Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:15](=O)[CH3:16])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12].[CH3:18][C:19]([S@:22]([NH2:24])=[O:23])([CH3:21])[CH3:20]>>[CH3:18][C:19]([S@:22]([NH:24][CH:15]([C:4]1[CH:5]=[N:6][C:7]([O:8][CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[C:2]([CH3:1])[CH:3]=1)[CH3:16])=[O:23])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1cnc(OCCC(F)(F)F)c(C)c1
Product: Cc1cc(C(C)N[S@](=O)C(C)(C)C)cnc1OCCC(F)(F)F
Yield: 65 %

Procedure:
The title compound is prepared in 65% yield (1.50 g, colorless oil) from 1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethanone (1.63 g, 6.59 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][C:8]1[CH:9]=[N:10][N:11]([CH:15]([CH2:19][CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[C:16](O)=[O:17])[C:12](=[O:14])[CH:13]=1.[NH2:31][C:32]1[CH:36]=[CH:35][N:34]([CH2:37][C:38]([CH3:41])([OH:40])[CH3:39])[N:33]=1>>[C:1]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][C:8]1[CH:9]=[N:10][N:11]([CH:15]([CH2:19][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24]2)[C:16]([NH:31][C:32]2[CH:36]=[CH:35][N:34]([CH2:37][C:38]([OH:40])([CH3:41])[CH3:39])[N:33]=2)=[O:17])[C:12](=[O:14])[CH:13]=1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2ccccc2-c2ccccc2)cc1=O
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCC2)n2ncc(Oc3ccccc3-c3ccccc3)cc2=O)n1
Yield: 50 %

Procedure:
Using the method described in Example 17, 2-[4-(biphenyl-2-yloxy)-6-oxo-6H-pyridazin-1-yl]-3-cyclopentyl-propionic acid (Intermediate 37) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 2-[4-(biphenyl-2-yloxy)-6-oxo-6H-pyridazin-1-yl]-3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide as a white solid (0.74 g, 50%); ES+-HRMS m/e calcd for C31H35N5O4 [M+H+] 542.2762 found 542.2759. 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.02 (m, 1H), 1.04 (s, 3H), 1.05 (s, 3H), 1.26 (m, 1H), 1.36-1.66 (m, 7H), 1.88 (m, 1H), 2.15 (m, 1H), 3.88 (s, 2H), 4.66 (s, 1H), 5.37 (dd, J=4.4, J=11.0 Hz, 1H), 5.62 (d, J=2.9 Hz, 1H), 6.37 (d, J=2.3 Hz, 1H), 7.29-7.36 (m, 1H), 7.37-7.43 (m, 3H), 7.44-7.60 (m, 6H), 7.97 (d, J=2.9 Hz, 1H), 10.73 (s, 1H).
Reaction SMILES: [C:1]1([S:7][CH:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][O:11][C:10]3[CH:19]=[CH:20][C:21]([C:23]([O:25]C)=[O:24])=[CH:22][C:9]2=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO.O>[C:1]1([S:7][CH:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][O:11][C:10]3[CH:19]=[CH:20][C:21]([C:23]([OH:25])=[O:24])=[CH:22][C:9]2=3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc2c(c1)C(Sc1ccccc1)c1ccccc1CO2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2c(c1)C(Sc1ccccc1)c1ccccc1CO2

Procedure:
Dissolve 650 mg of the ester of Step A in 15 ml of methanol. Add 10 ml of 20% aqueous sodium hydroxide and reflux for 10 minutes. Dilute with 200 ml of water and extract with ether. Acidify the aqueous extract concentrated hydrochloric acid and extract into ether. Evaporate to dryness and crystalline from methanol to obtain the title product.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[CH3:9][C:10](=[CH2:12])[CH3:11]>C1(C)C(C)=CC=CC=1>[C:10]([C:5]1[CH:6]=[CH:7][C:8]([C:10]([CH3:12])([CH3:11])[CH3:9])=[C:1]([OH:2])[C:3]=1[OH:4])([CH3:11])([CH3:9])[CH3:12]
Reactant: Oc1ccccc1O
Reactant: C=C(C)C
Solvent: Cc1ccccc1C
Product: CC(C)(C)c1ccc(C(C)(C)C)c(O)c1O

Procedure:
A mixture of freshly distilled TiCl4 (11 g, 58 mmol) and pyrocatechol (13.7 g, 0.124 mol) was refluxed in 80 mL of xylene during 20 hours. The resulting dark-brown solid was filtered, washed by xylene and dried under vacuum. Titanium catecholate (10.24 g, 66%) was isolated. This salt (2.3 g, 8.7 mmol), pyrocatechol (82.5 g, 0.749 mol), xylene (80 mL) and isobutylene (150 mL) were heated in autoclave during 1.5 hours at 140° C. The solvent was removed and the residue was distilled under vacuum (b.p. −140-145° C., ˜1 mm Hg; m.p. 96-96.5° C.). Yield: 157.4 g (95%). (Also see “Organic Chemistry of Free Radicals”, Moscow, Khimia, 1979, p. 134.)
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3](=[CH2:7])[C:4](O)=[O:5].[CH3:10][NH:11][C:12]([NH:14][CH3:15])=[O:13]>CN(C)C=O>[CH3:10][N:11]1[CH2:7][CH:3]([C:2]([F:9])([F:8])[F:1])[C:4](=[O:5])[N:14]([CH3:15])[C:12]1=[O:13]
Reactant: C=C(C(=O)O)C(F)(F)F
Reactant: CNC(=O)NC
Solvent: CN(C)C=O
Product: CN1CC(C(F)(F)F)C(=O)N(C)C1=O
Temperature: 90 °C
Reaction time: 28 h
Yield: 81.9 %

Procedure:
A mixture of α-trifluoromethylacrylic acid (700 mg; 5.0 mmoles) and 1,3-dimethylurea (441 mg; 5.0 mmoles) in dimethylformamide (DMF) (3 ml) was heated at 90° C. with stirring for 28 hours. DMF was evaporated under reduced pressure, and the residue was purified by a column chromatography on silicagel (chloroform) to give 861 mg (yield: 82%) of 1,3-dimethyl-5-trifluoromethyl-5,6-dihydrouracil (OF-1).
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C@H:5]([C:10]1[N:11]=[C:12]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]3)=[C:18]([O:28][CH3:29])[CH:17]=2)[S:13][CH:14]=1)[CH2:6][CH:7]([CH3:9])[CH3:8].[F:30][C:31]([F:37])([F:36])[CH2:32][C:33](Cl)=[O:34]>>[F:30][C:31]([F:37])([F:36])[CH2:32][C:33]([NH:4][C@H:5]([C:10]1[N:11]=[C:12]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]3)=[C:18]([O:28][CH3:29])[CH:17]=2)[S:13][CH:14]=1)[CH2:6][CH:7]([CH3:8])[CH3:9])=[O:34]
Reactant: COc1cc(Nc2nc([C@@H](N)CC(C)C)cs2)ccc1-n1cnc(C)c1
Reactant: O=C(Cl)CC(F)(F)F
Agent: Cl
Product: COc1cc(Nc2nc([C@H](CC(C)C)NC(=O)CC(F)(F)F)cs2)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared in analogy to example 36 from 96 mg (0.2 mmol) [4-((S)-1-amino-3-methyl-butyl)-thiazol-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine trihydrochloride and 30 mg (0.2 mmol) 3,3,3-trifluoropropionylchloride. The crude product was purified on silica gel with methylene chloride/methanol 19/1 yielding 32 mg (33%) 3,3,3-trifluoro-N—((S)-1-{2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-thiazol-4-yl}-3-methyl-butyl)-propionamide as a yellow solid. MS ISP (m/e): 482.1 (100) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.39 (s, 1H), 8.50 (d, 1H), 7.91 (s, 1H), 7.66 (s, 1H), 7.24 (d, 1H), 7.03 (s, 1H), 7.01 (d, 1H), 6.64 (s, 1H), 4.92 (q, 1H), 3.82 (s, 3H), 2.14 (s, 3H), 1.75 (m, 1H), 1.62 (m, 2H), 0.91 (d, 3H), 0.88 (d, 3H).
Reaction SMILES: [Br:1][CH2:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=3[O:20][CH2:21][O:22][CH3:23])[O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH3:24][O:25]C1C(OC)=CC(C2OC3C=CC=C(C)C=3N=2)=C(OCOC)C=1>>[Br:1][CH2:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:25][CH3:24])=[CH:14][C:13]=3[O:20][CH2:21][O:22][CH3:23])[O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COCOc1cc(OC)c(OC)cc1-c1nc2c(C)cccc2o1
Reactant: COCOc1ccc(OC)cc1-c1nc2c(CBr)cccc2o1
Product: COCOc1cc(OC)c(OC)cc1-c1nc2c(CBr)cccc2o1

Procedure:
4-bromomethyl-2-(4,5-dimethoxy-2-methoxymethoxyphenyl)benzoxazole (F13) was prepared in a similar manner for the preparation of 4-bromomethyl-2-(5-methoxy-2-methoxymethoxyphenyl)benzoxazole (F12) by using 2-(4,5-dimethoxy-2-methoxymethoxyphenyl)-4-methylbenzoxazole (F9) (1.39 g, 4.23 mmol) instead of 2-(5-methoxy-2-methoxymethoxyphenyl)-4-methylbenzoxazole (F8) in 66% (1.14 g): 1H-NMR (500 MHz, CDCl3) δ3.60 (s, 3H), 3.97 (s, 3H), 3.99 (s, 3H), 4.96 (s, 2H), 5.31 (s, 2H), 6.85 (s, 1H), 7.30 (t, 1H, J=8.0 Hz), 7.40 (d, 1H, J=8.0 Hz), 7.51 (d, 1H, J=8.0 Hz), 7.66 (s, 1H).
Reaction SMILES: [CH:1]([N:4]=[C:5]=[O:6])([CH3:3])[CH3:2].[NH2:7][CH2:8][CH2:9][N:10]1[C:22]2[C:21]3[CH:20]=[CH:19][C:18]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)=[CH:17][C:16]=3[N:15]=[C:14]([NH2:29])[C:13]=2[N:12]=[C:11]1[CH2:30][CH2:31][CH2:32][CH3:33]>C(Cl)(Cl)Cl>[NH2:29][C:14]1[C:13]2[N:12]=[C:11]([CH2:30][CH2:31][CH2:32][CH3:33])[N:10]([CH2:9][CH2:8][NH:7][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:6])[C:22]=2[C:21]2[CH:20]=[CH:19][C:18]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[CH:17][C:16]=2[N:15]=1
Reactant: CC(C)N=C=O
Reactant: CCCCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CCN
Solvent: ClC(Cl)Cl
Product: CCCCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CCNC(=O)NC(C)C
Yield: 47.8 %

Procedure:
Isopropyl isocyanate (0.29 mL, 3.1 mmol) was added slowly to a suspension of 1-(2-aminoethyl)-2-butyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine (1.13 g, 3.1 mmol) in chloroform (113 mL). A precipitate formed within 15 minutes, was isolated by filtration, and was dried overnight in an oven to provide 0.66 g of N-{2-[4-amino-2-butyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]ethyl}-N′-(1-methylethyl)urea as a white solid, mp 240-241° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[C:7](=[O:20])[CH2:6][CH2:5]2.I.[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27](SC)=[NH:28]>C(O)C.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[CH2:16]([N:15]([CH2:18][CH3:19])[CH2:14][CH2:13][CH2:12][N:8]1[C:9]2[C:4](=[CH:3][C:2]([NH:1][C:27]([C:23]3[S:22][CH:26]=[CH:25][CH:24]=3)=[NH:28])=[CH:11][CH:10]=2)[CH2:5][CH2:6][C:7]1=[O:20])[CH3:17]
Reactant: CCN(CC)CCCN1C(=O)CCc2cc(N)ccc21
Reactant: CSC(=N)c1cccs1
Agent: I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCN(CC)CCCN1C(=O)CCc2cc(NC(=N)c3cccs3)ccc21
Reaction time: 64 h

Procedure:
A solution of 6-Amino-1-(3-diethylamino-propyl)-3,4-dihydro-1H-quinolin-2-one (0.058 g, 0.211 mmol) in dry ethanol (5 mL) was treated with methyl thiophene-2-carbimidothioate hydroiodide (0.120 g, 0.421 mmol) at room temperature and the resulting mixture was stirred for 64 hours. The reaction was transferred to a separatory funnel and diluted with ethyl acetate (30 mL) and saturated sodium hydrogen carbonate (20 mL). The aqueous was partitioned twice more with ethyl acetate (2×20 mL). The combined organics were washed with brine and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2M ammonia in methanol:dichloromethane, 0-1: 10-9). The product 7 was dried under high vacuum. Yield: 35 mg of yellow solid (44%). 1H NMR (CDCl3) δ: 7.44 (d, J=5.4 Hz, 1H), 7.41 (d, J=3.3 Hz, 1H), 7.09 (t, J=4.2 Hz, 1H), 7.06 (d, J=8.4 Hz, 1H), 6.88 (d, J=2.1 Hz, 1H), 6.84 (d, J=4.2 Hz, 1H), 4.90 (br s, 2H), 4.03-3.99 (m, 2H), 2.90-2.85 (m, 2H), 2.77-2.62 (m, 8H), 2.03-1.93 (m, 2H), 1.15 (t, J=7.2 Hz, 6H). MS (ESI): 385.2 (M+1). ESI-HRMS calculated for C21H29N4SO2 (MH+): 385.2056, Observed: 385.2040.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH:16]3[CH2:20][CH2:19][N:18](C(OCC4C=CC=CC=4)=O)[CH2:17]3)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[H][H]>[Pd].CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH:16]3[CH2:20][CH2:19][NH:18][CH2:17]3)[CH2:11][CH2:10]2)=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1CCC(CN2CCC(Cc3ccc(F)cc3)CC2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Fc1ccc(CC2CCN(CC3CCNC3)CC2)cc1
Reaction time: 14 h

Procedure:
To a stirring solution of 3-[4-(4-flourophenylmethyl)piperidinomethyl]-N-(benzyloxycarbonyl)-pyrrolidine (600 mg, 1.47 mmol) and 5% palladium on carbon (60 mg, Aldrich) in MeOH (50 mL) was added 50 psi of hydrogen. The reaction was stirred for 14 h. The reaction was filtered and the filtrate was conc. in vacuo to a colorless oil. The oil can be used without further purification. MS (ESI) 277 (M+H).
Reaction SMILES: [CH3:1][CH:2]([CH:4]([OH:7])[CH2:5][CH3:6])[CH3:3].[CH3:8][C:9](=[CH:13][CH3:14])[C:10](O)=[O:11].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:5]([CH:4]([O:7][C:10](=[O:11])[C:9]([CH3:8])=[CH:13][CH3:14])[CH:2]([CH3:3])[CH3:1])[CH3:6]
Reactant: CCC(O)C(C)C
Reactant: CC=C(C)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC=C(C)C(=O)OC(CC)C(C)C
Temperature: 120 °C
Yield: 44 %

Procedure:
A reaction flask was charged with ethylmagnesium chloride (CH3CH2MgCl) (2 M, 2.17 L) and cooled to −10° C. Isobutyraldehyde ((CH3)2CHCHO) (295 g) was fed over about 1 hour while the temperature was kept under 15° C. The reaction mixture was aged to room temperature over about 6 hours and then poured into a mixture of ice and acetic acid (293 g). Hexanes (350 mL) were added and aqueous and organic layers were split. The organic layer was separated, washed sequentially with sodium bicarbonate (NaHCO3), brine, and water, and further distilled to provide 2-methyl-pentan-3-ol (336 g). 2-Methyl-pentan-3-ol (153 g), 2-methyl-but-2-enoic acid (100 g), toluene (200 mL), and PTSA (8 g) were charged into to 2-L reaction flask fitted with a Dean-Stark trap. The reaction mixture was heated to reflux at about 120° C. Water was removed. The reaction mixture was aged at reflux for about 13-14 hours till GC analysis showed completion of the reaction. The resulting reaction mixture was washed sequentially with sodium bicarbonate and brine, and further purified by fractional distillation to provide 2-methyl-but-2-enoic acid 1-ethyl-2-methyl-propyl ester (81 g) with a boiling point of 91° C. at 1.1 mmHg.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.N1C=CC=CC=1.[Cl:20][C:21](Cl)([O:23]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[Cl:20][C:21]([N:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:2]1)=[O:23]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(C(=O)Cl)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 248.9 %

Procedure:
A flask was charged with (R)-tert-butyl pyrrolidin-3-ylcarbamate (1.0 g, 5.4 mmol, Lancaster) in DCM (15 mL) to give a colorless solution. Pyridine (0.89 mL, 10.8 mmol) was added and the solution was cooled to about 0° C., followed by the addition of triphosgene (0.64 g, 2.1 mmol). The mixture was stirred for about 1 h while slowly warming to ambient temperature. To the reaction solution was added DCM (50 mL) and the solution was washed with water (20 mL) and HCl (1N, 10 mL). The organic portion was separated, dried over anhydrous MgSO4, filtered, and concentrated to dryness under reduced pressure to give (R)-tert-butyl 1-(chlorocarbonyl)pyrrolidin-3-ylcarbamate (1.3 g, 98%) as a yellow oil: 1H NMR (DMSO-d6) δ 7.28 (s, 1 H), 4.03 (m, 1 H), 3.73-3.20 (m, 4 H), 2.05 (m, 1 H), 1.81 (m, 1 H), 1.39 (s, 9 H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:42]=[CH:43][C:44]=1[O:45][CH3:46])[CH2:16][C:17]1[NH:22][C:21](=[O:23])[C:20]([CH:24]([NH:26][C:27](=[O:41])[CH:28]([CH:38]([OH:40])[CH3:39])[CH2:29]/[CH:30]=[CH:31]/[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH3:25])=[N:19][N:18]=1.C(N(CC)CC)C>>[C:38]([CH:28]([CH2:29]/[CH:30]=[CH:31]/[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:27]([NH:26][CH:24]([C:20]1[C:21](=[O:23])[NH:22][C:17]([CH2:16][C:15]2[CH:42]=[CH:43][C:44]([O:45][CH3:46])=[C:13]([O:12][CH3:11])[CH:14]=2)=[N:18][N:19]=1)[CH3:25])=[O:41])(=[O:40])[CH3:39]
Reactant: COc1ccc(Cc2nnc(C(C)NC(=O)C(C/C=C/c3ccccc3)C(C)O)c(=O)[nH]2)cc1OC
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(Cc2nnc(C(C)NC(=O)C(C/C=C/c3ccccc3)C(C)=O)c(=O)[nH]2)cc1OC

Procedure:
Analogously to Example 40A, 320 mg (2.50 mmol) of oxalyl chloride, 390 mg (5.00 mmol) of dimethyl sulphoxide, 800 mg (1.63 mmol) of (4E)-N-{1-[3-(3,4-dimethoxybenzyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]ethyl}-2-(1-hydroxyethyl)-5-phenyl-4-pentenamide and 1.82 g (18.0 mmol) of triethylamine are reacted to give (4E)-2-acetyl-N-{1-[3-(3,4-dimethoxybenzyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]-ethyl}-5-phenyl-4-pentenamide.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH2:5].[CH2:6]([N:18]=[C:19]=[O:20])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>CCOCC>[CH2:6]([NH:18][C:19]([NH:1][CH2:2][CH2:3][CH2:4][NH2:5])=[O:20])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: NCCCN
Reactant: CCCCCCCCCCCCN=C=O
Solvent: CCOCC
Product: CCCCCCCCCCCCNC(=O)NCCCN
Reaction time: 0.25 h
Yield: 101.4 %

Procedure:
In a 500 ml flask protected by a soda lime tube is placed 8 g (0.108 mole) of 1,3-diaminopropane in 150 ml ether. The solution is stirred in an ice bath for 30 minutes during the slow addition of a solution of 11.1 g (0.0525 mole) dodecyl isocyanate in 50 ml ether. After standing 15 minutes, the white solid precipitate was separated by filtration, washed well with ether, and dried. The 15.2 g solid obtained is crystallized from a mixture of 1100 ml alcohol and 600 ml water. From the 10.7 g which dissolved, there is obtained 9.2 g recrystallized product. An analytical sample recrystallized from acetonitrile melted at 97°-98°C.
Reaction SMILES: Cl.[CH3:2][NH:3][OH:4].C(N(CC)CC)C.[F:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)/[C:18](=[CH:22]\[C:23]1[CH:28]=[CH:27][C:26]([S:29][CH3:30])=[CH:25][CH:24]=1)/[C:17]([CH3:31])=[C:16]2[CH2:32][N:33]=[C:34]=[O:35]>C1COCC1>[F:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)/[C:18](=[CH:22]\[C:23]1[CH:28]=[CH:27][C:26]([S:29][CH3:30])=[CH:25][CH:24]=1)/[C:17]([CH3:31])=[C:16]2[CH2:32][NH:33][C:34]([N:3]([OH:4])[CH3:2])=[O:35]
Reactant: CNO
Reactant: CSc1ccc(/C=C2/C(C)=C(CN=C=O)c3cc(F)ccc32)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CSc1ccc(/C=C2/C(C)=C(CNC(=O)N(C)O)c3cc(F)ccc32)cc1
Reaction time: 0.17 h

Procedure:
To a suspension of N-methyl hydroxylamine hydrochloride (9.82 g, 117.6 mmol) in THF (150 mL) at room temperature there was added triethylamine (16.3 mL, 117.6 mmol) and the mixture stirred for 10 minutes. There was added, over 15 minutes, a solution of the isocyanate from Step 1 in THF (100 mL). After 2 hours of stirring at room temperature, the THF was evaporated and the residue, on trituration with water, afforded a yellow solid which was filtered. This solid was stirred in ether (150 mL) and filtered again. This crude material was chromatographed on silica gel eluting with 5% ethanol in methylene chloride. The more polar component of the mixture was stirred with methylene chloride (50 mL) for 2 hours and filtered and the solid crystallized from ethyl acetate to afford the pure title product as yellow crystals, mp 190-192° C. dec.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]([C:7]([F:10])([F:9])[F:8])=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[S:3]1.[K].[CH2:17](Br)[CH:18]=[CH2:19]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[O:1]=[C:2]1[N:6]([CH2:19][CH:18]=[CH2:17])[C:5]([C:7]([F:8])([F:9])[F:10])=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[S:3]1
Reactant: C=CCBr
Reactant: CCOC(=O)c1sc(=O)[nH]c1C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K]
Solvent: Cc1ccccc1
Product: C=CCn1c(C(F)(F)F)c(C(=O)OCC)sc1=O
Reaction time: 2 h

Procedure:
10 g of ethyl 2,3-dihydro-2-oxo-4-trifluoromethyl-5-thiazolcarboxylate (CA Vol. 92 110 998P), 200 ml of toluene, 2.6 g of potassium in pastilles, 6 ml of allyl bromide and 2.8 g of tetrabutylammonium bromide were heated at 90° C. for 3 hours and the mixture was allowed to return to ambient temperature followed by stirring for 2 hours. The mixture was washed with a N sodium hydroxide solution, with a N hydrochloric acid solution, with water and with a saturated sodium chloride solution. Drying, filtering and concentrating were carried out and the residue was chromatographed on silica and eluted with a hexane-ethyl acetate mixture (9-1) to obtain 8.65 g of the expected product with a Rf=0.25.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][N:4]1[C:9](=[O:10])[CH:8]=[N:7][C:6]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[CH:12]=2)=[N:5]1.[C:21](OCC)(=[O:23])C>CO>[F:20][C:2]([F:1])([F:19])[CH2:3][N:4]1[C:9](=[O:10])[CH:8]([O:23][CH3:21])[NH:7][C:6]([C:11]2[CH:12]=[C:13]([Cl:18])[CH:14]=[C:15]([Cl:17])[CH:16]=2)=[N:5]1
Reactant: CCOC(C)=O
Reactant: O=c1cnc(-c2cc(Cl)cc(Cl)c2)nn1CC(F)(F)F
Solvent: CO
Product: COC1NC(c2cc(Cl)cc(Cl)c2)=NN(CC(F)(F)F)C1=O
Reaction time: 0.33 h
Yield: 100 %

Procedure:
To a solution of 1-(2,2,2-trifluoroethyl)-3-(3,5-dichlorophenyl)-1,2,4-triazin-6-one (70 mg, 0.21 mmol) dissolved in 3 mL of a 1:1 mixture of ethyl acetate and methanol was added a small scoopula of neutral alumina. After stirring for 20 minutes, the mixture was filtered through a small plug of glass wool and concentrated. The product (80 mg) was afforded in 96% purity and 100% yield.
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:25])[CH3:24])=[C:18]([F:26])[CH:17]=3)[O:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:27][C:28]1[O:32][N:31]=[C:30]([CH:33]=O)[CH:29]=1.[Al+3].[Cl-].[Cl-].[Cl-]>>[CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:24])[CH3:25])=[C:18]([F:26])[CH:17]=3)[O:11][C:10](=[O:12])[C:9]([CH2:33][C:30]3[CH:29]=[C:28]([CH3:27])[O:32][N:31]=3)=[C:8]([OH:13])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc(C=O)no1
Reactant: CC(C)Oc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1F
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1cc(CC2=C(O)CC(CCc3ccc(OC(C)C)c(F)c3)(C3CCCC3)OC2=O)no1

Procedure:
The title compound was prepared by coupling 6-Cyclopentyl-6-[2-(3-fluoro-4-isopropoxy-phenyl)-ethyl]-dihydro-pyran-2,4-dione from Step 1 of Example B(14), to 5-Methyl-isoxazole-3-carbaldehyde using the AlCl3/reduction procedure described for Example B(13).
Reaction SMILES: [CH2:1]([C@@:3]12[CH2:16][C@:15]([OH:18])([CH3:17])[C@:14]([OH:25])([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:13][C@H:12]1[CH2:11][CH2:10][C:9]1[CH:8]=[C:7]([O:26][CH2:27][C:28](O)=[O:29])[CH:6]=[CH:5][C:4]2=1)[CH3:2].[NH2:31][CH2:32][C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1>>[CH2:1]([C@@:3]12[CH2:16][C@:15]([OH:18])([CH3:17])[C@:14]([OH:25])([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:13][C@@H:12]1[CH2:11][CH2:10][C:9]1[CH:8]=[C:7]([O:26][CH2:27][C:28]([NH:31][CH2:32][C:33]3[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=3)=[O:29])[CH:6]=[CH:5][C:4]2=1)[CH3:2]
Reactant: NCc1ccncc1
Reactant: CC[C@@]12C[C@@](C)(O)[C@](O)(c3ccccc3)C[C@H]1CCc1cc(OCC(=O)O)ccc12
Product: CC[C@@]12C[C@@](C)(O)[C@](O)(c3ccccc3)C[C@@H]1CCc1cc(OCC(=O)NCc3ccncc3)ccc12

Procedure:
The title compound was prepared from the compound of Example 70 according to the procedure of Example 97 using 4-(aminomethyl)pyridine in place of 1-methylpiperazine. Mass spectrum (m/e) 501 (M++1).
Reaction SMILES: Cl[C:2](Cl)(Cl)[C:3](=N)[O:4][CH2:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([Br:13])=[CH:8][C:7]=1[Cl:14].[C:18]12(O)[CH2:27]C3C[CH:24]([CH2:26][CH:20]([CH2:21]3)[CH2:19]1)[CH2:25]2.FC(F)(F)S(O)(=O)=O>C(Cl)Cl.C1CCCCC1>[Br:13][C:9]1[C:10]([F:12])=[CH:11][C:6]([CH2:5][O:4][C:3]23[CH2:27][CH:18]4[CH2:19][CH:20]([CH2:26][CH:24]([CH2:25]4)[CH2:2]2)[CH2:21]3)=[C:7]([Cl:14])[CH:8]=1
Reactant: N=C(OCc1cc(F)c(Br)cc1Cl)C(Cl)(Cl)Cl
Reactant: OC12CC3CC(CC(C3)C1)C2
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCCCC1
Product: Fc1cc(COC23CC4CC(CC(C4)C2)C3)c(Cl)cc1Br
Temperature: 25 °C
Reaction time: 56 h
Yield: 44 %

Procedure:
To a solution of 4-bromo-2-chloro-5-fluorobenzyl 2,2,2-trichloroacetimidate (3.95 g, 16.49 mmol) and 1-adamantanol (0.65 g, 4.26 mmol) in methylene chloride (15 mL) and cyclohexane (30 mL) was added trifluoromethanesulfonic acid (0.04 mL, 0.45 mmol) at 0° C. The reaction mixture was stirred for 56 h at ambient temperature and quenched by addition of saturated sodium bicarbonate solution (10 mL), and then diluted with methylene chloride (100 mL). The organic layer was separated and washed with brine; dried over anhydrous sodium sulfate and concentrated in vacuo. Purification of the residue by column chromatography (5% ethyl acetate in hexanes) and recrystallization from methanol afforded 1-((4-bromo-2-chloro-5-fluorobenzyl)-oxy)adamantane as a colorless solid (0.70 g, 43%): 1H NMR (300 MHz, CDCl3) δ 7.47 (d, J=6.3 Hz, 1H), 7.37 (d, J=9.3 Hz, 1H), 4.48 (s, 2H), 2.16 (br s, 3H), 1.82-1.80 (m, 6H), 1.70-1.55 (m, 6H).