Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10]1.[C:22](N1C=CN=C1)(N1C=CN=C1)=[O:23]>O1CCCC1>[O:23]=[C:22]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:11][CH2:10]2)[C:3]2[CH:4]=[N:5][CH:6]=[CH:7][C:2]=2[NH:1]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccncc1NC1CCN(Cc2ccccc2)CC1
Solvent: C1CCOC1
Product: O=c1[nH]c2ccncc2n1C1CCN(Cc2ccccc2)CC1
Yield: 91.7 %

Procedure:
A solution of 4-amino-3-[(1-benzylpiperidin-4-yl)amino)pyridine (2.8 g, 9.9 mmol) and carbonyldiimidazole (3.0 g, 18.5 mmol) in tetrahydrofuran (100 mL) was refluxed overnight. The reaction was cooled, concentrated and partitioned between chloroform (500 mL) and saturated sodium carbonate (100 mL). The organic phase was dried over magnesium sulfate and concentrated to give the title compound (2.8 g). MS 209 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:41])[C:5]([CH3:40])([CH3:39])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([N+]#[C-])(S(C1C=CC(C)=CC=1)(=O)=O)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([CH3:26])([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:2].Cl.[OH2:43]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:41])[C:5]([CH3:40])([CH3:39])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12](=[O:43])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([CH3:26])([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:2]
Reactant: [C-]#[N+]C(CCCCCCC(C)(C)C(=O)OCC)(CCCCCCC(C)(C)C(=O)OCC)S(=O)(=O)c1ccc(C)cc1
Reactant: O
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)CCCCCCC(=O)CCCCCCC(C)(C)C(=O)OCC
Temperature: 25 °C
Reaction time: 1.33 h
Yield: 40 %

Procedure:
To a solution of 208i (12.0 g, 20.3 mmol) in CH2Cl2 (200 mL) was added concd HCl (47 mL). The reaction mixture was stirred for 80 min at room temperature and diluted with water (200 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (3×70 mL). The combined organic layers were washed with saturated NaHCO3 solution (3×40 mL) and brine (50 mL), dried over anhydrous MgSO4, and concentrated in vacuo to yield the crude product (7.52 g). Purification by column chromatography (silica gel, ethyl acetate/hexanes=1/9) gave 209i (3.5 g, 40.0%) as a colorless oil. 1H NMR (CDCl3): δ (ppm): 4.14 (q, J=7.1, 4H), 2.41 (t, J=7.0, 4H), 1.66-1.45 (m, 8H), 1.35-1.20 (m, 12H), 1.25 (t, J=7.1, 6H), 1.17 (s, 12H). 13C NMR (CDCl3): δ (ppm): 211.24, 177.89, 60.01, 42.69, 42.07, 40.64, 29.86, 29.07, 25.13, 24.73, 23.74, 14.24. HRMS (LSIMS, gly): Calcd for C25H47O5 (MH+): 427.3423, found: 427.3430.
Reaction SMILES: C([NH:4][CH:5]([C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C(OCC)=O)(=O)C.[S:19](=[O:23])(=[O:22])([OH:21])[OH:20]>O>[S:19]([OH:23])([OH:22])(=[O:21])=[O:20].[CH2:5]([NH2:4])[C:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:18]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Product: NCC(=O)c1ccccc1
Reaction time: 10 h

Procedure:
24.9 g of ethyl 2-acetamido-3-oxo-3-phenylpropionate, 7.2 g of sulfuric acid (96%) and 50 ml of water are refluxed, with stirring, for 10 hours. The reaction mixture is filtered and the filtrate is concentrated on a rotary evaporator. The crystalline residue is made into a paste with 50 ml of isopropanol, the crystals are isolated by suction filtration, washed with petroleum ether (50°-70° C.) and dried.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.Br[CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:29])[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:29])[O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(NCCCBr)OCc1ccccc1
Reactant: Clc1cccc(N2CCNCC2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCCCN1CCN(c2cccc(Cl)c2)CC1)OCc1ccccc1
Temperature: 25 °C
Yield: 73.1 %

Procedure:
1-(3-Chlorophenyl)piperazine hydrochloride (5 g, 25.4 mmol), benzyl 3-bromopropylcarbamate (8.3 g, 30.5 mmol) and potassium carbonate (10.5 g, 75.9 mmol) were heated to 80° C. in dimethylformamide (100 ml) for overnight under nitrogen condition. After the reaction complete, the reaction mixture was cooled to room temperature and water was added. The organic layer was extracted with ethyl acetate, and washed with water and brine. After drying with MgSO4, the organic layer was filtered and evaporated under reduced pressure to give the title compound (7.2 g, 73%) as light yellow oil, which was used in the deprotection reaction without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[CH:17]([F:19])[F:18])[N:5]=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[N:3]=1.[C:26]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)(=[O:28])[CH3:27].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[C:26]([N:29]1[CH2:34][CH2:33][N:32]([C:2]2[N:3]=[C:4]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:5]=[C:6]([N:8]3[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=4[N:10]=[C:9]3[CH:17]([F:18])[F:19])[N:7]=2)[CH2:31][CH2:30]1)(=[O:28])[CH3:27]
Reactant: CC(=O)N1CCNCC1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)nc(N2CCOCC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4ccccc43)n2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
A mixture of 6-chloro-2-(2-difluoromethylbenzimidazol-1-yl)-4-morpholino-1,3,5-triazine (3.66 g, 10 mmol), 1-acetylpiperazine (1.40 g, 11 mmol), potassium carbonate (1.38 g, 10 mmol) and DMF (30 ml) was stirred at room temperature for 16 hours. The reaction mixture was poured into water, and extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, concentrated under vacuum, and the residue was purified by silica gel column to obtain 4-(4-acetylpiperazin-1-yl)-2-(2-difluoromethylbenzimidazol-1-yl)-6-morpholino-1,3,5-triazine (4.08 g, 9.0 mmol) in a yield of 90% as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[NH2:12][C@H:13]([C:15]1[N:16]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:17](=[O:26])[C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:25])[CH3:14].CCN(C(C)C)C(C)C>C1COCC1.C(Cl)Cl>[Cl:25][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:18]=1[C:17](=[O:26])[N:16]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:15]([C@@H:13]([NH:12][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=1)[CH3:14])=[CH:24]2
Reactant: C[C@H](N)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C[C@H](Nc1nc(Cl)ncc1[N+](=O)[O-])c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Temperature: -78 °C
Reaction time: 0.58 h

Procedure:
A solution of 2,4-dichloro-5-nitropyrimidine (250 mg, 1.29 mmol, 1.15 eq.) in THF (2 mL) was chilled in a −78° C. bath. To this solution was slowly added over 40 mins a mixture of compound 1 (335 mg, 1.12 mmol, 1.0 eq.) and DIEA (450 μL, 2.58 mmol, 2.3 eq.) in THF (4 mL). After addition was complete, the reaction was stirred at −78° C. during 30-40 mins, then allowed to warm slowly to 15° C. over 1 h. The reaction mixture was diluted with DCM (40 mL), washed with water and brine (15 mL each), dried over Na2SO4, and concentrated. This residue was purified by flash chromatography eluting with 300 mL each 10/20/30/40% EtOAc/hexanes to give (S)-8-chloro-3-(1-(2-chloro-5-nitropyrimidin-4-ylamino)ethyl)-2-phenylisoquinolin-1(2H)-one 75. ESI-MS m/z: 456.15 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=3)[C:11](=[O:19])[C:10]([CH3:21])([CH3:20])[CH2:9]2)=[CH:4][CH:3]=1.[CH2:22]([CH:24]1[O:26][CH2:25]1)Cl.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:22][CH:24]4[O:26][CH2:25]4)=[CH:15][CH:16]=3)[C:11](=[O:19])[C:10]([CH3:21])([CH3:20])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC1(C)CC(c2ccc(Cl)cc2)c2ccc(O)cc2C1=O
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1(C)CC(c2ccc(Cl)cc2)c2ccc(OCC3CO3)cc2C1=O
Yield: 93 %

Procedure:
A mixture of 4(4-chlorophenyl)-7-hydroxy-2,2-dimethyl-1-tetralone (17.6 g), epichlorohydrin (30 ml) and potassium carbonate (6.0 g) was heated under reflux in acetone (30 ml) for 24 hr. The hot mixture was filtered and evaporation of the filtrate in vacuo gave 4-(4-chlorphenyl)-7-(2,3-epoxypropoxy)-2,2-dimethyl-1-tetralone as a light yellow gum (8.4 g, 93%).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH3:13])[C:11]=1[OH:12])[C:6]([OH:8])=[O:7])[CH3:2].CN(C=O)C.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O>[CH2:19]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[C:10]([CH3:13])[C:11]([OH:12])=[C:3]([CH2:1][CH3:2])[CH:4]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: CCc1cc(C(=O)O)cc(C)c1O
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cc(C(=O)OCc2ccccc2)cc(C)c1O
Temperature: 50 °C
Reaction time: 18 h
Yield: 90 %

Procedure:
To a solution of 3-ethyl-4-hydroxy-5-methyl-benzoic acid (80.3 g, 0.446 mol) is DMF (500 mL), KHCO3 (53.5 g, 0.535 mol) followed by benzylbromide (114.3 g, 0.668 mol) is added. The mixture is stirred at 50° C. for 18 h before it is cooled to rt, diluted with water (250 mL), and extracted with TBME (2×250 mL). The org. extracts are washed with water, and then concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 19:1 to 9:1 to give 3-ethyl-4-hydroxy-5-methyl-benzoic acid benzyl ester (108.5 g) as a beige solid; 1H NMR (CDCl3): δ1.28 (t, J=7.5 Hz, 3H), 2.30 (s, 3H), 2.68 (q, J=7.8 Hz, 2H), 5.24 (s, 1H), 5.37 (s, 2H), 7.33-7.45 (m, 3H), 7.45-7.50 (m, 2H), 7.77 (s, 1H), 7.79 (s, 1H).
Reaction SMILES: C1C[N:4]([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)[CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.[CH3:44][N:45]([CH3:61])[CH:46]1[CH2:50][CH2:49][N:48]([C:51]2[CH:60]=[CH:59][C:54]([C:55]([NH:57][OH:58])=[NH:56])=[CH:53][CH:52]=2)[CH2:47]1.C(OC(NCC(O)=O)=O)(C)(C)C>O.C(OCC)(=O)C.CN(C=O)C.C(N(CC)CC)C>[NH2:4][CH2:3][C:2]1[O:58][N:57]=[C:55]([C:54]2[CH:59]=[CH:60][C:51]([N:48]3[CH2:49][CH2:50][CH:46]([N:45]([CH3:61])[CH3:44])[CH2:47]3)=[CH:52][CH:53]=2)[N:56]=1
Reactant: CN(C)C1CCN(c2ccc(C(=N)NO)cc2)C1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)NCC(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CN(C)C1CCN(c2ccc(-c3noc(CN)n3)cc2)C1
Reaction time: 0.17 h

Procedure:
PyBOP (546.4 mg), HOAt (136.1 mg) and triethylamine (0.279 ml) were added to a mixture of 4-(3-dimethylaminopyrrolidin-1-yl)-N-hydroxybenzamidine (248.3 mg), tert-butoxycarbonylaminoacetic acid (175.2 mg) and DMF (2.8 ml) at 0° C. and the mixture was stirred at this temperature for 10 min. It was subsequently stirred at room temperature for 2 h and then ethyl acetate and water were added to the reaction solution. The organic phase then washed twice each with 10% strength citric acid solution, saturated sodium bicarbonate solution and water, dried over sodium sulfate and filtered, and the solvent removed in vacuo. The residue was then taken up in 6.2 ml of THF, and EDC (105 mg) and triethylamine (0.09 ml) were added, and the mixture was stirred at 50° C. for 16 h. Ethyl acetate and water were then added to the reaction solution. The organic phase then washed twice each with 10% strength citric acid solution, saturated sodium bicarbonate solution and water and dried over sodium sulfate, and the solvent removed in vacuo. The crude product was taken up in methylene chloride (9.6 ml), and trifluoroacetic acid (2.3 ml) was added. The reaction was stirred at room temperature for 5 h and then the solvent was removed in vacuo. The residue was purified by preparative HPLC. The product with the molecular weight of 287.37 (C15H21N50) was obtained in this way; MS (ESI): 288.05 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[CH2:5][O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]2[C@H:13]3[C@H:23]([CH2:24][CH2:25][C@:8]12[CH3:9])[C@:21]1([CH3:22])[C:16]([N:17](C(=O)C2C=CC=CC=2)[C:18](=[O:26])[CH2:19][CH2:20]1)=[CH:15][CH2:14]3)[CH3:2].O.NN>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:35])[CH2:5][O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]2[C@H:13]3[C@H:23]([CH2:24][CH2:25][C@:8]12[CH3:9])[C@:21]1([CH3:22])[C:16]([NH:17][C:18](=[O:26])[CH2:19][CH2:20]1)=[CH:15][CH2:14]3)[CH3:2]
Reactant: CCOC(=O)CO[C@H]1CC[C@H]2[C@@H]3CC=C4N(C(=O)c5ccccc5)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: NN
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)CO[C@H]1CC[C@H]2[C@@H]3CC=C4NC(=O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
To the product of Step C, above, (90 mg) in CH2Cl2 (2.0 ml) was added hydrazine hydrate (0.2 ml). The mixture was shaken for a few minutes and purified via preparative TLC using two silica gel plates (1500μ) developed with EtOAc to give the title product (Rf =0.54).
Reaction SMILES: C([O:3][C:4](=[O:18])[C:5]([CH3:17])([S:7]([CH2:10][CH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)(=[O:9])=[O:8])[CH3:6])C.O.[OH-].[Li+]>C([O-])(O)=O.[Na+].[Cl-].[Na+].O>[CH3:17][C:5]([S:7]([CH2:10][CH:11]1[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1)(=[O:9])=[O:8])([CH3:6])[C:4]([OH:18])=[O:3]
Reactant: CCOC(=O)C(C)(C)S(=O)(=O)CC1CCOCC1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Product: CC(C)(C(=O)O)S(=O)(=O)CC1CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 105.9 %

Procedure:
To a solution of 769 mg (2.77 mmol) of 2-methyl-2-(tetrahydro-pyran-4-ylmethanesulfonyl)-propionic acid ethyl ester in THF/water (1/1, 10 mL) were added 228 mg (5.43 mmol) of lithium hydroxide monohydrate. The reaction was stirred at room temperature for 18 h. The reaction was concentrated under reduced pressure. The residue was dissolved in water (10 mL) and washed with diethyl ether (2×25 mL). The aqueous layer was cooled in an ice bath and then acidified with 1M aqueous HCl solution to pH 2. The acidic aqueous layer was extracted with ethyl acetate (2×50 mL) and with isopropanol/chloroform (3×50 mL). The combined organic extracts were dried over Na2SO4 and filtered. Concentration of the filtrate under reduced pressure afforded 734 mg of 2-methyl-2-(tetrahydro-pyran-4-ylmethanesulfonyl)-propionic acid.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].Cl[C:7]([CH3:11])([CH3:10])[C:8]#[CH:9].C(N(CC)CC)C>[Cu]Cl.C1COCC1>[CH2:1]([N:3]([CH2:4][CH3:5])[C:7]([CH3:11])([C:8]#[CH:9])[CH3:10])[CH3:2]
Reactant: CCNCC
Reactant: C#CC(C)(C)Cl
Agent: Cl[Cu]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C#CC(C)(C)N(CC)CC
Temperature: 25 °C
Reaction time: 4 h
Yield: 13.3 %

Procedure:
Prepared using methodology described by Zaragoza, F., et al. J. Med. Chem. 2004, 47, 2833. To a stirred mixture of diethylamine (10.3 mL, 99.6 mmol), 3-chloro-3-methylbut-1-yne (10.2 g, 99.6 mmol), triethylamine (16.7 mL, 119 mmol), and THF (100 mL) at 0° C. was added copper(I) chloride (0.986 g, 9.96 mmol). The resulting suspension was allowed to warm to room temperature, and stirring continued for 4 hours. The reaction mixture was partitioned between diethyl ether (250 mL) and a saturated aqueous solution of NaHCO3 (100 mL). The phases were separated, and the aqueous phase was re-extracted with diethyl ether (100 mL). The combined organic phases were dried (Na2SO4), filtered, and concentrated. The brown oil was distilled (105-110° C.) at atmospheric pressure under N2. The product was obtained as an oil (1.85 g, 9%). 1H NMR (400 MHz, CDCl3) δ 2.66 (q, J=7 Hz, 4H), 2.21 (s, 1H), 1.40 (s, 6H), 1.08 (t, J=7 Hz, 6H).
Reaction SMILES: [CH:1](=[CH:7][C:8](=O)C)[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[CH3:11]C(C)=O>>[CH3:11][C:5]1[O:6][C:2](=[C:1]=[CH:7][CH3:8])[CH2:3][CH:4]=1
Reactant: CC(C)=O
Reactant: CC(=O)C=Cc1ccco1
Product: CC=C=C1CC=C(C)O1

Procedure:
furfurylidene acetone, 5-methyl-2-furfurylidene, acetone,
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([NH:9][C:10]([C:13]2[N:19]([CH3:20])[C:17](=[O:18])[C:16]([OH:21])=[C:15]([C:22]([NH:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[O:23])[N:14]=2)([CH3:12])[CH3:11])=[O:8])=[N:4][N:3]=1.[OH-].[K+:34]>C1CCCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]([NH:9][C:10]([C:13]2[N:19]([CH3:20])[C:17](=[O:18])[C:16]([O-:21])=[C:15]([C:22]([NH:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[O:23])[N:14]=2)([CH3:12])[CH3:11])=[O:8])=[N:4][N:3]=1.[K+:34]
Reactant: Cc1nnc(C(=O)NC(C)(C)c2nc(C(=O)NCc3ccc(F)cc3)c(O)c(=O)n2C)o1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCCCC1
Product: Cc1nnc(C(=O)NC(C)(C)c2nc(C(=O)NCc3ccc(F)cc3)c([O-])c(=O)n2C)o1
Temperature: 25 °C
Reaction time: 25 h

Procedure:
A vial (20 ml) was charged with Raltegravir free hydroxy (500 mg) and cyclohexane (2.5 ml) at room temperature. A solution of 30% aqueous KOH (0.162 ml) was added. An additional amount of cyclohexane (5 ml) was added. The mixture was stirred for 25 h at room temperature. A gel solid precipitated and was removed Form the mixture using a spatula and was then filtered under reduced pressure to produce wet Raltegravir potassium crystalline Form V. The product was dried overnight in a vacuum oven at 40° C. to provide raltegravir potassium crystalline Form V.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH2:13][CH2:14][CH3:15])=[O:12])=[CH:7][C:6]=1[N+:16]([O-:18])=[O:17])(=O)C.[OH-].[Na+].CO>O>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH2:13][CH2:14][CH3:15])=[O:12])=[CH:7][C:6]=1[N+:16]([O-:18])=[O:17]
Reactant: CCCS(=O)c1ccc(NC(C)=O)c([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCS(=O)c1ccc(N)c([N+](=O)[O-])c1

Procedure:
1.5 G. of 1-acetamido-2-nitro-4-n-propylsulfinylbenzene is treated with 3 ml. of 5N sodium hydroxide solution and sufficient methanol to effect solution. After heating on a steam bath for 15 minutes, the mixture is diluted with water, cooled and filtered, yielding 1-amino-2-nitro-4-n-propylsulfinylbenzene.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([C:9](=[CH2:15])[CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:8])[CH:2]=1.[SH:16][CH2:17][CH2:18][NH:19][C:20](=[O:22])[CH3:21]>>[C:20]([NH:19][CH2:18][CH2:17][S:16][CH2:15][CH:9]([C:7](=[O:8])[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH2:10][C:11]([O:13][CH3:14])=[O:12])(=[O:22])[CH3:21]
Reactant: C=C(CC(=O)OC)C(=O)c1cccnc1
Reactant: CC(=O)NCCS
Product: COC(=O)CC(CSCCNC(C)=O)C(=O)c1cccnc1

Procedure:
The title compound was prepared from methyl 3-(3-pyridylcarbonyl)but-3-enoate and N-(2-sulfanylethyl)acetamide as described in Example 13 in quantitative yield, ESMS, (M+1)+325.
Reaction SMILES: O[N:2]1C(=O)C2=CC=CC=C2C1=O.[OH:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>ClCCl.C1(C)C=CC=CC=1>[NH2:2][O:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(NCCCCO)OCc1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: NOCCCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 84.3 %

Procedure:
A solution of N-hydroxyphthalimide (3.36 g), benzyl (4-hydroxybutyl)carbamate (4.18 g) and triphenylphosphine (7.41 g) in dichloromethane (100 mL) was chilled in an ice bath and approximately two-thirds of a solution of diisopropylazodicarboxylate (DIAD, 5.68 g) in dichloromethane (50 mL) was slowly added with stirring. The internal temperature of the reaction was monitored and the addition of the DIAD solution was stopped when an exotherm could no longer be detected. The ice bath was removed and the reaction was allowed to warm to room temperature. The reaction was concentrated under reduced pressure and the resulting residue was dissolved in ethanol (200 proof, 100 mL). Hydrazine (1.98 g, 35% in water) was added and the reaction was stirred for 6 hours. The reaction was cooled in the freezer and the resulting solid was removed by filtration. The solid was washed with ethanol (50 mL). The combined filtrate was concentrated under reduced pressure and diethyl ether (100 mL) was added. Insoluble impurities were removed by filtration and 2.0 M HCl in ether (10 mL) was added to the solution. A precipitate formed immediately. The crude product was added to toluene (100 mL) and heated at reflux temperature for one hour. After cooling to room temperature, the solid product was recovered by filtration, washed with toluene, and dried under vacuum to yield 3.76 g of benzyl (4-aminooxybutyl)carbamate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]2[CH:11]=[C:12]([NH2:16])[CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:4]=1.[CH3:27][O:28][C:29]1[C:30](=O)[C:31](=[O:35])[C:32]=1[O:33]C>CO>[CH3:27][O:28][C:29]1[C:32](=[O:33])[C:31](=[O:35])[C:30]=1[NH:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([CH:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[NH:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:11]=1
Reactant: COc1ccc(C(NCCCc2ccccc2)c2cccc(N)c2)cc1
Reactant: COc1c(OC)c(=O)c1=O
Solvent: CO
Product: COc1ccc(C(NCCCc2ccccc2)c2cccc(Nc3c(OC)c(=O)c3=O)c2)cc1

Procedure:
In a similar manner to that described in Example (1c), a solution of 3-[(4-methoxyphenyl)-(3-phenylpropylamino)methyl]phenylamine (2.02 g) [prepared as described in step (b) above] in methanol (40 ml) and 3,4-dimethoxy-3-cyclobutene-1,2-dione were reacted, to afford the title compound (1.82 g) as yellow foamy solid.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][CH2:11][OH:12])=[CH:5][CH:4]=1.N1C=CC=CC=1.Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)=[O:23]>C(Cl)Cl>[F:14][C:2]([F:13])([F:1])[C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][CH2:11][O:12][C:22](=[O:23])[O:24][C:25]2[CH:26]=[CH:27][C:28]([N+:31]([O-:33])=[O:32])=[CH:29][CH:30]=2)=[CH:5][CH:4]=1
Reactant: OCCSc1ccc(C(F)(F)F)cc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(OCCSc1ccc(C(F)(F)F)cc1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 86.2 %

Procedure:
2-(4-Trifluoromethyl-phenylsulfanyl)ethanol (15.00 g, 67.50 mmol) prepared in the above Step (1) was dissolved in anhydrous DCM (100 ml), pyridine (7.59 ml, 93.81 mmol) and 4-nitrophenyl chloroformate (13.61 g, 67.50 mmol) were added thereto at 0° C. in order, and the mixture was stirred for 2 hours at room temperature. The reaction was stopped by adding distilled water, and the reaction mixture was extracted with DCM. The organic layer thus extracted was washed with aqueous NH4Cl solution, dried over anhydrous MgSO4, and then concentrated. The concentrate was purified by silica gel column chromatography (DCM/n-hexane=5/1, v/v) to give carbonic acid 4-nitro-phenyl ester 2-(4-trifluoromethyl-phenylsulfanyl)-ethyl ester (22.54 g, 86.21%) of a pale yellow oil.