Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH2:6][C:7]1[N:8]=[C:9]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=2[C:23]([CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:24])=[O:14])[S:10][CH:11]=1)=[O:4].[CH3:30][S:31](Cl)(=[O:33])=[O:32]>>[CH:25]1([C:23]([C:17]2[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=2[NH:15][C:13](=[O:14])[NH:12][C:9]2[S:10][CH:11]=[C:7]([CH2:6][NH:5][C:3](=[O:4])[CH2:2][NH:1][S:31]([CH3:30])(=[O:33])=[O:32])[N:8]=2)=[O:24])[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: Cc1ccc(NC(=O)Nc2nc(CNC(=O)CN)cs2)c(C(=O)C2CCCC2)c1
Reactant: CS(=O)(=O)Cl
Product: Cc1ccc(NC(=O)Nc2nc(CNC(=O)CNS(C)(=O)=O)cs2)c(C(=O)C2CCCC2)c1
Yield: 83.5 %

Procedure:
N-{2-[3-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-ylmethyl}-2-methanesulfonylamino-acetamide (103 mg, 84%) was prepared from 2-amino-N-{2-[3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-ylmethyl}-acetamide (104 mg, 0.25 mmol) and methanesulfonyl chloride (0.04 mL, 0.5 mmol) following the general procedure L.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6](O)=[CH:7][CH:8]=2)[CH:3]=1.[NH3:13].O.S([O-])([O-])=O.[NH4+].[NH4+].Cl>C(OCC)(=O)C>[NH2:13][C:6]1[CH:7]=[CH:8][C:9]2[C:4](=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2)[CH:5]=1
Reactant: Oc1ccc2ccc(Br)cc2c1
Reactant: N
Agent: Cl
Agent: O=S([O-])[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1ccc2ccc(Br)cc2c1
Temperature: 150 °C
Reaction time: 27 h

Procedure:
According to the procedure described in the aforementioned reference [L. C. Anderson et al., Journal of the American Chemical Society (J. Am. Chem. Soc.), vol. 65, p.241, 1943], 2-bromo-7-hydroxynaphthalene (2.23 g, MAYB) was added with 30% aqueous ammonia (30 ml) and ammonium sulfite monohydrate (2.69 g, WAKO) and stirred in a shield tube at 150° C. for 27 hours. The reaction mixture was added with ethyl acetate (90 ml) for extraction and then added with 1 N aqueous hydrochloric acid (1.5 l). The aqueous layer was separated, washed with ethyl acetate, then neutralized by adding 5 N aqueous sodium hydroxide (300 ml) under ice cooling and extracted with ethyl acetate again. The organic layer was washed with saturated brine and dried, and then the solvent was evaporated under reduced pressure to obtain the title compound (Intermediate 26, 1.00 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH2:17])[C:14](/[N:18]=N/C4C=CC=CC=4)=[C:13]([NH2:26])[N:12]=3)=[N:9][N:8]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[F:34])[C:5]2=[N:6][CH:7]=1.[H][H]>CN(C=O)C.[Pd]>[F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH2:17])[C:14]([NH2:18])=[C:13]([NH2:26])[N:12]=3)=[N:9][N:8]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[F:34])[C:5]2=[N:6][CH:7]=1
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncc(F)cc23)nc(N)c1/N=N/c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Product: Nc1nc(-c2nn(Cc3ccccc3F)c3ncc(F)cc23)nc(N)c1N
Reaction time: 8 h

Procedure:
39.23 g (85.75 mmol) of the compound from example 29A were initially charged in DMF (800 ml) and then 4 g of palladium (10% on charcoal) were added. Hydrogenation was effected at standard hydrogen pressure while stirring overnight. The mixture was filtered through kieselguhr, washed through with a little DMF and a little methanol and concentrated to dryness. The residue was admixed with ethyl acetate and stirred vigorously, and the precipitate was filtered off with suction, washed with ethyl acetate and diisopropyl ether and dried under a high vacuum over Sicapent.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([OH:8])[C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:22][O:23][CH2:24][CH2:25]Br>CN(C)C=O>[CH3:22][O:23][CH2:24][CH2:25][O:8][C:4]1[C:3]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[C:2]([NH2:1])[N:6]([CH3:7])[N:5]=1
Reactant: Cc1ccc(-c2c(O)nn(C)c2N)cc1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1nn(C)c(N)c1-c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 51.4 %

Procedure:
5-Amino-1-methyl-4-(4-methylphenyl)-1H-pyrazol-3-ol (Preparation 3a) (305 mg) was dissolved in dimethylformamide (2 ml), potassium carbonate (622 mg) and 2-bromoethyl methyl ether (208 mg) were added. The reaction was stirred at room temperature for 1.5 hours and then at 50° C. for 12 hours. The solvent was removed under reduced pressure. The crude product was purified on silica (10 g) eluted with a solvent gradient of pentane:ethyl acetate (1:0 to 0:1) to yield the title compound as a white solid (201 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C@@H:7]2[CH2:11][CH2:10][C@H:9]([C@H:12]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:8]2[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:4][C:3]=1[N+:36]([O-])=O>C(O)(=O)C.[Zn]>[Si:20]([O:19][C@H:12]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C@H:9]1[CH2:10][CH2:11][C@@H:7]([CH2:6][C:5]2[CH:34]=[CH:35][C:2]([NH2:1])=[C:3]([NH2:36])[CH:4]=2)[N:8]1[C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])([C:23]([CH3:24])([CH3:25])[CH3:26])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(N)c([N+](=O)[O-])c2)CC[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)c1ccccc1
Agent: [Zn]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(N)c(N)c2)CC[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)c1ccccc1
Reaction time: 1 h

Procedure:
To a solution of 0.58 g (1.1 mmol) of tert-butyl(2S,5R)-2-(4-amino-3-nitrobenzyl)-5-[(R)-{[tertbutyl(dimethyl)silyl]oxy}(phenyl)methyl]pyrrolidine-1-carboxylate from Step A in 5 mL of acetic acid was added 0.35 g (5.4 mmol) of zinc dust and the resulting mixture was stirred under nitrogen for 1 h. The reaction mixture was then filtered through a pad of Celite. The pad was washed with dichloromethane (3×25 mL) and the combined filtrates were concentrated in vacuo. The crude residue was purified by reverse-phase HPLC (TMC Pro-Pac C18; 10-100% 0.1% trifluoroacetic acid in acetonitrile/0.1% trifluoroacetic acid in water gradient) to afford the title compound as a yellow solid. LC/MS: m/z (ES) 512.3 (MH)+.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH2:17][C:18]1[CH:30]=[C:29]([CH2:31][CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:28]=[CH:27][C:19]=1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>C(Cl)Cl>[C:8]([NH:17][C:18]1[CH:30]=[C:29]([CH2:31][CH2:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:28]=[CH:27][C:19]=1[C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)c1ccc(CCCc2ccccc2)cc1N
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(CCCc2ccccc2)cc1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
0.28 mL of triethylamine and 0.12 mL of benzoyl chloride were added to 3 mL of methylene chloride solution containing 0.31 g of tert-butyl 2-amino-4-(3-phenylpropyl)benzoate sequentially while ice-cooled and stirred at room temperature for 17 hours. The solvent was evaporated under reduced pressure, and the obtained residue was purified with silica gel column chromatography [eluent; hexane:ethyl acetate=20:1] to obtain 0.48 g of tert-butyl 2-(benzamido)-4-(3-phenylpropyl)benzoate as while solid.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[F:12][C:13]([F:24])([F:23])[CH2:14]OS(C(F)(F)F)(=O)=O>O>[CH2:1]([N:3]([CH2:4][CH3:5])[CH2:14][C:13]([F:24])([F:23])[F:12])[CH3:2]
Reactant: CCNCC
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCN(CC)CC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Diethyl 2,2,2-trifluoroethylamine was prepared as follows. Into a flask were placed diethylamine (5.5 g) and potassium carbonate (10.0 g). 2,2,2-Trifluoroethyl-trifluoromethanesulfonate (12 g) was slowly added to the flask. Heat was evolved. After addition, the reaction mixture was stirred at room temperature overnight. Approximately 100 mL of water was added and the organic layer was separated and dried over MgSO4. The organic liquid was distilled to receive a fraction (a clear liquid 7.25 g) at 88-89° C. under normal pressure. The clear liquid was sampled and analyzed by 1H and 19F NMR. 1H NMR: δ3.56 (q, 2H, J=9 Hz), 2.65 (q, 2H, J=7 Hz), 1.10 (t, 3H, J=7H); ·F NMR: δ−68.13 (t, 3F, J=9 Hz).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH:23]([C:24]#[N:25])[CH2:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:26]=[N+:27]=[N-:28].[Na+].[NH4+].[Cl-].Cl>CN(C)C=O>[CH2:1]([O:8][C:9]([N:11]1[CH:23]([C:24]2[NH:28][N:27]=[N:26][N:25]=2)[CH2:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CC1Cc2c([nH]c3ccccc23)CN1C(=O)OCc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1Cc2[nH]c3ccccc3c2CC1c1nnn[nH]1
Reaction time: 6 h
Yield: 47.8 %

Procedure:
A mixture of (3RS)-2-Benzyloxycarbonyl-3-cyano-1,2,3,4-tetrahydro-β-carboline (0.663 g), NaN3 (0.143 g), NH4Cl (0.118 g) and dimethylformamide (2 ml) is stirred at 95°-100° C. for 6 hours. The reaction mixture is cooled and then poured onto ice-water, adjusted to pH 2 with 10% HCl and extracted with ethyl acetate. The ethyl acetate layer is washed with water, dried and distilled to remove the solvent. The residue is crystallized from ethyl acetate to give the title compound (0.358 g), m.p. 218°-219° C. (decomp.).
Reaction SMILES: [CH3:1][CH:2]([CH:4]1[CH2:8][O:7][C:6](=[O:9])[NH:5]1)[CH3:3].C([Li])CCC.CCCCCC.[C:21]1([CH2:27][CH2:28][C:29](Cl)=[O:30])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1>[C:21]1([CH2:27][CH2:28][C:29]([N:5]2[C@H:4]([CH:2]([CH3:3])[CH3:1])[CH2:8][O:7][C:6]2=[O:9])=[O:30])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)C1COC(=O)N1
Reactant: O=C(Cl)CCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)[C@@H]1COC(=O)N1C(=O)CCc1ccccc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 82 %

Procedure:
To a stirred solution of 4-(2-propyl)-oxazolidine-2-one in anhydrous tetrahydrofuran (250 ml) under a nitrogen atmosphere at -78° C. was added in a dropwise fashion a solution of n-butyllithium in hexane (50 ml, 77.4 mmol) over 5 to 10 min. After stirring an additional 20 min at -78° C. 3-phenylpropionyl chloride (12.7 ml, 85.2 mmol) was added neat. The reaction was warmed to room temperature and stirred 1 to 2 h. The reaction was quenched by adding 100 ml of saturated aqueous ammonium chloride and the volatiles were removed by rotary evaporation. The resulting aqueous residue was extracted three times with ether and the combined organic phases were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. Recrystallization from hexanes/ethyl acetate provided the title compound (16.6 9, 82%). m.p.=86.5°-87.5° C. Mass spectrum: (M+NH4)+ =279, (M+H)+ =262.
Reaction SMILES: [OH:1][C:2]1([C@H:5]([NH:11][C:12]2[CH2:16][S:15][C:14](=[O:17])[N:13]=2)[C:6]([N:8]([CH3:10])[CH3:9])=[O:7])[CH2:4][CH2:3]1.[F:18][C:19]([F:40])([F:39])[C:20]1[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][C:21]=1[CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([CH:29]=O)[CH2:25][CH2:24]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:40][C:19]([F:18])([F:39])[C:20]1[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][C:21]=1[CH2:22][N:23]1[CH2:28][CH2:27][CH:26](/[CH:29]=[C:16]2/[C:12]([NH:11][C@@H:5]([C:2]3([OH:1])[CH2:3][CH2:4]3)[C:6]([N:8]([CH3:10])[CH3:9])=[O:7])=[N:13][C:14](=[O:17])[S:15]/2)[CH2:25][CH2:24]1
Reactant: CN(C)C(=O)[C@@H](NC1=NC(=O)SC1)C1(O)CC1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: CN(C)C(=O)[C@@H](NC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1)C1(O)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 34.5 %

Procedure:
To a solution of (2S)-2-(1-hydroxycyclopropyl)-N,N-dimethyl-2-[(2-oxo-2,5-dihydro-1,3-thiazol-4-yl)amino]ethanamide (13 mg) and 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (17 mg) in 2-propanol (1 mL) was added piperidinium acetate (7 mg) at room temperature. The reaction mixture was stirred at 60° C. overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate) to give the title compound (10 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[N:8]=[C:7]([NH:13][C:14]1[CH:25]=[CH:24][C:17]([C:18]([NH:20][CH:21]([CH3:23])[CH3:22])=[O:19])=[CH:16][CH:15]=1)[N:6]=[CH:5]2.C(N(CC)CC)C.[CH3:33][Si:34]([C:37]#[CH:38])([CH3:36])[CH3:35]>CN(C=O)C.C(OCC)(=O)C.[Cu]I>[OH:12][C:11]1[CH:10]=[C:9]2[C:4]([CH:5]=[N:6][C:7]([NH:13][C:14]3[CH:25]=[CH:24][C:17]([C:18]([NH:20][CH:21]([CH3:23])[CH3:22])=[O:19])=[CH:16][CH:15]=3)=[N:8]2)=[CH:3][C:2]=1[C:38]#[C:37][Si:34]([CH3:36])([CH3:35])[CH3:33]
Reactant: CC(C)NC(=O)c1ccc(Nc2ncc3cc(Br)c(O)cc3n2)cc1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)NC(=O)c1ccc(Nc2ncc3cc(C#C[Si](C)(C)C)c(O)cc3n2)cc1

Procedure:
To a 0.09M mixture of 4-(6-bromo-7-hydroxyquinazolin-2-ylamino)-N-isopropylbenzamide (0.17 mM), triethylamine (0.5 ml), Pd(dppf)2Cl2CH2Cl2 (0.1 eq), Copper(I) iodide (0.1 eq), in DMF was added trimethylsilylacetylene (10 eq). The suspension was microwaved at 120° C. for 20 min. Reaction mixture was diluted with ethyl acetate and was washed with water, brine, dried and concentrated to give crude product. ES/MS m/z 419 (MH+).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[S:21][CH:20]=[CH:19][N:5]2[C:6](=[O:18])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1.[CH:22]1([CH2:26][O:27][C:28]2[C:35]([O:36][CH3:37])=[CH:34][CH:33]=[CH:32][C:29]=2[CH:30]=O)[CH2:25][CH2:24][CH2:23]1.[O-]CC.[Na+]>C(O)C>[CH:22]1([CH2:26][O:27][C:28]2[C:35]([O:36][CH3:37])=[CH:34][CH:33]=[CH:32][C:29]=2/[CH:30]=[CH:1]/[C:2]2[N:3]=[C:4]3[S:21][CH:20]=[CH:19][N:5]3[C:6](=[O:18])[C:7]=2[C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:10][CH:9]=2)[CH2:23][CH2:24][CH2:25]1
Reactant: Cc1nc2sccn2c(=O)c1-c1ccc(C(F)(F)F)cc1
Reactant: COc1cccc(C=O)c1OCC1CCC1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(/C=C/c2nc3sccn3c(=O)c2-c2ccc(C(F)(F)F)cc2)c1OCC1CCC1
Yield: 46.9 %

Procedure:
The title compound was synthesized by condensation of Intermediate 5 (400 mg, 1.289 mmol) with 2-cyclobutylmethoxy-3-methoxybenzaldehyde (368 mg, 1.603 mmol) in the presence of sodium ethoxide (163 mg, 2.411 mmol) in ethanol (15 ml) according to the procedure described in Example 24 to give 310 mg of the desired product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.80-1.86 (m, 5H), 1.98-2.04 (m, 2H), 3.77 (s, 3H), 3.82 (d, J=6.9 Hz, 2H), 6.87-7.00 (m, 4H), 7.51 (d, J=7.5 Hz, 1H), 7.59 (d, J=7.8 Hz, 2H), 7.84 (d, J=7.8 Hz, 2H), 8.01 (d, J=4.8 Hz, 1H) 8.14 (d, J=15.6 Hz, 1H); ESI-MS (m/z) 513.30 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:28])/[CH:4]=[CH:5]/[CH:6]=[C:7](/[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)\[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[OH-].[Na+]>CO>[CH3:27][O:26][C:23]1[CH:22]=[CH:21][C:20](/[C:7](/[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:6]/[CH:5]=[CH:4]/[C:3]([OH:28])=[O:2])=[CH:25][CH:24]=1
Reactant: CCCCCCCCCCCC/C(=C\C=C\C(=O)OC)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCCC/C(=C\C=C\C(=O)O)c1ccc(OC)cc1
Yield: 68.5 %

Procedure:
As described in Example 99, (E,E)-5-(4-methoxyphenyl)-2,4-heptadecadienoic acid methyl ester (11.9 g) was saponified in a refluxing mixture of methanol (30 mL) and 2N NaOH (30 mL). After 2.5 hours the crude acid was isolated in the usual way and was crystallized from hexane to give 7.86 g of (E,E)-5-(4-methoxyphenyl)-2,4-heptadecadienoic acid. A sample was recrystallized from the same solvent to afford the analytical specimen, mp 85°-88° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:11]=[CH:12]/[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:6]2[C:10]=1[CH2:9][CH2:8][CH2:7]2.[H][H]>C(O)C.[Pd]>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:6]2[C:10]=1[CH2:9][CH2:8][CH2:7]2
Reactant: CCOC(=O)/C=C/c1ccc(O)c2c1CCC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(O)c2c1CCC2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Into a 25-mL round-bottom flask, was placed a solution of ethyl (2E)-3-(7-hydroxy-2,3-dihydro-1H-inden-4-yl)prop-2-enoate (87.4 mg, 0.38 mmol, 1.00 equiv) in ethanol (4 mL) and palladium on carbon (80 mg). The mixture was then subject to an atmosphere of hydrogen and stirred for 12 h at 25° C. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). This resulted in 79.8 mg (91%) of ethyl 3-(7-hydroxy-2,3-dihydro-1H-inden-4-yl)propanoate as yellow oil.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][N:8]([CH3:16])[CH2:9][CH2:10][CH2:11][CH2:12][NH:13][CH:14]=O.C(O)C>C1COCC1>[CH3:7][N:8]([CH3:16])[CH2:9][CH2:10][CH2:11][CH2:12][NH:13][CH3:14]
Reactant: CN(C)CCCCNC=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCO
Product: CNCCCCN(C)C
Temperature: 0 °C
Yield: 61.5 %

Procedure:
A solution of lithium aluminium hydride in THF (1M, 28 mL) was added dropwise to a stirred, cooled solution of N-(4-dimethylaminobutyl)formamide (Intermediate 79, 2.7 g) in THF (60 mL) while maintaining the temperature at 0° C. under an atmosphere of nitrogen. On completion of the addition, the mixture was stirred and heated at 75° C. for 2 hours. The reaction mixture was cooled to 0° C. and ethanol was added then the mixture was evaporated to dryness. The residue was diluted with a mixture of diethyl ether and DCM (30%) and the solid was filtered off. The filtrate was evaporated to dryness to give N-(4-dimethylaminobutyl)-N-methylamine (1.5 g) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1Cl.[F:9][C:10]([F:14])([F:13])[CH2:11][OH:12]>>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:12][CH2:11][C:10]([F:14])([F:13])[F:9]
Reactant: Clc1ccncc1Br
Reactant: OCC(F)(F)F
Product: FC(F)(F)COc1ccncc1Br

Procedure:
The title compound was synthesized in analogy to Example 53a, using 3-bromo-4-chloropyridine (CAN 36953-42-1) and 2,2,2-trifluoroethanol (CAN 75-89-8) as starting materials and isolated (7.4 g, 78%) as a yellow oil; MS (ESI, m/z): 256.1 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:25][OH:26])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C>CS(C)=O.ClCCl>[CH2:17]([O:16][C:15]([NH:14][CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:25]=[O:26])=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CCCCNC(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N[C@H](C=O)CCCCNC(=O)OCc1ccccc1
Reaction time: 23 h
Yield: 299.8 %

Procedure:
A solution of sulfur trioxide pyridine complex (53.0 g, 333 mmol) in dimethylsulfoxide (300 mL) was added to a solution of benzyl (5S)-5-{[t-butyloxycarbonyl]amino}-6-hydroxyhexylcarbamate (8.64 g, 34.4 mmol) and triethylamine (14.4 mL, 103 mmol) in dichloromethane (130 mL) at 0° C. The cold bath was removed, and the reaction mixture was stirred for 23 h. It was then poured slowly into a mixture of ice and saturated aqueous sodium chloride (1000 mL). The resulting mixture was extracted with three 600 mL portions of ether. The ether extracts were then combined, washed with three 150 mL portions of saturated aqueous sodium chloride, and concentrated to 1200 mL. The concentrated ether phase was further washed with three 200 mL aliquots of 5% aqueous citric acid, and a 200 mL portion of saturated aqueous sodium chloride. After drying over magnesium sulfate, volatiles were removed under vacuum to afford (2S)-6-{[(benzyloxy)carbonyl]amino}-2-[(tert-butoxycarbonyl)amino]hexanal (37.58 g. 93%). 1H NMR (300 MHz, DMSO-d6) δ 9.44 (s, 1H), 7.46-7.23 (m, 6H), 5.02 (s, 2H), 3.85-3.75 (m, 1H), 3.07-2.93 (m, 2H), 1.77-1.60 (m, 1H), 1.56-1.23 (m, 5H), 1.41 (s, 9H).
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[O:18][C:17]([CH3:23])([CH3:22])[CH2:16][C:15]3([CH3:25])[CH3:24])=[CH:6][C:5]=1[F:26].[OH-].[Na+]>CO>[F:26][C:5]1[CH:6]=[C:7]([C:10]#[C:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[O:18][C:17]([CH3:23])([CH3:22])[CH2:16][C:15]3([CH3:25])[CH3:24])[CH:8]=[CH:9][C:4]=1[C:3]([OH:27])=[O:2]
Reactant: COC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CC(C)(C)O3)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)CC(C)(C)c2cc(C#Cc3ccc(C(=O)O)c(F)c3)ccc2O1

Procedure:
Following general procedure L and using 2-fluoro-4-(2,2,4,4-tetramethyl-chroman-6-yl-ethynyl)-benzoic acid methyl ester (Compound 29, 0.14 g, 0.4 mmol), 5 mL of methanol and 1M sodium hydroxide solution (2 mL) followed by recrystallization from ethyl acetate, the title compound was obtained (0.083 g, 58%).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:11]([CH3:12])=[CH:10][C:7]([C:8]#[N:9])=[CH:6][C:5]=1[CH3:13].[Cl:14][C:15]1[N:16]=[C:17](Cl)[C:18]2[CH:23]=[CH:22][S:21][C:19]=2[N:20]=1>C1COCC1.O>[Cl:14][C:15]1[N:16]=[C:17]([O:3][C:4]2[C:5]([CH3:13])=[CH:6][C:7]([C:8]#[N:9])=[CH:10][C:11]=2[CH3:12])[C:18]2[CH:23]=[CH:22][S:21][C:19]=2[N:20]=1
Reactant: Clc1nc(Cl)c2ccsc2n1
Reactant: Cc1cc(C#N)cc(C)c1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C#N)cc(C)c1Oc1nc(Cl)nc2sccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28.1 %

Procedure:
A stirred suspension of NaH (85 mg, 2.12 mmol) in dry THF (12 mL) was added 4-hydroxy-3,5-dimethyl benzonitrile (311 mg, 2.12 mmol) and stirred at room temperature for 30 min under Argon. The reaction mixture was added to a solution of 2,4-dichlorothieno[2,3-d]pyrimidine (434 mg, 2.12 mmol) in dry THF (10 mL) and heated at 50° C. for 2 h, the resulting mixture was diluted with water and washed with EtOAc. The combined organic layers were washed with water, brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (5:1) to give the product as a white solid (188 mg, 28%):
Reaction SMILES: [C:1]1([C:7]2[N:11]([S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21]C4CCCCO4)[CH:16]=3)(=[O:14])=[O:13])[CH:10]=[C:9]([CH2:28][N:29]([CH3:37])[C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl-].[NH4+]>ClCCl>[C:1]1([C:7]2[N:11]([S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=3)(=[O:13])=[O:14])[CH:10]=[C:9]([CH2:28][N:29]([CH3:37])[C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:34])[CH3:35])[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CN(Cc1cc(C2=CCCCC2)n(S(=O)(=O)c2cccc(OC3CCCCO3)c2)c1)C(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: CN(Cc1cc(C2=CCCCC2)n(S(=O)(=O)c2cccc(O)c2)c1)C(=O)OC(C)(C)C
Reaction time: 3 h

Procedure:
tert-Butyl ((5-(cyclohex-1-en-1-yl)-1-((3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate 7c (600 mg, 1.1 mmol) was dissolved in 50 mL of dichloromethane, followed by addition of p-toluenesulfonic acid (195 mg, 1.1 mmol), and then the reaction solution was stirred for 3 h. 50 mL of saturated ammonium chloride solution were added, the reaction solution was separated, and the water phase was extracted with dichloromethane (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with elution system C to obtain the title product tert-butyl ((5-(cyclohex-1-en-1-yl)-1-((3-hydroxyphenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate 7d (384 mg, a colorless oil) in 76% yield.