Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C:2]1[CH:6]=C(C)[N:4]([C:8](=[NH:20])[NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[N:3]=1.CS(O)(=O)=O.N[N:27]1[CH2:32]CN(C)[CH2:29][CH2:28]1>>[NH2:20][C:8]([NH:4][N:3]1[CH2:2][CH2:6][N:27]([CH3:32])[CH2:28][CH2:29]1)=[N:9][S:10]([C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=1)(=[O:11])=[O:12]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)n2nc(C)cc2C)cc1
Reactant: CN1CCN(N)CC1
Agent: CS(=O)(=O)O
Product: Cc1ccc(S(=O)(=O)N=C(N)NN2CCN(C)CC2)cc1

Procedure:
The compound of Example 8 was prepared according to the accompanying synthesis procedure from 0.5 ml of N-[(3,5-dimethylpyrazol-1-yl)-iminomethyl]-4-methylbenzene-sulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of N-amino-4-methylpiperazine solution (1.0 M, acetonitrile) and filed in a substance databank. Calculated mol. wt. 311.40; found mol. wt. (M+H) 312.2; 623.0 (Dimer)
Reaction SMILES: C([N:3](C(=O)C1C=CC(O)=CC=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)C.[CH:38]12[N:44]([C:45](=O)[CH2:46]Br)[CH:41]([CH2:42][CH2:43]1)[CH2:40][CH2:39]2>>[CH:38]12[N:44]([CH2:45][CH2:46][O:10][C:8]3[CH:9]=[CH:4][C:5]([CH2:12][CH2:13][CH2:14][NH:3][C:4]4[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=4[CH:12]4[CH2:21][CH2:20][C:19]5[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=5[CH2:13]4)=[CH:6][CH:7]=3)[CH:41]([CH2:42][CH2:43]1)[CH2:40][CH2:39]2
Reactant: O=C(CBr)N1C2CCC1CC2
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCCc2ccc(OCCN3C4CCC3CC4)cc2)c1
Yield: 133.3 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphtha len-2-yl ester (20 mg) and 1-(7-azabicyclo[2.2.1]hept-7-yl)-2-bromoethanone (18 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (14 mg) was obtained.
Reaction SMILES: [Cl:1][C:2](=[CH2:12])[CH2:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[Cl:1][C:2](=[CH2:12])[CH2:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1
Reactant: C=C(Cl)Cc1ccc(C=O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: C=C(Cl)Cc1ccc(CO)cc1
Reaction time: 1 h

Procedure:
The aldehyde (0.25 g) of Example 1 in ether (5 ml) is added to lithium aluminum hydride (0.03 g) in ether (5 ml), and the mixture stirred at 20° for 1 hour. After successive dropwise additions of water (30 μl), 15% NaOH (30 μl) and water (90 μl), the resulting clear ether layer (+ washings) is evaporated to a residue of 4(2-chloroallyl)benzyl alcohol yield 0.22 g (86%) nD20 1.5504.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]=[C:9]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[NH:10][C:11]1[CH:15]=[N:14][N:13]2[CH2:16][CH2:17][NH:18][C:12]=12)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:27]1([C:33](Cl)([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(Cl)(Cl)Cl>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]=[C:9]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[NH:10][C:11]1[CH:15]=[N:14][N:13]2[CH2:16][CH2:17][N:18]([C:33]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:12]=12)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)Nc1cnn2c1NCC2
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)Nc1cnn2c1N(C(c1ccccc1)(c1ccccc1)c1ccccc1)CC2
Temperature: 50 °C
Reaction time: 5 h
Yield: 51.6 %

Procedure:
To a solution of 7-[2,3-bis(tert-butoxycarbonyl)guanidino]-2,3-dihydro-1H-imidazo[1,2-b]pyrazole (1.83 g) in pyridine (10 ml) was added triphenylmethyl chloride (1.67 g). The mixture was stirred at 50° C. for 5 hours. After cooling, chloroform (50 ml) was added to the reaction mixture, and the mixture was washed successively with 10% aqueous citric acid solution, brine and saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 2% methanol/chloroform to give 7-[-2,3-bis(tert-butoxycarbonyl)guanidino]-1-triphenylmethyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazole (1.57 g) as a solid.
Reaction SMILES: [CH2:1]([C:3]1[N:12]([CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23](C(F)(F)F)[CH:22]=3)[CH2:17][CH2:16]2)[C:11](=[O:31])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2].[CH2:32]([O:34]C1C=CC=CC=1N1CCNCC1)[CH3:33]>>[CH2:1]([C:3]1[N:12]([CH2:13][CH2:14][N:15]2[CH2:16][CH2:17][N:18]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=3[O:34][CH2:32][CH3:33])[CH2:19][CH2:20]2)[C:11](=[O:31])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2]
Reactant: CCOc1ccccc1N1CCNCC1
Reactant: CCc1nc2ccccc2c(=O)n1CCN1CCN(c2cccc(C(F)(F)F)c2)CC1
Product: CCOc1ccccc1N1CCN(CCn2c(CC)nc3ccccc3c2=O)CC1

Procedure:
This compound was prepared in compliance with the procedure described in 7d, using 1-(2-ethoxyphenyl)piperazine instead of 1-(3-(trifluoromethyl)phenyl)piperazine.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21](Cl)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=2)=[C:12]([O:28][CH3:29])[CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[NH2:30][C:31]1[CH:32]=[CH:33][C:34]([O:42][CH:43]([CH3:45])[CH3:44])=[C:35]2[C:39]=1[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]2>>[CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:30][C:31]3[CH:32]=[CH:33][C:34]([O:42][CH:43]([CH3:44])[CH3:45])=[C:35]4[C:39]=3[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]4)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=2)=[C:12]([O:28][CH3:29])[CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Reactant: CC(C)Oc1ccc(N)c2c1CN(C)C2=O
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(OC(C)C)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC

Procedure:
The title compound was prepared according to the procedure for Example 102 using diethyl(4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and 7-Amino-2-methyl-4-(propan-2-yloxy)-2,3-dihydro-1H-isoindol-1-one (Compound 207A). MS (ES+): m/z 638.26 (100) [MH+]; HPLC: tR=1.21 min (UPLC, purity).
Reaction SMILES: [C:1]12([OH:13])[CH2:10][C:5]3([OH:11])[CH2:6][CH:7]([CH2:9][C:3]([OH:12])([CH2:4]3)[CH2:2]1)[CH2:8]2.C(O[C:18](=[O:20])[CH3:19])(=O)C>S(=O)(=O)(O)O>[C:5]([O:13][C:1]12[CH2:10][C:5]3([O:11][C:3](=[O:12])[CH3:2])[CH2:6][CH:7]([CH2:9][C:3]([O:12][C:18](=[O:20])[CH3:19])([CH2:4]3)[CH2:2]1)[CH2:8]2)(=[O:11])[CH3:4]
Reactant: CC(=O)OC(C)=O
Reactant: OC12CC3CC(O)(C1)CC(O)(C3)C2
Agent: O=S(=O)(O)O
Product: CC(=O)OC12CC3CC(OC(C)=O)(C1)CC(OC(C)=O)(C3)C2
Temperature: 100 °C

Procedure:
92.12 g (0.5 mol) of 1,3,5-adamantanetriol are suspended in 153.14 g (1.5 mol) of acetic anhydride. Subsequently, 10 drops of concentrated sulfuric acid are added and the mixture is stirred on a rotary evaporator (without vacuum) until a homogeneous solution has formed. Subsequently, the mixture is heated to 100° C. under reflux for 2 h. After cooling, the reaction mixture is added to 300 ml of ice-water and extracted with dichloromethane. The combined organic phases are deacidified with sodium carbonate solution and washed with water. The mixture is dried over magnesium sulfate and filtered, and the solvent is removed under reduced pressure. 150.50 g (0.48 mol; 97.0%) of a colorless oil are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.Br[C:10]1[CH:21]=[CH:20]C2C(=O)CCCS[C:12]=2[CH:11]=1.C[Mg]I>CCOCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[CH:11]([CH3:12])[CH2:10][CH2:21][CH2:20][S:8][C:4]=2[CH:3]=1
Reactant: O=C1CCCSc2cc(Br)ccc21
Reactant: Sc1cccc(Br)c1
Agent: C[Mg]I
Solvent: CCOCC
Product: CC1CCCSc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
First, m-bromothiophenol was converted into 8-bromo-3,4-dihydro-1-benzothiepin-5(2H)-one. This ketone was methylated with MeMgI in ether and the resulting tertiary alcohol was deoxygenated as follows: 22.85 g were placed in 250 ml of hexane under argon and treated in succession with 75.1 g of sodium iodide (NaI), 26.4 ml of acetonitrile and 63.5 ml of Me3SiCl. The mixture was stirred at room temperature overnight, poured on to ice, extracted with ether, washed with bisulfite solution and water, dried and evaporated. Chromatography on silica gel with petroleum ether gave 18.1 g of 8-bromo-2,3,4,5-tetrahydro-5-methyl-1-benzothiepine as a pale yellow oil.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[O:7])[C:3]2[CH:14]=[CH:15][CH:16]=[CH:17][C:2]1=2.C(C(O)=O)(F)(F)F.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34]Br)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[S:1]1[CH:5]=[C:4]([C:6]([CH:8]2[CH2:9][CH2:10][N:11]([CH2:34][CH2:33][C:30]3[CH:31]=[CH:32][C:27]([O:26][CH3:25])=[CH:28][CH:29]=3)[CH2:12][CH2:13]2)=[O:7])[C:3]2[CH:14]=[CH:15][CH:16]=[CH:17][C:2]1=2
Reactant: O=C(c1csc2ccccc12)C1CCNCC1
Reactant: COc1ccc(CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc(CCN2CCC(C(=O)c3csc4ccccc34)CC2)cc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Mix (benzo[b]thiophene-3-yl)(4-piperidinyl)methanone.CF3CO2H (2.0 g, 5.56 mmol), 2-(4-methoxyphenyl)ethyl bromide (1.27 g, 5.93 mmol ), potassium carbonate (1.95 g, 1.41 mmol) and anhydrous dimethylformamide (20 mL). Warm to approximately 90° C. and stir overnight. Allow to cool to room temperature and partition between a 2:1 mixture of ethyl acetate: toluene and water. Separate the aqueous phase and wash the organic phase with water and saturated sodium chloride. Dry (Na2SO4) and evaporate the solvent Purify by chromatography (40% ethyl acetate/hexane) and recrystallize (cyclohexane) to give the title compound pale yellow plates; mp 114°-116° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([N:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][C:22]([OH:28])=[CH:23][CH:24]=2)[CH2:19]1)=[N:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:29]([O:36][C:37]([N:39]1[CH2:44][CH2:43][CH:42]([CH2:45]Br)[CH2:41][CH2:40]1)=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[OH-].[Na+].O>CS(C)=O>[CH2:29]([O:36][C:37]([N:39]1[CH2:44][CH2:43][CH:42]([CH2:45][O:28][C:22]2[CH:21]=[C:20]3[C:25]([CH2:26][CH2:27][N:18]([C:9](=[N:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:19]3)=[CH:24][CH:23]=2)[CH2:41][CH2:40]1)=[O:38])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCc2ccc(O)cc2C1
Reactant: O=C(OCc1ccccc1)N1CCC(CBr)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCc2ccc(OCC3CCN(C(=O)OCc4ccccc4)CC3)cc2C1
Temperature: 25 °C
Reaction time: 17 h
Yield: 69.1 %

Procedure:
To a solution of N,N′-di-tert-butoxycarbonyl-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine (50 mg) and 4-bromomethylpiperidine-1-carboxylic acid benzyl ester (120 mg) in dimethyl sulfoxide (1 ml) was added 4N aqueous sodium hydroxide solution (0.13 ml), and the mixture was stirred at room temperature for 17 hours. After completion of the reaction, water was added, and the mixture was extracted with ethyl acetate and washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane:acetone=5:1) and dried under reduced pressure to give the title compound (55 mg).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[C:17](Cl)[N:16]=3)=[C:9]([F:23])[CH:8]=1.C1COCC1.[Br-].[CH2:30]([Zn+])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>[NH4+].[Cl-].CCOC(C)=O.[Pd](Cl)Cl.C(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)(C)C.C(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)(C)C>[O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[C:17]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:16]=3)=[C:9]([F:23])[CH:8]=1
Reactant: [Zn+]Cc1ccccc1
Reactant: Fc1cc(C2OCCCO2)ccc1-c1nc2ccc(Cl)nc2s1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Fc1cc(C2OCCCO2)ccc1-c1nc2ccc(Cc3ccccc3)nc2s1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
A thick slurry of 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-chlorothiazolo[5,4-b]pyridine (2.50 g, 7.1 mmol) and bis(4-(di-tert-butylphosphino)-N,N-dimethyl-benzenamine) palladium dichloride (0.10 g, 0.14 mmol) in benzylzinc(II) bromide 0.5M in THF (21 mL, 11 mmol) was flushed with argon and sealed, and heated to 70° C. All solids eventually dissolved over 1 h to give a dark brown solution. After 3 h, the reaction mixture was cooled and diluted with sat'd aq. NH4Cl. Solid formed, and was taken up in EtOAc. The organic layer was washed sat'd aq. NH4Cl, brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting solid was suspended in 50 mL MTBE and stirred for 30 min, then filtered, rinsing with a minimum amount of MTBE, and dried in vacuo to give 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-benzylthiazolo[5,4-b]pyridine as a gray solid. MS (ESI) m/z: Calculated: 406.1; Observed: 407.1 (M++1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12]/[C:11](=[C:19]3/[C:20]([CH2:25][CH2:26][CH3:27])=[N:21][NH:22][C:23]/3=[O:24])/[CH:10]=2)=[CH:4][CH:3]=1.[C:28](Cl)(=[O:32])[CH2:29][CH2:30][CH3:31]>C1COCC1>[O:24]=[C:23]1[NH:22][N:21]=[C:20]([CH2:25][CH2:26][CH3:27])/[C:19]/1=[C:11]1/[NH:12][C:13]2[C:18]([C:9]([S:8][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:28](=[O:32])[CH2:29][CH2:30][CH3:31])=[CH:7][CH:6]=3)=[CH:10]/1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: CCCC(=O)Cl
Reactant: CCCC1=NNC(=O)/C1=C1/C=C(Sc2ccc(N)cc2)c2ccccc2N1
Solvent: C1CCOC1
Product: CCCC(=O)Nc1ccc(SC2=C/C(=C3/C(=O)NN=C3CCC)Nc3ccccc32)cc1

Procedure:
The title compound was synthesized using (Z)-4-(4-(4-aminophenylthio)quinolin-2(1H)-ylidene)-3-propyl-1H-pyrazol-5(4H)-one and butyryl chloride in THF according to the procedure described in the synthesis of Example 26. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.69 (t, J=7.33 Hz, 3H) 0.94 (t, J=7.33 Hz, 3H) 1.26-1.35 (m, J=7.36, 7.36, 7.36, 7.36, 7.20 Hz, 2H) 1.59-1.69 (m, J=7.38, 7.38, 7.38, 7.38, 7.38 Hz, 2H) 2.21 (t, J=7.20 Hz, 2H) 2.34 (t, J=7.20 Hz, 2H) 6.74 (s, 1H) 7.62 (t, J=7.71 Hz, 1H) 7.68 (d, J=8.59 Hz, 2H) 7.83-7.93 (m, 4H) 8.13 (d, J=8.34 Hz, 1H) 10.26 (s, 1H); ESI-MS: m/z calc'd for C25H26N4O2S 446.56. found 447.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[C:16](=[O:17])[O:15][CH2:14][CH2:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:23][OH:24]>>[CH3:23][O:24][C:16]([C:10]1[S:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:12][C:11]=1[CH2:13][CH2:14][OH:15])=[O:17]
Reactant: O=C1OCCc2nc(-c3ccc(Cl)cc3)sc21
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1sc(-c2ccc(Cl)cc2)nc1CCO
Temperature: 55 °C
Reaction time: 15 h

Procedure:
Dissolve 2-(4-chloro-phenyl)-6,7-dihydro-pyrano[4,3-d]thiazol-4-one (500 g, 1882 mmol) in MeOH (5 L) and add concentrated sulfuric acid (31 mL). Stir the solution at 55° C. for 15 h, then warm to 66° C. and continue stirring for an additional 4.5 h. Cool the solution to 45° C. and concentrate in vacuo to one half of the volume. Continue to cool the slurry to 20° C. Isolate the precipitate by filtration and wash the solid with cold MeOH. Dry the solid (420.5 g) under vacuum overnight. Concentrate the filtrate to about 600 mL, filter, and wash with cold MeOH to obtain more solid (40.7 g). Purify the crude materials by flash chromatography, using 10% EtOAc/CH2Cl2 as eluent, to give a total of (442 g, 80%) of the title compound. 1H NMR (400 MHz, CDCl3): δ 7.88 (dt, J=8.8, 4.7 Hz, 2H), 7.43 (dt, J=8.7, 4.3 Hz, 2H), 4.05 (t, J=5.6 Hz, 2H), 3.90 (s, 3H), 3.43 (t, J=5.6 Hz, 2H), 3.32 (bs, 1H).
Reaction SMILES: C[N:2](CC1C=CC=CC=1)[CH2:3][C:4]#C.O=[C:14]1O[C@H:19]([C@H:21]([CH2:23][OH:24])[OH:22])[C:17]([O-])=[C:15]1O.[Na+]>>[NH2:2][CH2:3][CH2:4][C:17]1[CH:15]=[CH:14][C:23]([OH:24])=[C:21]([OH:22])[CH:19]=1
Reactant: C#CCN(C)Cc1ccccc1
Reactant: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Product: NCCc1ccc(O)c(O)c1

Procedure:
The uptake reaction mixture was suspended in a final volume of 200 μl containing pargyline (final concentration of 10 μM) and sodium ascorbate (final concentration of 0.2 mg/ml) in each well of 96-well-round-bottom-plate.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=2)[N:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH3:26][O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O.[OH-].[K+]>O.O1CCOCC1>[CH3:26][O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:16]1[CH:17]=[CH:18][C:13]([O:12][CH2:11][C:7]2[N:6]=[C:5]([C:3]([OH:2])=[O:4])[CH:10]=[CH:9][CH:8]=2)=[CH:14][CH:15]=1
Reactant: COCc1ccccc1B(O)O
Reactant: COC(=O)c1cccc(COc2ccc(I)cc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COCc1ccccc1-c1ccc(OCc2cccc(C(=O)O)n2)cc1
Reaction time: 1 h

Procedure:
A first stock solution was prepared consisting of 6-(4-iodo-phenoxymethyl)-pyridine-2-carboxylic acid methyl ester (of intermediate 5; 1.77 g, 4.8 mmol), bis(tri -cyclohexyl-phosphine)palladium (available from Strem Chemicals, Inc., Newburyport, Mass.; 168 mg, 0.25 mmol), and dioxane (approximately 100 mL). A second stock solution was prepared consisting of potassium carbonate (1.99 g, 14.4 mmol) and water (approximately 10 mL). The solutions were sonicated and degassed by bubbling nitrogen gas through them. 4 mL of the first stock solution and 0.4 mL of the second stock solution were added to a reaction tube containing 2-methoxymethyl-phenylboronic acid (available from Apollo Scientific Ltd., Stockport, UK; 100 mg, 0.6 mmol). The mixture was heated in a microwave oven at 170 degrees for 25 min, and then 1 M KOH solution (1 equivalent) was added and the reaction mixture was heated in the microwave for 10 minutes at 120 degrees, for 10 minutes at 130 degrees, and at 170 degrees for one hour. The reaction mixture was then filtered through a silica column (1 g) and washed with dimethylacetamide (2×1 mL). The solvent was evaporated to give 6-(2′-methoxymethyl-biphenyl-4-yloxymethyl)-pyridine-2-carboxylic acid. Mass spectrum MH+=350.
Reaction SMILES: [CH2:1]1[C:7]2=[C:8]3[C:12](=[CH:13][CH:14]=[C:6]2[O:5][CH2:4][CH2:3][N:2]1C(OC(C)(C)C)=O)[NH:11][CH:10]=[CH:9]3.[H-].[Na+].CN(C=O)C.[S:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[S:34](Cl)(=[O:36])=[O:35]>N.CO>[S:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[S:34]([N:11]1[C:12]2[C:8](=[C:7]3[CH2:1][NH:2][CH2:3][CH2:4][O:5][C:6]3=[CH:14][CH:13]=2)[CH:9]=[CH:10]1)(=[O:36])=[O:35]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc3[nH]ccc3c2C1
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: O=S(=O)(c1cccs1)n1ccc2c3c(ccc21)OCCNC3
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 61 %

Procedure:
tert-Butyl 1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 18, 14 mg, 0.050 mmol), NaH (60% in mineral oil, 6.4 mg, 0.10 mmol) and dry DMF (0.2 mL) were shaken at room temperature for 10 minutes. Thiophene-2-sulfonyl chloride (18 mg, 0.10 mmol, in 0.15 mL of dry DMF) was added to the solution. The reaction mixture was shaken at room temperature for another 20 minutes and a mixture of MeOH/1 M HCl (3:1, 1 mL) was added. The reaction mixture was stirred overnight and evaporated. The residue was dissolved in 1 M NH3 in MeOH (1 mL, 1 mmol) and MeOH (1 mL). The crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound as an off-white solid (10.2 mg). MS m/z 335 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH2:12][CH2:13][NH:14][CH2:15][CH:7]1[C:6](=[O:16])[NH:5]2.[N:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][CH2:26]Cl)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl>C(O)C.CC(C)=O.C(N(CC)CC)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH2:12][CH2:13][N:14]([CH2:26][CH2:25][CH2:24][CH2:23][C:20]3[CH:21]=[CH:22][N:17]=[CH:18][CH:19]=3)[CH2:15][CH:7]1[C:6](=[O:16])[NH:5]2
Reactant: O=C1Nc2cc(F)ccc2N2CCNCC12
Reactant: ClCCCCc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: O=C1Nc2cc(F)ccc2N2CCN(CCCCc3ccncc3)CC12

Procedure:
A solution of 4.2 g. (0.02 mole) of 8-fluoro-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one, 7 g. (0.04 mole) of 4-(4-pyridyl)-1-chlorobutane, 8 g. of potassium carbonate, 5 g. of potassium iodide, and 0.5 ml. of triethylamine was stirred and refluxed in 200 ml. of acetone for 72 hours, cooled and filtered. The solvent was removed and the residue was dissolved in methylene chloride. This solution was washed with water and brine, dried over magnesium sulfate and filtered. The solvent was removed and the residue was chromatographed on 500 g. of Silicar, CC-7. Fractions eluted with 10% methanol in ethyl acetate afforded the product as a free base. This free base was dissolved in ethanol and treated with dry hydrogen chloride saturated ether. The product hydrochloride was filtered and recrystallized from methanol to give 2.3 g. of the title compound as the dihydrochloride salt, m.p. 262°-264° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:14][C@@H:15]([OH:37])[C@@H:16]([NH:25][C:26](=[O:36])[O:27][C@@H:28]3[C@H:35]4[C@H:31]([O:32][CH2:33][CH2:34]4)[O:30][CH2:29]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.F[C:43]1[C:51]([N+:52]([O-:54])=[O:53])=[C:50]([N+]([O-])=O)[C:49]([N+:58]([O-:60])=[O:59])=[CH:48][C:44]=1[C:45]([OH:47])=[O:46].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[O:30]1[C@H:31]2[O:32][CH2:33][CH2:34][C@H:35]2[C@@H:28]([O:27][C:26]([NH:25][C@H:16]([C@H:15]([OH:37])[CH2:14][N:13]([S:10]([C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][O:3][C:4]=3[CH:9]=2)(=[O:12])=[O:11])[CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:48]3[C:49]([N+:58]([O-:60])=[O:59])=[CH:50][C:51]([N+:52]([O-:54])=[O:53])=[CH:43][C:44]=3[C:45]([OH:47])=[O:46])=[CH:20][CH:19]=2)=[O:36])[CH2:29]1
Reactant: O=C(O)c1cc([N+](=O)[O-])c([N+](=O)[O-])c([N+](=O)[O-])c1F
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(O)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(Oc2c(C(=O)O)cc([N+](=O)[O-])cc2[N+](=O)[O-])cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 59 mg (0.1 mMol) of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-2-hydroxy-1-(4-hydroxybenzyl)propylcarbamate, 50 of 2-fluoro-3,5-dinitronitrobenzoic acid and 65 mg (0.2 mMol) of cesium carbonate in 0.5 mL of dimethyl formamide was stirred at rt for 2 h. The mixture was diluted with ethyl acetate and extracted with 1N HCl. Evaporation of the solvent and chromatography on silica gel (5% methanolic ammonia in dichloromethane) gave the title compound (25 mg) as a yellow foam. H NMR: 0.82(6H,dd), 1.42(1H,m), 1.63(1H,m), 1.90(2H,m), 2.46(1H,dd), 2.8(1H,dd), 2.82-3.02(5H,m), 3.2(1H,m), 3.6-3.95(6H,m), 4.94(1H,q), 5.58(1H,d), 6.02(2H,s), 6.61(1H,d), 6.75(2H,d), 6.82(1H,d), 7.05(2H,d), 7.3(1H,d), 7.45(1H,s), 8.6(2H,ss).