Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:43](=[O:44])[N:13]3[C:14]([C:27]([O:29]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:28])=[C:15]([S:18][CH2:19][CH2:20][C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.C(OC(C)C)(C)C>ClCCl.C1(OC)C=CC=CC=1>[C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:43](=[O:44])[N:13]3[C:14]([C:27]([OH:29])=[O:28])=[C:15]([S:18][CH2:19][CH2:20][C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SCCc3cccnc3)CS[C@H]12
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)O)=C(SCCc3cccnc3)CS[C@H]12
Reaction time: 1.5 h
Yield: 79 %

Procedure:
To a solution of benzhydryl 7β-(2-phenylacetamido)-3-[2-(3-pyridyl)ethylthio]-3-cephem-4-carboxylate (632 mg) in a mixture of dichloromethane (1.8 ml) and anisole (0.6 ml) was added trifluoroacetic acid (1.2 ml) under ice-cooling. The mixture was stirred at the same temperature for 1.5 hours. The reaction mixture was poured into diisopropyl ether (60 ml), and the resulting precipitate was collected by filtration and dried in vacuo. The precipitate was dissolved in a mixture of aqueous sodium hydrogen carbonate (188 mg/50 ml), tetrahydrofuran (20 ml) and ethyl acetate (40 ml). To the separated aqueous layer was added tetrahydrofuran (20 ml) and ethyl acetate (40 ml), adjusted to pH 3.0 with 1N-hydrochloric acid. The resulting precipitate was collected by filtration, washed with water, ethyl acetate and n-hexane, and dried to give 7β-(2-phenylacetamido)-3-[2-(3-pyridyl)ethylthio]-3-cephem-4-carboxylic acid (366 mg).
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:5]([C@H:14]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[O:16])[CH2:4]1)=O.Cl.[CH:34]1[C:39]2[CH2:40][CH2:41][N:42]([CH:46]3[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]3)[C:43](=[O:45])[O:44][C:38]=2[CH:37]=[CH:36][CH:35]=1>>[CH:34]1[C:39]2[CH2:40][CH2:41][N:42]([CH:46]3[CH2:51][CH2:50][N:49]([CH2:1][C@@H:3]4[C@@H:7]([C:8]5[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=5)[CH2:6][N:5]([C@H:14]([CH:27]5[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]5)[C:15]([O:17][CH2:18][C:19]5[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=5)=[O:16])[CH2:4]4)[CH2:48][CH2:47]3)[C:43](=[O:45])[O:44][C:38]=2[CH:37]=[CH:36][CH:35]=1
Reactant: O=C1Oc2ccccc2CCN1C1CCNCC1
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](c3ccccc3)[C@@H](C=O)C2)cc1
Agent: Cl
Product: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](CN3CCC(N4CCc5ccccc5OC4=O)CC3)[C@@H](c3ccccc3)C2)cc1
Yield: 76 %

Procedure:
The title compound (36 mg) was prepared by reductive amination of 31 mg of α-(R)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)- cyclohexaneacetic acid, 4-methoxybenzyl ester (prepared above as Aldehyde 5) with 22 mg of 4-(8,9-dihydro-7H-5-oxa-7-aza-benzocyclo-hepten-6-one-7-yl)-piperidine hydrochloride according to the procedure of Example 1, step D. 1H NMR (500MHz, CDCl3): δ0.9-1.3 (m, 5H), 1.5-2.0 (m, 12H), 2.25-3.3 (m, 13H), 3.63 (m, 2H), 3.82 (s, 3H), 3.96 (m, 1H), 5.13 (ABq, 2H), 6.9-7.4 (m, 13H).
Reaction SMILES: C(O[CH:4]=[C:5]([C:11](=[O:22])[C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[C:14]([Cl:20])[C:13]=1F)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[NH2:23][C:24]1[N:29]=[C:28]([NH:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C:27]([F:35])=[CH:26][N:25]=1>C(Cl)(Cl)Cl>[C:31]([NH:30][C:28]1[C:27]([F:35])=[CH:26][N:25]=[C:24]([N:23]2[C:13]3[C:12](=[CH:17][C:16]([F:18])=[C:15]([F:19])[C:14]=3[Cl:20])[C:11](=[O:22])[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4]2)[N:29]=1)([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)Nc1nc(N)ncc1F
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(Cl)c1F
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(-c2ncc(F)c(NC(C)(C)C)n2)c2c(Cl)c(F)c(F)cc2c1=O
Temperature: 90 °C
Reaction time: 0.17 h

Procedure:
To 3 ml of chloroform solution of ethyl 3-ethoxy-2-(3-chloro-2,4,5-trifluorobenzoyl)acrylate prepared from 210 mg of ethyl 3-chloro-2,4,5-trifluorobenzbylacetate by normal process was added 340 mg of 2-amino-4-(t-butylamino)-5-fluoropyrimidine. The solution was concentrated under reduced pressure. To the residue were added 550 mg of anhydrous potassium carbonate and 2 ml of N,N-dimethylformamide, and the mixture was stirred at 90° C. for 1 hour and 10 minutes and allowed to cool. The solution was separated by adding 30 ml of chloroform and 300 ml of distilled water, and the chloroform layer was washed twice with 300 ml of distilled water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography (silica gel, 16 g; eluent: chloroform:methanol, 200:1), and the corresponding fractions were collected and concentrated under reduced pressure. To the residue was added 0.5 ml of ethanol, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 98 mg of the title compound as a colorless powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][NH2:10])[CH:5]=[CH:4][C:3]=1[OH:11].N([O-])=O.[Na+].[N-:16]=[N+:17]=[N-].[Na+]>Cl.O>[NH2:10][CH2:9][CH2:8][C:6]1[CH:5]=[CH:4][C:3]([OH:11])=[C:2]([N:1]=[N+:16]=[N-:17])[CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: NCCc1ccc(O)c(N)c1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=Nc1cc(CCN)ccc1O
Temperature: 0 °C

Procedure:
2-Amino-4-(2-amino-ethyl)-phenol (1) (1 mmol) is dissolved in aqueous HCl. The solution is cooled to 0° C. and 1 mmol of NaNO2 dissolved in H2O is added slowly with stirring. The reaction mixture is maintained at 0° C. for 1 hr, then NaN3 (2 mmol) dissolved in water is added dropwise with stirring. The resulting mixture is maintained at 0° C. for 1 hr, then the cooling bath is removed and the mixture stirred overnight at ambient temperature. The product is extracted with ethyl acetate, washed with saturated NaHCO3 and H2O. The organic phase is dried with Na2SO4, then the solvent removed under vacuum. The crude product is purified by column chromatography to yield 4-(2-amino-ethyl)-2-azido-phenol (2).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].[Br:18][C:19]1[CH:20]=[N:21][C:22](I)=[N:23][CH:24]=1>CS(C)=O.O>[Br:18][C:19]1[CH:20]=[N:21][C:22]([O:15][CH2:14][CH:11]2[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]2)=[N:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: Brc1cnc(I)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(COc2ncc(Br)cn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.2 %

Procedure:
A solution of N-Boc-4-piperidinemethanol (1.0 g, 4.50 mmol) in DMSO (2 mL) was added dropwise to a suspension of NaH (60% in mineral oil, 0.27 g, 6.76 mmol) in DMSO (4 mL). The mixture was stirred at ambient temperature for 1 h, then 30 minutes at 50° C. Cooled to ambient temperature, a solution of 5-bromo-2-iodopyrimidine (1.38 g, 4.73 mmol) in DMSO (4 mL) was added dropwise, and the reaction mixture was stirred at ambient temperature overnight, then heated at 100° C. for 5 h. Cooled to ambient temperature, the mixture was poured in water, extracted with EtOAc. The organic extract was washed with water and brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as a dark brown oil. The crude product was purified by chromatography on ISCO silica gel column eluted with a EtOAc:hexane gradient (hexane to 15% EtOAc) to give 0.455 g (28%) of 1,1-dimethylethyl 4-{[(5-bromo-2-pyrimidinyl)oxy]methyl}-1-piperidinecarboxylate as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.51 (s, 2H), 4.20-4.10 (m, 4H), 2.80-2.65 (m, 2H), 2.05-1.95 (m, 1H), 1.90-1.75 (m, 2H), 1.45 (s, 9H), 1.35-1.20 (m, 2H); LRMS (ESI), m/z 372/374 (M+H).
Reaction SMILES: Cl.[O:2]=[C:3]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[CH2:4][NH:5][C:6](=[O:20])[C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:9][CH:8]=1.[C:27]1([S:33](Cl)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>C(Cl)Cl>[C:27]1([S:33]([N:24]2[CH2:23][CH2:22][N:21]([C:3](=[O:2])[CH2:4][NH:5][C:6](=[O:20])[C:7]3[CH:8]=[CH:9][C:10]([O:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)=[CH:11][CH:12]=3)[CH2:26][CH2:25]2)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(Oc2ccccc2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: O=C(NCC(=O)N1CCN(S(=O)(=O)c2ccccc2)CC1)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 47 %

Procedure:
TEA (0.074 mL, 0.53 mmol) was added dropwise to a chilled (0° C.) mixture of N-(2-Oxo-2-piperazin-1-yl-ethyl)-4-phenoxy-benzamide hydrochloride (100 mg, 0.27 mmol) in DCM (5 mL). After 5 minutes, benzenesulfonyl chloride (0.032 mL, 0.26 mmol) was added and the resulting mixture was stirred at room temperature for 5 hours. DCM was added, followed by the addition of iced water. The product was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography (using silica gel of mesh size of 60-120 and 70:30 EtOAc:hexane as eluent) to afford N-[2-(4-benzenesulfonyl-piperazin-1-yl)-2-oxo-ethyl]-4-phenoxy-benzamide in 47% yield. LC-MS purity: 98%, 1H NMR (DMSO-D6): δ 8.5 (t, 1H), 7.9 (d, 2H), 7.8 (m, 3H), 7.6 (m, 2H), 7.4 (t, 2H), 7.2 (t, 1H), 7.1 (d, 2H), 7 (d, 2H), 4.1 (d, 2H), 3.6 (m, 4H), 2.9 (m, 4H).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16]Br)[N:11]=1>CN(C)C=O>[CH3:8][O:7][C:5](=[O:6])[CH2:4][O:3][CH2:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([Br:9])[N:11]=1
Reactant: COC(=O)CO
Reactant: BrCc1cccc(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COCc1cccc(Br)n1
Reaction time: 5 h

Procedure:
To a suspension of sodium hydride (0.50 g, 12.38 mmol) in N,N-dimethylformamide (20 mL) at 0° C. was added a mixture of methyl hydroxyacetate (1.0 g, 11.25 mmol) and 2-bromo-6-(bromomethyl)pyridine (Example 190, Step 1) (3.4 g, 13.5 mmol) dropwise. After stirring for 5 hours, the reaction was quenched with iso-propanol/methanol solution. The reaction mixture was poured onto iced water and extracted with ether. The organic phase was dried over MgSO4, filtered and evaporated. The crude mixture was purified by silica gel column and eluted with ethyl acetate:petroleum ether (1:10) to afford the title compound. 1H NMR (400 MHz, CDCl3): δ 7.55 (t, 1H), 7.48 (d, 1H), 7.39 (d, 1H), 4.71 (s, 2H), 4.22 (s, 2H), 3.77 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[N:5][CH:4]=[N:3]1.C([Li])CCC.CCCCCC.Br[C:19]1[S:20][C:21]([C:25]2[N:29]3[N:30]=[C:31]([CH3:39])[CH:32]=[C:33]([CH:34]([CH2:37][CH3:38])[CH2:35][CH3:36])[C:28]3=[N:27][C:26]=2[CH3:40])=[C:22]([CH3:24])[N:23]=1>C1COCC1.[Cl-].[Zn+2].[Cl-].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:35]([CH:34]([C:33]1[C:28]2[N:29]([C:25]([C:21]3[S:20][C:19]([C:6]4[N:2]([CH3:1])[N:3]=[CH:4][N:5]=4)=[N:23][C:22]=3[CH3:24])=[C:26]([CH3:40])[N:27]=2)[N:30]=[C:31]([CH3:39])[CH:32]=1)[CH2:37][CH3:38])[CH3:36]
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)nc3C)c(C)nc12
Reactant: Cn1cncn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cl-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nn2c(-c3sc(-c4ncnn4C)nc3C)c(C)nc12
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 21.8 %

Procedure:
82 mg of 1-Methyl-1,2,4-triazole (0.99 mmol) is dissolved in 2 ml of dry THF and cooled to −78° C. and 0.4 ml of n-butyllithium 2.5 M in hexane (0.99 mmol) is added. The reaction mixture is stirred at −78 C to room temperature for 10 min and cooled to −78° C. again. 1.98 ml of 0.5 M zinc chloride 0.5 M solution in THF (0.99 mmol) is added and stirred at −78 C to room temperature for 15 min. 265 mg of 3-(2-bromo-4-methyl-thiazol-5-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.66 mmol) and 27 mg of PdCl2(dppf) (0.033 mmol) are added and the vial is capped with a Teflon cap and heated at 80° C. for 2 days. The reaction is cooled to room temperature and quenched with sat. NH4Cl and extracted with CH2Cl2. The separated CH2Cl2 layer is dried over Na2SO4 and evaporated. The crude product is applied onto a silica-gel chromatography column (Hexane:AcOEt:2 M NH3 in MeOH=10:2:1) to give 57 mg of the title product. Yield 22%. mass spectrum (m/e): 396 (M+1). 1H-NMR (CDCl3): δ 7.96 (s, 1H), 6.77 (s, 1H), 4.45 (s, 3H), 3.36 (m, 1H), 2.55 (s, 3H), 2.52 (s, 3H), 2.47 (s, 3H), 1.88 (m, 4H), 0.92 (t, J=7.3 Hz, 6H).
Reaction SMILES: [CH:1]([C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6].[H][H]>C(O)C.[Pd]>[CH2:1]([C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: [H][H]
Reactant: CCCCC=Cc1cc2ccccc2[nH]1
Agent: [Pd]
Solvent: CCO
Product: CCCCCCc1cc2ccccc2[nH]1

Procedure:
2-Hex-1-enyl-1H-indole was dissolved in ethanol and 10% palladium on carbon was added to the solution. The reaction flask was sealed and exposed to hydrogen gas under pressure and was stirred until the hydrogen gas consumption was completely stopped. The reaction mixture was filtered through Celite. The solvent was evaporated to afford the product.
Reaction SMILES: [NH3:1].[C:2]([C:4](=[C:7](SCC)[S:8][CH2:9][CH3:10])[C:5]#[N:6])#[N:3]>C(O)C>[NH2:1][C:7]([S:8][CH2:9][CH3:10])=[C:4]([C:5]#[N:6])[C:2]#[N:3]
Reactant: N
Reactant: CCSC(SCC)=C(C#N)C#N
Solvent: CCO
Product: CCSC(N)=C(C#N)C#N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Into 2.0 liters of ethanol, previously saturated with ammonia, was added 378 g of 2-cyano-3,3-bis(ethylthio)propenenitrile. The mildly exothermic reaction warmed the mixture to 38°. The mixture was stirred at ambient temperature for 0.5 hour, then heated under reflux (ca 55°) for 1.0 hour. The mixture was concentrated by distillation of about one liter of solvent. To the mixture was added 1.5 liters of ice-water and the mixture was cooled in an ice-bath. The yellow solid was isolated and dried to give 223 g of 3-amino-2-cyano-3-(ethylthio)propenenitrile, m.p. 180°-182°. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: CN(C=O)C.[OH:6][C@@H:7]([CH2:14]/[CH:15]=[C:16](/[CH3:20])\[CH2:17][CH:18]=[CH2:19])[C:8]([N:10]([O:12][CH3:13])[CH3:11])=[O:9].[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].N1C=CN=C1>C(OCC)C.C(OCC)(=O)C>[C:24]([Si:21]([CH3:23])([CH3:22])[O:6][C@@H:7]([CH2:14]/[CH:15]=[C:16](/[CH3:20])\[CH2:17][CH:18]=[CH2:19])[C:8]([N:10]([O:12][CH3:13])[CH3:11])=[O:9])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=CC/C(C)=C\C[C@H](O)C(=O)N(C)OC
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C=CC/C(C)=C\C[C@H](O[Si](C)(C)C(C)(C)C)C(=O)N(C)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
To an anhydrous DMF (250 mL) solution of the alcohol 4 (70.7 g, 329 mmol) was added tert-butyldimethylsilyl chloride (TBSCl, 55 g, 364 mmol) and imidazole (30 g, 441 mmol) at 0° C. The reaction was allowed to warm to room temperature, and was stirred overnight. The reaction progress was followed by TLC (5:1/hexanes:ethyl acetate). The reaction mixture was poured to a 4 L separation funnel containing diethyl ether (1.7 L), and was separated. The organics were washed with water (4×500 mL) and brine (1×250 mL), dried over magnesium sulfate. Filtration and evaporation under vacuum afforded the crude product 5 as yellowish oil (107 g, 99%), which was used directly for the next step without further purification.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]([S:18]([C:21]3[CH:22]=[CH:23][CH:24]=[C:25]4[C:30]=3[N:29]=[CH:28][CH:27]=[CH:26]4)(=[O:20])=[O:19])[CH:10]=2)O1.I[C:33]1[CH:38]=[CH:37][N:36]=[C:35]([S:39][CH3:40])[N:34]=1.C(OCC)(=O)C>C(=O)([O-])[O-].[K+].[K+].O.O1CCCC1.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>[CH3:40][S:39][C:35]1[N:36]=[C:37]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]([S:18]([C:21]3[CH:22]=[CH:23][CH:24]=[C:25]4[C:30]=3[N:29]=[CH:28][CH:27]=[CH:26]4)(=[O:20])=[O:19])[CH:10]=2)[CH:38]=[CH:33][N:34]=1
Reactant: CC1(C)OB(c2cn(S(=O)(=O)c3cccc4cccnc34)c3ncccc23)OC1(C)C
Reactant: CSc1nccc(I)n1
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: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CSc1nccc(-c2cn(S(=O)(=O)c3cccc4cccnc34)c3ncccc23)n1
Temperature: 120 °C

Procedure:
In a microwave reaction tube, 8-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrrolo[2,3-b]pyridine-1-sulfonyl]-quinoline (47, 70 mg, 0.16 mmol), 4-iodo-2-methylsulfanyl-pyrimidine (101 mg, 0.402 mmol), and tetrakis(triphenylphosphine)palladium(0) (9.3 mg, 0.008 mmol) were mixed in 1.0 M potassium carbonate in water (0.48 mL) and tetrahydrofuran (0.77 mL). The resulting mixture was heated at 120° C. in a CEM Discover microwave unit for 10 minutes. Ethyl acetate and water were added, and the two layers were separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate. Concentration under reduced pressure afforded the crude material, which was purified by column chromatography (50% ethyl acetate in hexane) to yield the desired product in light yellow solid (46, 10 mg, 0.023 mmol). MS(ESI) [M+H+]+=434.0.
Reaction SMILES: Br[C:2]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7](=[O:8])[NH:6][C:5](=[O:9])[NH:4][C:3]1=[O:10].[OH:17][CH2:18][CH:19]=[C:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(N(CC)CC)C>C(O)C>[C:11]1([C:2]2([N:23]3[CH2:24][CH2:25][C:20](=[CH:19][CH2:18][OH:17])[CH2:21][CH2:22]3)[C:7](=[O:8])[NH:6][C:5](=[O:9])[NH:4][C:3]2=[O:10])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OCC=C1CCNCC1
Reactant: O=C1NC(=O)C(Br)(c2ccccc2)C(=O)N1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C1NC(=O)C(c2ccccc2)(N2CCC(=CCO)CC2)C(=O)N1
Yield: 16.5 %

Procedure:
A mixture of 5-bromo-5-phenylbarbituric acid (2.45 g), 4-(hydroxyethylidene)piperidine (1.053 g) and triethylamine (1.15 ml) in 50 ml of ethanol is refluxed for 2 hours. The solvent is evaporated under reduced pressure and the residue is purified by silica gel chromatography (40 g; eluent: ethyl acetate/petroleum ether 8:2), to give 450 mg of the product.
Reaction SMILES: [Cl:1][C:2](Cl)(Cl)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.ClCCCl.[OH2:15]>>[C:2]([Cl:1])(=[O:15])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: ClC(Cl)(Cl)c1ccccc1
Reactant: O
Solvent: ClCCCl
Product: O=C(Cl)c1ccccc1

Procedure:
α, α,α-Trichlorotoluene (19.6 g; 0.1M), ferric chloride (4.1 g; 0.02M) and 1,2-dichloroethane (500 ml) were stirred under reflux under heavier than water Dean and Stark apparatus. Water (1.8 g) was then added to the Dean and Stark apparatus and the mixture was refluxed for 4 hours. By this time, all of the water had been consumed. The mixture was then filtered through Hyflo (Trade Mark) to remove the ferric chloride.
Reaction SMILES: [N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(OC(=O)C)(=O)C.[OH-].[Na+]>>[CH:11](=[C:9]1[C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:6][CH2:7][CH2:8]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: c1cnc2c(c1)CCCC2
Reactant: O=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Product: C(=C1CCCc2cccnc21)c1ccccc1
Temperature: 25 °C

Procedure:
A solution of 5,6,7,8-tetrahydroquinoline (18.2 g, 137 mmol), benzaldehyde (17.67 g, 166.0 mmol), and acetic anhydride (24.5 mL, 254 mmol) was heated under a nitrogen environment at 165° C. for 16 hours. The reaction mixture was cooled to room temperature. Crushed ice was added, and the mixture was slowly basified with NaOH (solid then 2 N NaOH) to pH around 7. The aqueous layer was extracted with hexane/ethyl acetate (1:1 solution) 3 times. The pooled organic layers were dried over magnesium sulfate. The mixture was filtered, and the solvents were removed under vacuum to give 8-benzylidene-5,6,7,8-tetrahydro-quinoline (Intermediate 1) as a brown solid. A solution of Intermediate 1 in dichoromethane (100 mL) and methanol (500 mL) was cooled to −78° C. (dry ice/acetone bath), and charged with ozone/oxygen (3 psi, 1.5 ampere). The dark brown solution turned yellow after several hours. When Intermediate 1 was consumed (TLC), ozone/oxygen flow was stopped. The reaction mixture was purged with nitrogen for 10 minutes. Methyl sulfide (6 mL) was added, and the mixture was stirred for 30 minutes at room temperature. The solvents were removed under vacuum. The residue was dissolved in 1 N HCl (500 mL), and washed with diethyl ether (4×150 mL). The aqueous layer was basified to pH˜7 with NaOH (s), and extracted with ethyl acetate (2×200 mL). The pooled ethyl acetate layers were dried over magnesium sulfate. The mixture was filtered and the solvent was removed under vacuum. The residue was purified by chromatography on silica gel with 90% EtOAc:hexane to give a clean product. The aqueous layer was extracted with chloroform/isopropanol (3:1) several times. The pooled chloroform/isopropanol layers were dried over magnesium sulfate. The mixture was filtered and the solvents were removed under vacuum to give 6,7-dihydro-5H-quinolin-8-one (Intermediate 2), 17.89 g (122.0 mmol, 89% over 2 steps).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH2:2][CH3:3].N1C=CC=CC=1.[NH2:20][C:21]1[CH:22]=[CH:23][C:24]2[O:28][C:27]([CH3:29])=[N:26][C:25]=2[CH:30]=1.C([O-])(O)=O.[Na+]>ClCCl>[CH3:29][C:27]1[O:28][C:24]2[CH:23]=[CH:22][C:21]([NH:20][S:10]([C:7]3[CH:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=3)(=[O:12])=[O:11])=[CH:30][C:25]=2[N:26]=1
Reactant: Cc1nc2cc(N)ccc2o1
Reactant: CCCc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCc1ccc(S(=O)(=O)Nc2ccc3oc(C)nc3c2)cc1
Reaction time: 0.08 h
Yield: 84.7 %

Procedure:
To a solution of 4n-propylbenzenesulphonyl chloride (93 mg, 0.43 mmol) in dichloromethane (2 mL) was added pyridine (80 μL, 1.0 mmol) and the mixture was stirred under N2 for 5 min, after which time 5-amino-2-methylbenzoxazole (60 mg, 0.40 mmol) was added. The resulting mixture was stirred for 1 h at room temperature, then saturated NaHCO3 solution was added (8 mL) and the mixture was extracted into ethyl acetate (15 mL). The organic phase was washed with brine, dried (Na2SO4), filtered and evaporated to give a residue that was purified using flash chromatography to afford a pale pink oil (112 mg, 85%), single spot at Rf 0.53 (1:1 hexane:ethyl acetate). HPLC purity 99+% (tR 2.38 min in 10% water-acetonitrile) 1H NMR (CDCl3): δ 7.64 (2H, dt, J=8.1, 1.8 Hz), 7.31 (2H, m), 7.18 (2H, d, J=8.4 Hz), 7.06 (1H, dd, J=8.6, 2.4 Hz), 2.59 (5H, m), 1.58 (2H, sextet, J=7.3 Hz), 0.89 (3H, t, J=7.3 Hz). LCMS: 329.15 (M−). FAB-MS (MH+, C17H18N2O3S): calcd 331.1116, found 331.1118.