Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[C:11]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:16]=1[OH:25])([CH3:14])([CH3:13])[CH3:12]>ClC(Cl)C>[Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([C:19]1[CH:18]=[C:17]([C:21]([CH3:22])([CH3:23])[CH3:24])[C:16]([OH:25])=[C:15]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:20]=1)=[O:5]
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Solvent: CC(Cl)Cl
Product: CC(C)(C)c1cc(C(=O)c2cccnc2Cl)cc(C(C)(C)C)c1O
Reaction time: 0.83 h
Yield: 79.8 %

Procedure:
To a solution of 282 g of 2-chloronicotinoyl chloride and 400 g of 2,6-di-tertiary butylphenol in 1000 ml of dichloroethane under ice-cooling is added dropwise a solution of 500 g of anhydrous stannic chloride in 250 ml of dichloroethane with stirring over 50 minutes. The reaction temperature is kept below 5° C. during the addition. After completion of the addition, the mixture is stirred at room temperature for 1.5 hours. The resulting reaction mixture is poured into ice-cold water and stirred for a while. The organic layer is separated, washed with water, dried and then concentrated. The obtained residue is recrystallized from an aqueous solution of 80% methanol to give 442 g of 4-(2-chloronicotinoyl)-2,6-di-tertiary butylphenol as pale yellow crystals, melting at 135°-137° C.
Reaction SMILES: [CH:1]1([CH:7]([N:11]2[CH2:16][CH2:15][C:14]([C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[CH:38]=3)([CH2:17][CH2:18][N:19]3[C@H:24]4[CH2:25][CH2:26][C@@H:20]3[CH2:21][CH:22]([N:27]3[C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=5[N:29]=[C:28]3[CH3:36])[CH2:23]4)[CH2:13][CH2:12]2)[C:8](O)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.NO.O[N:47]1C2C=CC=CC=2N=N1.CN1CCOCC1.C(Cl)CCl>O.CN(C=O)C.CCOC(C)=O>[CH:1]1([CH:7]([N:11]2[CH2:12][CH2:13][C:14]([C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[CH:38]=3)([CH2:17][CH2:18][N:19]3[C@H:20]4[CH2:26][CH2:25][C@@H:24]3[CH2:23][CH:22]([N:27]3[C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=5[N:29]=[C:28]3[CH3:36])[CH2:21]4)[CH2:15][CH2:16]2)[C:8]([NH2:47])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: On1nnc2ccccc21
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(C(=O)O)C2CCCCC2)CC1
Agent: NO
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(C(N)=O)C2CCCCC2)CC1
Reaction time: 24 h
Yield: 35.5 %

Procedure:
To a solution of cyclohexyl(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1-yl)acetic acid (22.0 mg, 0.037 mmol), hydroxylamine (0.2 mL of a 28% solution in water, 3.3 mmol), N-hydroxybenzotriazole (10.1 mg, 0.075 mmol) and N-methylmorpholine (0.10 mL, 0.094 mmol) in 1 mL DMF was added EDC (14 mg, 0.075 mmol). The reaction mixture was stirred for 24 h, then diluted with 4:1 EtOAc:hex and washed with saturated aqueous NaHCO3, dried (Na2SO4) and chromatographed (5% (2M NH3/MeOH) in CHCl3) to provide 2-cyclohexyl-2-(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1-yl)acetamide (7.7 mg, 35%) as a solid. 1H NMR (400 MHz, CDCl3), δ 7.66 (m, 1H), 7.34-7.27 (m, 2H), 7.20-7.12 (m, 2H), 7.06 (m, 1H), 6.99 (m, 1H), 6.90 (m, 1H), 4.61 (m, 1H), 3.27-3.19 (m, 2H), 2.73-2.62 (m, 2H), 2.58 (s, 3H), 2.47-0.78 (m, 27H); ESI-MS 589 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[NH:7][C@H:8]([CH2:31][N:32]([O:36]C(=O)C)[C:33](=[O:35])[CH3:34])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+]>CO>[C:1]([O:5][C:6](=[O:40])[NH:7][C@H:8]([CH2:31][N:32]([C:33](=[O:35])[CH3:34])[OH:36])[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)=[CH:19][CH:18]=2)=[CH:14][CH:15]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)ON(C[C@H](Cc1ccc(Oc2ccc(Oc3ccc(Cl)cc3)cc2)cc1)NC(=O)OC(C)(C)C)C(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)N(O)C[C@H](Cc1ccc(Oc2ccc(Oc3ccc(Cl)cc3)cc2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.4 %

Procedure:
To a solution of the product from step 2 (0.12 g, 0.21 mmol) in methanol (5 mL) was added NaOMe (25% in MeOH, 0.23 g, 1.1 mmol) at 0° C. and stirred at room temperature for 4 h. After the methanol was removed, the residue was partitioned in EtOAc/H2O, dried over Na2SO4 and concentrated to yield the title compound (0.1 g, 90%). 1HNMR (CDCl3) δ 1.40 (s, 9H), 2.10 (s, 3H), 2.81 (m, 2H), 3.05 (m, 1H), 4.11 (m, 1H), 4.01 (br, 1H), 4.66 (m, 1H), 6.91 (m, 4H), 6.98 (s, 4H), 7.14 (d, J=8 Hz, 2H), 7.27 (d, J=8 Hz, 2H), MS m/z 427 (M−100).
Reaction SMILES: [OH:1][CH:2]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[O:11][CH3:12]>CO.[Rh]>[OH:1][CH:2]([CH:13]1[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]1)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[O:11][CH3:12]
Reactant: COc1cccc(C(O)c2ccncc2)c1OC
Agent: [Rh]
Solvent: CO
Product: COc1cccc(C(O)C2CCNCC2)c1OC

Procedure:
4-[1-Hydroxy-1-(2,3-dimethoxyphenyl)methyl]pyridine (10) (10.1 g, 41 mmol) was dissolved in 100 mL of methanol and hydrogenated using a 5% rhodium on carbon catalyst. At the conclusion of the reaction, the catalyst was removed by filtration. The filtrate weighed 111.51 g. The reactor and catalyst cake were washed with methanol. The combined washes weighed 170.27 g and contained 7.6% of the title compound (11).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:8][C:7]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]([CH3:26])[C:16]2=[O:27])=[C:6]([F:28])[CH:5]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>O1CCCC1>[Cl:3][C:4]1[C:9]([N:10]([S:30]([CH3:29])(=[O:32])=[O:31])[S:11]([CH3:14])(=[O:13])=[O:12])=[CH:8][C:7]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]([CH3:26])[C:16]2=[O:27])=[C:6]([F:28])[CH:5]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(NS(C)(=O)=O)c(Cl)cc2F)c1=O
Reactant: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(N(S(C)(=O)=O)S(C)(=O)=O)c(Cl)cc2F)c1=O
Temperature: 0 °C

Procedure:
To a suspension of 0.05g of sodium hydride(purity:60%) and 5 ml of tetrahydrofuran, 0.5g of 3-(4-chloro-2-fluoro-5-methanesulfonylaminophenyl)-1-methyl-6-trifluoromethyl-2,4(1H, 3H)-pyrimidinedione was added at a temperature of 0° C. Then 0.11 ml of methanesulfonyl chloride was added dropwise to the resultant suspension. After stirring for 7 hburs, the reaction mixture was poured into ice water and extracted with ethyl acetate. The extract of the ethyl acetate layer was washed with a saturated sodium chloride agueous solution and dried over anhydrous sodium sulfate. Then ethyl acetate was distilled off to obtain a crude product. The obtained product was washed with diethyl ether to obtain 0.50g of the objective product as white crystals.
Reaction SMILES: [F:1][C:2]([F:53])([F:52])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([C:34]5[CH:43]=[CH:42][C:37]([C:38]([NH:40][NH2:41])=[O:39])=[CH:36][C:35]=5[CH3:44])[CH:29]=[N:30][C:31]=4[O:32][CH3:33])=[CH:24][N:23]=[C:22]([N:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)[N:21]=3)[C@H:14]2[CH3:51])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C1N=CN([C:59](N2C=NC=C2)=[O:60])C=1>C1COCC1>[F:53][C:2]([F:1])([F:52])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([C:34]5[CH:43]=[CH:42][C:37]([C:38]6[O:39][C:59](=[O:60])[NH:41][N:40]=6)=[CH:36][C:35]=5[CH3:44])[CH:29]=[N:30][C:31]=4[O:32][CH3:33])=[CH:24][N:23]=[C:22]([N:45]4[CH2:46][CH2:47][O:48][CH2:49][CH2:50]4)[N:21]=3)[C@H:14]2[CH3:51])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COc1ncc(-c2ccc(C(=O)NN)cc2C)cc1-c1cnc(N2CCOCC2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1ncc(-c2ccc(-c3n[nH]c(=O)o3)cc2C)cc1-c1cnc(N2CCOCC2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-{5-[4-({(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-(morpholin-4-yl)pyrimidin-5-yl]-6-methoxypyridin-3-yl}-3-methylbenzohydrazide (Step A, 108 mg, 0.145 mmol) was dissolved in THF (1.5 mL) and treated with N,N-carbonyldiimidazole (70.5 mg, 0.435 mmol). The reaction was stirred at room temperature overnight. The reaction was purified directly by silica gel chromatography, eluting with a gradient of 25-100% ethyl acetate/hexanes to give the title compound. LCMS (M+H)+: 772.5. 1H NMR (CDCl3, 500 MHz): δ 9.09 (s, 1H), 8.22 (m, 2H), 7.88 (s, 1H), 7.78 (s, 1H), 7.72 (s+d, 3H), 7.48 (d, 1H), 7.35 (d, 1H), 5.63 (d, 1H), 4.75 (d, 1H), 4.33 (m, 1H), 4.01 (m, s, 4H), 3.86 (m, 4H), 3.81 (m, 4H), 2.38 (s, 3H), 0.73 (d, 3H). RTA IC50: 29 nM.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:24])[C:7]3[C:14](=[O:15])[N:13]([NH:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:12](=[O:23])[C:8]=3[NH:9][C:10]=2[CH:11]=1.CS(O)(=O)=O>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:24])[C:7]3[C:14](=[O:15])[NH:13][N:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:12]([OH:23])[C:8]=3[NH:9][C:10]=2[CH:11]=1
Reactant: O=C1c2[nH]c3cc(Cl)ccc3c(=O)c2C(=O)N1Nc1ccccc1
Agent: CS(=O)(=O)O
Solvent: CO
Product: O=C1NN(c2ccccc2)C(O)c2[nH]c3cc(Cl)ccc3c(=O)c21
Temperature: 25 °C
Yield: 28.1 %

Procedure:
6-Chloro-2-anilino-2,3,4,9-tetrahydro-1H-pyrrolo[3,4-b]-quinoline-1,3,9-trione (1.70 g, 5.00 mM) was stirred in methanol (0.85 L), and methanesulfonic acid (85 mL) was added. The yellow suspension was heated to reflux for 16 hours and cooled to room temperature. The resulting mixture was filtered (the filtrate was saved for use in Example 6), and the collected solids were washed with methanol and dried to give 7-chloro-4-hydroxy-3-phenyl-1,2,5,10-tetrahydropyridazino[4,5-b]-quinoline-1,10-dione (0.48 g, 28%) as a yellow powder. This powder was stirred in methanol, and choline hydroxide (45 weight% in methanol, 0.5 mL) was added to give an amber solution. This solution was concentrated and the residue diluted with toluene and concentrated. The residue was diluted with toluene and concentrated two additional times, and the resulting solid residue was triturated with ethanol/toluene (20%, 25 mL) to provide a crystalline solid. The solid was collected to give the title compound (0.49 g, 78%) as a yellow powder, mp 253-257° C.; MS(CI): 340 (M+H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:13][NH2:14])[CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[NH2:15][C:16]1[C:17]([C:24]([NH:26][C:27](=N)SC)=[O:25])=[N:18][C:19]([Cl:23])=[C:20]([NH2:22])[N:21]=1>CC(O)C>[OH:12][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][CH2:3][C@@H:2]2[CH2:13][NH:14]/[C:27](=[N:26]\[C:24]([C:17]3[C:16]([NH2:15])=[N:21][C:20]([NH2:22])=[C:19]([Cl:23])[N:18]=3)=[O:25])/[NH:1]2)=[CH:11][CH:10]=1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: NC[C@H](N)CCCc1ccc(O)cc1
Solvent: CC(C)O
Product: Nc1nc(N)c(C(=O)/N=C2\NC[C@@H](CCCc3ccc(O)cc3)N2)nc1Cl
Temperature: 30 °C
Reaction time: 18 h

Procedure:
To a stirred solution of (4-((R)-4,5-Diamino-pentyl)-phenol (intermediate K) (1.5 g, 7.72 mmol) in propan-2-ol (100 ml) at 30° C. is added in one portion 1-(3,5-Diamino-6-chloro-pyrazine-2-carbonyl)-2-methyl-isothiourea (Intermediate A) and the reaction is heated at 30° C. for 18 hours followed by 50° C. for a further 18 hours. The reaction mixture is filtered hot and the filtrate solvent is removed in vacuo to afford a yellow foam. The foam is purified by chromatography (SiO2, DCM/MeOH/5% NH3) to afford the title compound; [M+H]+ 390
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.N1C=CN=C1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>CN(C=O)C>[Si:15]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To a solution of 4-hydroxybenzaldehyde, Compound 63 (10.00 g, 81.89 mmol) and imidazole (16.72 g, 245.59 mmol) in dry DMF (30 mL) cooled in an ice-water bath (0° C.) was added a solution of t-butyldimethylsilyl chloride (18.55 g, 123.07 mmol) in dry DMF (50 mL) followed by stirring at room temperature for 1 hour. The reaction mixture was then quenched with brine (60 mL) and extracted with Et2O (60 mL×3). The combined organic layer was dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 5 percent EtOAc in hexane) to give Compound 64 (19.02 g, 98 percent): pale yellow oil; Rf=0.44 (10 percent EtOAc in hexane); IR (neat) 2956, 2931, 1698, 1598, 1273, 1156 cm−1; 1H NMR (300 MHz, CDCl3) δ9.89 (s, 1H), 7.81-7.77 (AA′BB′, 2H), 6.96-6.92 (AA′BB′, 2H), 0.98 (s, 9H), 0.25 (s, 6H); 13C NMR (75 MHz, CDCl3) δ190.9, 161.5, 131.9, 130.4, 120.5, 25.5, 18.2, −4.4; MS (+CI) m/z (relative intensity) 237 (M+H+, 100).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:18])[C:10]([Br:17])([CH3:16])[C:11]([O:13]CC)=[O:12])=[C:4]([CH3:19])[CH:3]=1.O.[OH-].[K+].[K].Cl>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:18])[C:10]([Br:17])([CH3:16])[C:11]([OH:13])=[O:12])=[C:4]([CH3:19])[CH:3]=1
Reactant: CCOC(=O)C(C)(Br)C(=O)Nc1ccc(Br)cc1C
Agent: Cl
Agent: [K+]
Agent: [K]
Solvent: O
Product: Cc1cc(Br)ccc1NC(=O)C(C)(Br)C(=O)O

Procedure:
A 1.25 gram (0.003 mole) portion of ethyl 3-[(4-bromo-2-methylphenyl)amino]-2-bromo-2-methyl-3-oxopropanoate prepared in Example XV (Compound 144) was hydrolyzed with water (0.06 gram, 0.003 mole) and ethanolic potassium hydroxide (0.21 gram, 0.003 mole). The potassium salt of the acid was then acidified with concentrated HCl and worked up in a manner similar to that described in Example VII to give 1.04 grams (0.003 mole) of 3-[(4-bromo-2-methylphenyl)amino]-2-bromo-2-methyl-3-oxopropanoic acid as a white solid having a melting point of 133° C.-136° C. NMR analysis of the product indicated the following:
Reaction SMILES: [C:1]1([N:7]2[C:11]3([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:10](=[O:17])[NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>ClCCl>[O:17]=[C:10]1[C:11]2([CH2:12][CH2:13][N:14]([C:25]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])[CH2:15][CH2:16]2)[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][NH:9]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC2(CC1)C(=O)NCN2c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (5 g, 21.6 mmol) in dichloromethane (50 mL) and pyridine (3.5 mL, 43.2 mmol, d=0.978), was added benzyl chloroformate (3.15 mL, 22.04 mmol, d=1.195). After stirring at room temperature for 16 hours, the reaction mixture was diluted with dichloromethane (100 mL), washed with dilute citric acid, water and brine. The organic phase was dried over MgSO4, filtered and concentrated to cream solid (6 g, 76%); 1H NMR (DMSO-d6): δ 1.65 (d, 2H, J=13.6 Hz), 2.32-2.40 (m, 2H), 3.51 (br, 2H), 3.95-3.99 (m, 2H), 4.59 (s, 2H), 5.11-5.15 (m, 2H), 6.68 (d, 2H, J=8 Hz), 6.75 (t, 1H, J=7.2 Hz), 7.18 (t, 2H, J=7.6 Hz), 7.30-7.38 (m, 5H), 8.81 (s, 1H); MS for C21H23N3O3 m/z 366 (M+H)+.
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1([SH:17])C=CC=CC=1.C1OC1.[OH-].[K+].NC(N)=S.Cl.O.NN>C1(C)C=CC=CC=1>[C:1]1([S:7][CH:8]([SH:17])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1ccccc1
Reactant: OCCSc1ccccc1
Agent: Cl
Agent: NC(N)=S
Agent: NN
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CO1
Product: CC(S)Sc1ccccc1

Procedure:
77 g of 2-phenylthioethanol, (0.5 mol, prepared from thiophenol and ethylene oxide in the presence of some potassium hydroxide) are maintained for 4 hours under reflux with 40 g of thiourea and 50 g of 37% hydrochloric acid. At 40° C., the reaction mixture is stirred with 50 g of 50% hydrazine hydrate solution for 30 minutes. 100 ml of toluene are added, this is maintained for 30 minutes in the steam bath, the toluene phase is separated off and compressed under vacuum.
Reaction SMILES: [C:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:24])(=O)=O>C(Cl)Cl>[Cl:24][CH:12]([O:11][C:10]1[CH:9]=[CH:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:20][CH:19]=1)[C:13](=[O:18])[C:14]([CH3:16])([CH3:17])[CH3:15]
Reactant: O=S(=O)(Cl)Cl
Reactant: CC(C)(C)C(=O)COc1ccc(-c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)C(=O)C(Cl)Oc1ccc(-c2ccccc2)cc1

Procedure:
1,292 g (4.83 moles) of 1-(4'-phenyl-phenoxy)-3,3-dimethylbutan-2-one were dissolved in 2.5 l of methylene chloride and 400 ml (4.9 moles) of sulfuryl chloride were added dropwise at the boil. The mixture was heated under reflux for 15 hours and was then concentrated by distilling off the solvent. After adding 250 ml of carbon tetrachloride, the solvent was again distilled off under a water-pump vacuum (bath temperature 65° C.). Crude 1-chloro-1-(4'-phenyl-phenoxy)-3,3-dimethylbutan-2-one was obtained quantitatively, and was used further in the form obtained. ##STR3##
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:4][CH:3]1[CH2:5][CH2:6][C:7]([CH3:14])=[C:8]=[CH:9][CH2:10][C:11](=[O:13])[CH3:12].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.C1(C)C=CC=CC=1.CCOCC>[CH3:1][C:2]1([CH3:15])[CH2:4][CH:3]1[CH2:5][CH2:6][C:7]([CH3:14])=[CH:8][CH:9]=[CH:10][C:11](=[O:13])[CH3:12]
Reactant: CC(=O)CC=C=C(C)CCC1CC1(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(=O)C=CC=C(C)CCC1CC1(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
8-(2',2'-Dimethylcyclopropyl)-6-methyl-4,5-octadien-2-one, 5 g, is dissolved in a mixture of 6 ml of methanol and 6 ml of toluene, then 200 mg of p-toluenesulphonic acid are added. The mixture is stirred at room temperature for 63/4 hours. It is diluted with ether, washed neutral with saturated bicarbonate and carbonate solution and with saturated sodium chloride solution, dried and concentrated. The crude product (4.5 g) is distilled in a bulb-tube. In this manner there are obtained 4.2 g (84%) of 8-(2',2'-dimethyl-cyclopropyl)-6-methyl-3,5-octadien-2-one. EZ/EE=4/6.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:26])=[C:4]([CH3:25])[C:5]2[O:9][C:8]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([C:18]([O:20]CC)=[O:19])[CH2:14][CH2:13]3)([CH3:10])[CH2:7][C:6]=2[C:23]=1[CH3:24].[OH-].[Na+:28]>C(O)C>[NH2:1][C:2]1[C:3]([CH3:26])=[C:4]([CH3:25])[C:5]2[O:9][C:8]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([C:18]([O-:20])=[O:19])[CH2:14][CH2:13]3)([CH3:10])[CH2:7][C:6]=2[C:23]=1[CH3:24].[Na+:28]
Reactant: CCOC(=O)C1CCN(CC2(C)Cc3c(C)c(N)c(C)c(C)c3O2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCC(C(=O)[O-])CC1)O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
To a solution of ethyl 1-[(5-amino-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran-2-yl)methyl]-4-piperidinecarboxylate (10 g) in ethanol (40 mL) was added 5.7 mL of 5N-aqueous sodium hydroxide and the mixture was stirred under nitrogen gas at room temperature for 2 hours. The precipitate was collected by filtration and washed with diethyl ether to provide 7.5 g of the title compound. Yield 75%. The filtrate was concentrated under reduced pressure and the solid residue was washed thoroughly with diethyl ether to provide an additional 1.4 g of the title compound. Yield 14%. These products were not further purified but directly submitted to the next reaction.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[CH2:5][CH:6]1[CH2:11][CH:10]([C:12]([O:14]C)=[O:13])[CH2:9][CH2:8][N:7]1[C:16]([O:18][CH3:19])=[O:17].[Br-].[Li+].C(N(CC)CC)C.CC(OC)(C)C>C(#N)C.O>[CH3:19][O:18][C:16]([N:7]1[CH2:8][CH2:9][CH:10]([C:12]([OH:14])=[O:13])[CH2:11][CH:6]1[CH2:5][C:4]1[CH:20]=[CH:21][CH:22]=[CH:23][C:3]=1[C:2]([F:25])([F:24])[F:1])=[O:17]
Reactant: COC(=O)C1CCN(C(=O)OC)C(Cc2ccccc2C(F)(F)F)C1
Agent: [Br-]
Agent: [Li+]
Solvent: COC(C)(C)C
Solvent: CC#N
Solvent: O
Product: COC(=O)N1CCC(C(=O)O)CC1Cc1ccccc1C(F)(F)F
Yield: 90.2 %

Procedure:
Crude dimethyl 2-(2-(trifluoromethyl)benzyl)piperidine-1,4-dicarboxylate (5.42 g, 15.15 mmol) was dissolved in acetonitrile (40 mL) and water (0.800 mL). lithium bromide (9.66 g, 111.20 mmol) and triethylamine (7.71 mL, 55.60 mmol) were added and the mixture was heated at reflux for 1 h 45 min. Water (90 mL) and MTBE were added. The organic phase was extracted with water. To the pooled aqueous layer was added MTBE and the solution was acidified to pH 1 with 2 M HCl and then extracted with MTBE (×2). The combined organic layer was dried over Na2SO4 and evaporated to give 1-(methoxycarbonyl)-2-(2-(trifluoromethyl)benzyl)piperidine-4-carboxylic acid (4.72 g, 98%) as a slightly yellow semisolid. MS m/z 346 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:16]([O:18][C:19]([C:21]1[NH:22][C:23]2[C:28]([CH:29]=1)=[CH:27][C:26]([NH2:30])=[CH:25][CH:24]=2)=[O:20])[CH3:17]>>[CH2:16]([O:18][C:19]([C:21]1[NH:22][C:23]2[C:28]([CH:29]=1)=[CH:27][C:26]([NH:30][C:13]([C:11]1[O:12][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)=[CH:9][CH:10]=1)=[O:15])=[CH:25][CH:24]=2)=[O:20])[CH3:17]
Reactant: O=C(O)c1ccc(-c2cccc(Cl)c2)o1
Reactant: CCOC(=O)c1cc2cc(N)ccc2[nH]1
Product: CCOC(=O)c1cc2cc(NC(=O)c3ccc(-c4cccc(Cl)c4)o3)ccc2[nH]1

Procedure:
5-(3-Chloro-phenyl)-furan-2-carboxylic acid (65) (54 mg, 0.24 mmol) was coupled to ethyl ester (58) (50 mg, 0.24 mmol) using Method C. The crude residue was purified by column chromatography eluting with 20% EtOAc in heptane to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH:13][CH:14]([CH3:17])[CH2:15][OH:16])[S:11][CH:12]=2)=[CH:4][CH:3]=1.[C:18](OCC)(=[O:20])C>CCCCCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([N:13]3[CH:14]([CH3:17])[CH2:15][O:16][C:18]3=[O:20])[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: CC(CO)Nc1nc(-c2ccc(Br)cc2)cs1
Reactant: CCOC(C)=O
Solvent: CCCCCC
Product: CC1COC(=O)N1c1nc(-c2ccc(Br)cc2)cs1
Yield: 64 %

Procedure:
In the same manner as described in step 4 of Example 1, replacing (2R)-2-{[4-(4-bromophenyl)-1,3-thiazol-2-yl]amino}propan-1-ol with 2-{[4-(4-bromophenyl)-1,3-thiazol-2-yl]amino}propan-1-ol, prepared in the previous step, and purification by flash chromatography using a solvent gradient of 10 to 30% ethyl acetate in hexane gave the title compound (293 mg, 64%) as a white solid; mp 189-190° C.; MS (ESI) m/z 339 [M+H]+. Anal. Calcd for C13H11BrN2O2S: C, 46.03; H, 3.27; N, 8.26. Found: C, 45.83; H, 3.25; N, 8.07. HRMS: calcd for C13H, BrN2O2S+H+, 338.97973; found (ESI, [M+H]+), 338.9784.