Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:25]1([CH:31]([CH3:35])[C:32](Cl)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1(C)C=CC=CC=1.C1COCC1>[O:1]=[C:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH:7]1[C:32](=[O:33])[CH:31]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:35]
Reactant: CC(C(=O)Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O)c1ccccc1
Temperature: 0 °C
Yield: 67.1 %

Procedure:
tert-Butyl 4-oxopiperidine-1-carboxylate (2.363 g, 11.86 mmol) was dissolved in toluene (7 mL) and cooled to 0° C. LHMDS (12.45 mL, 12.45 mmol) in THF was added. After 2 min 2-phenylpropanoyl chloride (0.855 mL, 5.93 mmol) was added. After 2 min the cooling bath was removed and after 5 min 1:1 acetic acid:water (3 ml) was added. The water phase was separated after hard stirring and the organic phase was dried with MgSO4 and the solvent was evaporated. Purification by flash column chromatography (0-25% EtOAc in heptane) yielded tert-butyl 4-oxo-3-(2-phenylpropanoyl)piperidine-1-carboxylate (1.319 g, 67.1%). MS (ES−) m/z 330.1 (M−H)−
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.[Si:27](OS(C(F)(F)F)(=O)=O)([CH:34]([CH3:36])[CH3:35])([CH:31]([CH3:33])[CH3:32])[CH:28]([CH3:30])[CH3:29]>C(Cl)Cl>[CH:28]([Si:27]([CH:34]([CH3:36])[CH3:35])([CH:31]([CH3:33])[CH3:32])[O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])=[CH:6][CH:7]=1)([CH3:30])[CH3:29]
Reactant: O=C(Cc1ccc(O)cc1)OCc1ccccc1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)[Si](Oc1ccc(CC(=O)OCc2ccccc2)cc1)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
To benzyl 2-(4-hydroxyphenyl)acetate (E301) in CH2Cl2 at 0° C. was added 2,6-lutidine and TIPS-OTf and the solution stirred for 2.5 h at 0° C. The mixture was poured into NH4Cl(sat) and extracted with CH2Cl2. The combined organics were dried (Na2SO4), filtered, and evaporated. Column chromatography (SiO2, 0-15% EtOAc/Hex) gave pure benzyl 2-(4-(triisopropylsiloxy)phenyl)acetate (E302).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[O:15]=[C:16]1[O:20][CH:19]([O:21][CH2:22][CH2:23][C:24]2C=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:18]([NH:30][C:31]([CH:33]2[CH2:37][CH2:36][CH2:35][N:34]2[C:38](=[O:52])[CH:39]([NH:41]C(=O)C2C=CC(N)=C(Cl)C=2)[CH3:40])=[O:32])[CH2:17]1>>[CH2:22]([O:21][CH:19]1[CH:18]([NH:30][C:31]([CH:33]2[CH2:37][CH2:36][CH2:35][N:34]2[C:38](=[O:52])[CH:39]([NH:41][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([NH2:1])=[C:3]([C:11]([F:14])([F:13])[F:12])[CH:4]=2)[CH3:40])=[O:32])[CH2:17][C:16](=[O:15])[O:20]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCCc1ccccc1
Reactant: Nc1ccc(C(=O)O)cc1C(F)(F)F
Product: CC(NC(=O)c1ccc(N)c(C(F)(F)F)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCc1ccccc1
Yield: 48 %

Procedure:
Prepared from {2-[2-(2-benzyloxy-5-oxo-tetrahydro-furan-3-ylcarbmoyl)-pyrrolidin-1-yl]-1-methyl-2-oxo-ethyl}-carbamic acid tert-butyl ester and 4-amino-3-trifluoromethyl-benzoic acid according to the procedure used to prepare 98a to afford 56 mg of title compound (48% yield). 1H-NMR (500 MHz, 1:1 CDCl3:CD3OD) δ 1.20-1.55 (m, 3H), 1.75-2.50 (m, 4H), 2.50-3.10 (m, 2H), 3.50-4.00 (m, 2H), 4.30-5.00 (m, 5H), 5.42 (s, 0.4H), 5.51 (s, 0.2H), 5.62 (d, 0.3H), 5.78 (d, 0.1H), 6.84 (d, 1H), 7.20-8.15 (m, 7H). Analytical HPLC: 14.90, 15.20 min. LC-MS (ES+): m/e=563.2 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][N:9]=[C:10]([C:15]#[N:16])[C:11]([NH:13][CH3:14])=[O:12].[Cl-:17].[Al+3].[Cl-].[Cl-].Cl>C1(C)C=CC=CC=1>[ClH:17].[NH2:16][C:15]1[C:4]2[C:3](=[C:2]([Br:1])[CH:7]=[CH:6][CH:5]=2)[N:8]=[N:9][C:10]=1[C:11]([NH:13][CH3:14])=[O:12]
Reactant: [Cl-]
Reactant: CNC(=O)C(C#N)=NNc1ccccc1Br
Agent: Cl
Agent: [Al+3]
Solvent: Cc1ccccc1
Product: CNC(=O)c1nnc2c(Br)cccc2c1N
Temperature: 25 °C
Yield: 89.3 %

Procedure:
A 250 mL round-bottomed flask was charged with 2-[(2-bromophenyl)-hydrazono]-N-methyl-2-cyanoacetamide (2.00 g, 7.12 mmol), aluminum chloride (3.46 g, 25.97 mmol), and anhydrous toluene (68 mL). The reaction was gently refluxed for 45 minutes, cooled to room temperature, and slowly treated with 2N HCl (68 mL). A precipitate formed. The mixture was heated to 90° C. for 10 minutes, cooled to room temperature, and filtered. The solids were dried under high vacuum at 50° C. to afford the title compound (2.02 g, 90%). 1H NMR (300.132 MHz, DMSO) δ 9.08 (d, J=4.7 Hz, 1H), 8.56 (dd, J=8.4, 0.8 Hz, 1H), 8.28 (dd, J=7.6, 0.7 Hz, 1H), 7.65 (t, J=8.0 Hz, 1H), 2.89 (d, J=4.7 Hz, 3H). MS APCI, m/z=281/283 (M+H). HPLC 1.61 min.
Reaction SMILES: I[C:2]1[C:6]2=[N:7][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:10]=[C:5]2[N:4]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH:3]=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:31][CH:32]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Cl>CC(O)C.O>[CH3:25][O:26][C:27]1[CH:28]=[C:29]([C:2]2[C:6]3=[N:7][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:10]=[C:5]3[N:4]([S:15]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:3]=2)[CH:30]=[N:31][CH:32]=1
Reactant: COc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: COC(=O)c1ccc2c(n1)c(I)cn2S(=O)(=O)c1ccc(C)cc1
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: COC(=O)c1ccc2c(n1)c(-c1cncc(OC)c1)cn2S(=O)(=O)c1ccc(C)cc1
Temperature: 100 °C
Yield: 59.1 %

Procedure:
A glass microwave reaction vessel was charged with methyl 3-iodo-1-((4-methylphenyl)sulfonyl)-1H-pyrrolo[3,2-b]pyridine-5-carboxylate (0.300 g, 0.658 mmol), 5-methoxy-3-pyridineboronic acid pinacol ester (0.216 g, 0.921 mmol, Sigma-Aldrich), and K3PO4 (0.419 g, 1.973 mmol) in 70% i-PrOH in H2O (3.30 mL). The reaction was stirred and heated in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 100° C. for 10 min. 2 M HCl (aq.) was added and the mixture was extracted with DCM (3×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The crude material was absorbed onto a plug of silica gel and purified by column chromatography (eluting with 0-10% MeOH in DCM) to provide methyl 3-(5-methoxy-3-pyridinyl)-1-((4-methylphenyl)sulfonyl)-1H-pyrrolo[3,2-b]pyridine-5-carboxylate (0.170 g, 0.389 mmol, 59.1%) as a pale yellow solid. MS (ESI, pos. ion) m/z: 438.0 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 2.37 (3H, s), 3.96 (3H, s), 4.00 (3H, s), 7.29 (2H, d, J=8.22 Hz), 7.79-7.85 (2H, m), 8.16-8.21 (2H, m), 8.27-8.34 (2H, m), 8.42 (1H, d, J=8.61 Hz), 8.81 (1H, d, J=1.56 Hz).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1.[O:17]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[O:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[O:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1
Reactant: O=C(OCc1ccccc1)N1CCC(O)C1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC(OC2CCCCO2)C1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Into a 250 mL 3-necked round bottom flask was placed a solution of benzyl 3-hydroxypyrrolidine-1-carboxylate (10 g, 45.23 mmol) in CH2Cl2 (100 mL). To this was added 3,4-dihydro-2H-pyran (19 g, 226.19 mmol). To the mixture was added p-toluenesulfonic acid (389 mg, 2.26 mmol) and the resulting solution was allowed to react, with stirring, for 10 minutes while the temperature was maintained at 0° C. The resulting solution was allowed to react, with stirring, for an additional 1 hour at room temperature. The reaction progress was monitored by TLC (ethyl acetate/petroleum ether=1:2). The reaction mixture was then quenched by the adding 100 mL of NaHCO3. The resulting mixture was washed with 100 mL of NaHCO3 and 100 mL of brine. The mixture was dried over MgSO4 and concentrated under vacuum using a rotary evaporator. This resulted in 15 g (98%) of benzyl 3-(tetrahydro-2H-pyran-2-yloxy)pyrrolidine-1-carboxylate as yellow oil.
Reaction SMILES: C([O:8][C:9](=[O:30])[CH2:10][NH:11][CH:12](C(OC(C)(C)C)=O)[C:13]([O:15]CC1C=CC=CC=1)=[O:14])C1C=CC=CC=1.Cl.CCOCC>O1CCOCC1>[NH:11]([CH2:12][C:13]([OH:15])=[O:14])[CH2:10][C:9]([OH:30])=[O:8]
Reactant: CC(C)(C)OC(=O)C(NCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: O=C(O)CNCC(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 247.2 %

Procedure:
Boc-Iminodiacetic acid dibenzyl ester (4.5 g, 10.88 mmol) was dissolved in dioxane (15 mL), then 4.6 M HCl in dioxane (20 mL) was added. The mixture was stirred for 90 min at room temperature and Et2O (200 mL) was added. The crystalline product was filtered off, washed twice with Et2O and dried in vacuo to afford the title compound (3.58 g, 94.2%).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([CH2:18][N:19]3[C:23]4[CH:24]=[CH:25][C:26]([C:28]#N)=[CH:27][C:22]=4[N:21]=[CH:20]3)[CH:15]=[CH:14][C:12]=2[N:13]=1.[CH3:30][Si:31]([C:34]#C)([CH3:33])[CH3:32].CCN(C(C)C)C(C)C>CC#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:30][Si:31]([C:34]#[C:28][C:26]1[CH:25]=[CH:24][C:23]2[N:19]([CH2:18][C:16]3[CH:15]=[CH:14][C:12]4[N:13]=[C:9]([NH:8][C@@H:3]5[CH2:4][CH2:5][CH2:6][CH2:7][C@H:2]5[OH:1])[S:10][C:11]=4[CH:17]=3)[CH:20]=[N:21][C:22]=2[CH:27]=1)([CH3:33])[CH3:32]
Reactant: C#C[Si](C)(C)C
Reactant: N#Cc1ccc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)C#Cc1ccc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Temperature: 80 °C
Yield: 53.5 %

Procedure:
A stirred mixture of (1R,2R)-2-((6-((5-bromo-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (109 mg, 0.24 mmol) from Step 6 of Example 108, (trimethylsilyl)acetylene (68 μL, 0.48 mmol), and DIEA (62 μL, 0.36 mmol) in CH3CN (2 mL), was purged with a stream of argon for 5 min. To the mixture was added tetrakis(triphenylphosphine)palladium (0) (57 mg, 0.05 mmol) and argon was bubbled into the mixture for an additional 5 min. The reaction vessel was sealed and the mixture was heated at 80° C. for 5 h. The mixture was cooled to rt and was partitioned between EtOAc (100 mL) and 1 M aq NaHCO3 (50 mL). The organic layer was washed with brine (50 mL), dried over Mg2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 5% MeOH in DCM to afford (1R,2R)-2-((6-((5-((trimethylsilyl)ethynyl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (61 mg, 54%) as an amber oil. LCMS (ESI) m/z 476 (M+H)+.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([S:11](Cl)(=[O:13])=[O:12])=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[CH2:15]([NH:17][CH2:18][CH3:19])[CH3:16]>O1CCCC1>[CH2:15]([N:17]([CH2:18][CH3:19])[S:11]([C:7]1[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=1[CH3:10])(=[O:13])=[O:12])[CH3:16]
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)Cl)s1
Reactant: CCNCC
Solvent: C1CCOC1
Product: CCN(CC)S(=O)(=O)c1sc(NC(C)=O)nc1C
Reaction time: 4 h

Procedure:
2-Acetamido-4methylthiazole-5-sulfonyl chloride (5.2 g) in tetrahydrofuran (100 cm3) was stirred at ambient temperature and treated portionwise with diethylamine (4.5 cm3). The mixture was stirred for 4 hours, evaporated under reduced pressure and the residue extracted into ethyl acetate (200 cm3), washed with water (2×100 cm3), dried (MgSO4) and re-evaporated under reduced pressure to give N,N-diethyl 2-acetamido-4-methylthiazole-5-sulfonamide (4.9 g). 1H NMR: δ 1.20(6H,t); 2.28(3H,s); 2.57(3H,s); 3.32(4H,q); 9.7(1H,br s); (solid).
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)C(=O)OC(C)(C)C)[CH3:2].O1CCOCC1.O.[OH-].[Na+]>Cl>[CH2:1]([NH:3][CH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)[CH3:2]
Reactant: CCN(CCCN1CCOCC1)C(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCNCCCN1CCOCC1
Reaction time: 0.75 h
Yield: 22.3 %

Procedure:
3-(4-Morpholinyl)propan-1-amine (35.0 g, 243 mmol) was dissolved in tetrahydrofuran (THF, 250 mL), di-tert-butyl dicarbonate (58.0 g, 266 mmol) and N,N-diisopropylethylamine (DIPEA, 84 mL, 484 mmol) were added, and the solution was stirred overnight. The solvent was removed and the residue partitioned between ethyl acetate (EA) and 1.2M hydrochloric acid (300 mL). The pH was raised to 7 with saturated aqueous sodium bicarbonate and the layers separated. The aqueous layer was extracted twice with EA (150 mL each), and the EA layers were combined, washed with brine, and dried over magnesium sulfate. The solvent was removed, giving tert-butyl 3-(4-morpholinyl)propylcarbamate (39 g). Tent-butyl 3-(4-morpholinyl)propylcarbamate (3.5 g, 14.3 mmol) was dissolved in THF (30 mL), and sodium hydride (60% dispersion in mineral oil, 1.03 g, 25.8 mmol) was added in portions. After stirring for 5 min, ethyl iodide (13.4 g, 86.0 mmol) was added and the mixture was heated to 60° C. for 7 hr then stirred at room temperature overnight. Water (5 mL) was added and the solvent removed. The residue was dissolved in EA, and the solution was washed with brine, dried over magnesium sulfate, and the solvent removed to give crude tert-butyl ethyl[3-(4-morpholinyl)propyl]carbamate (2.5 g). Purification by silica gel chromatography eluting with 92:8 dichloromethane/methanol (DCM/MeOH) gave purified tert-butyl ethyl[3-(4-morpholinyl)propyl]carbamate (1.4 g). Purified tert-butyl ethyl[3-(4-morpholinyl)propyl]carbamate (350 mg, 1.3 mmol) was dissolved in 4.0M hydrogen chloride in dioxane (5 mL, 20 mmol) and stirred for 45 min. Water was added and the solution made basic with 2M aqueous sodium hydroxide. The product was extracted into EA, and the EA extract washed with brine and dried over magnesium sulfate. Removal of the EA gave N-ethyl-3-(4-morpholinyl)propan-1-amine (50 mg).
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C@@:6]([C:16]([OH:18])=[O:17])([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[NH2:7].[CH3:19]O>>[CH3:19][O:17][C:16](=[O:18])[C@:6]([CH3:5])([CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[NH2:7]
Reactant: C[C@](N)(CCc1ccccc1)C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@](C)(N)CCc1ccccc1
Reaction time: 8.5 h

Procedure:
430 ml methanol are cooled to -10° C. in an ice/sodium chloride mixture and reacted with 21.3 ml thionyl chloride (exothermic reaction). 44.5 g (0.23 mol) α-methyl-homo-phenylalanine are added dropwise at room temperature. Boiling under reflux occurs for 8.5 hours, the mixture is concentrated in a rotary evaporator, taken up with H2O (350 ml) and reacted with 150 ml 25% NH4OH solution. Extraction with dichloromethane occurs 5× and the combined extracts are dried over calcium carbonate and concentrated in a rotary evaporator. Yellowish oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([S:15]([CH2:18][C:19]3([CH2:26][CH2:27][CH2:28][NH:29]C(=O)OC(C)(C)C)[C:23](=[O:24])[NH:22][C:21](=[O:25])[NH:20]3)(=[O:17])=[O:16])[CH2:11][CH2:10]2)=[N:6][CH:7]=1.[C:37]([OH:43])([C:39]([F:42])([F:41])[F:40])=[O:38]>C(Cl)Cl>[F:40][C:39]([F:42])([F:41])[C:37]([OH:43])=[O:38].[NH2:29][CH2:28][CH2:27][CH2:26][C:19]1([CH2:18][S:15]([N:12]2[CH2:13][CH2:14][CH:9]([O:8][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)[CH2:10][CH2:11]2)(=[O:16])=[O:17])[NH:20][C:21](=[O:25])[NH:22][C:23]1=[O:24]
Reactant: CC(C)(C)OC(=O)NCCCC1(CS(=O)(=O)N2CCC(Oc3ccc(Cl)cn3)CC2)NC(=O)NC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCCC1(CS(=O)(=O)N2CCC(Oc3ccc(Cl)cn3)CC2)NC(=O)NC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
1,1-dimethylethyl 3-{4-[({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)methyl]-2,5-dioxoimidazolidin-4-yl}propylcarbamate (426 mg, 0.78 mmol) was dissolved in 10 mL CH2Cl2 and 4 mL of TFA was added. The reaction was stirred at rt for 1 hour. The solvent was removed to give 408 mg (93%) of the title compound as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)#[N:2].[C:12](O)([CH3:15])([CH3:14])[CH3:13].Cl.CN(C)CCCN=C=NCC>CN(C=O)C.CN(C)C1C=CN=CC=1>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C(=O)O)cc1
Reactant: CC(C)(C)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dissolve 22.1 g 4-cyanobenzoic acid and 28.2 ml t-butanol in 500 ml DMF. Add 9.15 g 4-(dimethylamino) pyridine and 31.5 g 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. Stir the mixture overnight at RT. Remove the DMF in vacuo, and partition the resultant residue between ethyl acetate and water. Wash the organic layer successively with cold 0.5 N aqueous HCl, water, 5% aqueous NaHC03 and brine. Dry the organic layer over MgSO4 and evaporate the solvent to obtain the title compound. m.p. 75°-78° C. Rf (silica gel; 5% EtOAc in hexane)=0.3; IR 2240 cm-1 ; 1730 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:27])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:23][C:22](=[O:24])[N:21]([CH3:25])[C:20]=2[CH:26]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[CH3:28][O:29][C:30]([C:32]1[N:33]=[N:34][C:35](Cl)=[CH:36][CH:37]=1)=[O:31]>>[CH3:28][O:29][C:30]([C:32]1[N:33]=[N:34][C:35]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:27])[C:10]([OH:15])([C:16]3[CH:17]=[CH:18][C:19]4[O:23][C:22](=[O:24])[N:21]([CH3:25])[C:20]=4[CH:26]=3)[C:11]([F:12])([F:13])[F:14])=[C:2]([Cl:1])[CH:7]=2)=[CH:36][CH:37]=1)=[O:31]
Reactant: COC(=O)c1ccc(Cl)nn1
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc2oc(=O)n(C)c2c1)C(F)(F)F
Product: COC(=O)c1ccc(Oc2ccc(C(C)C(O)(c3ccc4oc(=O)n(C)c4c3)C(F)(F)F)c(Cl)c2)nn1

Procedure:
The title compound was prepared in analogy to Example 196 from 5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-3-methyl-3H-benzooxazol-2-one (obtained in Example 172) by alkylation with methyl-6-chloropyridazine-3-carboxylate [CAS Reg. No. 65202-50-8]. MS (m/e)=538.2 [M+H+].
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1([C:19]([O:21]CC)=[O:20])[CH2:14][C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+].Cl>CO>[CH2:1]([O:8][CH2:9][C:10]1([C:19]([OH:21])=[O:20])[CH2:14][C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1(COCc2ccccc2)Cc2ccccc2O1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1(COCc2ccccc2)Cc2ccccc2O1
Reaction time: 3 h
Yield: 92.3 %

Procedure:
A solution of ethyl 2-benzyloxymethyl-2,3-dihydrobenzofuran-2-carboxylate (1.62 g, 5.47 mmol) in methanol (70 ml) was added with a solution of 1M lithium hydroxide (54.7 ml). The mixture was refluxed under stirring for 3 h, after that was neutralized with 1M HCl and methanol was evaporated off under reduced pressure. The resulting crude was suspended in water (20 ml) and extracted with ethyl acetate (4×25 ml). The organic phase was dried and the solvent was evaporated off under reduced pressure, to obtain 1.436 g of the title compound, which was purified by crystallization in methanol (97% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][CH:15]=[CH:14]2>O1CCCC1.[O-2].[Mn+4].[O-2]>[Br:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[C:16]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH:15]=[CH:14]2
Reactant: Brc1ccc2ncccc2c1
Reactant: Fc1ccc([Mg]Br)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: Fc1ccc(-c2ccc3cc(Br)ccc3n2)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 66.7 %

Procedure:
4-Fluorophenylmagnesium bromide (1.0M in tetrahydrofuran, 30 mL, 30 mmol) was added dropwise to a solution of 6-bromoquinoline (5.0 g, 24 mmol) in tetrahydrofuran (50 mL) at −5° C. The reaction was stirred, maintaining the temperature below 0° C. for 1.5 hours, then allowed to warm to room temperature for 70 hours. Further 4-fluorophenylmagnesium bromide was added and the reaction heated to reflux for 20 hours. The cooled reaction mixture was quenched with saturated ammonium chloride solution then poured into water and extracted with ethyl acetate (x2). The combined organic layers were washed with brine, dried over MgSO4 and evaporated. The residue was dissolved in dichloromethane (100 mL). Manganese (IV) oxide (2.22 g, 25.5 mmol) was added and the reaction stirred at room temperature for 1 hour. Further manganese(IV) oxide (4.51 g) was added and stirring continued for 3.5 hours. The reaction mixture was filtered through a plug of silica, washing with dichloromethane. The filtrate was concentrated in vacuo. The residue was stirred in methanol (100 mL) for 5 minutes then removed by filtration to give 6-bromo-2-(4-fluorophenyl)quinoline (4.84 g, 67%). 1H NMR (500 MHz, CDCl3) δ 8.17-8.11 (3H, m), 8.02-7.98 (2H, m), 7.85 (1H, d, J=8.6 Hz), 7.79 (1H, dd, J=2.1, 8.9 Hz), 7.21 (2H, t, J=8.6 Hz); m/z (ES+) 302, 304 [MH+].
Reaction SMILES: C([O:6][C@@H:7]([C:9]1[N:14]=[C:13]([Cl:15])[CH:12]=[CH:11][N:10]=1)[CH3:8])(=O)CCC.Cl>O1CCOCC1>[Cl:15][C:13]1[CH:12]=[CH:11][N:10]=[C:9]([C@H:7]([OH:6])[CH3:8])[N:14]=1
Reactant: CCCC(=O)O[C@H](C)c1nccc(Cl)n1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H](O)c1nccc(Cl)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 71 %

Procedure:
To a solution of (R)-1-(4-chloro-pyrimidin-2-yl)-ethyl butyrate (prepared according to the method of Preparation Seven, 250 mg, 1.1 mmol) in, dioxane (0.9 mL) was added concentrated hydrochloric acid (0.9 mL). This mixture was allowed to stir at room temperature for 5 h, quenched with saturated aqueous sodium bicarbonate followed by solid sodium bicarbonate until no more gas evolution was evident. Dichloromethane was added and the layers were separated. The aqueous phase was extracted with dichloromethane (3×) and the combined organic extracts were dried over sodium sulfate, filtered, and evaporated to give 125 mg (71%) of the title compound as a pale yellow oil. 1H NMR (CDCl3, 400 MHz) δ 8.59 (d, 1H), 7.25 (d, 1H), 4.92 (q, 1H), 3.81 (br s, 1H), 1.56 (d, 3H); MS (APCI) 159, 161 (MH+).
Reaction SMILES: [C:1]([CH:3]([NH:9][C:10]([C:12]1[S:16][C:15]([NH:17][CH:18]2[CH2:20][CH2:19]2)=[N:14][C:13]=1[CH3:21])=[O:11])[C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)#[N:2].C(N(CC)CC)C.[SH2:29]>C(O)C>[C:1]([CH:3]([NH:9][C:10]([C:12]1[S:16][C:15]([NH:17][CH:18]2[CH2:20][CH2:19]2)=[N:14][C:13]=1[CH3:21])=[O:11])[C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)(=[S:29])[NH2:2]
Reactant: S
Reactant: Cc1nc(NC2CC2)sc1C(=O)NC(C#N)c1cccs1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1nc(NC2CC2)sc1C(=O)NC(C(N)=S)c1cccs1
Yield: 88 %

Procedure:
0.72g of 2-cyclopropylamino-4-methyl-thiazole-5-carboxylic acid (cyano-thiophen-2-yl-methyl)-amide (12) was dissolved in 10ml of ethanol and then 0.63ml of triethylamine was added thereto. The reaction solution was stirred under reflux for 8 hours while introducing hydrogen sulfide gas. After removing the solvent, water was added to the residue and then the solid product which is not dissolved in water was filtered. The filtered solid product was washed with diethylether and then dried to obtain 0.70g (Yield 88%) of the title compound.