Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](Br)=[CH:13][C:12]([CH3:16])=[N:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(OCC)(=O)CC(C)=O.P(Br)(Br)Br.[CH:30]([Si:33]([C:40]#[CH:41])([CH:37]([CH3:39])[CH3:38])[CH:34]([CH3:36])[CH3:35])([CH3:32])[CH3:31]>C(#N)C.C(N(CC)CC)C.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+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([C:41]#[C:40][Si:33]([CH:30]([CH3:32])[CH3:31])([CH:37]([CH3:39])[CH3:38])[CH:34]([CH3:36])[CH3:35])=[CH:13][C:12]([CH3:16])=[N:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C#C[Si](C(C)C)(C(C)C)C(C)C
Reactant: Cc1cc(Br)n(-c2ccc([N+](=O)[O-])cc2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: BrP(Br)Br
Solvent: CCOC(=O)CC(C)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(C#C[Si](C(C)C)(C(C)C)C(C)C)n(-c2ccc([N+](=O)[O-])cc2)n1
Temperature: 70 °C
Yield: 95 %

Procedure:
To a solution of 1-(4′-nitrophenyl)-5-bromo-3-methylpyrazole (prepared as described for Example 19 except using ethyl acetoacetate instead of ethyl trifluoroacetoacetate and using PBr3 in acetonitrile and refluxing for 72 hr for the halogenation step) (100 mg, 0.35 mmol) in triethylamine (5 mL) was added Pd(PPh3)4 (20 mg, 0.017 mmol) and CuBrSMe2 (8 mg, 0.036 mmol), followed by triisopropylsilylacetylene (72 mg, 0.39 mmol). The mixture was heated to 70° C. for 1 hour and cooled to room temperature. The solid was filtered off and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (hexane/acetate, 4:1) to give the title compound (127 mg, 95%). mp: 71-73° C.
Reaction SMILES: [Br:1][C:2]1[C:10]2[S:9][C:8]([C:11]([OH:13])=O)=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[ClH:14].Cl.[NH2:16][C@@H:17]1[CH:22]2[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]2)[CH2:18]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[ClH:14].[N:19]12[CH2:24][CH2:23][CH:22]([CH2:21][CH2:20]1)[CH:17]([NH:16][C:11]([C:8]1[S:9][C:10]3[C:2]([Br:1])=[CH:3][CH:4]=[CH:5][C:6]=3[CH:7]=1)=[O:13])[CH2:18]2
Reactant: O=C(O)c1cc2cccc(Br)c2s1
Reactant: N[C@H]1CN2CCC1CC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CN2CCC1CC2)c1cc2cccc(Br)c2s1

Procedure:
903.8 mg (3.52 mmol) of 7-bromo-1-benzothiophene-2-carboxylic acid (Example 7A), 700 mg (3.52 mmol) of (R)-3-aminoquinuclidine dihydrochloride, 1604.0 mg (4.22 mmol) of HATU, 1635.7 mg (12.66 mmol) of N,N-diisopropylethylamine and 7.0 ml of DMF are reacted by general method C. The reaction mixture is purified by preparative HPLC. The product is dissolved in a 1:1 mixture of 4 M hydrogen chloride in dioxane and 1N hydrochloric acid and then concentrated and dried under high vacuum. 1087 mg (77% of theory) of the title compound are obtained.
Reaction SMILES: [CH2:1]([N:8]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:9]1[C:18]2[N:19]=[CH:20][N:21]([CH2:22][CH2:23][CH2:24][CH2:25]Cl)[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34]1([S-:40])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[Na+]>CN(C)C=O>[CH2:1]([N:8]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:9]1[C:18]2[N:19]=[CH:20][N:21]([CH2:22][CH2:23][CH2:24][CH2:25][S:40][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCCCCn1cnc2c(N(Cc3ccccc3)Cc3ccccc3)nc3ccccc3c21
Reactant: [S-]c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(CN(Cc2ccccc2)c2nc3ccccc3c3c2ncn3CCCCSc2ccccc2)cc1
Temperature: 60 °C
Yield: 92.3 %

Procedure:
A round bottom flask was charged with a magnetic stir bar, N,N-dibenzyl-1-(4-chlorobutyl)-1H-imidazo[4,5-c]quinolin-4-amine (7.0 g, 15.38 mmol), sodium benzenethiolate (3.46 g, 26.15 mmol), and anhydrous dimethyl formamide (77 mL) under a nitrogen atmosphere. The reaction mixture was heated to 60° C. to give a heterogeneous mixture that was maintained at 60° C. for 4 hours at which time the starting material was completely consumed. The cooled solution was partitioned between ethyl acetate and water. The layers were separated. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to afford a colorless oil. The material was purified by chromatography over silica gel (80/20 hexanes/ethyl acetate) to provide N,N-dibenzyl-1-[4-(phenylthio)butyl]-1H-imidazo[4,5-c]quinolin-4-amine (7.5 g, 14.19 mmol) as a colorless oil. MS (CI) for C34H32N4S m/z 529 (MH+), 439, 349
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[C:9]([OH:19])=[C:10]([S:15]([Cl:18])(=[O:17])=[O:16])[CH:11]=[C:12]([Cl:14])[CH:13]=1.[C:20](Cl)(=[O:22])[CH3:21].S(Cl)(Cl)(=O)=O>C(Cl)Cl>[C:20]([O:19][C:9]1[C:8]([Cl:7])=[CH:13][C:12]([Cl:14])=[CH:11][C:10]=1[S:15]([Cl:18])(=[O:17])=[O:16])(=[O:22])[CH3:21]
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1O
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O=S(=O)(Cl)Cl
Product: CC(=O)Oc1c(Cl)cc(Cl)cc1S(=O)(=O)Cl

Procedure:
A pyridine solution (1.1 g of pyridine in 10 ml of methylene chloride) was added dropwise over 30 minutes to a solution of 3.37 g of 3,5-dichloro-2-hydroxybenzenesulfonyl chloride, 25 ml of methylene chloride and 1.1 g of acetyl chloride. After two hours of stirring at room temperature the starting sulfonyl chloride was no longer present and one major product had formed. The reaction was concentrated and used immediately.
Reaction SMILES: [H-].[Na+].[C:3]1(=[O:16])[N:7]([CH2:8][CH2:9][SH:10])[C:6](=[O:11])[C:5]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:4]12.[O:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH2:22][CH2:23]O.CC1C=CC(S([O-])(=O)=O)=CC=1.C(N1C(=O)C2C(=CC=CC=2)C1=O)C>CN(C)C=O>[O:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH2:22][CH2:23][S:10][CH2:9][CH2:8][N:7]1[C:6](=[O:11])[C:5]2[C:4](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]1=[O:16]
Reactant: O=C1c2ccccc2C(=O)N1CCS
Reactant: OCCc1ccco1
Agent: CCN1C(=O)c2ccccc2C1=O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [H-]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCSCCc1ccco1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
80% Sodium hydride (0.155 g) was added portionwise to a solution of 2-phthalimido-ethanethiol (1.03 g) in dry dimethylformamide at 0°. After 20 mins a solution of 2-furanethanol, 4-methylbenzenesulphonate (1.33 g) in dry dimethylformamide was added dropwise and the solution stirred overnight at room temperature. The mixture was poured into ice-water and 2-[[2-furanyl)ethyl]thio]ethyl-1H-isoindole-1,3(2H)-dione isolated as a white solid (1.3 g) m.p. 53°-55°.
Reaction SMILES: [NH2:1][OH:2].[NH:3]1[C:11]2[C:6](=[C:7]([C:12]3[N:13]=[C:14]([N:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)[C:15]4[S:20][C:19]([CH2:21][N:22]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:23][CH2:24][CH2:25][C:26]([O:28]CC)=O)=[CH:18][C:16]=4[N:17]=3)[CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4]1>>[NH:3]1[C:11]2[C:6](=[C:7]([C:12]3[N:13]=[C:14]([N:38]4[CH2:39][CH2:40][O:41][CH2:42][CH2:43]4)[C:15]4[S:20][C:19]([CH2:21][N:22]([CH2:23][CH2:24][CH2:25][C:26]([NH:1][OH:2])=[O:28])[C:31](=[O:32])[O:33][C:34]([CH3:37])([CH3:35])[CH3:36])=[CH:18][C:16]=4[N:17]=3)[CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4]1
Reactant: CCOC(=O)CCCN(Cc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1)C(=O)OC(C)(C)C
Reactant: NO
Product: CC(C)(C)OC(=O)N(CCCC(=O)NO)Cc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Yield: 91 %

Procedure:
The freshly prepared hydroxylamine solution (6.00 mL) was placed in 50 mL flask. Compound 0405-41 (300 mg, 0.51 mmol) was added to this solution and degassed at room temperature for 30 minutes. The reaction process was monitored by TLC. The mixture was neutralized with dry ice, filtered, and the precipitation was washed with methanol and water to give tert-butyl (2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl(4-(hydroxyamino)-4-oxobutyl)carbamate (267 mg, 91%) as a white solid. LCMS: 568 [M+1]+; 1H NMR (400 MHz, DMSO-d6): δ1.45 (s, 9H), 1.74 (m, 2H), 1.96 (t, J=7.2 Hz, 2H), 3.23 (m, 2H), 3.83 (m, 4H), 4.00 (m, 4H), 7.47 (t, J=8.0 Hz, 1H), 7.50 (s, 1H), 7.67 (d, J=8.0 Hz, 1H), 8.22 (d, J=8.0 Hz, 1H), 8.70 (s, 1H), 8.88 (s, 1H), 10.39 (s, 1H), 13.22 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+].Br[CH2:40][C:41]1[C:42]([C:49]2[C:54]([Cl:55])=[CH:53][CH:52]=[CH:51][C:50]=2[Cl:56])=[N:43][O:44][C:45]=1[CH:46]1[CH2:48][CH2:47]1>C1COCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:40][C:41]2[C:42]([C:49]3[C:50]([Cl:56])=[CH:51][CH:52]=[CH:53][C:54]=3[Cl:55])=[N:43][O:44][C:45]=2[CH:46]2[CH2:48][CH2:47]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Clc1cccc(Cl)c1-c1noc(C2CC2)c1CBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(OCc2c(-c3c(Cl)cccc3Cl)noc2C2CC2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 79.2 %

Procedure:
To a solution of 13.05 g (64.83 mmol) of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester in THF (120 mL) is added at 0° C. (ice bath) 18-crown-6 (19.6 g, 73.48 mmol) and potassium tertiary butoxide (8.68 g, 73.48 mmol). The resulting mixture is stirred for 20 min at room temperature, and added dropwise to a solution of 4-bromomethyl-5-cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazole (15 g, 43.22 mmol) in 75 mL of THF. The resulting mixture was stirred at room temperature for 14 h. To the reaction mixture is added water (500 mL), and it is extracted with EtOAc (3×200 mL). The organics are washed with brine (2×250 mL), dried (Na2SO4), filtered and concentrated to afford a crude which is purified by flash chromatography eluting with Hexanes/EtOAc 8:2, to obtain the title compound as a pale yellow oil (16 g (79%)). MS (m/e): 467 (M+1)
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([CH3:14])[CH:8]=1.[CH3:15][CH:16]([CH3:32])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:21]=1)=[O:18]>>[CH3:14][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][C:10]=1[CH3:13])[O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:29]1[CH2:30][CH2:31][CH:26]([C:22]2[CH:21]=[C:20]([NH:19][C:17](=[O:18])[CH:16]([CH3:15])[CH3:32])[CH:25]=[CH:24][CH:23]=2)[CH2:27][CH2:28]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: Cc1ccc(OCCCCCl)cc1C
Product: Cc1ccc(OCCCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)cc1C

Procedure:
Prepared by Procedure G and Scheme B1 using 4-(4-chlorobutoxy)-1,2-dimethylbenzene and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 423.2 (M+H)+.
Reaction SMILES: [CH2:1]([N:4]1[C:9](=[O:10])[C:8]([C:11]([O:13]CC)=[O:12])=[CH:7][N:6]=[C:5]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:2]=[CH2:3].[OH-].[Na+].ClCCl>O1CCCC1>[CH2:1]([N:4]1[C:9](=[O:10])[C:8]([C:11]([OH:13])=[O:12])=[CH:7][N:6]=[C:5]1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH:2]=[CH2:3]
Reactant: C=CCn1c(-c2ccccc2)ncc(C(=O)OCC)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=CCn1c(-c2ccccc2)ncc(C(=O)O)c1=O
Reaction time: 1 h
Yield: 48.1 %

Procedure:
To a solution of ethyl 1-allyl-2-phenylpyrimidin-6(1H)-one-5-carboxylate (25.6 g) in tetrahydrofuran (300 mL) at 0° C. was added a solution of 0.5N sodium hydroxide (198 mL). The resulting solution was allowed to stir for 1 h, was poured into dichloromethane and the organic layer removed. The remaining basic aqueous fraction was extracted with dichloromethane, made acidic with 1N hydrochloric acid (to pH 2), and extracted with dichloromethane. The organic layers from the acidic extractions were dried and evaporated to give an oil which crystallized upon addition of ether. The resulting white solid was collected and washed with ether:hexane (1:1) to give 1-allyl-2-phenylpyrimidin-6(1H)-one-5-carboxylic acid (11.1 g); 300 MHz NMR: 13.0 (s broad,1), 8.69 (s,1), 7.58 (m,5), 5,82 (m,1), 5.16 (d,1), 4.87 (d,1), 4.51 (d,2).
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2([C:17]([O:19]CC)=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+]>C(O)C>[C:1]1([S:7]([CH2:10][C:11]2([C:17]([OH:19])=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C1(CS(=O)(=O)c2ccccc2)CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1(CS(=O)(=O)c2ccccc2)CCCCC1
Yield: 93.9 %

Procedure:
Further, 1.43 g (4.6 mmol) of the ethyl 1-phenylsulfonylmethylcyclohexanecarboxylate and 1.52 g (23.0 mmol) of potassium hydroxide were dissolved in aqueous solution of 90% ethanol. After heating reflux for 18 hours, the reaction mixture was concentrated under reduced pressure. The obtained residue was dissolved in water and washed with ether. The resulting water layer was made acid (pH=2) by the addition of 4N-hydrochloric acid thereto and then extracted with ethyl acetate and washed with 1N-hydrochloric acid and saturated brine. The obtained organic layer was dried over anhyrous sodiumsulfate and concentrated under reduced pressure, whereby 1.22 g of the captioned 1-phenylsulfonylmethylcyclohexane-carboxylic acid was obtained in a yield of 60%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][N:3]=1.[NH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)=[O:19])[CH2:14][CH2:13]1>>[CH3:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][O:20][C:18]([N:15]2[CH2:16][CH2:17][CH:12]([CH2:11][NH:10][C:2]3[N:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][N:3]=3)[CH2:13][CH2:14]2)=[O:19])=[CH:27][CH:26]=1
Reactant: Cc1cnc(Cl)nc1C
Reactant: Cc1ccc(COC(=O)N2CCC(CN)CC2)cc1
Product: Cc1ccc(COC(=O)N2CCC(CNc3ncc(C)c(C)n3)CC2)cc1

Procedure:
The title compound was prepared from 2-chloro-4,5-dimethylpyrimidine (EXAMPLE 148, STEP 1) and INTERMEDIATE 2A as described in a manner similar to that described in EXAMPLE 144, STEP 2 to give the title compound. M.S.(M+1): 369
Reaction SMILES: [F:1][C@H:2]1[C@H:7]([O:8][C:9]2[CH:10]=[C:11]([F:33])[CH:12]=[C:13]3[C:18]=2[N:17]=[C:16]([C:19]2[N:23]4[CH:24]=[CH:25][C:26]([O:28][CH2:29][CH2:30][O:31][CH3:32])=[CH:27][C:22]4=[N:21][CH:20]=2)[CH:15]=[CH:14]3)[CH2:6][CH2:5][N:4](C(OCC2C=CC3C(=CC=CC=3)C=2)=O)[CH2:3]1.CCO.CCOC(C)=O.[ClH:57]>O1CCOCC1.[Pd]>[F:33][C:11]1[CH:12]=[C:13]2[C:18](=[C:9]([O:8][C@@H:7]3[CH2:6][CH2:5][NH:4][CH2:3][C@H:2]3[F:1])[CH:10]=1)[N:17]=[C:16]([C:19]1[N:23]3[CH:24]=[CH:25][C:26]([O:28][CH2:29][CH2:30][O:31][CH3:32])=[CH:27][C:22]3=[N:21][CH:20]=1)[CH:15]=[CH:14]2.[ClH:57]
Reactant: COCCOc1ccn2c(-c3ccc4cc(F)cc(O[C@@H]5CCN(C(=O)OCc6ccc7ccccc7c6)C[C@H]5F)c4n3)cnc2c1
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCO
Product: COCCOc1ccn2c(-c3ccc4cc(F)cc(O[C@@H]5CCNC[C@H]5F)c4n3)cnc2c1
Reaction time: 48 h

Procedure:
Pd/C (45 mg, 0.042 mmol) 10% wet was added to a solution of (3R,4R)-naphthalen-2-ylmethyl 3-fluoro-4-(6-fluoro-2-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl)quinolin-8-yloxy)piperidine-1-carboxylate (270 mg, 0.42 mmol) in a 1:1 mixture of EtOH/EtOAc (10 mL) and 500 uL of 6 N HCl. The mixture was purged with H2, and then allowed to stir under a balloon of hydrogen for 48 hours. The mixture was filtered through GF paper removing the desired product salt as a precipitate, with the palladium catalyst. The combined solids were washed into a beaker with 30 mL of MeOH and the palladium removed by subsequent filtration through GF filter paper. The organic phase was concentrated in vacuo, followed by flash column chromatography (1-20% MeOH/DCM (4% NH4OH). The resulting product was dissolved in chloroform and subject to four equivalents of 4 M HCl in dioxane. The desired product was then isolated as the bis-HCl salt. MS APCI (+) m/z 455.2 (M+1) detected.
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]>CN1CCCC1=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: CN1CCCC1=O
Product: Cc1nnc(C(=O)NC(C)(C)c2nc(C(=O)NCc3ccc(F)cc3)c([O-])c(=O)n2C)o1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
A vial (20 ml) was charged with Raltegravir free hydroxy (500 mg) completely dissolved in N-methyl-pyrrolidone (NMP) (1.5 ml) at room temperature. A solution of 30% aqueous KOH (0.162 ml) was added. The mixture was stirred for 21 h at room temperature. Additional NMP (7.5 ml) was added and the mixture was stirred for an additional 6.5 h at room temperature. A solid precipitated and was filtered under reduced pressure to provide wet Raltegravir potassium crystalline Form IV. The wet product was dried overnight in a vacuum oven at 40° C. to provide Raltegravir potassium crystalline Form IV.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([OH:10])=O)=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[CH:4][CH:3]=1>CCCCCC>[CH3:1][C:2]1[C:7]2[C:8](=[O:10])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:6]=2[N:5]=[CH:4][CH:3]=1
Reactant: Cc1ccnc(-c2ccccc2)c1C(=O)O
Solvent: CCCCCC
Product: Cc1ccnc2c1C(=O)c1ccccc1-2
Yield: 91 %

Procedure:
To a stirred, cooled (0°) solution of ethyl benzoylacetate (200 g) and concentrated ammonia in ethanol (1 L) was added crotonaldehyde (110 g) at a rate 2.5 ml/min while the temperature was kept below 10° . The mixture was warmed to room temperature overnight and concentrated in vacuo to give a yellow oily residue (260 g). The residue was treated with a mixture of con H2SO4 (100 ml), con HNO3 (130 ml) and water (580 ml) and the mixture cautiously heated on a steam bath until the evolution of NO2 had subsided, then heated for another 30 min. After cooling, the supernatant was basified with con NH4OH and extracted with diethyl ether (300 ml×10). The combined ether extracts were concentrated to leave a dark brown oily residue (38 g). Purification of the residue by silica gel column chromatography (70-230 mesh, 400 g, 42×5 cm, three times) using n-hexane-ethyl acetate (2:1) as eluent afforded 15 g of ethyl-4-methyl-2-phenylnicotinate. Hydrolysis of ethyl-4-methyl-2-phenylnicotinate (15 g) with refluxing ethanolic KOH, followed by work-up afforded 4-methyl-2-phenylnicotinic acid (9 g) as colorless prisms, mp 210-212° . Treatment of 4-methyl-2-phenylnicotinic acid (9 g) with polyphosphoric acid (166.7 g) at 130° for 3 hr., afforded 1-methyl-4-azafluoren-9-one (7.5 g) as yellow prisms from n-hexane, mp 130-131° C.
Reaction SMILES: B(Cl)(Cl)Cl.C([O:12][N:13]1[C:19](=[O:20])[N:18]2[CH2:21][C@H:14]1[CH2:15][CH2:16][C@H:17]2[C:22]1[S:23][CH:24]=[N:25][N:26]=1)C1C=CC=CC=1.CO>C(Cl)Cl>[OH:12][N:13]1[C:19](=[O:20])[N:18]2[CH2:21][C@H:14]1[CH2:15][CH2:16][C@H:17]2[C:22]1[S:23][CH:24]=[N:25][N:26]=1
Reactant: O=C1N2C[C@@H](CC[C@H]2c2nncs2)N1OCc1ccccc1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: O=C1N(O)[C@@H]2CC[C@@H](c3nncs3)N1C2
Temperature: 0 °C
Reaction time: 6 h
Yield: 80.8 %

Procedure:
BCl3 (1 M in CH2Cl2, 9.0 mL, 9.0 mmol) was added dropwise to a solution of (2S,5R)-6-(benzyloxy)-2-(1,3,4-thiadiazol-2-yl)-1,6-diaza-bicyclo[3.2.1]octan-7-one (560 mg, 1.8 mmol) in dry CH2Cl2 (20 mL) at −78° C. The mixture was stirred under a N2 atmosphere at 0° C. for 6 hrs., then, MeOH (9 mL) was slowly added dropwise at −78° C. The solvents were evaporated under vacuum at 0° C. to give (2S,5R)-6-hydroxy-2-(1,3,4-thiadiazol-2-yl)-1,6-diaza-bicyclo[3.2.1]octan-7-one (329 mg, 81%) as a yellow solid, which was used directly in the next step. ESI-MS (EI−, m/z): 227.1 [M+H]−.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:20])[C:4](=[O:19])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][C:8]([CH3:18])([CH3:17])[CH2:7]2)[N:6]=1.[C:21]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)#[N:22].C([O-])([O-])=O.[Na+].[Na+]>CC1C=CC=CC=1C.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>[NH2:1][C:2]1[N:3]([CH3:20])[C:4](=[O:19])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:27]4[CH:28]=[C:23]([CH:24]=[CH:25][CH:26]=4)[C:21]#[N:22])[CH:14]=3)[O:9][C:8]([CH3:18])([CH3:17])[CH2:7]2)[N:6]=1
Reactant: CN1C(=O)C2(CC(C)(C)Oc3ccc(Br)cc32)N=C1N
Reactant: N#Cc1cccc(B(O)O)c1
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: [Na+]
Solvent: Cc1ccccc1C
Product: CN1C(=O)C2(CC(C)(C)Oc3ccc(-c4cccc(C#N)c4)cc32)N=C1N
Temperature: 90 °C
Yield: 21.3 %

Procedure:
Pd(PPh3)4 (15.13 mg, 0.013 mmol) is added to the solution of 2′-amino-6-bromo-1′,2,2-trimethylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (44.15 mg, 0.13 mmol) and 3-cyanophenylboronic acid (19.25 mg, 0.13 mmol) in dimethyl-benzene (5 mL) and an aqueous solution of Na2CO3 (2 M, 0.24 mL). The mixture is heated at 90° C. in an oil bath overnight. The mixture is concentrated to give the crude product, which is purified by preparative TLC to give the desired product 3-(2′-amino-1′,2,2-trimethyl-5′-oxo-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)benzonitrile (10 mg, 15%).
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:9][C:10]1[CH:11]=[C:12](I)[CH:13]=[C:14]([CH3:16])[CH:15]=1.[NH:18]1[CH2:22][CH2:21][CH2:20][C:19]1=[O:23].CCCCCCCCCCCC>C1(C)C=CC=CC=1>[CH3:9][C:10]1[CH:11]=[C:12]([N:18]2[CH2:22][CH2:21][CH2:20][C:19]2=[O:23])[CH:13]=[C:14]([CH3:16])[CH:15]=1
Reactant: Cc1cc(C)cc(I)c1
Reactant: O=C1CCCN1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCCCCCCCCCCC
Product: Cc1cc(C)cc(N2CCCC2=O)c1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
An oven-dried Schlenk flask was evacuated and backfilled with argon. The flask was charged with bis(trans-N,N′-dimethyl-1,2-cyclohexanediamine)copper(II) bromide (12.8 mg, 0.025 mmol) and K3PO4 (330 mg, 1.55 mmol) and then evacuated and backfilled with argon, and toluene (1 mL), 3,5-dimethyliodobenzene (240 mg, 1.03 mmol), 2-pyrrolidinone (108 mg, 1.26 mmol), and dodecane (160 mg, 0.94 mmol, GC internal standard) were added through a rubber septum. The septum was removed: the flask was sealed with a Teflon screwcap, and the mixture was stirred at room temperature for 2 min and then heated to 80° C. with stirring until the starting aryl iodide had been completely consumed as judged by GC analysis. The mixture was cooled to room temperature, diluted with ethyl acetate, and filtered through Celite to give 96% GC yield of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH2:13](O)[CH2:14][CH2:15][OH:16]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]2[O:16][CH2:15][CH2:14][CH2:13][O:7]2)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: O=Cc1ccc(O)c([N+](=O)[O-])c1
Reactant: OCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cc(C2OCCCO2)ccc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.2 %

Procedure:
A mixture of 4-hydroxy-3-nitro-benzaldehyde (5.0 g, 29.9 mmol), 1,3-propanediol (3.4 g, 44.9 mmol) and 0.1 g of p-toluene sulfonic acid in 100 mL of toluene is warmed to reflux. The water generated is removed by a Dean-Stark trap. After 2 hours, the reaction mixture is cooled to room temperature and extracted with 2×100 mL of saturated sodium bicarbonate followed by 100 mL of brine. Drying over sodium sulfate and evaporation of the solvent gives 5.6 g (83% yield) of 2-[4-hydroxy-3-nitro-phenyl]-1,3-dioxane oil.