Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:12][C:13](=[O:15])[NH:14][C:7]=12.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](Cl)=[S:25]>>[O:15]=[C:13]1[NH:12][C:8]2=[N:9][CH:10]=[CH:11][C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:24](=[S:25])[C:23]4[CH:27]=[CH:28][CH:29]=[C:21]([C:20]([F:19])([F:30])[F:31])[CH:22]=4)[CH:18]=[CH:17][CH:16]=3)=[C:7]2[NH:14]1
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Reactant: FC(F)(F)c1cccc(C(=S)Cl)c1
Product: O=c1[nH]c2nccc(Oc3cccc(NC(=S)c4cccc(C(F)(F)F)c4)c3)c2[nH]1
Yield: 17 %

Procedure:
Method H was used with 7-(3-aminophenoxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one and 3-trifluoromethylthio-benzoyl chloride to afford the title compound (16 mg, 17.0%). 1H-NMR (δ, ppm, DMSO-d6): 6.49 (d, 1H, HPy,5, J=5.9 Hz), 6.93 (ddd, 1H, Harom, J=0.6 Hz, J=2.4 Hz, J=8.2 Hz), 7.44 (t, 1H, Harom, J=8.2 Hz), 7.62 (t, 1H, Harom, J=2.1 Hz), 7.66 (dd, 1H, Harom, J=1.1 Hz, J=8.2 Hz), 7.71 (t, 1H, Harom, J=7.8 Hz), 7.81 (d, 1H, HPy,6, J=5.9 Hz), 7.94 (d, 1H, Harom, J=7.8 Hz), 8.16 (m, 1H, Harom), 8.26 (s, 1H, Harom), 10.50 (s, 1H, NHamide), 11.19 (s, 1H, NHPy7), 11.39 (s, 1H, NHPy9). LC-MS, tR=4.87 minutes, m/z: 447.07 (M+H)+, calculated for C20H14N4O3SF3. HRMS (EI): m/z [M+H] calculated for C20H14N4O3SF3: 447.0739; found: 447.0743.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[C:20]([C:30]([O:32]C)=[O:31])[CH:19]=1)[C:14](O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:41]([NH2:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>>[CH2:41]([NH:48][C:14](=[O:15])[C@@H:13]([NH:12][C:10](=[O:11])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([CH:19]=1)[C:30]([OH:32])=[O:31])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: NCc1ccccc1
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1C(=O)OC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccc(OCC(=O)O)c(C(=O)O)c1)C(=O)NCc1ccccc1

Procedure:
Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-[3-(methoxycarbonyl)-4-(2-methoxy-2-oxoethoxy)phenyl]propanoic acid and benzylamine (31 μL) according to Method A to give a material which was re-purified by reversed phase C-18 HPLC in absence of trifluoroacetic acid to give the title compound (29 mg). 1H-NMR (400 MHz, CD3OD) d 7.78 (s, 1H), 7.36 (dd, J=2.0 Hz, J=8.6 Hz, 1H), 7.30-7.13 (m, 10H), 6.96 (d, J=8.5 Hz, 1H), 4.79 (s, 2H), 4.58 (t, J=6.9 Hz, 1H), 3.11-2.94 (m, 4H), 2.76 (dd, J=10 Hz, J=13.4 Hz, 1H), 1.33 (s, 9H); IR (KBr) 3304, 2979, 1694, 1640 cm−1; HRMS m/z 619.2511 (calc. of monoisotopic mass for C33H37N3O9 gives 619.2530).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH3:21])[CH2:9][N:10]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:4][CH:3]=1.NN>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([CH3:21])[CH2:9][NH2:10])=[CH:6][CH:7]=1
Reactant: C[C@H](CN1C(=O)c2ccccc2C1=O)c1ccc(F)cc1
Agent: NN
Solvent: Cc1ccccc1
Product: C[C@H](CN)c1ccc(F)cc1
Temperature: 80 °C
Yield: 100.2 %

Procedure:
To a room-temperature solution of (S)-2-(2-(4-fluorophenyl)propyl)isoindoline-1,3-dione (900 mg, 3.2 mmol, 1.0 equiv) in toluene (14 mL) was added hydrazine (1.4 mL, 45 mmol, 14 equiv) by syringe. The resulting mixture was heated to 80° C. for 30 minutes and then cooled to room temperature. The resulting solution was decanted from the solid in the reaction mixture, and the solid was washed with additional toluene. The combined organic layers were concentrated in vacuo to provide the title compound (491 mg, 99%), which was used without further purification. m/z=154.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH:5]([CH2:11][C:12]1[C:13]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:14][N:15]2[C:20]=1[C:19](Cl)=[C:18]([C:22]#[N:23])[CH:17]=[N:16]2)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[O:30]([C:37]1[CH:42]=[CH:41][C:40]([NH2:43])=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:29])[CH:5]([CH2:11][C:12]1[C:13]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:14][N:15]2[C:20]=1[C:19]([NH:43][C:40]1[CH:39]=[CH:38][C:37]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:42][CH:41]=1)=[C:18]([C:22]#[N:23])[CH:17]=[N:16]2)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CCOC(=O)c1cn2ncc(C#N)c(Cl)c2c1CC(C(=O)OCC)C(=O)OCC
Reactant: Nc1ccc(Oc2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c2c1CC(C(=O)OCC)C(=O)OCC

Procedure:
A solution of 2-(4-Chloro-3-cyano-6-ethoxycarbonyl-pyrrolo[1,2-b]pyridazin-5-ylmethyl)-malonic acid diethyl ester 369B (6.5 mg, 0.015 mmol) and 4-phenoxyphenylamine (4.2 mg, 0.023 mmol) in DMF (0.5 ml) was heated at 110° C. for 4 hrs. The reaction mixture was purified by silica gel flash chromatography to isolate 369 as a yellow film (1.7 mg, 20%). [M+H]+32 571.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([NH2:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:19]([N:21]=[C:22]=[O:23])[CH3:20]>C1(C)C=CC=CC=1>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([NH:10][C:22]([NH:21][CH2:19][CH3:20])=[O:23])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC(=O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Reactant: CCN=C=O
Solvent: Cc1ccccc1
Product: CCNC(=O)NC(=O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Yield: 24.6 %

Procedure:
A solution of 3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionamide (98 mg, 0.33 mmol) in toluene (10 mL) was treated with ethyl isocyanate (0.03 mL, 0.42 mmol). The resulting solution was heated under reflux for 24 h. At this time, the reaction was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230400 mesh, 90/10 hexanes/ethyl afforded 1-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-3-ethyl-urea (29 mg, 26%) as a white foam: EI-HRMS m/e calcd for C17H22Cl2N2O2 (M+) 356.1058, found 356.1066.
Reaction SMILES: [Mn]([O-])(=O)(=O)=O.[K+].[CH3:7][O:8][C:9]([NH:11][C@@H:12]([CH:33]([CH3:35])[CH3:34])[C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20]([NH:22][C@H:23]([C@@H:27]([OH:32])[C:28]([F:31])([F:30])[F:29])[CH:24]([CH3:26])[CH3:25])=[O:21])=[O:14])=[O:10].[OH-].[Na+].CCCCCC>O.C(O)(C)(C)C.C(OCC)(=O)C>[CH3:7][O:8][C:9]([NH:11][C@@H:12]([CH:33]([CH3:35])[CH3:34])[C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20]([NH:22][C@H:23]([C:27](=[O:32])[C:28]([F:31])([F:30])[F:29])[CH:24]([CH3:26])[CH3:25])=[O:21])=[O:14])=[O:10]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)[C@@H](O)C(F)(F)F)C(C)C
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CC(C)(C)O
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)N[C@H](C(=O)C(F)(F)F)C(C)C)C(C)C
Reaction time: 2 h
Yield: 63.3 %

Procedure:
A solution of potassium permanganate (16.6 g) in water (100 ml) was added dropwise to a 0° C. solution of (S)-1-[(S)-2-(methoxycarbonylamino)-3-methylbutyryl]-N-[(S)-2-methyl-1-((R)-2,2,2-trifluoro-1-hydroxyethyl)propyl]pyrrolidine-2-carboxamide (15 g) in tert-butyl alcohol (175 ml), water (100 ml), and 0.6 M sodium hydroxide solution (175 ml). The solution was stirred for 2 hours and then quenched by addition of methanol (70 ml), followed by stirring for 1 hour. The mixture was filtered through diatomaceous earth and the filtrate made acidic to pH 2 using 1M hydrochloric acid, and saturated with sodium chloride. The product was extracted into ether (5×100 ml) and the solvent removed under vacuum. The resulting oil was chromatographed (methanol:dichloromethane 5:95) and the solvent removed to give an oil. Hexane (40 ml) was added to a stirred solution of the oil in ethyl acetate (which had been presaturated with water) (40 ml) and stirring was continued for 24 hours over which time a crystalline solid formed. Another portion of hexane (40 ml) was added and the solid was collected and dried under vacuum (40° C.) to give (S)-1-[(S)-2-(methoxycarbonylamino)-3-methylbutyryl]-N-[(S)-2-methyl-1-(2,2,2-trifluoroacetyl)propyl]-pyrrolidine-2-carboxamide (9.45 g) as a white crystalline solid (as substantially or essentially Form A); 1H NHR (300 MHz, DMSO/D2O): 4.42 (m, 1H) 4.02 (d, 1H), 3.73 (m, 1H), 3.59 (m, 1H), 3.54 (s, 3H), 2.23 (m, 1H), 2.00-1.76 (m, 6H), 0.91 (m, 6H), 0.85 (d, 3H), 0.80 (d, 3H); Analysis for C18H28F3N3O5.H2O: Calculated; C, 48.97; H, 6.85; N, 9.51; Found: C, 49.02, H, 6.80; N, 9.66; (XDS shown in FIG. 1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[N:23]1([C:28]2[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=2)[CH:27]=[N:26][CH:25]=[N:24]1>CC#N.O>[N:23]1([C:28]2[CH:29]=[CH:30][C:31]([NH:32][C:6]3[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)=[CH:33][CH:34]=2)[CH:27]=[N:26][CH:25]=[N:24]1
Reactant: CCOC(=O)c1cnc(Cl)nc1Cl
Reactant: Nc1ccc(-n2cncn2)cc1
Solvent: CC#N
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnc(Cl)nc1Nc1ccc(-n2cncn2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of ethyl 2,4-dichloropyrimidine-5-carboxylate (1.4) (600 mg, 2.714 mmol), in CH3CN (12 mL), was added DIEA (0.750 mL, 4.313 mmol, 1.589 equiv), followed by 4-(1H-1,2,4-triazol-1-yl)aniline (465 mg, 2.902 mmol, 1.07 equiv). The mixture was stirred at room temperature for 20 h, then diluted with water (6×) to precipitate ii. The solid product was collected by filtration, rinsed with water (100 mL), and air dried; Yield, 850 mg (91%).
Reaction SMILES: [NH2:1][C@@H:2]([C@H:5]([O:7][CH3:8])[CH3:6])[CH2:3][OH:4].[Cl:9][C:10]1[N:15]=[C:14](Cl)[CH:13]=[CH:12][N:11]=1.CCN(C(C)C)C(C)C>C(#N)C>[Cl:9][C:10]1[N:15]=[C:14]([NH:1][C@@H:2]([C@H:5]([O:7][CH3:8])[CH3:6])[CH2:3][OH:4])[CH:13]=[CH:12][N:11]=1
Reactant: CO[C@H](C)[C@H](N)CO
Reactant: Clc1ccnc(Cl)n1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CO[C@H](C)[C@@H](CO)Nc1ccnc(Cl)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 40.3 %

Procedure:
To a round bottom flask containing (2R,3R)-2-amino-3-methoxybutan-1-ol (2.1 g, 9.0 mmol) and a stir bar was added acetonitrile (100 mL) followed by the addition of 2,4-dichloropyrimidine (1.34 g, 9.0 mmol) and DIEA (4.7 mL, 27.0 mmol). Resulting reaction mixture allowed to stir 18 hr at room temperature. Volatiles were then removed. Residue was partitioned between EtOAc and water. Aqueous layer extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na2SO4), filtered and concentrated to afford (2R,3R)-2-((2-chloropyrimidin-4-yl)amino)-3-methoxybutan-1-ol (1.68 g, 3.63 mmol, 40% yield) which contains some unreacted 2,4-dichloropyrimidine. LCMS m/z 232.0 (M+H)+, Rt 0.38 min.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([NH2:8])[N:5]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[N:11]=[C:4]2[CH:3]=1.[C:18]1([OH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN1CCCC1=O>[O:24]([C:2]1[CH:7]=[C:6]([NH2:8])[N:5]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[N:11]=[C:4]2[CH:3]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Oc1ccccc1
Reactant: Nc1cc(Br)cc2nc(-c3ccccn3)nn12
Solvent: CN1CCCC1=O
Product: Nc1cc(Oc2ccccc2)cc2nc(-c3ccccn3)nn12

Procedure:
A mixture of 1 eq. 7-bromo-2-pyridin-2-yl-[1,2,4]triazolo[1,5-a]pyridin-5-ylamine, 5 eq. phenol and a catalytic amount of CS2CO3 in 200 μl N-methyl-pyrrolidon was heated for 2 h to 160°. The mixture was, after filtration, purified with reversed phase column chromatography eluting with an acetonitrile/water gradient yielding the title compound, MS m/e (%): 303 M+H+ (100%).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]2[C:12]([C:17]#[N:18])=[N:13][CH:14]=[CH:15][CH:16]=2)[N:7]([CH3:19])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-:20].[K+]>CO>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]2[C:12]([C:17]([NH2:18])=[O:20])=[N:13][CH:14]=[CH:15][CH:16]=2)[N:7]([CH3:19])[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1nc(C(C)(C)C)cc1Nc1cccnc1C#N
Reactant: [OH-]
Agent: [K+]
Solvent: CO
Product: Cn1nc(C(C)(C)C)cc1Nc1cccnc1C(N)=O
Temperature: 40 °C
Reaction time: 48 h
Yield: 6 %

Procedure:
To a solution of 3-[(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)amino]pyridine-2-carbonitrile (100 mg, 0.39 mmol) in MeOH (1 mL) was added an aqueous solution of KOH (3 M, 1 mL), and the mixture was stirred at 40° C. for 48 h. The organic solvent was removed under reduced pressure, and the aqueous layer was acidified to pH 1 to 2 with 1 N aqueous HCl. The mixture was extracted with ethyl acetate (3×). After removal of the solvent under reduced pressure, the crude residue was subjected to preparative HPLC purification with a gradient elution from 20% to 90% acetonitrile in water to give the above product as an oil (6.2 mg, 6%). 1H NMR (400 MHz, CD3OD) δ 1.35 (s, 9H), 3.72 (s, 3H), 6.80 (s, 1H), 7.39-7.42 (m, 2H), 8.08-8.11 (m, 1H). ES-MS m/z 274.1 (MH+), HPLC RT (min) 1.47.
Reaction SMILES: [N:1]1([C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=2[C:8]#[N:9])[CH:5]=[N:4][N:3]=[N:2]1.N>C(O)C.[Ni]>[N:1]1([C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=2[CH2:8][NH2:9])[CH:5]=[N:4][N:3]=[N:2]1
Reactant: N#Cc1ccccc1-n1cnnn1
Agent: [Ni]
Agent: N
Solvent: CCO
Product: NCc1ccccc1-n1cnnn1

Procedure:
A solution of 2-Tetrazol-1-yl-benzonitrile (1.3 g, 7.6 mmol) in ethanol saturated with ammonia (125 ml) was stirred in the presence of Raney nickel (50% slurry in water, washed with ethanol, catalytic amount) under a hydrogen atmosphere overnight. The reaction mixture was filtered over celite and concentrated to give 2-Tetrazol-1-yl-benzylamine; 1H NMR (CDCl3, 400 MHz) δ9.28 (s, 1H), 7.59 (m, 2H), 7.47 (m, 2H), 3.70 (s, 2H).
Reaction SMILES: [OH:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:12].[C:13](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O.O>CN(C)C=O>[CH3:13][O:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:12]
Reactant: Cc1ccc2c(c1O)CCC2=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Product: COc1c(C)ccc2c1CCC2=O
Temperature: 62.5 °C
Reaction time: 16 h
Yield: 82.9 %

Procedure:
To a suspension of 4-Hydroxy-5-methyl-indan-1-one (50.0 gm, 0.308 mole) and Potassium carbonate (127.0 gm, 0.928 mole) in Dimethylformamide (250 ml), Dimethyl sulphate (90 ml, 0.928 mole) was added at 0° C. The reaction mixture was heated at 60-65° C. and stirred for 16 hours. The reaction mixture was poured into water (1 liter) and extracted with Ethylacetate (3×250 ml). The organic layer was dried over Sodium sulphate and distilled under vacuum to give 10.0 gm of crude product which was purified by column chromatography using Hexane as a mobile phase. The collected fractions were distilled under vacuum to give 45.0 gm of desired product as a viscous oil.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Br:11][C:12]1[CH:13]=[C:14]([CH2:26][O:27][C:28](=[O:30])[CH3:29])[C:15]2[CH:16]([OH:25])[C:17]3[C:22]([C:23]=2[CH:24]=1)=[CH:21][CH:20]=[CH:19][CH:18]=3.C(N(CC)CC)C>C(Cl)Cl>[Br:11][C:12]1[CH:13]=[C:14]([CH2:26][O:27][C:28](=[O:30])[CH3:29])[C:15]2[C:16](=[O:25])[C:17]3[C:22]([C:23]=2[CH:24]=1)=[CH:21][CH:20]=[CH:19][CH:18]=3
Reactant: CC(=O)OCc1cc(Br)cc2c1C(O)c1ccccc1-2
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCc1cc(Br)cc2c1C(=O)c1ccccc1-2
Reaction time: 0.17 h

Procedure:
Dichloromethane (5 ml) was cooled to -60° C. under N2, oxalyl chloride (1.65 ml, 1M soln in CH2Cl2, 1.1 eq) was added followed by DMSO (234 μl in 1 ml of (CH2Cl2). The resulting solution was stirred at -60° for 10 minutes. The 3-bromo-1-acetoxymethyl-9-fluorenol (0.480 g) in a suspension of CH2Cl2 (2 ml) was added dropwise and the solution stirred at -60° for 0.5 hour. Triethylamine (1.06 ml) was added dropwise and the solution stirred at -60° for 15 minutes. The cooling bath was removed and water (5 ml) was added and the reaction mixture stirred at room temperature for 20 minutes. The organic phase was separated and the aqueous phase was extracted with EtOAc, the combined organic extract was dried and evaporated which gave product, one spot on tlc, used without further purification in the next step. ##STR37##
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[C:33]([Cl:38])[CH:32]=1)=[O:30]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]3[CH:36]=[CH:35][C:34]([CH3:37])=[C:33]([Cl:38])[CH:32]=3)=[O:30])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: Cc1ccc(C(=O)CCCCCBr)cc1Cl
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCC(=O)c2ccc(C)c(Cl)c2)CC1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride as starting compound and 6-bromo-1-(3-chloro-4-methylphenyl)-1-hexanone are reacted and treated in the same manner as in Example 199 to give 4-amino-5-chloro-2-methoxy-N-((1-(6-(3-chloro-4-methylphenyl)-6-oxohexyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.[CH3:14][O:15][C:16](=[O:23])[C@H:17]([CH2:19][CH2:20][CH2:21][CH3:22])[NH2:18]>>[CH3:14][O:15][C:16](=[O:23])[CH:17]([NH:18][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: O=C(O)Cc1cc(Cl)cc(Cl)c1
Reactant: CCCC[C@H](N)C(=O)OC
Agent: Cl
Product: CCCCC(NC(=O)Cc1cc(Cl)cc(Cl)c1)C(=O)OC

Procedure:
Following General Procedure F′ above, an using 3,5-dichlorophenylacetic acid (from Example C′ above) and L-norleucine methyl ester hydrochloride (Bachem), the title compound was prepared as a solid having a melting point of 77°-78° C. The reaction was monitored by tlc on silica gel (Rf=0.70 in 40% EtOAC/hexanes) and purification was by flash chromatography on silica gel using 40% EtOAc/hexanes as the eluant.
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][CH:5]=[C:6]([CH2:8][C:9](=[O:21])[NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:7]=1.[C:22](Cl)(=[O:26])[CH:23]([CH3:25])[CH3:24].O>N1C=CC=CC=1>[C:22]([N:2]([C:3]1[S:4][CH:5]=[C:6]([CH2:8][C:9](=[O:21])[NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:7]=1)[CH3:1])(=[O:26])[CH:23]([CH3:25])[CH3:24]
Reactant: CNc1nc(CC(=O)Nc2cccc(C(F)(F)F)c2)cs1
Reactant: CC(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(C)C(=O)N(C)c1nc(CC(=O)Nc2cccc(C(F)(F)F)c2)cs1
Yield: 60.2 %

Procedure:
A solution containing 7.6 g (0.025 mole) of 2-methylamino-4-(3-trifluoromethylphenylcarbamoylmethyl)thiazole and 2.9 g (0.027 mole) of isobutyryl chloride in 25 ml of pyridine was heated at about 45° for 24 hours. The mixture was poured into water. The thick oil failed to crystallize. The aqueous phase was decanted and the residue was dissolved in benzene. The organic phase was washed with water, dried over sodium sulfate and cooled. With stirring, hexane was added and a crystalline product precipitated. There was obtained 5.8 g of the desired amide, m.p. 122°-23°. N.M.R. (dimethyl-d6 sulfoxide) ∂ 1.1-1.3 (2×CH3), 2.7-3.4 (CH, septet), 3.6 (NCH3), 3.7 (CH2), 6.9 (hetero-aromatic), 7.3-8.1 (aromatic), 10.4 (HNC=0).
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.[OH:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1.[OH-].[Na+]>C(Cl)Cl.O>[N:15]1([CH2:25][C:24]2[CH:27]=[CH:28][C:21]([OH:20])=[CH:22][CH:23]=2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: C1CCNC1
Reactant: O=Cc1ccc(O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Oc1ccc(CN2CCCC2)cc1
Yield: 58.5 %

Procedure:
NaB(OAc)3H (43.4 g, 0.21 mol) was added in portions during 30 min to a mixture of pyrrolidine (17 mL, 0.21 mol) and 4-hydroxybenzaldehyde 1 (20 g, 0.16 mol) in CH2Cl2 (200 mL) under vigorous stirring and cooling with an ice bath in an atmosphere of argon. The mixture was stirred for 3 h and cooled. Then 10 N NaOH (20.5 mL) and water (300 mL) were added. The organic layer was separated, the aqueous one was extracted with chloroform (3×200 mL). The organic fractions were evaporated. The residue was dissolved in water, concentrated HCl (15 mL) was added, and the mixture was extracted with ether (3×200 mL). The organic fractions were discarded. The aqueous layer was alkalized with 10 N NaOH (16 mL) and extracted with CH2Cl2 (3×200 mL). The combined extracts were washed with brine, dried with Na2SO4, and evaporated. The title compound (16.6 g, 57%) was obtained as yellow crystals. 1H NMR-data (DMSO-d6): 9.18 (br.s, 1H, OH); 7.00 (d, 2H, Ph, J=8.6 Hz); 6.68 (d, 2H, Ph, J=8.6 Hz); 3.43 (s, 2H, CH2); 2.33-2.42 (m, 4H); 1.62-1.71 (m, 4H).
Reaction SMILES: Cl.[C:2]([NH:5][C@:6]([CH3:14])([C:11](O)=[O:12])[CH2:7][CH:8]([CH3:10])[CH3:9])(=[O:4])[NH2:3]>>[CH3:14][C@:6]1([CH2:7][CH:8]([CH3:10])[CH3:9])[C:11](=[O:12])[NH:3][C:2](=[O:4])[NH:5]1
Reactant: CC(C)C[C@](C)(NC(N)=O)C(=O)O
Agent: Cl
Product: CC(C)C[C@]1(C)NC(=O)NC1=O
Temperature: 80 °C

Procedure:
Water phase treated with ethyl acetate extraction was adjusted to a pH value of 1.0 and again extracted with 100 ml×2 of ethyl acetate. After distilling away ethyl acetate from an extract under reduced pressure, 1.10 g of (S)-N-carbamoyl-α-methylleucine was obtained as a white crystal [α]D25 =+8.0 (c=0.5, 0.1N NaOH)). To 25 ml of a 2N aqueous solution of HCl was added 1.00 g of the thus obtained (S)-N-carbamoyl-α-methylleucine and a mixture was heated at 80° C. for 2 hours in order to cyclize to give 0.83 g of (S)-4-methyl-4-isobutylimidazolidine-2,5-dione as a white crystal.
Reaction SMILES: [CH3:1][CH:2]1[C:7](=O)[CH2:6][CH2:5][N:4]([C:9]([O:11][CH3:12])=[O:10])[CH2:3]1.C(N)CN.[N+:17]([CH3:20])([O-:19])=[O:18]>>[CH3:1][CH:2]1[C:7]([CH2:20][N+:17]([O-:19])=[O:18])=[CH:6][CH2:5][N:4]([C:9]([O:11][CH3:12])=[O:10])[CH2:3]1
Reactant: C[N+](=O)[O-]
Reactant: COC(=O)N1CCC(=O)C(C)C1
Solvent: NCCN
Product: COC(=O)N1CC=C(C[N+](=O)[O-])C(C)C1
Yield: 87.2 %

Procedure:
A mixture of 64 parts of methyl 3-methyl-4-oxo-1-piperidinecarboxylate, 305 parts of nitromethane and 3.02 parts of 1,2-ethanediamine was stirred and refluxed for 4 hours. The reaction mixture was evaporated. The residue was taken up in trichloromethane. The solution was washed twice with a dilute hydrochloric acid solution, dried, filtered and evaporated, yielding 70 parts (87.2%) of methyl 3,6-dihydro-3-methyl-4-(nitromethyl)-1(2H)-pyridinecarboxylate as a residue (intermediate 1).
Reaction SMILES: [CH3:1][N:2]([C:6]1[C:15]([N+:16]([O-])=O)=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][C:7]=1[N+:19]([O-])=O)[C:3](=[O:5])[CH3:4]>[Pd].CO>[NH2:19][C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([NH2:16])[C:6]=1[N:2]([CH3:1])[C:3](=[O:5])[CH3:4])[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(N(C)C(C)=O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(N)c(N(C)C(C)=O)c(N)c1

Procedure:
9.7 G. of methyl 4-(N-methylacetamido)-3,5-dinitrobenzoate in 100 ml. of methanol were hydrogenated under normal pressure and at room temperature in the presence of 1 g. of palladium/carbon. After uptake of the theoretical amount of hydrogen, the solution was filtered off from the catalyst and evaporated. the residue was recrystallized from methanol, there being obtained methyl 3,5-diamino-4-(N-methylacetamido)-benzoate having a melting point of 221°-222° C.