Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:22])=[CH:8][C:9]=2[NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)(=[O:14])=[O:13])[S:4][C:3]=1[CH3:23].CC1(C)C(C)(C)OB([C:32]2[CH:33]=[N:34][N:35](C(OC(C)(C)C)=O)[CH:36]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:21][C:17]1[CH:16]=[C:15]([S:12]([NH:11][C:9]2[CH:8]=[C:7]([CH3:22])[N:6]=[C:5]3[S:4][C:3]([CH3:23])=[C:2]([C:32]4[CH:33]=[N:34][NH:35][CH:36]=4)[C:10]=23)(=[O:14])=[O:13])[CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(Br)c(C)sc2n1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(-c3cn[nH]c3)c(C)sc2n1
Temperature: 100 °C
Yield: 11 %

Procedure:
Under nitrogen, N-(3-bromo-2,6-dimethylthieno[2,3-b]pyridin-4-yl)-3-chlorobenzenesulfonamide (Example 61) (100 mg, 0.232 mmol) was dissolved in 1,4-dioxane (2.5 mL) and water (1 mL). 1,1-Dimethylethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (102 mg, 0.347 mmol), bis(triphenylphosphine)palladium(II) chloride (16.26 mg, 0.023 mmol) and potassium carbonate (96 mg, 0.695 mmol) were added and the mixture heated in a microwave at 100° C. for 15 min (×3). The solution was concentrated, ethyl acetate (10 mL) added and the mixture washed with water (2×5 mL). The organic layer was dried over MgSO4, filtered and the solvent removed in vacuo. The residue was purified by normal phase chromatography, eluting with a gradient of 0-60% ethyl acetate in cyclohexane, to give the title compound (10.7 mg). LCMS (A) m/z: 419 [M+1]+, Rt 1.20 min (acidic).
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][C:5]1[CH:13]=[CH:12][C:8]2[O:9][CH2:10][O:11][C:7]=2[CH:6]=1.ClC1C=CC=C(C(OO)=[O:22])C=1.O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:1][S:2]([CH2:3][CH2:4][C:5]1[CH:13]=[CH:12][C:8]2[O:9][CH2:10][O:11][C:7]=2[CH:6]=1)=[O:22]
Reactant: CSCCc1ccc2c(c1)OCO2
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CS(=O)CCc1ccc2c(c1)OCO2

Procedure:
3 g of 5-{2-(methylthio)ethyl}-1,3-benzodioxole was dissolved in 100 ml of chloroform. An equimolar amount of m-chloroperbenzoic acid was added to the solution under stirring under reflux with dry ice/alcohol to conduct the reaction for 1 h. 300 ml of chloroform and 300 ml of water were added thereto and then sodium carbonate was added to the mixture until the aqueous layer became alkaline. After separation of the layers, the chloroform layer was washed with water twice and dried over sodium sulfate. The solvent was distilled off under reduced pressure. The oily product was purified according to silica gel column chromatography (chloroform: methanol=20:1) to obtain 1.6 g of the intended compound in the form of a colorless oil.
Reaction SMILES: Cl.Cl.[OH:3][CH:4]([C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][C:19]=1[F:30])[CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH:8]1[CH2:13][C:14]([O:16][CH3:17])=[O:15].Br[CH2:32][CH2:33][S:34][C:35]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:36]=1[F:42].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(#N)C.C(N(CC)CC)C>[OH:3][CH:4]([C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][C:19]=1[F:30])[CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([CH2:32][CH2:33][S:34][C:35]2[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:36]=2[F:42])[CH2:9][CH:8]1[CH2:13][C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)CC1CNCCC1CCC(O)c1c(F)cnc2ccc(OC)cc12
Reactant: Fc1ccc(F)c(SCCBr)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)CC1CN(CCSc2cc(F)ccc2F)CCC1CCC(O)c1c(F)cnc2ccc(OC)cc12
Temperature: 70 °C
Reaction time: 22 h
Yield: 21.5 %

Procedure:
A mixture of 6.5 g of methyl (3RS,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]piperidine-3-acetate dihydrochloride, 3.9 g of 2-(2-bromoethylthio)-1,4-difluorobenzene dissolved in 10-cm3 of dimethylformamide, 2.32 g of potassium iodide, 5.8 g of potassium carbonate and 3.93-cm3 of trietylamine in 200-cm3 of acetonitrile was heated with stirring and under an inert atmosphere, for 22 hours at a temperature in the region of 70° C. After cooling to a temperature in the region of 20° C., the reaction mixture was filtered and the insoluble matter was washed twice with 30-cm3 of acetonitrile. The filtrate was concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The evaporation residue was taken up in 100-cm3 of distilled water and 150-cm3 of ethyl acetate. The organic phase was washed 3 times with 100-cm3 of distilled water and twice with 100-cm3 of a saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated to dryness according to the conditions described above. The oil obtained was purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 4 cm), eluting with a cyclohexane-ethyl acetate (50/50 by volume) mixture and collecting 60-cm3 fractions. The fractions containing the expected product were combined and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 1.7 g of methyl (3RS,4RS)-4-[3-(R,S) -hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,5-difluorophenylthio)ethyl]piperidine-3-acetate were obtained in the form of an orange-colored pourer viscous oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:16]([C:17](=S)[CH:18]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[CH3:20])=[CH:5][CH:4]=1.Cl.[NH2:22][OH:23]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:16]([C:17](=[N:22][OH:23])[CH:18]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[CH3:20])=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc(=S)c3cccc(C)c3o2)cc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(-c2cc(=NO)c3cccc(C)c3o2)cc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
To a solution of 2-(4-Methoxy-phenyl)-8-methyl-chromene-4-thione (160.0 mg, 0.57 mmol) in 3.5 mL of pyridine was added 118.4 mg (1.70 mmol) of hydroxylamine hydrochloride. The solution was stirred at 110° C. for 1 h. The solvent was removed under vacuum and the residue was treated with ice. The resulting slurry was filtered. The filter cake was washed with H2O and then dried overnight under vacuum to afford 137.0 mg (85.7% yield) of desired compound I-23 as a yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 10.86 (s, 1H), 7.89 (d, 2H), 7.71 (d, 1H), 7.35 (d, 1H), 7.15 (t, 1H), 7.09 (d, 2H), 7.00 (s, 1H), 3.84 (s, 3H), 2.44 (s, 3H) ppm. LC/MS: 282.1 (M+H), 280.0 (M−H), HPLC/Method A (Rt 6.268 min, 95.4% purity).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4]/[N:5]=[C:6](/[C:8]1[N:13]=[C:12]2[N:14]([CH2:17][C:18]3[CH:19]=[C:20]4[C:25](=[CH:26][CH:27]=3)[N:24]=[CH:23][CH:22]=[CH:21]4)[N:15]=[N:16][C:11]2=[N:10][CH:9]=1)\[CH3:7].Cl[C:29]([O:31][CH3:32])=[O:30].C(N(CC)CC)C>C(Cl)Cl>[N:24]1[C:25]2[C:20](=[CH:19][C:18]([CH2:17][N:14]3[C:12]4=[N:13][C:8](/[C:6](=[N:5]/[O:4][CH2:3][CH2:2][NH:1][C:29](=[O:30])[O:31][CH3:32])/[CH3:7])=[CH:9][N:10]=[C:11]4[N:16]=[N:15]3)=[CH:27][CH:26]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: C/C(=N\OCCN)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)NCCO/N=C(\C)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Temperature: 25 °C
Reaction time: 10 h
Yield: 47.6 %

Procedure:
To a solution of (E)-1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone O-2-aminoethyl oxime (example 34) (6 mg, 0.017 mmol) in DCM (5 mL) were added methyl chloroformate (2.66 mg, 0.028 mmol) and triethyl amine (3.35 mg, 0.033 mmol). The mixture was stirred at rt for 10 h. After concentration, the crude was purified by chromatography on silica gel to afford 3.4 mg (46%) of the title compound. 1H-NMR (400 MHz, CDCl3) δ ppm 9.41 (s, 1H), 8.93 (s, 1H), 8.14 (dd, 2H), 7.92 (s, 1H), 7.84 (dd, 1H), 7.44 (m, 1H), 6.12 (s, 2H), 4.42 (t, 2H), 3.69 (s, 3H), 3.60 (m, 2H), 2.39 (s, 3H). LCMS (method B): [MH]+=421, tR=1.95 min.
Reaction SMILES: [O:1]([C:8]1[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:25](Cl)(=[O:34])[CH:26]=[CH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl>C1COCC1>[O:1]([C:8]1[CH2:13][CH2:12][CH:11]([C:25](=[O:34])[CH:26]=[CH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:10](=[O:14])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: O=C1C=C(Oc2ccccc2)CCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(C=Cc1ccccc1)C1CCC(Oc2ccccc2)=CC1=O
Reaction time: 0.25 h
Yield: 43.2 %

Procedure:
A solution of 3-phenoxy-cyclohex-2-enone (301 mg, 1.6 mmol) in 1 mL of THF was added to a stirred solution of 1.0 M solution of lithium bis(trimethylsilyl)amide in THF (3.2 mL) at −78° C. After 15 min, cinnamoyl chloride (266 mg, 1.6 mmol) was added all at once. After 15 min, the reaction mixture was poured into 0.5 N HCl and extracted with EtOAc (2×). The combined organic layers were washed with saturated NaCl solution, dried (MgSO4), filtered, and concentrated under reduced pressure. Chromatography of the residue with 4:1 hexanes/ethyl acetate as eluant provided 220 mg (43%) of 3-phenoxy-6-(3-phenyl-acryloyl)-cyclohex-2-enone as a yellow solid (220 mg, 43%): 1H NMR (CDCl3) (enol form) δ 2.66 (t, 2H, J=7.2 Hz), 2.84 (t, 2H, J=7.1 Hz), 5.11 (s, 1H), 6.86 (d, 1H, J=15.6 Hz), 7.02 (d, 2H, J=8.1 Hz), 7.20 (m,2H), 7.28–7.38 (m, 3H). HRMS M+H+ calc: 319.1334. found 319.1340.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([O:25][C:26](=[O:28])[CH3:27])[C:7](=[O:24])[NH:8][C:9]1[C:14]([I:15])=[C:13]([C:16](Cl)=[O:17])[C:12]([I:19])=[C:11]([C:20]([Cl:22])=[O:21])[C:10]=1[I:23])(=[O:3])[CH3:2].[CH3:29][C:30]1([CH3:40])[O:34][CH:33]([CH2:35][NH:36][CH2:37][CH2:38][OH:39])[CH2:32][O:31]1.C(N(CC)CC)C>CC(N(C)C)=O>[C:1]([O:4][CH2:5][CH:6]([O:25][C:26](=[O:28])[CH3:27])[C:7](=[O:24])[NH:8][C:9]1[C:14]([I:15])=[C:13]([C:16](=[O:17])[N:36]([CH2:35][CH:33]2[CH2:32][O:31][C:30]([CH3:40])([CH3:29])[O:34]2)[CH2:37][CH2:38][OH:39])[C:12]([I:19])=[C:11]([C:20]([Cl:22])=[O:21])[C:10]=1[I:23])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(OC(C)=O)C(=O)Nc1c(I)c(C(=O)Cl)c(I)c(C(=O)Cl)c1I
Reactant: CC1(C)OCC(CNCCO)O1
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: CC(=O)OCC(OC(C)=O)C(=O)Nc1c(I)c(C(=O)Cl)c(I)c(C(=O)N(CCO)CC2COC(C)(C)O2)c1I
Temperature: 25 °C
Reaction time: 24 h
Yield: 38.5 %

Procedure:
To a ice cooled solution of acetic acid 2-acetoxy-1-(3,5-bis-chlorocarbonyl-2,4,6-triiodo-phenylcarbamoyl)-ethyl ester (20 g, 0.026 mol) in anhydrous DMAC (20 ml) were added dropwise a solution of 2-[(2,2-Dimethyl-[1,3]dioxolan-4-yl-methyl)-amino]-ethanol (4.6 g, 0.026 mol) in DMAC (20 mL) followed by triethylamine (˜3 g). The mixture was stirred at room temperature for 24 h and then poured over icewater (0.75 liter). A white precipitate formed. This was collected and washed with cold water. The filter cake was then dissolved in ethyl acetate and washed with brine. The organics were collected, dried over MgSO4, filtered and evaporated to dryness. The product was purified by silica column chromatography eluting with Petroleum ether/ethyl acetate. Two peaks closely eluting at 80% ethyl acetate were analysed by NMR and mass spec, and show to both contain the desired material. These were combined post analysis to give the desired product (10 mmol, Yield=38%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].S(Cl)([Cl:16])=O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:16])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: c1ccccc1
Product: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1

Procedure:
To a solution of 14.1 g (0.07 mole) of 4-chloro-3-nitrobenzoic acid in 200 ml of dry benzene, 10 ml of thionyl chloride is added and the mixture is refluxed for 10 hours. The excess of thionyl chloride is removed in vacuo and the acid chloride is purified by repeated addition of fresh benzene and subsequent removal in vacuo.
Reaction SMILES: O1C=C(CN)N=C1.[NH:8]1[CH:12]=[CH:11][C:10]([CH2:13][NH2:14])=[N:9]1.[F:15][C:16]1[CH:37]=[CH:36][C:19]([CH2:20][N:21]2[CH2:25][CH2:24][N:23]([C:26]3[CH:27]=[C:28]([CH:32]=[CH:33][N:34]=3)[C:29](O)=[O:30])[C:22]2=[O:35])=[CH:18][CH:17]=1>>[NH:8]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:29](=[O:30])[C:28]2[CH:32]=[CH:33][N:34]=[C:26]([N:23]3[CH2:24][CH2:25][N:21]([CH2:20][C:19]4[CH:18]=[CH:17][C:16]([F:15])=[CH:37][CH:36]=4)[C:22]3=[O:35])[CH:27]=2)=[N:9]1
Reactant: O=C(O)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Reactant: NCc1cc[nH]n1
Agent: NCc1cocn1
Product: O=C(NCc1cc[nH]n1)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Yield: 23 %

Procedure:
Following the procedure as described in Example 14, making variations as required to replace oxazol-4-ylmethanamine with (1H-pyrazol-3-yl)methanamine to react with 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinic acid, N-((1H-pyrazol-3-yl)methyl)-2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinamide was obtained as a colorless solid in 23% yield: mp 178-180° C.; 1H NMR (300 MHz, CDCl3) δ 8.60 (s, 1H), 8.33-8.24 (m, 2H), 7.45-7.37 (m, 2H), 7.32-7.17 (m, 3H), 7.04-6.94 (m, 2H), 6.27 (s, 1H), 4.70 (d, J=5.7 Hz, 2H), 4.43 (s, 2H), 4.03 (t, J=8.1 Hz, 2H), 3.37 (t, J=8.1 Hz, 2H); MS (ES+) m/z 394.9 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:13]=[CH:12][C:11]([OH:14])=[C:7]([C:8]([OH:10])=[O:9])[CH:6]=1)[CH3:2].CI.[C:18](=O)([O-])O.[Na+]>CN(C=O)C>[CH3:18][O:9][C:8](=[O:10])[C:7]1[CH:6]=[C:5]([CH:13]=[CH:12][C:11]=1[OH:14])[C:4]([O:3][CH2:1][CH3:2])=[O:15]
Reactant: O=C([O-])O
Reactant: CCOC(=O)c1ccc(O)c(C(=O)O)c1
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(O)c(C(=O)OC)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
To a solution of 4-hydroxyisophthalic acid 1-ethyl ester (4.51 g) in DMF (36 mL) were added methyl iodide (3.66 g) and sodium hydrogen carbonate (2.16 g). The mixture was stirred at 60° C. for 2 hours and then allowed to stand for cooling down to room temperature. The resulting precipitated solid formed upon addition of water was filtered off to give the title compound (4.20 g).
Reaction SMILES: BrBr.[C:3]([C:5]([C:17]([O:19][CH3:20])=[O:18])=[N:6][C:7]([CH3:16])=[C:8]([NH2:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)#[N:4].C(Cl)Cl.C[O-].[Na+]>CO>[CH3:20][O:19][C:17]([C:5]1[C:3]([NH2:4])=[N:15][C:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[C:7]([CH3:16])[N:6]=1)=[O:18]
Reactant: COC(=O)C(C#N)=NC(C)=C(N)c1ccccc1
Agent: BrBr
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1nc(C)c(-c2ccccc2)nc1N

Procedure:
A reactor provided with a stirring device, a bromine feed and a calcium chloride tube is filled with a solution of 4 parts of 1-cyano-1-methoxycarbonyl-3-methyl-4-amino-4-phenyl-2-aza-1,3-butadiene in 120 parts by volume of a mixture of dry methanol and dry methylene chloride (10 : 1 by volume.) 0.9 parts of sodium methylate dissolved in dry methanol are added rapidly at the ambient temperature with stirring. The reaction is finished at the end of 15 minutes, and the greater part of the solvents is evaporated under reduced pressure. The 2-methoxycarbonyl-3-amino-5-phenyl-6-methyl pyrazine which is precipitated is filtered off, then recrystallised from methanol and 3 parts of pyrazine are obtained. M.p. 162°C.
Reaction SMILES: [CH2:1]1[O:10][C:4]([CH2:6][CH2:7][CH2:8]Cl)([CH3:5])[O:3][CH2:2]1.[CH3:11][NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[CH2:1]1[O:10][C:4]([CH2:6][CH2:7][CH2:8][N:12]([CH3:11])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH3:5])[O:3][CH2:2]1
Reactant: CC1(CCCCl)OCCO1
Reactant: CNc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(CCCC1(C)OCCO1)c1ccccc1

Procedure:
Combine 5-chloro-2-pentanone ethylene ketal (80 g=0.49 mol), N-methylaniline (52 g=0.49 mol), potassium carbonate (67 g=0.49 mol) and potassium iodide (8.1 g) in 250 ml dimethylformamide and heat at 100° C. for 16 hours. Allow to cool, partition between ether and water, and wash the ether twice with water. Dry, concentrate and distill to obtain 5-(N-methylanilino)-2-pentanone ethylene ketal, boiling point 104°-109° C./0.1 mm. Dissolve this (47 g=0.20 mol) in 400 ml 1.0 N hydrochloric acid with 100 ml ethanol. Let stand 2 hours, concentrate and adjust pH to about 8. Extract with ethyl ether, dry, concentrate and distill to obtain the product, having a boiling point 100°-104° C./0.1 mm pressure.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:20]=[C:12]2[N:13]=[C:14]([CH3:19])[C:15]([Cl:18])=[C:16](O)[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:23])=O>>[CH2:1]([S:8][C:9]1[N:20]=[C:12]2[N:13]=[C:14]([CH3:19])[C:15]([Cl:18])=[C:16]([Cl:23])[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc2nc(SCc3ccccc3)nn2c(O)c1Cl
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nc2nc(SCc3ccccc3)nn2c(Cl)c1Cl
Yield: 68 %

Procedure:
This material was prepared in 68% yield from 2-benzylthio-6-chloro-7-hydroxy-5-methyl-1,2,4-triazolo[1,5-a]pyrimidine and phosphorus oxychloride following the general procedure described in Example 20. The desired product was isolated as a solid, m.p. 103°-105° C. IR and 1H NMR spectra were in agreement with the assigned structure.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH2:16]([O:23][C:24]([NH:26][C@H:27]([C:34]([OH:36])=O)[CH2:28][C:29]1[N:33]=[CH:32][NH:31][CH:30]=1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.ON1C(=O)CCC1=O.Cl.[CH3:46][O:47][C:48](=[O:61])[C@@H:49]([CH2:51][C:52]1[C:60]2[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=2)[NH:54][CH:53]=1)[NH2:50].C(NC1CCCCC1)(NC1CCCCC1)=O>CN(C=O)C>[CH3:46][O:47][C:48](=[O:61])[C@@H:49]([CH2:51][C:52]1[C:60]2[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=2)[NH:54][CH:53]=1)[NH:50][C:34](=[O:36])[C@H:27]([CH2:28][C:29]1[N:33]=[CH:32][NH:31][CH:30]=1)[NH:26][C:24]([O:23][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:25]
Reactant: O=C(N[C@@H](Cc1c[nH]cn1)C(=O)O)OCc1ccccc1
Reactant: COC(=O)[C@H](N)Cc1c[nH]c2ccccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: O=C(NC1CCCCC1)NC1CCCCC1
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Dicyclohexylcarbodiimide (DCC, ca. 95 g, 0.46 mol) was added to a -5° C. (ice-ethanol bath) solution of Nα -benzyloxycarbonyl-histidine (19, 143.5 g, 0.50 mol), N-hydroxysuccinimide (HOSU, 23, 77.5 g, 0.62 mol) and the freshly prepared free base form of 22 (114.5 g, ca. 0.52 mol) in DMF (ca. 3L). The resulting reaction solution was allowed to stir for 24 hours while warming to room temperature. HPLC analysis at this point showed the reaction to be incomplete. The reaction solution was then cooled to ca. -5° C. and an additional portion of dicyclohexylcarbodiimide (ca. 35 g, ca. 0.17 mol) was added to the reaction. The reaction mixture was then allowed to stir for an additional 24 hours while warming to room temperature. The mixture was then filtered to remove dicyclohexylurea (DCU). Water (1 L) was added to the filtrate and the resulting solution was concentrated in vacuo. The resulting residue was taken up in aqueous 1N HCl (ca. 1 L until the pH of the aqueous phase reached a pH of 1). The aqueous phase was then extracted with two portions of ethyl acetate (1 L each). The pH of the aqueous phase was then adjusted by addition of cold 2 N sodium hydroxide (500 mL) and sodium hydroxide pellets. During this neutralization, the solution was kept cold by addition of cold ethyl acetate (1 L). When the pH of the aqueous phase had reached 7, copious precipitation of a white solid resulted. This solid was collected by vacuum filtration and washed sequentially with half saturated sodium carbonate (2×1500 mL), water (6×1500 mL) and ethyl acetate (3×1500 mL). The resulting filter cake was dried under high vacuum to constant weight. The 1H NMR spectrum of this material (187.1 g, ca. 0.38 mol, ca. 77%) was consistent with a product containing 25 as a single isomer in the presence of small amounts of dicyclohexylurea. This material was hydrolyzed directly without further purification.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Br:7])[N:6]=1.[N:8]1([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.C(N(CC)CC)C.CN(C)C=O>O>[Br:7][C:5]1[N:6]=[C:2]([N:11]2[CH2:10][CH2:9][N:8]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:13][CH2:12]2)[S:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Brc1csc(Br)n1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(Br)cs2)CC1
Temperature: 120 °C
Reaction time: 18 h
Yield: 24.4 %

Procedure:
A 100-mL round-bottom flask was charged with 2,4-dibromothiazole (1.00 g, 4.12 mmol), tert-butyl piperazine-1-carboxylate (0.918 g, 4.93 mmol), triethylamine (1.72 mL, 12.35 mmol) and N,N-dimethylformamide (20 mL). The resulting solution stirred for 18 h at 120° C. The reaction mixture was cooled to room temperature, poured into water (50 mL), and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 10:1, dichloromethane/methanol) to afford tert-butyl 4-(4-bromothiazol-2-yl)piperazine-1-carboxylate (0.350 g, 23%) as brown oil. MS (ESI, pos. ion) m/z 348, 350 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@@:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl[CH2:31][C:32]1[CH:33]=[N:34][CH:35]=[C:36]([F:38])[CH:37]=1.[I-].[K+]>CC(=O)CC.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:38][C:36]1[CH:37]=[C:32]([CH2:31][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C@@:3]3([C:21]4[C:12](=[CH:13][C:14]5[O:19][CH2:18][CH2:17][O:16][C:15]=5[CH:20]=4)[O:11][CH2:10]3)[C:2]2=[O:22])[CH:33]=[N:34][CH:35]=1
Reactant: O=C1Nc2ccccc2[C@]12COc1cc3c(cc12)OCCO3
Reactant: Fc1cncc(CCl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCC(C)=O
Product: O=C1N(Cc2cncc(F)c2)c2ccccc2[C@]12COc1cc3c(cc12)OCCO3
Temperature: 25 °C
Reaction time: 72 h
Yield: 18.7 %

Procedure:
To a solution of (8S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.40 g, 1.35 mmol) in 2-butanone (15 mL) was added cesium carbonate (1.76 g, 5.40 mmol), 3-(chloromethyl)-5-fluoropyridine hydrochloride (0.49 g, 2.69 mmol) and potassium iodide (0.085 g, 38 mol %). This mixture was stirred under nitrogen at ambient temperature for 72 h. Further, cesium carbonate (1.76 g, 5.40 mmol), 3-(chloromethyl)-5-fluoropyridine hydrochloride (0.49 g, 2.69 mmol) and tetra-n-butylammonium iodide (0.08 g, 0.22 mmol) were added and the reaction mixture was heated at reflux for 48 h, allowed to cool to ambient temperature, filtered and concentrated in vacuo. The residue was purified by column chromatography and eluted with a 10% to 40% gradient of ethyl acetate in hexanes and recrystallized from diethyl ether to afford (8S)-1′-[(5-fluoropyridin-3-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (102.1 mg, 19%) as a yellow solid: mp 197-200° C. (diethyl ether); 1H NMR (300 MHz, CDCl3) δ 8.48-8.42 (m, 2H), 7.40-7.37 (m, 1H), 7.26-7.17 (m, 2H), 7.08-7.03 (m, 1H), 6.78-6.76 (m, 1H), 6.50 (s, 1H), 6.18 (s, 1H), 5.06-4.88 (m, 3H), 4.66-4.63 (m, 1H), 4.20-4.09 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 177.7, 155.3, 144.8, 144.4, 141.3, 138.4, 138.0, 137.7, 132.1, 129.0, 124.3, 124.0, 122.4, 122.2, 120.5, 111.4, 108.7, 99.5, 80.1, 64.5, 63.9, 58.0, 41.1; MS (ES+) m/z 404.9 (M+1).