc2C(C)C)cc1C
Temperature: 0 °C

Procedure:
A mixture of 2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-propan-1-ol, (0.18 g, 0.5745 mmol), (4-Hydroxy-2-methyl-phenyl)-acetic acid methyl ester (0.114 g) and toluene (10 mL) and azodicarboxylic dipiperidide (0.19 g, 0.747 mmol) is stirred at −20 deg C. Neat tri-n-butyl phosphine (0.19 mL, 0.747 mmol) is added dropwise and the resulting mixture is allowed to reach room temperature with stirring 18 hr. The mixture is diluted with ether (25 mL) and cooled in ice/water for 30 min. The mixture is filtered, concentrated, and purified via silica gel chromatography eluting with 95:5 hexanes:ethyl acetate to afford the title compound as a thick oil, 0.065 g, 24%. MS M++1 476. The structure is confirmed by 1H NMR spectroscopy.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH3:30])=[C:6]([CH:28]=1)[C:7]([NH:9][CH2:10][CH:11]1[C:20]2[C:15](=[CH:16][C:17]([O:25][CH2:26][CH3:27])=[C:18]([S:21](=[O:24])(=[O:23])[NH2:22])[CH:19]=2)[O:14][CH2:13][CH2:12]1)=[O:8].[CH3:31][NH:32][C:33](=[O:38])C(Cl)(Cl)Cl>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH3:30])=[C:6]([CH:28]=1)[C:7]([NH:9][CH2:10][CH:11]1[C:20]2[C:15](=[CH:16][C:17]([O:25][CH2:26][CH3:27])=[C:18]([S:21]([NH:22][C:33]([NH:32][CH3:31])=[O:38])(=[O:23])=[O:24])[CH:19]=2)[O:14][CH2:13][CH2:12]1)=[O:8]
Reactant: CNC(=O)C(Cl)(Cl)Cl
Reactant: CCOc1cc2c(cc1S(N)(=O)=O)C(CNC(=O)c1cc(Cl)ccc1OC)CCO2
Product: CCOc1cc2c(cc1S(=O)(=O)NC(=O)NC)C(CNC(=O)c1cc(Cl)ccc1OC)CCO2

Procedure:
4-(5-Chloro-2-methoxybenzamidomethyl)-6-(methylaminocarbonylaminosulfonyl)-7-ethoxychroman ##STR39## 4-(5-Chloro-2-methoxy-benzamidomethyl)-6-(methylaminocarbonylaminosulfonyl)-7ethoxychroman is prepared as described in Example 1 from 4-(5-Chloro-2-methoxybenzamidomethyl)6-sulfamoyl-7-ethoxy-chroman and N-methyltrichloroacetamide. Melting point: 207°-208° C.