Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:11]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][N:13]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[N:12]=1.C(O)C.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N+:16]([C:15]1[C:11]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:12][N:13]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:14]=1)([O-:18])=[O:17]
Reactant: OB(O)c1ccccc1
Reactant: O=[N+]([O-])c1cn(-c2cccnc2)nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=[N+]([O-])c1cn(-c2cccnc2)nc1-c1ccccc1
Temperature: 110 °C
Yield: 125.6 %

Procedure:
To a suspension of phenylboronic acid (0.546 g, 4.47 mmol) in toluene (6.63 ml) was added 3-(3-chloro-4-nitro-1H-pyrazol-1-yl)pyridine (0.335 g, 1.492 mmol) followed by ethanol (3.31 ml) and 2 M aqueous potassium carbonate (1.492 ml, 2.98 mmol). The solution was degassed by applying vacuum and then purging with nitrogen (3 times). To the reaction mixture was added palladium tetrakis (0.086 g, 0.075 mmol) and the flask was heated at 110° C. under nitrogen for 16 hours. The aqueous layer was removed and the organic layer was concentrated. The crude product was purified via silica gel chromatography (0-100% ethyl acetate/hexanes) to give 3-(4-nitro-3-phenyl-1H-pyrazol-1-yl)pyridine (499 mg, 1.874 mmol, 80%) as a yellow solid: mp 144.0-146.0° C.; 1H NMR (400 MHz, CDCl3) δ 9.09 (d, J=2.3 Hz, 1H), 8.82 (s, 1H), 8.71 (dd, J=4.8, 1.4 Hz, 1H), 8.16 (ddd, J=8.3, 2.7, 1.5 Hz, 1H), 7.82-7.74 (m, 2H), 7.55-7.48 (m, 4H); EIMS m/z 266.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:12][CH2:13][NH2:14])=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[CH2:15]([O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=O)[CH2:16][CH3:17].[BH4-].[Na+].[CH3:29]N1CCCC1=O>ClCCl.C(O)(=O)C.CO>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:12][CH2:13][N:14]([CH2:22][C:21]3[CH:24]=[CH:25][CH:26]=[C:19]([O:18][CH2:15][CH2:16][CH3:17])[CH:20]=3)[CH3:29])=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: Cn1cc(CCN)c2ccc(F)cc21
Reactant: CCCOc1cccc(C=O)c1
Reactant: CN1CCCC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: CCCOc1cccc(CN(C)CCc2cn(C)c3cc(F)ccc23)c1
Reaction time: 8 h

Procedure:
Combine N-methyl-N-(2-(6-fluoro-1-methyl-1H-indol-3-yl)ethylamine (0.2 mmol) in 1-methyl-2-pyrrolidinone (0.5 mL) and 3-propyloxybenzaldehyde (0.32 mmol) in dichloromethane (1 mL) and rotate. After overnight rotation, add sodium borohydride (1.0 mmol) as a stock solution in 1-methyl-2-pyrrolidinone (0.5 mL) and rotate. After rotation for 3 h, dilute the reaction mixture with 1 mL of 10% acetic acid/methanol, and directly apply the resulting solution to a 2 g SCX column. After thoroughly washing with methanol, elute the column with 2 M ammonia-methanol and concentrate the eluent to a residue, which was further purified by Gilson UV prep system.
Reaction SMILES: [NH2:1][C:2]1[C:10]([NH2:11])=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.[N:12]1[CH:17]=[CH:16][C:15]([CH:18]=O)=[CH:14][CH:13]=1.Cl.C>>[N:12]1[CH:17]=[CH:16][C:15]([C:18]2[NH:1][C:2]3[CH:3]=[C:4]4[N:8]=[CH:7][NH:6][C:5]4=[CH:9][C:10]=3[N:11]=2)=[CH:14][CH:13]=1
Reactant: Nc1cc2nc[nH]c2cc1N
Reactant: O=Cc1ccncc1
Agent: Cl
Product: c1cc(-c2nc3cc4[nH]cnc4cc3[nH]2)ccn1

Procedure:
14.8 g. (100 mMole) 5,6-diaminobenzimidazole, 10.7 g. (100 mMole) pyridine-4-aldehyde and 5 ml. concentrated hydrochloric acid are heated to the boil under reflux. After the solution has been clarified with active charcoal, it is evaporated and the residue is digested with a little water. After suction filtration and drying, there are obtained 6.98 g. (29% of theory) of the desired product in the form of colourless crystals of the hydrochloride; m.p.>280° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH:17]1[CH2:22][CH2:21][S:20](=[O:24])(=[O:23])[CH2:19][CH2:18]1>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:17]2[CH2:22][CH2:21][S:20](=[O:24])(=[O:23])[CH2:19][CH2:18]2)=[CH:4][CH:3]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: O=S1(=O)CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S1(=O)CCN(Cc2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
A mixture of 4-bromobenzyl bromide (1.0 g, 4.0 mmol), triethylamine (0.84 mL, 6.0 mmol) and thiomorpholine 1,1-dioxide (1.09 g, 8.0 mmol) in THF (10 mL) was stirred at ambient temperature for 16 h. The solvent was evaporated and the resultant residue diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (2×50 mL). The combined organic layer was dried over sodium sulfate, filtered and evaporated to afford the title compound (0.90 g, 74%). 1H NMR (CDCl3, 300 MHz): 7.50-7.44 (m, 2H), 7.22-7.16 (m, 2H), 3.60 (s, 2H), 3.09-3.02 (m, 4H), 3.00-2.94 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13].ClC1C=CC(O[CH2:22][C:23]#[N:24])=CC=1.CC([O-])(C)C.[K+].Cl>CN(C=O)C>[CH3:1][O:2][C:3]1[C:4]([C:12]([F:13])([F:14])[F:15])=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[C:7]([CH2:22][C:23]#[N:24])[CH:8]=1
Reactant: COc1ccc([N+](=O)[O-])cc1C(F)(F)F
Reactant: N#CCOc1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(CC#N)c([N+](=O)[O-])cc1C(F)(F)F
Temperature: 0 °C
Yield: 77.7 %

Procedure:
A mixture of 1-methoxy-4-nitro 2-trifluoromethylbenzene (D8) (93 g, 0.421 mol) and 4-chlorophenoxyacetonitrile (77.55 g, 0.463 mol) in dry DMF (500 ml) was added dropwise over 0.75 h to a stirred solution of KOtBu (103.85 g, 0.927 mol) in dry DMF (400 ml) at −10° C. After complete addition the resulting purple solution was maintained, at −10 C. for 1 h then poured into a mixture of ice/water (1.51) and 5 M aqueous HCl (1.5 l). The resulting mixture was extracted with dichloromethane (3×1 l). The combined extracts were washed with water (3 l), dried (Na2SO4) and evaporated under reduced pressure. The residue was chromatographed on silica using 10-40% ethyl acetate/petroleum ether as eluant to give the crude product which was recrystallised from ethyl acetatelpetroleum ether to afford the title compound (85.13 g, 78%) as a white solid. Mp 103-104° C.
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:26][C:27]4[CH:28]=[N:29][C:30]([O:34][CH3:35])=[C:31]([F:33])[CH:32]=4)=[N:18][CH:19]=[C:20]([CH:25]=3)[C:21]([O:23][CH3:24])=[O:22])[N:10]=2)=CC=1.OS(C(F)(F)F)(=O)=O.C(=O)(O)[O-].[Na+].C(Cl)Cl>C(O)(C(F)(F)F)=O>[NH2:8][C:9]1[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]2[C:17]([NH:26][C:27]3[CH:28]=[N:29][C:30]([O:34][CH3:35])=[C:31]([F:33])[CH:32]=3)=[N:18][CH:19]=[C:20]([CH:25]=2)[C:21]([O:23][CH3:24])=[O:22])[N:10]=1
Reactant: COC(=O)c1cnc(Nc2cnc(OC)c(F)c2)c(-c2nc(C)nc(N(Cc3ccc(OC)cc3)Cc3ccc(OC)cc3)n2)c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cnc(Nc2cnc(OC)c(F)c2)c(-c2nc(C)nc(N)n2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.3 %

Procedure:
A solution of methyl 5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)nicotinate (0.965 g, 1.542 mmol) and triflic acid (0.685 mL, 7.71 mmol), in 6 mL TFA was heated in a flask fitted with a reflux condenser and drying tube at 80° C. for 30 min. The dark red reaction was cooled and triflic acid (0.685 mL, 7.71 mmol) was added, and the reaction was reheated to 80° C. After 30 min, the reaction was judged complete. The reaction was cooled to 0° C., and ice was added, along with solid sodium bicarbonate, in portions, with rapid stirring. DCM was added. Upon complete quenching of acid, the thick mixture was extracted with 3×10% iPrOH/DCM, 2×10% iPrOH/EtOAc (EtOAc layers were washed 1×brine). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. The solid was suspended in diethyl ether, sonicated, and filtered, rinsing with 3× diethyl ether to give methyl 5-(4-amino-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)nicotinate (0.400 g, 1.038 mmol, 67.3% yield) as an orange solid. m/z (ESI, +ve ion) 386 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 12.37 (s, 1H), 9.26 (d, J=2.3 Hz, 1H), 8.83 (d, J=2.3 Hz, 1H), 8.41 (d, J=2.3 Hz, 1H), 8.31 (dd, J=12.4, 2.2 Hz, 1H), 8.01 (br. s., 1H), 7.84 (br. s., 1H), 3.95 (s, 3H), 3.88 (s, 3H), 2.46 (s, 3H).
Reaction SMILES: [CH3:1][C@@:2]12[C:8]([CH3:10])([CH3:9])[C@@H:5]([CH2:6][CH2:7]1)[C:4](=O)[C:3]2=O.COP([CH2:19][C:20]([C:22]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]([F:30])=[CH:24][C:23]=1[Cl:31])=O)(=O)OC.O.[NH2:33][NH2:34]>>[Cl:31][C:23]1[CH:24]=[C:25]([F:30])[C:26]([O:28][CH3:29])=[CH:27][C:22]=1[C:20]1[CH:19]=[C:4]2[C:3]([C@:2]3([CH3:1])[C:8]([CH3:10])([CH3:9])[C@H:5]2[CH2:6][CH2:7]3)=[N:34][N:33]=1
Reactant: CC1(C)[C@H]2CC[C@]1(C)C(=O)C2=O
Reactant: COc1cc(C(=O)CP(=O)(OC)OC)c(Cl)cc1F
Reactant: NN
Solvent: O
Product: COc1cc(-c2cc3c(nn2)[C@@]2(C)CC[C@@H]3C2(C)C)c(Cl)cc1F

Procedure:
yellow solid. MS (EI): 347.1 (M+). Prepared from (1S,4R)-1,7,7-trimethyl-bicyclo[2.2.1]heptane-2,3-dione, [2-(2-Chloro-4-fluoro-5-methoxy-phenyl)-2-oxo-ethyl]-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: C([Li])CCC.[CH:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1Br)([CH3:8])[CH3:7].[CH2:16]([N:18]([CH2:22][CH3:23])[C:19](Cl)=[O:20])[CH3:17].O>CCOCC>[CH:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:19]([N:18]([CH2:22][CH3:23])[CH2:16][CH3:17])=[O:20])([CH3:8])[CH3:7]
Reactant: CCN(CC)C(=O)Cl
Reactant: CC(C)c1ccccc1Br
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: CCN(CC)C(=O)c1ccccc1C(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 80 %

Procedure:
n-Butyllithium (2.5M, 100 mL) was added with stirring under nitrogen at 0°-5° C. during ten minutes to a solution of 2-isopropylbromobenzene in anhydrous ether (500 mL). The mixture was allowed to warm to room temperature, stirred at room temperature for six hours, and cooled to -60° C. A solution of diethylcarbamyl chloride (34 g) in anhydrous ether (50 mL) was added during 20 minutes while maintaining the temperature below -50° C. The temperature was allowed to rise to room temperature during one hour. Water (100 mL) was added. The ether layer was washed with saturated aqueous sodium chloride (200 mL), dried over magnesium sulfate and stripped of ether. Distillation of the residue (80°-90° C./0.1 mm Hg) gave 2-isopropyl-N,N-diethylbenzamide (44 g, 80% yield).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH3:28])([CH3:27])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:16][C:15]=2[O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].[O:39]1CCCC1>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:39])[CH:10]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH3:27])([CH3:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:16][C:15]=2[O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCC(C)(C)c1ccc(C2=CCCN(Cc3ccccc3)C2)c(OCc2ccccc2)c1
Reactant: C1CCOC1
Agent: [BH4-]
Agent: [Na+]
Product: CCCCCCC(C)(C)c1ccc(C2CN(Cc3ccccc3)CCC2O)c(OCc2ccccc2)c1
Reaction time: 2 h

Procedure:
To a mixture of 39.9 g. (80 mmols.) of 1-benzyl-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-1,2,5,6-tetrahydropyridine and 4.8 g. (115 mmols.) of sodium borohydride in 50 ml. of tetrahydrofuran is added 21.6 ml. (180 mmols.) of borontrifluoride etherate complex in 40 ml. of tetrahydrofuran during a 2 hour period at 0°-5° C. Stirring is continued 2 hours longer at 25° C. The reaction mixture is cooled in ice and quenched with 6.5 ml. of water and then 20 ml. of 2 N sodium hydroxide and 20 ml. of 30% hydrogen peroxide are added dropwise. After several minutes stirring the reaction is cooled and 20 ml. of concentrated hydrochloric acid is added dropwise. The reaction mixture is partially evaporated and then made basic with 6 N sodium hydroxide. The concentrated mixture is extracted with 250 ml. of ether, the ether extract washed with 100 ml. of saturated sodium chloride, dried over magnesium sulfate and evaporated. The residue is purified via column chromatography on 400 g. of silica gel eluted with 50% ether-cyclohexane to yield the title compound.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[F:43][C:44]1[C:52]2[C:51]([NH2:53])=[CH:50][C:49]([C:54]3[CH:62]=[CH:61][CH:60]=[C:59]4[C:55]=3[CH:56]=[CH:57][NH:58]4)=[CH:48][C:47]=2[NH:46][N:45]=1>CN(C=O)C.C(Cl)(Cl)Cl>[F:43][C:44]1[C:52]2[C:47](=[CH:48][C:49]([C:54]3[CH:62]=[CH:61][CH:60]=[C:59]4[C:55]=3[CH:56]=[CH:57][NH:58]4)=[CH:50][C:51]=2[NH:53][C:7]([C:5]2[N:6]=[C:2]([CH3:1])[S:3][CH:4]=2)=[O:9])[NH:46][N:45]=1
Reactant: Cc1nc(C(=O)O)cs1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]nc(F)c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: Cc1nc(C(=O)Nc2cc(-c3cccc4[nH]ccc34)cc3[nH]nc(F)c23)cs1
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 10.7 %

Procedure:
To 2-methyl-1,3-thiazole-4-carboxylic acid (24 mg) in DMF (0.375 ml) was added HATU (69 mg) followed by DIPEA (0.043 ml), and the solution stirred for 10 min at 20° C. To this was then added a solution of 3-fluoro-6-(1H-indol-4-yl)-1H-indazol-4-amine (67 mg) in DMF (0.375 ml) and the top was placed on the vial which had been pierced with a needle. The solution was stirred at 20° C. for 73 h, heated at 50° C. for 3 h, then left to stand for 3.5 days. A further portion of 2-methyl-1,3-thiazole-4-carboxylic acid (0.024 g) in DMF (0.375 ml) was treated with HATU (0.069 g) followed by DIPEA (0.043 ml). This solution was stirred for 15 min at 20° C. then added to the original reaction mixture. This was then stirred at 20° C. for a further 72 h then loaded onto a dried aminopropyl SPE cartridge (1 g) which had been preconditioned with chloroform. The material was left on the cartridge for 2 h, then the cartridge was eluted with methanol (3 column volumes) and the solvent blown off. This was purified directly by mass directed preparative HPLC (Method A). The residue was azeotroped with methanol (5 ml) to give the title compound (7 mg) as a beige solid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].Cl[C:25](Cl)([O:27][C:28](=[O:34])OC(Cl)(Cl)Cl)Cl.[CH:36]1(CO)[CH2:39][CH2:38][CH2:37]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:28](=[O:34])[O:27][CH2:25][CH:36]1[CH2:39][CH2:38][CH2:37]1
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Reactant: OCC1CCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OCC4CCC4)c(Cl)c3)c2cc1OC
Yield: 68.8 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, cyclobutylmethanol (20 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (46 mg, yield 59%).
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]>CCO.O>[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: O
Solvent: CCO
Product: Cc1nnc(C(=O)NC(C)(C)c2nc(C(=O)NCc3ccc(F)cc3)c([O-])c(=O)n2C)o1
Temperature: 50 °C
Reaction time: 5.5 h

Procedure:
A vial (20 ml) was charged with Raltegravir free hydroxy (200 mg) slurry in EtOH:H2O (1000:1, 0.2 ml) at room temperature. The slurry was heated to 50° C. A solution of 45% aqueous KOH (0.044 ml) was added at 50° C. to the mixture. The resulting mixture was stirred for 5.5 h at 50° C. To this mixture was added distilled H2O (1.5 ml) dropwise to produce a colorless solution. The solvent was then removed under reduced pressure to provide wet Raltegravir potassium crystalline Form VI. The product was dried in a vacuum oven at 40° C. for 3.5 hours to provide Raltegravir potassium crystalline Form VI.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].[CH2:17]([N:24]1[CH2:30][CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O>[CH2:17]([N:24]1[CH2:30][CH2:29][CH2:28][N:27]([C:6]2[CH:5]=[CH:4][C:3]([N+:8]([O-:10])=[O:9])=[CH:2][CH:7]=2)[CH2:26][CH2:25]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: c1ccc(CN2CCCNCC2)cc1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CCCN(Cc3ccccc3)CC2)cc1
Temperature: 90 °C

Procedure:
Fluoronitrobenzene (3.09 g, 21.9 mmol) is dissolved in water (14 ml), and then potassium carbonate (3.64 g, 26.28 mmol) and 1-benzylhomopiperazine (5 g, 26.28 mmol) are added. The medium is heated at 90° C. for 4 h 20 min and then cooled to room temperature. The precipitate formed is filtered, and a yellow solid is obtained. 6.30 g (92.5%) of product are recovered.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([S:18]([NH:21][C:22](=[O:61])[C:23]4[CH:28]=[CH:27][C:26]([N:29]5[CH2:34][CH2:33][N:32]([CH2:35][C:36]6[CH2:41][CH2:40][C:39]([CH3:43])([CH3:42])[CH2:38][C:37]=6[C:44]6[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][CH:45]=6)[CH2:31][CH2:30]5)=[CH:25][C:24]=4[O:51][C:52]4[CH:53]=[C:54]5[CH:60]=[CH:59][NH:58][C:55]5=[N:56][CH:57]=4)(=[O:20])=[O:19])=[CH:14][C:13]=3[N+:62]([O-:64])=[O:63])[CH2:7][CH2:6]2)[O:4]CC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O.O.ClCCl>[NH:58]1[C:55]2=[N:56][CH:57]=[C:52]([O:51][C:24]3[CH:25]=[C:26]([N:29]4[CH2:30][CH2:31][N:32]([CH2:35][C:36]5[CH2:41][CH2:40][C:39]([CH3:43])([CH3:42])[CH2:38][C:37]=5[C:44]5[CH:45]=[CH:46][C:47]([Cl:50])=[CH:48][CH:49]=5)[CH2:33][CH2:34]4)[CH:27]=[CH:28][C:23]=3[C:22]([NH:21][S:18]([C:15]3[CH:16]=[CH:17][C:12]([NH:11][CH:8]4[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]4)=[C:13]([N+:62]([O-:64])=[O:63])[CH:14]=3)(=[O:20])=[O:19])=[O:61])[CH:53]=[C:54]2[CH:60]=[CH:59]1
Reactant: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(NC5CCC6(CC5)OCCO6)c([N+](=O)[O-])c4)c(Oc4cnc5[nH]ccc5c4)c3)CC2)=C(c2ccc(Cl)cc2)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Solvent: ClCCl
Product: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(NC5CCC(=O)CC5)c([N+](=O)[O-])c4)c(Oc4cnc5[nH]ccc5c4)c3)CC2)=C(c2ccc(Cl)cc2)C1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
To a solution of EXAMPLE 340B (386 mg) in acetone (10 mL) and water (5 mL) was added para-toluenesulfonic acid monohydrate (50 mg). The mixture was stirred at 120° C. in a Biotage Initiator microwave reactor for 30 minutes. The mixture was diluted with dichloromethane (300 mL) and washed with aqueous NaHCO3, water, brine and dried over Na2SO4. Filtration and evaporation of the solvent gave the title compound.