Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#N)=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1.[H-].C([Al+]CC(C)C)C(C)C.C1C[O:25]CC1>ClCCl>[NH2:1][C:2]1[C:7]([CH:8]=[O:25])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1
Reactant: CSc1ncc(C#N)c(N)n1
Reactant: C1CCOC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: CSc1ncc(C=O)c(N)n1
Yield: 39 %

Procedure:
To a stirred solution of 4-amino-2-methylsulfanyl-pyrimidine-5-carbonitrile (4.50 g, 27.1 mmol) in 120 mL of THF is slowly added 27 mL of a 1 M solution of diisobutyl-aluminum hydride in dichloromethane for 5 minutes at 0° C. The ice bath is removed, and an additional 27 mL of 1M solution of diisobutylaluminum hydride in dichloromethane is added. After 30 minutes an additional 13 mL of 1 M solution of diisobutylaluminum hydride in dichloromethane is added. After 30 minutes the reaction is carefully quenched by the addition of 45 mL of methanol. This mixture is partitioned between 250 mL of EtOAc and 160 mL of 1 N HCl. The aqueous layer is treated with 80 mL of 2 N NaOH and extracted with EtOAc. The organic layer is dried over MgSO4, filtered, concentrated under reduced pressure and purified by flash column chromatography (SiO2, EtOAc/hexane=1/3) to give pure 4-amino-2-methylsulfanyl-pyrimidine-5-carbaldehyde (1.80 g, 39%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:24]=[CH:23][C:12]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=3)=[O:14])=[CH:11][C:10]=2[N+:25]([O-:27])=[O:26])=[CH:4][CH:3]=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>N1C=CC=CC=1>[Br:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:13](=[O:14])[C:12]2[CH:23]=[CH:24][C:9]([S:8][C:5]3[CH:6]=[CH:7][C:2]([NH:1][S:29]([CH3:28])(=[O:31])=[O:30])=[CH:3][CH:4]=3)=[C:10]([N+:25]([O-:27])=[O:26])[CH:11]=2)=[CH:17][CH:18]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(Sc2ccc(C(=O)Nc3ccc(Br)cc3)cc2[N+](=O)[O-])cc1
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(Sc2ccc(C(=O)Nc3ccc(Br)cc3)cc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 99.1 %

Procedure:
The product of Example 13A (200 mg, 0.4501 mmol) was dissolved in anhydrous pyridine (4 mL) under a nitrogen atmosphere, treated with methanesulfonyl chloride (0.084 mL, 1.080 mmol), and stirred at room temperature for 19 hours. The solvent was removed by rotary evaporation under vacuum, and the residue dissolved in methylene chloride (100 mL) and washed with 1N aqueous hydrochloric acid (2×50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford the title compound as a yellow solid (233 mg, 99%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[C:6]([N:8]([CH2:17][CH2:18][CH2:19][C:20](O)=[O:21])[C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:16])=[O:7].[NH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35]>>[CH3:29][O:28][C:24]1[CH:23]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:25]=1[O:26][CH3:27])[C:6]([N:8]([CH2:17][CH2:18][CH2:19][C:20]([NH:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])=[O:21])[C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:16])=[O:7]
Reactant: COc1cc(C(=O)N(CCCC(=O)O)c2c(C)cccc2C)cc(OC)c1OC
Reactant: COC(=O)CCCN
Product: COC(=O)CCCNC(=O)CCCN(C(=O)c1cc(OC)c(OC)c(OC)c1)c1c(C)cccc1C

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(3,4,5-trimethoxybenzoyl)-4-(2,6- dimethylanilino)butyric acid and methyl 4-aminobutyrate and suitable processing produces methyl N-[N-(3,4,5-trimethoxybenzoyl)-4-(2,6-dimethylanilino)butyryl]-4-aminobutyrate (M.P. 97° to 99°), saponification of which and processing of the reaction product yields N-[N-(3,4,5-trimethoxybenzoyl)-4-(2,6-dimethylanilino)butyryl]-4-aminobutyric acid (M.P. 100° to 101°).
Reaction SMILES: [S:1]([C:4]1[S:8][C:7]([NH:9][C:10]2[N:15]=[CH:14][C:13]([CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:12][CH:11]=2)=[N:6][CH:5]=1)[C:2]#N.SC[C@H]([C@@H](CS)O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].ClC1[CH:47]=[CH:46][N:45]=[C:44]([C:48]([O:50][CH3:51])=[O:49])[C:43]=1[F:52]>CO.CN(C=O)C>[C:20]([O:19][C:18]([NH:17][CH2:16][C:13]1[CH:12]=[CH:11][C:10]([NH:9][C:7]2[S:8][C:4]([S:1][C:2]3[CH:47]=[CH:46][N:45]=[C:44]([C:48]([O:50][CH3:51])=[O:49])[C:43]=3[F:52])=[CH:5][N:6]=2)=[N:15][CH:14]=1)=[O:24])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Nc2ncc(SC#N)s2)nc1
Reactant: COC(=O)c1nccc(Cl)c1F
Agent: O=P([O-])([O-])[O-]
Agent: O[C@H](CS)[C@H](O)CS
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)c1nccc(Sc2cnc(Nc3ccc(CNC(=O)OC(C)(C)C)cn3)s2)c1F
Temperature: 23 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
Tert-butyl (6-(5-thiocyanatothiazol-2-ylamino)pyridin-3-yl)methylcarbamate (1.5 g, 4.13 mmol) was dissolved in methanol (30 mL) and treated with dithiothreitol (0.637 g, 4.13 mmol). The reaction was stirred at 23° C. for 1 hour. DMF (30 mL) was then added, followed by K3PO4 (0.351 g, 1.65 mmol) and methyl 4-chloro-3-fluoropicolinate (0.861 g, 4.53 mmol). The reaction was stirred at 23° C. for 1 hour, then methanol was evaporated. The title material was precipitated by adding water (˜200 mL), collected by filtration and dried under high vacuum to give the title material (1.875 g, 92%) as a solid. The compound was purified by silica gel chromatography (Biotage, dichloromethane/methanol) to give the title material as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm: 1.38 (9H, s) 3.91 (3H, s), 4.08 (2H, d, J=5.81 Hz), 7.09 (1H, d, J=8.34 Hz), 7.14 (1H, t, J=5.31 Hz), 7.41 (1H, t, J=5.94 Hz), 7.66 (1H, dd, J=8.46, 2.15 Hz), 7.82-7.85 (1H, m), 8.17 (1H, d, J=1.77 Hz), 8.33 (1H, d, J=5.05 Hz), 11.89 (1H, s). HPLC ret. time: 5.868 min. (Condition B).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)[N:11]=[C:10]([CH3:20])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([NH:28][C:2]1[CH:7]=[C:6]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)[N:11]=[C:10]([CH3:20])[CH:9]=2)[CH:5]=[CH:4][N:3]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Cc1cc(-c2ccnc(Cl)c2)n(-c2cccc(F)c2)n1
Reactant: NCc1ccccc1
Product: Cc1cc(-c2ccnc(NCc3ccccc3)c2)n(-c2cccc(F)c2)n1
Temperature: 180 °C
Yield: 90 %

Procedure:
A mixture of 2-chloro-4-[1-(3-fluorophenyl)-3-methyl-1H-pyrazol-5-yl]pyridine (Example 47; 1.11 g, 0.0039 mol) and benzylamine (30 mL) was heated at 180° C. overnight (about eighteen hours). The excess benzylamine was removed under vacuum and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude was purified by chromatography on silica gel (ethyl acetate/hexane, 2:8) to give 1.24 g (90% yield) of the titled compound as a clear oil, which solidified upon standing: mp: 94-96° C.; Anal. Calc'd. for C22H19FN4: C, 73.72; H, 5.34; N, 15.63. Found: C, 73.62; H, 5.62; N, 15.34.
Reaction SMILES: [C:1]([C:3]1([C:8]([O:10][CH3:11])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4]1)#N.[OH2:12]>[Ni].C(O)=O>[CH:1]([C:3]1([C:8]([O:10][CH3:11])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4]1)=[O:12]
Reactant: O
Reactant: COC(=O)C1(C#N)CCCC1
Agent: [Ni]
Solvent: O=CO
Product: COC(=O)C1(C=O)CCCC1
Temperature: 45 °C
Yield: 69 %

Procedure:
To a 12 L flask equipped with a mechanical stirrer, thermometer and condenser containing a nitrogen inlet was added Raney nickel (1 kg, 50% slurry in water, as sold by the Aldrich Chemical Co.). This material was washed with distilled water and decanted (3×0.8 L). Formic acid (88% 7 L) was added (stirring started) followed by a solution of methyl 1-cyanocyclopentanecarboxylate (696 g, 4.54 mol) in formic acid (88%, 1 L). Gas evolved and the exothermic mixture (temperature increased to 45° C.) was stirred at 75° C. for 5 h. After the reaction mixture cooled to room temperature and the catalyst settled, the majority of the solvent was decanted off through a fiberglass filter. The residue was mixed with water (6 L) and filtered. The collected solid was washed with water (1 L) and CH2Cl2 (1 L) and all the filtrates were combined. The aqueous phase was separated and extracted with CH2Cl2 (6 L), and the combined organic phases were washed with saturated aqueous NaHCO3 and brine. Drying (MgSO4), filtering, and concentrating afforded material that was immediately distilled (Vigreux® column, fraction boiling at 93° C., 16 mm Hg collected) to provide methyl 1-formylcyclopentanecarboxylate as a clear colorless liquid (491 g, 69% yield). 1H-NMR (400 MHz, CDCl3) δ 9.65 (s, 1 H), 3.76 (s, 3 H), 2.19-2.04 (m, 4 H), 1.78-1.58 (m, 4 H); 13C NMR (100.6 MHz, CDCl3) δ 197.0, 172.6, 64.3, 51.9, 31.0, 25.3; EI-MS exact mass calcd for: C8H13O3 ; 157.0865; found: 157.0864. This compound has been reported previously by C. R. Davis et al., J. Org. Chem. 1993, 58, 6843.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([CH3:3])[CH3:2].[Br-:11].[Br-].O1CCOCC1>CCOCC>[Br:11][C:8]1[CH:7]=[CH:6][C:5]([OH:10])=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:9]=1
Reactant: CC(C)c1ccccc1O
Reactant: [Br-]
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(C)c1cc(Br)ccc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.9 %

Procedure:
To a solution of 2-isopropylphenol (12) (2.0 g, 14.6 mmol) in 15 ml of Et2O at 0° C. was added dioxane dibromide (3.62 g, 14.6 mmol, 1 eqv). The solution was allowed to stir for 30 min at rt. The reaction mixture was washed with sat. NaCl and 10% NaHCO3. The Et2O phase was concentrated in vacuo and then vacuum distilled (142-145° C., 20 mm Hg) to yield 2.07 g of a clear oil (66%) which solidified upon standing: 1H NMR (500 MHz, CDCl3) δ 1.23 (d, J=3.7 Hz, 6H), 3.16 (m, 1H), 4.84 (s, 1H), 6.61 (d, J=8.6 Hz, 1H), 7.15 (d, J=11.0 Hz, 1H), 7.28 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 22.33, 27.17, 113.24, 116.99, 129.34, 129.50, 136.91, 151.81; LRMS (EI) (M+, 214/216).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([C:13]2[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[CH:15][C:14]=2[CH3:22])[S:11][CH:12]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>C(O)(=O)C.C(OCC)(=O)C>[CH3:22][C:14]1[CH:15]=[CH:16][C:17]([NH:19][C:23](=[O:25])[CH3:24])=[CH:18][C:13]=1[C:10]1[S:11][CH:12]=[C:8]([C:3]2[CH:4]=[N:5][CH:6]=[CH:7][C:2]=2[CH3:1])[N:9]=1
Reactant: Cc1ccncc1-c1csc(-c2cc([N+](=O)[O-])ccc2C)n1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(C)c(-c2nc(-c3cnccc3C)cs2)c1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
4-Methyl-3-[2-(2-methyl-5-nitrophenyl)-1,3-thiazol-4-yl]pyridine (100 mg) and reduced iron (180 mg) were suspended in acetic acid (2 ml)-acetic anhydride (0.04 ml) and the mixture was stirred at 70° C. for 4 hrs. The reaction mixture was diluted with ethyl acetate and the insoluble material was filtered off. The organic layer was neutralized with saturated aqueous sodium hydrogen carbonate. The organic layer was separated and concentrated by drying. The residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=1:1–0:1) for purification. Recrystallization from ethyl acetate gave the title compound (43 mg) as colorless powder crystals.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:7]1([CH3:14])[C:8]([CH3:13])=[CH:9][CH:10]=[CH:11][CH:12]=1>>[CH2:6]([NH2:1])[CH2:5][CH2:4][CH2:3][CH2:2][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:13][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:7][CH3:14]
Reactant: Cc1ccccc1C
Reactant: c1ccncc1
Product: CCCCCCCCCCCCCCCCCCN
Yield: 686.5 %

Procedure:
A mixture of 39.4 g of the solid obtained in Intermediate Preparation Example 12, 26.9 g of n-octadecylamine, 2.3 g of pyridine and 100 g of xylene was stirred at a temperature of 120° C. for 5 hours. After cooling, the reaction mixture was added in 1.0 L of methanol with stirring over 15 minutes, and the mixture was further stirred for one hour as it was. A precipitated solid was collected by filtration and dried in vacuo to obtain 57 g of a pale yellowish white solid. The resulting compound had a molecular weight measured by high-performance liquid chromatography of 19,000. As a result of neutralization titration, a proportion of the half-amide maleic acid component to the maleinimide component was found to be 4/6.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[C:28]([NH:30][CH3:31])[CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([C:14](=[O:24])[NH:15][S:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])(=[O:18])=[O:17])=[CH:12][CH:13]=[C:8]2[N:7]=[C:6]1[CH3:25].N1C=CC=CC=1.[C:38](Cl)(=[O:42])[O:39][CH2:40][CH3:41]>ClCCl>[CH2:40]([O:39][C:38]([N:30]([C:28]1[CH:27]=[CH:26][C:3]([CH2:4][N:5]2[C:9]3=[N:10][C:11]([C:14](=[O:24])[NH:15][S:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])(=[O:17])=[O:18])=[CH:12][CH:13]=[C:8]3[N:7]=[C:6]2[CH3:25])=[C:2]([Cl:1])[CH:29]=1)[CH3:31])=[O:42])[CH3:41]
Reactant: CCOC(=O)Cl
Reactant: CCCCCS(=O)(=O)NC(=O)c1ccc2nc(C)n(Cc3ccc(NC)cc3Cl)c2n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCS(=O)(=O)NC(=O)c1ccc2nc(C)n(Cc3ccc(N(C)C(=O)OCC)cc3Cl)c2n1
Reaction time: 24 h
Yield: 39.2 %

Procedure:
To a suspension of 3-(2-chloro-4-(methylamino)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine (278 mg) in dichloromethane (3 ml) were added pyridine (148 mg) and ethyl chlorocarbonate (129 mg) under ice-cooling, and the mixture was stirred for 24 hr. The solvent was evaporated and the residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from ethyl acetate-hexane to give 3-(4-(N-(ethoxycarbonyl)-N-methylamino)-2-chlorobenzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine (126 mg) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][C:12](=[O:18])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:5][CH:4]=1.CC(O)C.[B-].[Na+].Cl>O>[OH:18][CH:12]([CH2:11][CH2:10][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[CH2:13][CH2:14][C:15]([OH:17])=[O:16]
Reactant: COc1ccc(CCCC(=O)CCC(=O)O)cc1
Agent: Cl
Agent: [B-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: COc1ccc(CCCC(O)CCC(=O)O)cc1

Procedure:
To a suspension of 79 parts of 4-methoxy-γ-oxobenzeneheptanoic acid in 630 parts of 2-propanol at 0°-5° is added, with stirring during one-half hour, 80 parts of sodium tetrahydroborate(1-). Stirring is continued at 0°-5° for 31/2 hours after the addition is complete, at which point the reaction mixture is consecutively diluted with an equal volume of water and acidified with cold 10% hydrochloric acid. The mixture thus obtained is extracted with cold dichloromethane. The dichloromethane extract is washed with water, dried over anhydrous sodium sulfate, and stripped of solvent by vacuum distillation at temperatures less than 40°. The residue is crystallized from a mixture of cold ether and hexane to give γ-hydroxy-4-methoxybenzeneheptanoic acid melting at approximately 67°-68°, and having the formula ##STR7##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]#[N:19])[CH:16]=3)[NH:11][N:10]=2)=[CH:5][CH:4]=1.[OH:20]O.[OH-].[Na+].Cl>O.C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([NH2:19])=[O:20])[CH:16]=3)[NH:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2n[nH]c3ccc(C#N)cc23)cc1
Reactant: OO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2n[nH]c3ccc(C(N)=O)cc23)cc1
Temperature: 50 °C
Yield: 41.6 %

Procedure:
A mixture of 20 mg (0.080 mmol) of 3-(4-methoxyphenyl)-1H-indazole-5-carbonitrile, 0.428 mL of 95% denatured ethanol, 0.021 mL of H2O, 0.32 mL of 30% aqueous hydrogen peroxide (aq. H2O2) and 0.032 mL of 6.0 N aq. NaOH (0.192 mmol, 2.4 equiv.) was heated at 50° C. for 3 h, and then acidified to pH=6.0 with 0.052 mL of 6.0 N 10 aq. HCl. The mixture was extracted with 2× EtOAc. The combined organics were washed with 2× sat. aq. NaHCO3, dried (Na2SO4), filtered, and concentrated affording the title compound (8.9 mg, 41.6% yield): 1H NMR (CDCl3/DMSO-d6) δ 12.5 (br s, 1H), 8.60 (s, 1H), 7.95 (d, 2H), 7.85 (d, 2H), 7.55 (d, 1H), 7.05 (d, 2H), 3.89 (s, 3H); ES-MS (m/z) 268 [M+1]+.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C:10](=[O:13])[NH:9][C:8]=2[CH:14]=1.[CH2:15](Cl)[C:16]#[CH:17].O>CN(C)C=O>[NH2:3][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C:10](=[O:13])[N:9]([CH2:17][C:16]#[CH:15])[C:8]=2[CH:14]=1
Reactant: Nc1ccc2c(c1)NC(=O)CO2
Reactant: C#CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCN1C(=O)COc2ccc(N)cc21
Temperature: 0 °C
Yield: 58.5 %

Procedure:
Sodium hydride (0.08 g) was suspended in dry N,N-dimethylformamide (3 ml), and the suspension was cooled to 0° C. While stirring, 6-amino-2H-1,4-benzoxazin-3(4H)-one (0.5 g) was portionwise added to the suspension at 0°, and the resultant mixture was stirred at the same temperature for 30 minutes. To the mixture, propargyl chloride (0.25 g) was dropwise added, and the mixture was stirred at room temperature for 6 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The extract was washed with water, dried and concentrated to give 6-amino-4-(2-propynyl)-2H-1,4-benzoxazin-3(4H)-one (0.36 g). m.p., 260.1° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20]#[CH:21])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.Br[C:23]1[CH:24]=[C:25]([S:29]([NH:32][C:33]([CH3:37])([CH3:36])[CH2:34][OH:35])(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20]#[C:21][C:23]4[CH:24]=[C:25]([S:29]([NH:32][C:33]([CH3:37])([CH3:36])[CH2:34][OH:35])(=[O:30])=[O:31])[CH:26]=[CH:27][CH:28]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(CO)NS(=O)(=O)c1cccc(Br)c1
Reactant: C#Cc1cnn2c(C3CC3)cc(-c3ccc(Cl)cc3)nc12
Product: CC(C)(CO)NS(=O)(=O)c1cccc(C#Cc2cnn3c(C4CC4)cc(-c4ccc(Cl)cc4)nc23)c1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-cyclopropyl-3-ethynyl-pyrazolo[1,5-a]pyrimidine (example C.5) (118 mg, 0.4 mmol) and 3-bromo-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzenesulfonamide (148 mg, 0.48 mmol) (example B.6) according to general procedure II. Obtained as a yellow solid (46 mg, 22%). MS (ISP) 521.5 [(M+H)+]; mp 202-204° C.
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[O:19][CH:20]=[CH:21][N:22]=3)=[CH:14][CH:13]=2)[CH2:7]1)(=O)=O.[NH2:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]1[NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34]>C(#N)C>[O:19]1[CH:20]=[CH:21][N:22]=[C:18]1[C:15]1[CH:16]=[CH:17][C:12]([N:8]2[CH2:9][CH2:10][CH2:11][CH:6]([NH:23][C@@H:24]3[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]3[NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])[CH2:7]2)=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1N
Reactant: CS(=O)(=O)OC1CCCN(c2ccc(-c3ncco3)cc2)C1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1NC1CCCN(c2ccc(-c3ncco3)cc2)C1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(4-(oxazol-2-yl)phenyl)piperidin-3-yl methane sulfonate (110 mg, 0.341 mmol) in acetonitrile (4 mL) was added tert-butyl (1R,2R)-2-aminocyclohexylcarbamate (110 mg, 0.512 mmol). The reaction was stirred in a microwave at 120° C. for 30 min. After this time, LC/MS showed two pairs of products formed. The reaction mixture was concentrated. The residue was diluted with EtOAc and washed with water. The remaining EtOAc organic layer was concentrated. The resulting residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 50-100% EtOAc/Hex. Under these conditions, the two diastereomers separated and the desired diastereomer tert-butyl (1R,2R)-2-((1-(4-(oxazol-2-yl)phenyl)pyrrolidin-2-yl)methylamino)cyclohexylcarbamate (156 mg total) as a white foam.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH2:8])=[O:7].Br[CH2:15][C:16]([C:18]1[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=1)=O>>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:4]=[C:5]([C:6]2[O:7][CH:15]=[C:16]([C:18]3[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=3)[N:8]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)c1ccc(C(=O)CBr)cc1
Reactant: NC(=O)c1cccc(C(F)(F)F)c1
Product: CCOC(=O)c1ccc(-c2coc(-c3cccc(C(F)(F)F)c3)n2)cc1
Yield: 22 %

Procedure:
In the same manner as in Example 1, 3-trifluoromethylbenzamide was reacted with ethyl 4-bromoacetylbenzoate to obtain ethyl 4-[2-(3-trifluoromethylphenyl)-4-oxazolyl]benzoate. The product was recrystallized from ethanol. Yield: 22%. Pale yellow prisms. Melting Point: 132 to 133° C.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:18])[CH2:9]P(OCC)(OCC)=O)([CH3:6])([CH3:5])[CH3:4].[CH2:19]([O:26][C:27]([C:29]1[S:30][C:31]([CH:34]=O)=[CH:32][CH:33]=1)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1.C(OCC)(=O)C>[CH2:19]([O:26][C:27]([C:29]1[S:30][C:31]([CH:34]=[CH:9][C:8]([O:7][C:3]([CH3:4])([CH3:5])[CH3:6])=[O:18])=[CH:32][CH:33]=1)=[O:28])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Reactant: O=Cc1ccc(C(=O)OCc2ccccc2)s1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C=Cc1ccc(C(=O)OCc2ccccc2)s1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 86.7 %

Procedure:
To a suspension of 60% sodium hydride (1.64 g, 41 mmol) in tetrahydrofuran (50 ml) was added dropwise diethylphosphonoacetic acid tert-butyl ester (12.0 g, 47.6 mmol) at 0° C. After stirring at room temperature for 20 minutes, a solution of 5-formyl-2-thiophenecarboxylic acid benzyl ester (8.75 g, 35.5 mmol) in tetrahydrofuran (10 ml) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, and washed successively with 1N hydrochloric acid and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated and the residue was purified by column chromatography (10 to 30% ethyl acetate/hexane mixed solvent) to give the title compound (10.6 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.[CH3:13][NH:14][CH3:15]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([S:8]([N:14]([CH3:15])[CH3:13])(=[O:10])=[O:9])[CH:7]=1
Reactant: Cc1ccc(F)cc1S(=O)(=O)Cl
Reactant: CNC
Solvent: C1CCOC1
Product: Cc1ccc(F)cc1S(=O)(=O)N(C)C
Reaction time: 0.08 h
Yield: 90 %

Procedure:
To a solution of 5-fluoro-2-methyl-benzenesulfonyl chloride (4.18 g, 20 mmol) in tetrahydrofuran (25 mL) was added, dropwise, a solution of dimethylamine in tetrahydrofuran (2M, 25 mL, 50 mmol) over 15 min. and the mixture stirred for 5 min. The insoluble materials were filtered and the filtrate concentrated. The residue was purified by column chromatography (SiO2, 5% ether in CH2Cl2) to provide 4.3 g (Yield 90%) of the title compound as a clear oil: 1H NMR (500 MHz, CDCl3) δ ppm: 2.57 (3H, s) 2.82 (3H, s) 2.82 (3H, s) 7.12-7.18 (1H, m) 7.28 (1H, dd, J=8.2, 5.5 Hz) 7.59 (1H, dd, J=8.2, 2.1 Hz); LC/MC m/z 218 (M+H).