Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.C([Li])CCC.[CH3:17][N:18]1[CH:22]2[CH2:23][C:24]([CH2:26][CH:19]1[CH2:20][CH2:21]2)=[O:25]>O1CCCC1>[OH:25][C:24]1([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=2)[CH2:23][CH:22]2[N:18]([CH3:17])[CH:19]([CH2:20][CH2:21]2)[CH2:26]1
Reactant: CN1C2CCC1CC(=O)C2
Reactant: Brc1ccc2ccccc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN1C2CCC1CC(O)(c1ccc3ccccc3c1)C2
Temperature: -78 °C
Reaction time: 2 h
Yield: 49.7 %

Procedure:
A solution of 5.0 gm (24.1 mMol) 2-bromonaphthalene in 80 mL tetrahydrofuran was cooled to -78° C. To this solution was then added 15.8 mL (25.3 mMol) n-butyllithium (1.6M in tetrahydrofuran) followed by a solution of 4.03 gm (29 mMol) 3-tropinone in 35 mL tetrahydrofuran. The reaction mixture was stirred at -78° C. for 2 hours and was then allowed to warm gradually to room temperature. The reaction mixture quenched by the addition of saturated aqueous ammonium chloride. The resulting mixture was extracted well with ethyl acetate. The organic phases were combined, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with dichloromethane containing from 2-10% methanol and 30% dichloromethane saturated with ammonia. Fractions containing product were combined and concentrated under reduced pressure to provide 3.2 gm (50%) of 3-hydroxy-3-(naphth-2-yl)-8-methyl-8-azabicyclo[3.2.1]octane.
Reaction SMILES: [Br-].[CH:2]([S:15][C:16](N)=[NH2+])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.ClC[C:21]([NH2:23])=[O:22]>>[CH:2]([S:15][CH2:16][C:21]([NH2:23])=[O:22])([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: NC(=O)CCl
Reactant: NC(=[NH2+])SC(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: NC(=O)CSC(c1ccccc1)c1ccccc1

Procedure:
In Steps 2 and 3, the S-benzhydrylthiouronium bromide formed in step 1 is converted to the corresponding thiol, and then reacted with chloroacetamide to form 2-(benzhydrylthiyl)acetamide. For example, the thiourea can be converted to the thiol by reaction with a suitable base. The reaction steps 2 and 3 can be carried out in the same reaction vessel as was employed in step 1, without isolation of any intermediates.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([Cl:13])[CH:3]=1.[CH3:14][NH2:15]>CC#N>[Cl:13][C:4]1[CH:3]=[C:2]([NH:15][CH3:14])[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=1
Reactant: CN
Reactant: CCOC(=O)c1cnc(Cl)cc1Cl
Solvent: CC#N
Product: CCOC(=O)c1cnc(Cl)cc1NC
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
A 0° C. solution of ethyl 4,6-dichloronicotinate (5 g, 22.8 mmol) in MeCN (30 mL) was treated drop-wise with aqueous methylamine (65%, 5.2 g, 45.6 mmol), warmed to RT and stirred for 8 h. The mixture was concentrated to dryness, the residue suspended in H2O and extracted with EtOAc (3×). The combined extracts were washed with brine, dried (MgSO4) and concentrated to give ethyl 6-chloro-4-(methylamino)nicotinate (4 g, 82% yield), which was used in the next step without further purification. 1H NMR (300 MHz, DMSO-d6): δ 8.48 (s, 1H), 8.04 (d, J=4.5 Hz, 1H), 6.71 (s, 1H), 4.27 (q, J=6.9 Hz, 2H), 2.85 (d, J=5.1 Hz, 3H), 1.29 (t, J=6.9 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH3:19])[C:13]([CH3:18])([CH3:17])[C:14](O)=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=[N:26]C=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.N>C1COCC1.O>[NH2:26][C:14](=[O:15])[C:13]([CH3:18])([CH3:17])[C@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:19]
Reactant: On1nnc2ccccc21
Reactant: C[C@@H](NC(=O)OCc1ccccc1)C(C)(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](NC(=O)OCc1ccccc1)C(C)(C)C(N)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (R)-3-(((benzyloxy)carbonyl)amino)-2,2-dimethylbutanoic acid (6.5 g, 23.27 mmol) in THF (60 mL) was added HOBT (3.00 g, 19.60 mmol), EDCI (3.76 g, 19.60 mmol) and DIPEA (10.27 ml, 58.8 mmol) and stirred at 0° C. for 30 min. 3M ammonia in THF (50 ml, 1848 mmol) was added to afford a white suspension. The reaction mixture was allowed to stir for 12 h at RT. Reaction mass was diluted with water (80 ml). The aqueous layer was treated with EtOAC (3×80 ml). The organic layer was dried over Na2SO4 and concentrated under vacuum to get desired crude product. Crude product was purified by column chromatography (60-120 mesh, 30% EtOAc: Pet-Ether) to get desired product as off white solid (2.7 g, 52%). 1HNMR (400 MHz, CDCl3) δ ppm: 1.15-1.17 (d, J=6.8 Hz, 3H), 1.23-1.27 (m, 6H), 3.66-3.76 (m, 1H), 5.10-5.13 (s, 2H), 5.41-5.89 (m, 3H), 7.26-7.36 (m, 5H).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[C:11]([NH2:12])=[CH:10][CH:9]=[CH:8][N:7]=2)[CH2:3][CH2:2]1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=O)[C:21](O)=[O:22])=[CH:16][CH:15]=1>CO>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21](=[O:22])[N:5]([CH2:4][CH:1]3[CH2:2][CH2:3]3)[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[N:12]=2)=[CH:16][CH:15]=1
Reactant: Nc1cccnc1NCC1CC1
Reactant: O=C(O)C(=O)c1ccc(Cl)cc1
Solvent: CO
Product: O=c1c(-c2ccc(Cl)cc2)nc2cccnc2n1CC1CC1

Procedure:
430 mg (2.63 mM) of N2-(cyclopropylmethyl)pyridine-2,3-diamine and 485.4 mg (2.63 mM) of (4-chlorophenyl)(oxo)acetic acid in 6 ml of methanol were refluxed for 16 h. A solid crystallized. The compound was filtered and washed with methanol to give
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].C(=O)(O)[O-].[Na+].Br[CH:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13].O>C(O)C>[CH2:1]([NH:4][CH:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13])[CH:2]=[CH2:3]
Reactant: C=CCN
Reactant: COC(=O)C(C)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C=CCNC(C)C(=O)OC
Yield: 60.1 %

Procedure:
To a mixture of 10 g (0.18 mole) of allylamine, 10.8 g (0.2 mole) of sodium bicarbonate in 50 ml of ethanol is added 30 g (0.18 mole) of methyl 2-bromopropionate dropwise. The resulting mixture is heated under reflux for 5 hours. The reaction mixture is cooled, poured into water, and extracted with ether. The combined ether extracts are washed with water and dried over magnesium sulfate. The drying agent is filtered and the filtrate is concentrated under reduced pressure to give 15.5 g of a light yellow oil. This material is further purified by distillation to give 10.5 g of pure product.
Reaction SMILES: [O:1]=[C:2]1[C:15]2[C:6]([S:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[N:14]=2)=[CH:5][CH:4]=[CH:3]1.CS(O[CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]=[O:31])=[CH:26][CH:25]=1)(=O)=O>>[O:1]=[C:2]1[C:15]2[N:14]([CH2:21][CH2:22][O:23][C:24]3[CH:29]=[CH:28][C:27]([CH:30]=[O:31])=[CH:26][CH:25]=3)[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[S:7][C:6]=2[CH:5]=[CH:4][CH2:3]1
Reactant: CS(=O)(=O)OCCOc1ccc(C=O)cc1
Reactant: O=c1cccc2sc3ccccc3nc1-2
Product: O=Cc1ccc(OCCN2C3=C(C=CCC3=O)Sc3ccccc32)cc1
Yield: 65.1 %

Procedure:
The title compound (2.2 g, 67%) was prepared as a thick liquid from 9-oxophenothiazin (2.0 g, 9.3 mmol) and 2-(4-formylphenoxy)ethyl methanesulfonate (2.7 g, 11 mmol) using a similar procedure to that described in preparation 3.
Reaction SMILES: Cl.C([O:4][CH:5](OCC)[CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH2:14][CH2:15][OH:16])[CH:11]=[CH:12][CH:13]=1)C>O1CCOCC1.O>[OH:16][CH2:15][CH2:14][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=1)[O:7][CH2:6][CH:5]=[O:4]
Reactant: CCOC(COc1cccc(CCO)c1)OCC
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: O=CCOc1cccc(CCO)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Concentrated hydrochloric acid (1.5 mL) was added to a solution of 2-(3-(2,2-diethoxyethoxy)phenyl)ethanol (example 24 step a) (0.256 g) in 1,4-dioxane (3 mL) and the resulting mixture was stirred at room temperature for 1.5 hours. The solution was then diluted with water and extracted twice with ethyl acetate. The combined extracts were washed with brine, dried over anhydrous magnesium sulphate and concentrated in vacuo to afford the subtitled compound as a white foam. Yield 0.150 g.
Reaction SMILES: C(OC1C=CC(C(C2CCN(CC(O)=O)CC2)=O)=CC=1)C.FC1C=CC(C(C2CCN(CC(O)=O)CC2)=O)=CC=1.[CH2:41]([O:44][C:45]1[CH:62]=[CH:61][C:48]([C:49]([CH:51]2[CH2:56][CH2:55][N:54]([CH2:57][C:58]([OH:60])=[O:59])[CH2:53][CH2:52]2)=[O:50])=[CH:47][CH:46]=1)[CH2:42][CH3:43].[NH2:63][CH2:64][C:65]1[NH:66][C:67](=[O:75])[C:68]2[CH2:74][O:73][CH2:72][CH2:71][C:69]=2[N:70]=1.C(O)(C(F)(F)F)=O>C(#N)C.O.C(O)CC>[CH2:41]([O:44][C:45]1[CH:46]=[CH:47][C:48]([C:49]([CH:51]2[CH2:56][CH2:55][N:54]([CH2:57][C:58]([OH:60])=[O:59])[CH2:53][CH2:52]2)=[O:50])=[CH:61][CH:62]=1)[CH2:42][CH3:43].[O:75]=[C:67]1[NH:66][C:65]([CH2:64][NH:63][C:58](=[O:60])[CH2:57][N:54]2[CH2:53][CH2:52][CH:51]([C:49](=[O:50])[C:48]3[CH:47]=[CH:46][C:45]([O:44][CH2:41][CH2:42][CH3:43])=[CH:62][CH:61]=3)[CH2:56][CH2:55]2)=[N:70][C:69]2[CH2:71][CH2:72][O:73][CH2:74][C:68]1=2
Reactant: NCc1nc2c(c(=O)[nH]1)COCC2
Agent: CCCOc1ccc(C(=O)C2CCN(CC(=O)O)CC2)cc1
Agent: CCOc1ccc(C(=O)C2CCN(CC(=O)O)CC2)cc1
Agent: O=C(O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: CCCO
Product: CCCOc1ccc(C(=O)C2CCN(CC(=O)NCc3nc4c(c(=O)[nH]3)COCC4)CC2)cc1

Procedure:
2-(4-(4-Propoxybenzoyl)piperidin-1-yl)acetic acid was prepared following the general procedures for the synthesis of 2-(4-(4-ethoxybenzoyl)piperidin-1-yl)acetic acid from 2-(4-(4-fluorobenzoyl)piperidin-1-yl)acetic acid and propan-1-ol. The title compound (76.1 mg, 0.15 mmol) was prepared following the general procedure of Example 1 from 2-(4-(4-propoxybenzoyl)piperidin-1-yl)acetic acid and 2-aminomethyl-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one. MS (ESI) m/z 469.4 (M+H+); HPLC (Insertsil ODS3 100×3 mm C-18 column: mobile phase: 5-95% acetonitrile/water with 0.1% TFA, at 1 mL/min over 7.75 min.) t=1.39 min. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.99 (t, 3H), 1.60-1.88 (m, 6H), 2.14-2.33 (m, 2H), 2.43-2.65 (m, 4H), 2.98 (br. s., 2H), 3.23-3.42 (m, 1H), 3.83 (br. s., 2H), 3.95-4.10 (m, 2H), 4.20 (br. s., 2H), 4.34 (br. s., 2H), 7.03 (d, J=4.55 Hz, 2H), 7.95 (d, J=4.55 Hz, 2H), 8.22 (br. s., 1H), 12.38 (br. s., 1H). HRMS calculated for C26H33N4O6: 469.2451 (M+H). found (ESI, [M+H]+): 469.2459.
Reaction SMILES: [Na+].[I-].[C:3]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].[H][H]>O>[OH:6][CH:5]([CH3:7])[CH2:4][C:3]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)CC(C)=O
Reactant: [H][H]
Agent: [I-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CC(C)O
Temperature: 65 °C
Reaction time: 40 h
Yield: 62.6 %

Procedure:
Under a nitrogen gas atmosphere, 0.0096 g (7.3×10-6 mol) of [RuI(p-Cymene)((+)-SO3Na--BINAP)]I, 0.1164 g (7.8×10-4 mol) of NaI, 1 ml (7.5×10-3 mol) of ethyl acetoacetate, and 1.5 ml of water were charged in a 100 milli-liter autoclave. After displacing the inside atmosphere of the autoclave with a hydrogen gas, the autoclave was pressed at a hydrogen pressure of 50 kg/cm2 and the mixture was stirred for 40 hours at 65° C. After the reaction was over, the hydrogen gas was removed, and after added thereto 100 ml of water and 100 ml of ether, the ether extraction was carried out. The ether extract was recovered, dried with anhydrous sodium sulfate, and further ether was distilled off to provide 0.62 g (percent yield 63%) of ethyl 3-hydroxybutyrate. By the analysis of gas chromatography (PEG-HT), the conversion ratio was determined to be 99%.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.C(N(CC)C(C)C)(C)C.[C:24]1([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:25]([C:30]([NH:32][C:33]2[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[C:35]([Cl:42])[CH:34]=2)=[O:31])=[CH:26][CH:27]=[CH:28][CH:29]=1.[Si]([O-])([O-])([O-])[O-].[Mg+2].[Mg+2]>C(Cl)Cl>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:37]([C:36]3[CH:40]=[CH:41][C:33]([NH:32][C:30]([C:25]4[C:24]([C:43]5[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=5)=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:31])=[CH:34][C:35]=3[Cl:42])=[O:38])[CH2:6][C:5]=12
Reactant: O=C(Cl)c1ccc(NC(=O)c2ccccc2-c2ccccc2)cc1Cl
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Agent: [Mg+2]
Agent: [O-][Si]([O-])([O-])[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)c(Cl)c1)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.2 %

Procedure:
To a solution of 0.52 g of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine and 0.39 g of N,N-diisopropylethylamine in 25 ml of methylene chloride is added 1.1 g of 4-[([1,1'-biphenyl]-2-carbonyl)amino]-2-chlorobenzoyl chloride followed by stirring at room temperature for 18 hours. The reaction mixture is washed with water and saturated aqueous NaHCO3 and the organic layer dried (Na2SO4). The organic layer is passed through hydrous magnesium silicate and the filtrate concentrated in vacuo to give a residue which is dissolved in methylene chloride and passed through hydrous magnesium silicate two additional times to give upon concentration in vacuo 1.10 g of the desired product as a residue. M+=516,518,520.
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:19])[N:7]([CH2:20][CH2:21][CH2:22][OH:23])[C:6](=[O:24])[N:5]([CH3:25])[C:4]=2[N:3]=1.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[OH:33].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:10]2[C:9]3[C:8](=[O:19])[N:7]([CH2:20][CH2:21][CH2:22][OH:23])[C:6](=[O:24])[N:5]([CH3:25])[C:4]=3[N:3]=[C:2]2[O:33][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[F:26])=[CH:13][CH:14]=1
Reactant: Cn1c(=O)n(CCCO)c(=O)c2c1nc(Br)n2Cc1ccc(F)cc1
Reactant: Oc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(=O)n(CCCO)c(=O)c2c1nc(Oc1ccccc1F)n2Cc1ccc(F)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 37 %

Procedure:
To a solution of 8-bromo-7-(4-fluorobenzyl)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (50 mg, 0.121 mmol, intermediate 62) in DMF (1 mL) was added 2-fluorophenol (16.4 mg, 0.146 mmol) followed by potassium carbonate (25.2 mg, 0.182 mmol). The reaction was stirred at 80° C. for 4 h. The mixture was partitioned between ethyl acetate and brine. The organic phase was washed with saturated aqueous ammonium chloride, dried and concentrated to give crude product, which was purified by preparative HPLC to give 7-(4-fluorobenzyl)-8-(2-fluorophenoxy)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (19.8 mg, 36.9% yield) as white solid. 1H-NMR (CD3OD) δ 7.52-7.56 (m, 2H), 7.43-7.45 (t, 1H), 7.2-7.38 (m, 3H), 7.08-7.13 (t, 1H), 5.51 (s, 2H), 4.09-4.13 (t, 2H), 3.60-3.63 (t, 2H), 3.37 (s, 3H), 1.86-1.90 (m, 2H). LCMS retention time 2.604; LCMS MH+ 443.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][C:11]2[S:15][C:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:13][C:12]=2[CH2:26][N:27]2[CH2:32][CH2:31][S:30][CH2:29][CH2:28]2)[CH:6]=[CH:5][C:4]=1[C:33]1[NH:37][C:36](=[O:38])[O:35][N:34]=1.Cl.C[OH:41]>C(OCC)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][C:11]2[S:15][C:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:23])([F:25])[F:24])=[CH:18][CH:17]=3)=[N:13][C:12]=2[CH2:26][N:27]2[CH2:32][CH2:31][S:30](=[O:41])[CH2:29][CH2:28]2)[CH:6]=[CH:5][C:4]=1[C:33]1[NH:37][C:36](=[O:38])[O:35][N:34]=1
Reactant: CO
Reactant: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CN2CCSCC2)ccc1-c1noc(=O)[nH]1
Agent: Cl
Solvent: CCOCC
Product: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CN2CCS(=O)CC2)ccc1-c1noc(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 80 mg of 3-{2-methoxy-4-[4-thiomorpholin-4-ylmethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl}-4H-[1,2,4]oxadiazol-5-one in 1 mL of methanol was added 2 mL of a 2N solution of hydrochloric acid in diethylether. The resulting mixture was concentrated under reduced pressure. To a solution of the residue in 1 mL of acetonitrile were added 1 mL of water and 88 mg of Oxone®. The resulting mixture was stirred at room temperature for 1 h, then poured into water and extracted with dichloromethane. The organic extracts were washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (gradient of methanol in dichloromethane) to give 10.5 mg of 3-{2-methoxy-4-[4-(1-oxo-1λ4-thiomorpholin-4-ylmethyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl}-4H-1,2,4-oxadiazol-5-one as white solid.
Reaction SMILES: [CH2:1]1[CH:3]([CH:4](O)C#N)[CH2:2]1.[C:8]([O:12][C:13](=[O:16])[NH:14][NH2:15])([CH3:11])([CH3:10])[CH3:9]>CO>[C:8]([O:12][C:13]([NH:14][N:15]=[CH:4][CH:3]1[CH2:2][CH2:1]1)=[O:16])([CH3:11])([CH3:10])[CH3:9]
Reactant: N#CC(O)C1CC1
Reactant: CC(C)(C)OC(=O)NN
Solvent: CO
Product: CC(C)(C)OC(=O)NN=CC1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cyclopropylcarboxaldehyde (4.07 mL, 14.3 mmol) is dissolved in 3 mL MeOH and tert-butylcarbazate (1.89 g, 14.3 mmol) is added. The reaction mixture is stirred overnight at RT and subsequently concentrated in vacuo. Yield: 2.57 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[CH2:14][CH2:15][C:16](=[O:19])[NH:17][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([OH:12])=[O:11].[N+](C1C=C(S([O-])(=O)=O)C=CC=1)([O-])=O.[Na+].Cl>[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:14]=[CH:15][C:16](=[O:19])[NH:17][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: O=C(O)COc1ccc(C2=NNC(=O)CC2)cc1Cl
Agent: Cl
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: [Na+]
Product: O=C(O)COc1ccc(-c2ccc(=O)[nH]n2)cc1Cl
Temperature: 120 °C
Reaction time: 2 h
Yield: 63.3 %

Procedure:
1.91 g of 6-[3-chloro-4-(carboxymethoxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone (Compound No. 1a, prepared as described in Example 2) was dissolved in 55 ml of a 2% w/v aqueous sodium hydroxide solution, and 1.6 g of sodium m-nitrobenzenesulfonate was added thereto. The mixture was heated, with stirring, over an oil bath at 120° C. for 2 hours. The mixture was then cooled to room temperature and then acidified with 6N hydrochloric acid to a pH value of 2-3. The resulting precipitate was collected by filtration, to give 1.2 g of the title compound, melting at 227°=232° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[C:17]([S:18][CH3:19])=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12].[C:24]1(=O)[CH2:29][CH2:28][CH2:27][C:26](=[O:30])[CH2:25]1.C(N(CC)CC)C.Cl>CN(C)C=O.ClCCl>[CH3:7][O:8][C:9]1[C:17]([S:18][CH3:19])=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=[CH:14][C:10]=1[C:11]([O:13][C:24]1[CH2:29][CH2:28][CH2:27][C:26](=[O:30])[CH:25]=1)=[O:12]
Reactant: O=C1CCCC(=O)C1
Reactant: COc1c(C(=O)O)ccc(C(F)(F)F)c1SC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(C(=O)OC2=CC(=O)CCC2)ccc(C(F)(F)F)c1SC
Temperature: 25 °C
Reaction time: 16 h
Yield: 47 %

Procedure:
133 mg (1.05 mmol) of oxalyl dichloride and three drops of N,N-dimethylformamide were added in succession to 200 mg (purity 78% by weight, 0.59 mmol) of 2-methoxy-3-methylthio-4-(trifluoromethyl)benzoic acid in 20 ml of dichloromethane. After the elimination of gas had ceased, the mixture was heated under reflux for another 10 min. The content was then cooled to RT and freed from the solvent. 93 mg (0.83 mmol) of 1,3-cyclohexanedione were added to the residue in 20 ml of dry dichloromethane, and 152 mg (1.50 mmol) of triethylamine were then added dropwise. The mixture was stirred at RT for 16 h. For work-up, 3 ml of 1M hydrochloric acid were added to the contents. After phase separation, the organic phase was freed from the solvent. The residue was purified chromatographically, which isolated 100 mg of 3-(2-methoxy-3-methylthio-4-(trifluoromethyl)benzoyloxy)-cyclohex-2-enone.
Reaction SMILES: [C:1]([C:3]([CH:5]([OH:8])[CH2:6][CH3:7])=[CH2:4])#[N:2].[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CO>[CH2:9]([NH:16][CH2:4][CH:3]([C:1]#[N:2])[CH:5]([OH:8])[CH2:6][CH3:7])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C=C(C#N)C(O)CC
Reactant: NCc1ccccc1
Solvent: CO
Product: CCC(O)C(C#N)CNCc1ccccc1
Reaction time: 8 h

Procedure:
To a solution of 2-cyano-3-hydroxy-1-pentene (10 g) in methanol (100 ml) was added benzylamine (10 ml). After stirring for 8 hours under reflux, the solvent was evaporated, and the residue was chromatographed on silica gel with eluting a mixture of n-hexane and ethyl acetate (1:1, V/V) to give 1-benzylamino-2-cyano-3-hydroxypentane (10 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH:13]=[CH:14][N+:15]([O-])=[O:16])=[C:11]([CH:18]([CH3:20])[CH3:19])[N:10]([CH:21]([CH3:23])[CH3:22])[C:9]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.B.O.[OH-].[Na+]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][CH2:14][NH:15][OH:16])=[C:11]([CH:18]([CH3:19])[CH3:20])[N:10]([CH:21]([CH3:23])[CH3:22])[C:9]=2[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:4][CH:3]=1
Reactant: CC(C)c1c(C=C[N+](=O)[O-])c(-c2ccc(F)cc2)c(-c2ccccc2)n1C(C)C
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1c(CCNO)c(-c2ccc(F)cc2)c(-c2ccccc2)n1C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 30 g (76.5 mmol) of the compound of example 5 in 200 ml of warm tetrahydrofuran is added dropwise to 19.1 ml (0.19 mol) of a 1N solution of borane acid in tetrahydrofuran at 0° C. under an argon atmosphere; 0.5 g (13.2 mmol) of sodium hydridoborate are then added and the mixture is stirred for 2 h at room temperature. Then 180 ml of cold water are added dropwise with care and the mixture is boiled for 1 h under reflux. The mixture is adjusted to a pH of 13 with 10 ml of 6N sodium hydroxide solution, extracted three times, each time with 200 ml of ethyl acetate and the combined organic phases are dried over sodium sulphate and evaporated to dryness. The residue is chromatographed on 500 g of silica gel (230 to 400 mesh) with dichloromethane, dichloromethane/methanol (10:1) and dichloromethane/methanol/concentrated ammonia (100:10:1) until the main product emerges with the lowest Rf -value.
Reaction SMILES: Cl.[C:2]([NH:5][C:6]1[N:11]=[CH:10][N:9]=[C:8]([O:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[C:19]([C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([N:32]4[CH2:37][CH2:36][CH2:35][C@H:34]([NH:38]C(=O)OC(C)(C)C)[CH2:33]4)=[C:28]([C:46]([F:49])([F:48])[F:47])[CH:27]=2)=[O:24])=[CH:18][CH:17]=[CH:16]3)[CH:7]=1)(=[O:4])[CH3:3].C([O-])(O)=O.[Na+]>O1CCOCC1>[NH2:38][C@H:34]1[CH2:35][CH2:36][CH2:37][N:32]([C:29]2[CH:30]=[CH:31][C:26]([NH:25][C:23]([C:19]3[C:20]4[C:15](=[CH:14][C:13]([O:12][C:8]5[CH:7]=[C:6]([NH:5][C:2](=[O:4])[CH3:3])[N:11]=[CH:10][N:9]=5)=[CH:22][CH:21]=4)[CH:16]=[CH:17][CH:18]=3)=[O:24])=[CH:27][C:28]=2[C:46]([F:49])([F:48])[F:47])[CH2:33]1
Reactant: CC(=O)Nc1cc(Oc2ccc3c(C(=O)Nc4ccc(N5CCC[C@H](NC(=O)OC(C)(C)C)C5)c(C(F)(F)F)c4)cccc3c2)ncn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(=O)Nc1cc(Oc2ccc3c(C(=O)Nc4ccc(N5CCC[C@H](N)C5)c(C(F)(F)F)c4)cccc3c2)ncn1
Reaction time: 1.5 h

Procedure:
A solution of 2.3 ml hydrogen chloride (4 M in dioxane) is added to a stirred solution of 0.24 g (0.38 mmol) [(3S)-1-[4-[[[6-(6-acetylamino-pyrimidin-4-yloxy)-naphthalen-1-yl]carbonyl-]-amino]-2-(trifluoromethyl)phenyl]-3-piperidinyl]-carbamic acid, 1,1-dimethylethyl ester (Ex. 35) in 2.3 ml dioxan at room temperature. After 90 min, the mixture is poured into an excess of saturated aqueous NaHCO3. The crude product is filtered and purified by chromatography (SiO2, CH2Cl2/EtOH/NH3 90:9:1) to afford the title compound as a beige solid: m.p.: 218-228° C.