Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[O:21][C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1)(OC(C)(C)C)=O.C(Cl)[Cl:23]>C(O)(C(F)(F)F)=O.Cl>[ClH:23].[ClH:23].[NH:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[O:21][C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1cc2ncccc2o1
Reactant: ClCCl
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: c1cnc2cc([C@@H]3CCCN3)oc2c1
Temperature: 25 °C

Procedure:
A 980 mg sample of 2-(1-BOC-2-(S)-pyrrolidinyl)furo[3,2-b]pyridine, from Example 1d above, was dissolved in a solution of TFA in CH2Cl2 at 0° C. and stirred under N2 while warming to room temperature. The reaction mixture was diluted with 1 N HCl, and the aqueous layer was separated. The aqueous solution was adjusted to pH 10 with K2CO3, and the mixture was extracted with CH2Cl2. The solution was dried over MgSO4 and concentrated. The residue was purified by chromatography on silica gel and treated with HCl in Et2O as described in Example 1e to obtain 280 mg of title compound: 1H NMR (CDCl3, 300 MHz) δ 2.17-2.52 (m, 3H), 2.65 (m, 1H), 3.57 (dt, 2H, J=1.5, 7.5 Hz), 5.15 (t, 1H, J=8 Hz), 7.44 (s, 1H), 7.84 (dd, 1H, J=6, 8.5 Hz), 8.5 (dt, 1H, J=1, 8.5 Hz), 8.70 (dd, 1H, J=1, 6 Hz). MS m/z: 189 (M+H)+, 206 (M+NH4)+ ; Anal. Calcd for C11H12N2O.2.0 HCl: C, 50.59; H, 5.40; N, 10.73. Found: C, 50.52; H, 5.26; N, 10.50.
Reaction SMILES: Br[CH:2]([C:4]1[N:13]([CH3:14])[C:12](=[O:15])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=2)[N:5]=1)[CH3:3].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)(=[O:30])=[O:29])=[CH:24][CH:23]=1>C(#N)C>[CH3:19][S:16]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([CH:2]([N:34]1[CH2:33][CH2:32][N:31]([S:28]([C:25]3[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[CH:27][CH:26]=3)(=[O:30])=[O:29])[CH2:36][CH2:35]1)[CH3:3])[N:13]([CH3:14])[C:12]2=[O:15])(=[O:18])=[O:17]
Reactant: COc1ccc(S(=O)(=O)N2CCNCC2)cc1
Reactant: CC(Br)c1nc2ccc(S(C)(=O)=O)cc2c(=O)n1C
Solvent: CC#N
Product: COc1ccc(S(=O)(=O)N2CCN(C(C)c3nc4ccc(S(C)(=O)=O)cc4c(=O)n3C)CC2)cc1
Temperature: 80 °C
Yield: 51.9 %

Procedure:
In a test tube containing of 2-(1-Bromo-ethyl)-6-methanesulfonyl-3-methyl-3H-quinazolin-4-one (40.0 mg, 0.12 mmol) in acetonitrile (2 ml) was added KI (28.0 mg, 0.18 mmol), and (1-(4-Methoxy-benzenesulfonyl)-piperazine (39.6 mg, 0.18 mmol). The reaction was heated at 80° C. for 18 hours. The solution was concentrated under reduced pressure. The residue was partitioned between water (2 ml) and dichloromethane (5 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The solvent was removed under vacuum. The resulting residue was dissolvent in DMSO (2 ml) and purified by HPLC (Gilson-215, 0.035% TFA in acetonitrile and 0.05% water as mobile phase). The product was collected and dried under reduced pressure to give 6-Methanesulfonyl-2-{1-[4-(4-methoxy-benzenesulfonyl)-piperazin-1-yl]-ethyl}-3-methyl-3H-quinazolin-4-one (Yield 32.4 mg, 55.2%). 1H NMR (400 MHz, CDCl3): δ 1.82 (d, 3H, J=7.07 Hz), 3.12 (s, 3H), 3.64-3.40 (m, 4H), 3.70 (s, 3H), 4.00-3.86 (m, 7H), 4.89 (q, 1H, J=14.40, 6.03 Hz), 7.05 (d, 2H, J=9.09 Hz), 7.68 (d, 2H, J=9.09, Hz), 7.84 (d, 1H, J=8.84 Hz), 8.25 (dd, 1H J=8.84, 2.02 Hz), 8.82 (d, 1H, J=2.02 Hz). MS m/z calc. 490.1, found (ESI); 491.2 (M+1)+. Retention time 2.17 minutes.
Reaction SMILES: [CH:1]1([C:10](Cl)=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[NH:13]1[CH2:18][CH:17]=[C:16]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1.C(N(CC)CC)C.[NH4+].[OH-]>ClCCl.C1COCC1>[CH:1]1([C:10]([N:13]2[CH2:14][CH:15]=[C:16]([C:19]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[NH:21][CH:20]=3)[CH2:17][CH2:18]2)=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CCc2ccccc21
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(C1CCc2ccccc21)N1CC=C(c2c[nH]c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.1 %

Procedure:
1-Indanecarboxylic acid chloride (4.5 g), prepared as described in International Patent Application No. WO 9533721-A1 in dichloromethane (25 ml) was added drop-wise at 0-5° C. to a mixture of 3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (5 g) (see general method for preparation in Guillaume et al. Eur. J. Med. Chem. 1987, 22, 33-43) and triethylamine (3.8 ml) in THF (50 ml). The resulting mixture was stirred overnight at room temperature. The mixture was poured into diluted aqueous NH4OH (500 ml) and extracted several times with dichloromethane (4×100 ml). The combined organic phases were worked up according to the general procedure above. Column chromatography (eluted with ethyl acetate/heptane 70/30) of the crude product afforded pure title compound 4a as a visceous oil (4.7 g) which was used without further purification.
Reaction SMILES: Cl[C:2](=[CH2:5])[C:3]#[N:4].Br.[CH2:7]([O:9][C:10]([C:12]([NH2:14])=[NH:13])=[O:11])[CH3:8].C(N(CC)CC)C>C(O)C>[NH2:4][C:3]1[CH:2]=[CH:5][N:14]=[C:12]([C:10]([O:9][CH2:7][CH3:8])=[O:11])[N:13]=1
Reactant: CCOC(=O)C(=N)N
Reactant: C=C(Cl)C#N
Agent: Br
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1nccc(N)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 57.5 %

Procedure:
To a solution of 2-chloroacrylonitrile (437 mg) and 1-ethoxycarbonylformamidine hydrobromide (985 mg) in ethanol (5 ml) was added dropwise triethylamine (1.01 g) at 0° C. The reaction mixture was stirred for 4 hours at ambient temperature and evaporated to dryness. The residue was dissolved in a mixture of ethyl acetate and water, and extracted with ethyl acetate three times. The combined extracts were dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was triturated with diethyl ether to give ethyl 4-aminopyrimidine-2-carboxylate (480 mg), which was recrystallized from a mixture of ethyl acetate and benzene, mp. 101°-104° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([C@@H:20]([N:22]3[CH2:27][CH2:26][C@:25]([CH2:34][C:35]([OH:38])([CH3:37])[CH3:36])([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[O:24][C:23]3=[O:39])[CH3:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].CO.[H][H]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([C@@H:20]([N:22]3[CH2:27][CH2:26][C@:25]([CH2:34][C:35]([OH:38])([CH3:37])[CH3:36])([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[O:24][C:23]3=[O:39])[CH3:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: C[C@@H](c1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: C[C@@H](c1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
A mixture of 4-(4-{(S)-1-[(S)-6-(2-hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]ethyl}-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.34 g) and 10% palladium on carbon (60 mg) in methanol (10 mL) was shaken in hydrogen atmosphere (50 psi) for 4 h. Then, the catalyst was separated by filtration and the filtrate was concentrated to yield the title compound.
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](\[C:11]([NH:13][C@@H:14]1[C:17](=[O:18])[N:16]2[C:19]([C:23]([O-:25])=[O:24])=[CH:20][CH2:21][S:22][C@H:15]12)=[O:12])/[C:5]1[N:9]=[C:8]([NH2:10])[S:7][CH:6]=1.[Na+].C(O)(=O)C>O>[CH3:1][O:2]/[N:3]=[C:4](\[C:11]([NH:13][C@@H:14]1[C:17](=[O:18])[N:16]2[C:19]([C:23]([OH:25])=[O:24])=[CH:20][CH2:21][S:22][C@H:15]12)=[O:12])/[C:5]1[N:9]=[C:8]([NH2:10])[S:7][CH:6]=1
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=CCS[C@H]12)c1csc(N)n1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(N)n1
Yield: 91.8 %

Procedure:
A solution of 5.40 mmol of ceftizoxime sodium salt (equivalent to 2 g of ceftizoxime) in 20 ml of water was acidified with 5.40 ml of 1 N acetic acid. The resulting solid was collected and washed with ice water to give 1.90 g of ceftizoxime. A suspension of 1.85 g of ceftizoxime (dried at 80° C./0.1 mm) in 60 ml of methylene chloride was stirred overnight under argon with 2.03 g of N,O-bis(trimethylsilyl) acetamide and 1.73 g of diethyl chlorophosphate, whereupon the solid had dissolved. After a month the reaction mixture was evaporated to dryness and the residue was washed with water. The aqueous washes were extracted with chloroform, back-washing the chloroform extracts with water. Evaporation of the dried (MgSO44) chloroform extracts left 0.049 g of a colorless gum; NMR (CDCl3, 80 MHz) δ 1.37 (t, CH3) δ 1.41 (t, CH3), 4.17 (OCH2, NOCH3); IR (KBr) 1032 (P=O), 1787 (β-lactam).
Reaction SMILES: [C:1]([NH:4][C@@H:5]([CH2:12]Cl)[C:6]([O:8][CH2:9][CH2:10][CH3:11])=[O:7])(=[O:3])[CH3:2].N1([C:19]2[CH2:23][CH2:22][CH2:21][CH:20]=2)CCCC1.CN(C)CC.[OH2:29]>C(#N)C>[C:1]([NH:4][CH:5]([CH2:12][CH:20]1[CH2:21][CH2:22][CH2:23][C:19]1=[O:29])[C:6]([O:8][CH2:9][CH2:10][CH3:11])=[O:7])(=[O:3])[CH3:2]
Reactant: C1=C(N2CCCC2)CCC1
Reactant: CCCOC(=O)[C@H](CCl)NC(C)=O
Reactant: O
Agent: CCN(C)C
Solvent: CC#N
Product: CCCOC(=O)C(CC1CCCC1=O)NC(C)=O
Temperature: 20 °C
Reaction time: 21 h
Yield: 87 %

Procedure:
(R)-propyl 2-acetamido-3-chloropropanoate (2.50 g, 12.0 mmol) was dissolved in acetonitrile (25 mL) and 1-pyrrolidino-1-cyclopentene (2.27 mL, 2.14 g, 15.6 mmol) was added. While the reaction was kept at 20° C., dimethylethylamine (1.70 mL, 1.14 g, 15.6 mmol) was added via an addition funnel during 10 min. The homogeneous reaction was stirred at 20° C. for 21 h. Then, water (0.50 mL) was added and the reaction was further stirred for 2.5 h. The solvents were removed in vacuo at 50° C. and the residual oil was purified by silica gel flash chromatography using an EtOAc:petroleum benzene gradient. The product is a yellowish oil. Weight 2.67 g, approx. 87% yield (two diastereomers). 1H NMR: (CDCl3, 300 MHz): δ 6.62 (br d, 0.5H), 6.38 (br d, 0.5H), 4.61-4.49 (m, 1H), 4.05-4.00 (m, 2H), 2.38-1.92 (m, 8H), 1.80-1.47 (m, 6H), 0.90-0.84 (m, 3H).
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[C:11]([NH:15][C:16]#[N:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:18](N(C(C)C)CC)(C)C.CI>C(#N)C>[CH2:1]([S:8][C:9]1[CH:10]=[C:11]([N:15]([CH3:18])[C:16]#[N:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CNc1cccc(SCc2ccccc2)c1
Reactant: CCN(C(C)C)C(C)C
Solvent: CI
Solvent: CC#N
Product: CN(C#N)c1cccc(SCc2ccccc2)c1
Temperature: 82.5 °C
Yield: 80 %

Procedure:
To a solution of 3-(benzylthio)phenylcyanamide (0.80 g, 3.33 mmol) dissolved in acetonitrile (8 mL) was added diisopropylethylamine (0.65 g, 5.0 mmol), followed by addition of methyl iodide (0.94 g, 6.66 mmol). The reaction mixture was refluxed at 80-85° C. for 3 hours. After removal of solvents the residue was taken by dichloromethane (40 ml) and the organic solution was washed by water (40 ml). After dried over MgSO4 and filtered, dichloromethane solution was then concentrated in vacuo to afford yellow oil as crude product. Purification by column chromatography (SiO2, Hexane/CH2Cl2, 50% to 100%) to afford 3-(benzylthio)phenyl-N-methylcyanamide as a pale yellow oil (0.67, 80% yield): CH2Cl2 Rf=0.45; 1H-NMR (CDCl3) δ (ppm) 7.3-6.8 (m, 9H, Ar—H), 4.06 (s, S—CH2, 2H), 3.57 (s, 3H, N—CH3).
Reaction SMILES: C([O:3][C:4]([C:6]1[O:10][N:9]=[C:8]([CH3:11])[CH:7]=1)=[O:5])C.[OH-].[Na+].CO.Cl>O1CCCC1.O>[CH3:11][C:8]1[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[O:10][N:9]=1
Reactant: CCOC(=O)c1cc(C)no1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(C(=O)O)on1
Temperature: 25 °C
Reaction time: 19 h
Yield: 89.5 %

Procedure:
A round bottom flask with magnetic stirrer was charged with 3-methyl-isoxazole-5-carboxylic acid ethyl ester (900 mg, 5.8 mmol) in tetrahydrofuran (2.0 mL). To the reaction was added a solution of sodium hydroxide (465 mg, 11.6 mmol) in water (2 mL), followed by methanol (4 mL). The reaction was stirred at room temperature for 18-20 hours under an argon atmosphere. The reaction was transferred to a separatory funnel and the pH adjusted to 2 via addition of 1N hydrochloric acid. The mixture was extracted with ethyl acetate (3×35 mL) and the combined extractions were washed with brine (1×50 mL), dried over magnesium sulfate, and filtered. The filtrate was concentrated in vacuo to yield 3-methyl-isoxazole-5-carboxylic acid as a white solid (660 mg, 90%). The solid was used without purification in the next reaction.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.I[C:13]1[C:21]2[C:16](=[N:17][CH:18]=[N:19][C:20]=2[NH2:22])[N:15]([CH:23]([CH3:25])[CH3:24])[N:14]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.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>[CH:23]([N:15]1[C:16]2=[N:17][CH:18]=[N:19][C:20]([NH2:22])=[C:21]2[C:13]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[N:14]1)([CH3:25])[CH3:24]
Reactant: COc1ccc(B(O)O)cc1
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
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: COCCOC
Solvent: CCO
Product: COc1ccc(-c2nn(C(C)C)c3ncnc(N)c23)cc1
Temperature: 80 °C
Yield: 15.9 %

Procedure:
A solution of (4-Methoxyphenylboronic acid (17 mg, 0.11 mmol) in EtOH (3.3 ml) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (30 mg, 0.10 mmol) in DME (12 ml). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (1.9 ml) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA48 (4.5 mg, 16% yield). ESI-MS (M+H)+ m/z calcd 284.1, found 284.1.
Reaction SMILES: [CH3:1][SiH:2]1[O:9][SiH:8]([CH3:10])[O:7][SiH:6]([CH3:11])[O:5][SiH:4]([CH3:12])[O:3]1.[OH:13][CH2:14][CH2:15][O:16][C:17]([CH:19]1[CH2:24][CH:23]2[CH2:25][CH:20]1[CH:21]=[CH:22]2)=[O:18].C1C=CC=CC=1>[Zn](OC(C)=O)OC(C)=O.O>[CH:20]12[CH2:25][CH:23]([CH:22]=[CH:21]1)[CH2:24][CH:19]2[C:17]([O:16][CH2:15][CH2:14][O:13][Si:8]1([CH3:10])[O:9][SiH:2]([CH3:1])[O:3][SiH:4]([CH3:12])[O:5][SiH:6]([CH3:11])[O:7]1)=[O:18]
Reactant: C[SiH]1O[SiH](C)O[SiH](C)O[SiH](C)O1
Reactant: O=C(OCCO)C1CC2C=CC1C2
Agent: CC(=O)O[Zn]OC(C)=O
Solvent: c1ccccc1
Solvent: O
Product: C[SiH]1O[SiH](C)O[Si](C)(OCCOC(=O)C2CC3C=CC2C3)O[SiH](C)O1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution containing 1M of 2,4,6,8-tetramethylcyclotetrasiloxane and 0.01 g of (CH3CO2)2Zn was slowly added 1M of 2-hydroxyethyl-5-norbornene-2-carboxylate. The resulting mixture was stirred for 24 hours at a room temperature. Thereafter, 200 mL of benzene and 200 mL of cold water were added. The organic layer was separated, washed with 200 mL of cold water, dried over MgSO4, filtered and concentrated by distillation to provide the title compound of Formula 1A (yield: 97%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]#[N:17])[CH:14]=3)[NH:9][CH:8]=2)[CH2:3][CH2:2]1.[O:18]([CH2:25][CH2:26][CH2:27]Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>CO>[O:18]([CH2:25][CH2:26][CH2:27][N:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]#[N:17])[CH:14]=3)[NH:9][CH:8]=2)[CH2:3][CH2:2]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: N#Cc1ccc2[nH]cc(C3CCNCC3)c2c1
Reactant: BrCCCOc1ccccc1
Solvent: CO
Solvent: CCN(CC)CC
Product: N#Cc1ccc2[nH]cc(C3CCN(CCCOc4ccccc4)CC3)c2c1
Yield: 44.3 %

Procedure:
A stirred solution of 3-(4-piperidinyl)-5-cyanoindole (0.71 g, 2.2 mmol), 3-phenoxypropyl bromide (0.52 g, 2.4 mmol), and triethylamine (0.6 ml, 4.4 mmol) in methanol (10 mL) was heated at reflux for 18 hours. The solution was concentrated in vacuo. Purification by flash chromatography yielded the product (0.35 g, 44%). 1H-NMR δ(CD3OD) 8.11 (s, 1 H), 7.49 (d, 1 H), 7.40 (d, 1 H), 7.28 (m, 3 H), 6.94 (m, 3 H), 4.12 (t, 2 H), 3.59 (br d, 2 H), 3.26-3.18 (m, 3 H), 3.04 (br t, 2 H), 2.25 (m, 4 H), 2.02 (br q, 2 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10](Cl)=[O:11])[CH:6]=[CH:7][CH:8]=1.[NH2:13][C:14]1[CH:15]=[C:16]([C:20]2[C:24]([Br:25])=[CH:23][N:22]([CH3:26])[N:21]=2)[CH:17]=[CH:18][CH:19]=1.C(N(CC)CC)C>ClCCl.[Cl-].[Na+].O>[Br:25][C:24]1[C:20]([C:16]2[CH:15]=[C:14]([NH:13][C:10](=[O:11])[CH2:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:19]=[CH:18][CH:17]=2)=[N:21][N:22]([CH3:26])[CH:23]=1
Reactant: COc1cccc(CC(=O)Cl)c1
Reactant: Cn1cc(Br)c(-c2cccc(N)c2)n1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1cccc(CC(=O)Nc2cccc(-c3nn(C)cc3Br)c2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 18.7 %

Procedure:
A solution of 3-methoxyphenylacetyl chloride (0.02 ml, 0.12 mmol) in dichloromethane (0.75 ml) was added dropwise at 0° C. to a solution of 3-(3-aminophenyl)-4-bromo-1-methylpyrazole (30 mg, 0.12 mmol) and triethylamine (0.02 ml, 0.13 mmol) in dichloromethane (0.75 ml). The resulting mixture was stirred at room temperature for 16 h and then poured into brine. The organic layer was washed with more brine then dried over magnesium sulphate and concentrated in vacuo. The crude product was purified by column chromatography (ethyl acetate-toluene, 1:1), giving the title compound (9 mg, 19%). Rf 0.30 (ethyl acetate-toluene, 1:1).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:14])=[CH:4][C:5]([O:12][CH3:13])=[C:6]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:7]=1.CN(P(N(C)C)(N(C)C)=O)C.[Li+].CC([N-]C(C)C)C.[C:34](=[O:36])=[O:35]>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([S:8](=[O:10])(=[O:9])[NH2:11])[C:5]([O:12][CH3:13])=[CH:4][C:3]=1[CH2:14][C:34]([OH:36])=[O:35]
Reactant: COc1cc(C)c(Br)cc1S(N)(=O)=O
Reactant: O=C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: COc1cc(CC(=O)O)c(Br)cc1S(N)(=O)=O
Temperature: -75 °C
Reaction time: 1.5 h
Yield: 3 %

Procedure:
A dry 25 mL 3-neck RBF, fitted with a magnetic stirring bar, a thermometer and septum with Ar inlet was charged with 5-bromo-2-methoxy-4-methylbenzene-sulfonamide 12e (0.586 g, 2.1 mmol), anhydrous THF (5 mL) and HMPA (0.37 mL, 2.1 mmol). The mixture was cooled to −75° C. and a 2.0 M solution of LDA (4.2 mL, 8.4 mmol) was added drop wise via a syringe. The reaction mixture was stirred at −75° C. for 1.5 hours and then cannulated into a flask containing 20 g of dry ice and 5 mL THF and left to warm up slowly to RT. The solvent was removed under reduced pressure and H2O (20 mL) was added to the residue. At this point, some of the unreacted starting material precipitated and was removed by filtration. The filtrate was acidified and the solution was extracted with EtOAc (3×20 mL). The combined organic layers were evaporated to dryness, the residue was treated with an aqueous solution of saturated NaHCO3 (10 mL) and the insoluble material was separated by filtration. The filtrate was acidified with concentrated HCl and the cloudy solution extracted again with EtOAc (3×5 mL). The combined organic layers were concentrated to ˜1 mL, causing crystallization of the product, which was collected by filtration to give pure (2-bromo-5-methoxy-4-sulfamoylphenyl)acetic acid (20 mg) 12f (˜3% yield).
Reaction SMILES: [NH:1]([C:33]([O:35][CH2:36][CH:37]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:43]2[C:38]1=[CH:39][CH:40]=[CH:41][CH:42]=2)=[O:34])[C@H:2]([C:10]([N:12]([CH3:32])[C@H:13]([C:17]([NH:19][C@H:20]([C:29]([NH2:31])=[O:30])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)=[O:18])[CH:14]([CH3:16])[CH3:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.[N+:51]([O-])([OH:53])=[O:52]>C(Cl)Cl.C(O)(=O)C>[NH:1]([C:33]([O:35][CH2:36][CH:37]1[C:38]2[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:44]2[C:49]1=[CH:48][CH:47]=[CH:46][CH:45]=2)=[O:34])[C@H:2]([C:10]([N:12]([CH3:32])[C@H:13]([C:17]([NH:19][C@H:20]([C:29]([NH2:31])=[O:30])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([N+:51]([O-:53])=[O:52])[CH:23]=1)=[O:18])[CH:14]([CH3:16])[CH3:15])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])O
Reactant: CC(C)[C@@H](C(=O)N[C@@H](Cc1ccc(O)cc1)C(N)=O)N(C)C(=O)[C@H](Cc1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: CC(C)[C@@H](C(=O)N[C@@H](Cc1ccc(O)c([N+](=O)[O-])c1)C(N)=O)N(C)C(=O)[C@H](Cc1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
To a solution of Fmoc-Phe-N-Me-Val-Tyr-NH2 (230 mg, 0.340 mmol) in methylene chloride (1 ml) and acetic acid (1 ml), fuming nitric acid (0.03 ml) was added under cooling with ice, followed by stirring at room temperature for 1 hour. The reaction mixture was mixed with water and extracted with methylene chloride. The organic layer was washed with saturated brine, dried over magnesium sulfate and evaporated to remove the solvent under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=2:1) to give the titled compound (204 mg, 83%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:12][CH:13]([CH3:23])[CH2:14][O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=O)=O.[CH3:24][C:25]1([CH3:37])[C:29]([CH3:31])([CH3:30])[O:28][B:27]([C:32]2[CH:33]=[N:34][NH:35][CH:36]=2)[O:26]1>CN(C=O)C>[CH2:16]([O:15][CH2:14][CH:13]([CH3:23])[CH2:12][N:35]1[CH:36]=[C:32]([B:27]2[O:26][C:25]([CH3:37])([CH3:24])[C:29]([CH3:31])([CH3:30])[O:28]2)[CH:33]=[N:34]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC(COCc1ccccc1)COS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(COCc1ccccc1)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Potassium carbonate (0.855 g, 6.18 mmol) and 3-(benzyloxy)-2-methylpropyl methanesulfonate (Compound 18F, 1.46 g, 5.67 mmol) were added to a solution of 4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (1.0 g, 5.2 mmol) in DMF (4 mL) and the mixture was allowed to stir at 80° C. overnight. The reaction was quenched with water (20 mL) and extracted with EtOAc (50 mL). The organic layer was washed with water (2×30 mL), washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on a Teledyne ISCO Combiflash® Rf system using Heptane/EtOAc (70:30→30:70) as eluent to give the desired product as a light-yellow oil. 1H NMR (CDCl3, 400 MHz): δ=7.80 (s, 1H), 7.65 (s, 1H), 7.29-7.37 (m, 5H), 4.49 (s, 2H), 4.26, 4.04 (ABX, JAB=13.4 Hz, JAX=6.3 Hz, JBX=7.1 Hz, 2H), 3.32 (d, J=5.6 Hz, 2H), 2.41 (m, 1H), 1.33 (s, 12H), 0.95 (d, J=6.8 Hz, 3H).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4](=O)[CH:5]([CH2:7][CH2:8][CH3:9])O.[CH2:11]([SH:15])[CH:12]([SH:14])[CH3:13].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:13][CH:12]1[CH2:11][S:15][C:4]([CH2:3][CH2:2][CH3:1])=[C:5]([CH2:7][CH2:8][CH3:9])[S:14]1
Reactant: CC(S)CS
Reactant: CCCC(=O)C(O)CCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCCC1=C(CCC)SC(C)CS1

Procedure:
The method of Example 4 was followed, using butyroin (12 g), propane-1,2-dithiol (9 g) and p-toluenesulfonic acid (0.5 g). 2,3-Dihydro-2-methyl-5,6-dipropyl-1,4-dithiin was obtained as a greenish liquid, boiling range 76°-85°/0.055 mm, yield 7.5 g (35%). NMR (CDCl3) 0.92 δ (triplet), 1.25-2.4 δ (complex overlapping doublet, multiplet, and quartet) 2.6-3.6 δ (complex multiplet).