Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1([CH3:27])[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:24](=O)[CH3:25])[CH:22]=2)[O:17][CH2:16][CH2:15]1.P(Cl)(OCC)(OCC)=O.C([N-]C(C)C)(C)C.[Li+]>O1CCCC1.CCCCCC>[CH3:13][C:14]1([CH3:27])[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:24]#[CH:25])[CH:22]=2)[O:17][CH2:16][CH2:15]1
Reactant: CC(=O)c1ccc2c(c1)C(C)(C)CCO2
Agent: CC(C)[N-]C(C)C
Agent: CCOP(=O)(Cl)OCC
Agent: [Li+]
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C#Cc1ccc2c(c1)C(C)(C)CCO2
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 2.47 g (24.41 mmol) of diisopropylamine in 40 ml dry tetrahydrofuran under argon at -78 degrees C was added dropwise 15.2 ml of 1.6M (24.32 mmol) n-butyl lithium in hexane. This mixture was stirred at -78 degrees C for 1 hour and then treated dropwise with a solution of 4.98 g (24.38 mmol) of 4,4-dimethyl-6-acetylchroman (Compound 77) in 1 ml dry of tetrahydrofuran. After stirring at 78 degrees C for 1 hour, the solution was treated with 4.2g (24.36 mmol) of diethyl chlorophosphate. The cooling bath was then removed and the reaction mixture stirred at room temperature for 2.75 hours. This solution was then transferred using a double ended needle to a solution of lithium diisopropyl amide [prepared using 4.95 g (48.92 mmol) of diisopropylamine and 30.5 ml of 1.6M (48.8 mmol) n-butyllithium in hexane] in 80 ml dry tetrahydrofuran at -78 degrees C. The cooling bath was removed and mixture stirred at room temperature for 18 hours and then quenched with 50 ml water and 25 ml of 3N hydrogen chloride. The mixture was extracted with 2×100 ml and 3×50 ml of pentane and the combined organic fractions washed with 3N hydrogen chloride, water, saturated NaHCO3 and saturated NaCl solutions and then dried (MgSO4). Solvent was then removed in vacuo and the residue purified by flash chromatography (silica; 10% ethyl acetate in hexane) followed by kugelrohr distillation (70 degrees C; 0.35 mm) to give the title compound as a colorless crystalline solid. PMR (CDCl3): & 1.33 (6H), 1.81-1.86 (2H, m), 3.00 (1H, s), 4.19-4.24 (2H, m), 6.75 (1H, d, J~8.5 Hz), 7.22 (1H, dd, J~8.5 Hz, 2.3 Hz), 7.44 (1H, d, J~2.3 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=2)[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].C1(C)C=CC=CC=1.[Cl:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][C:32]=1[CH3:40].C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.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]>[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([C:2]2[CH:3]=[C:4]([NH:14][C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=3)[CH:5]=[N:6][C:7]=2[O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:33][C:32]=1[CH3:40]
Reactant: Cc1cc(B(O)O)ccc1Cl
Reactant: O=C(Nc1cnc(OCC(F)(F)F)c(Br)c1)c1cccnc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1cc(-c2cc(NC(=O)c3cccnc3)cnc2OCC(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
In a 25 ml sealed tube N-(5-bromo-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)nicotinamide (520 mg, 1.38 mmol) was combined with toluene (20 mL). Under argon atmosphere, were added 4-chloro-3-methylphenylboronic acid (471 mg, 2.77 mmol), an aqueous solution of sodium carbonate (2M, 1.38 mL) and Pd(dppf)2Cl2 (30 mg, 0.041 mmol). After two hours at 90° C., the dark re suspension was cooled to room temperature, diluted with ethyl acetate (10 mL), and washed with water (10 mL) and brine (10 mL). The aqueous layer was back-extracted with ethyl acetate (15 mL). The organic layers were dried over MgSO4 and concentrated in vacuo. The crude material (760 mg) was purified by flash chromatography (silica gel, 20 g, 20% to 100% ethyl acetate in heptane) to give the title compound as a light brown solid (575 mg, 98%); MS (EI): 422.8 (M+H).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH:6]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]([OH:9])=[O:8])[C:3]2[CH:18]=[CH:19][CH:20]=[CH:21][C:2]1=2.[N:22]12[CH2:29][CH2:28][CH:25]([CH2:26][CH2:27]1)[C@@H:24](O)[CH2:23]2.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1>C1COCC1>[S:1]1[CH:5]=[C:4]([CH:6]([NH:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:7]([O:9][C@@H:24]2[CH:25]3[CH2:28][CH2:29][N:22]([CH2:27][CH2:26]3)[CH2:23]2)=[O:8])[C:3]2[CH:18]=[CH:19][CH:20]=[CH:21][C:2]1=2
Reactant: O[C@H]1CN2CCC1CC2
Reactant: O=C(O)C(NCc1ccccc1)c1csc2ccccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)C(NCc1ccccc1)c1csc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.8 %

Procedure:
A mixture of 2-(benzo[b]thiophen-3-yl)-2-(benzylamino)acetic acid (I37) (303 mg, 1.02 mmol), (R)-quinuclidin-3-ol (156 mg, 1.22 mmol), DCC (252 mg, 1.22 mmol), and HOBT (187 mg, 1.22 mmol) in dry THF (20 ml) was stirred at room temperature overnight. The solvent was evaporated, and the crude product was partitioned between EtOAc and 2M K2CO3. The organic phase was washed with 2M K2CO3 and brine, dried over Na2SO4, filtered and evaporated to dryness. The crude product was purified by flash chromatography (CH3CN/MeOH=8/2+0.2% NH4OH) to obtain (R)-quinuclidin-3-yl 2-(benzo[b]thiophen-3-yl)-2-(benzylamino)acetate (53 mg, 12.8% yield).
Reaction SMILES: C([NH:4][C:5]1([C:17]([O:19]C)=[O:18])[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15]C)[CH:11]=2)[CH2:6]1)(=O)C.[BrH:21]>>[BrH:21].[NH2:4][C:5]1([C:17]([OH:19])=[O:18])[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:15])[CH:11]=2)[CH2:6]1
Reactant: COC(=O)C1(NC(C)=O)CCc2cc(OC)ccc2C1
Agent: Br
Product: NC1(C(=O)O)CCc2cc(O)ccc2C1

Procedure:
Optical isomer A of methyl 2-acetylamino-6-methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxylate (3.45 g., 12.5 mM) was added to 48% w/v aqueous hydrobromic acid (34 ml.). The mixture was stirred and refluxed for 4 hr. The mixture was cooled, whereupon the product crystallised. It was collected by filtration and washed with ethyl acetate. The solid was dried in vacuo at 60° to give optical isomer A of 2-amino-6-hydroxy-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid hydrobromide.
Reaction SMILES: [CH3:1][C:2]([NH2:7])([CH:4]([CH3:6])[CH3:5])[CH3:3].[S:8](Cl)([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)(=[O:10])=[O:9]>N1C=CC=CC=1>[S:8]([NH:7][C:2]([CH3:3])([CH:4]([CH3:6])[CH3:5])[CH3:1])([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)(=[O:10])=[O:9]
Reactant: CC(C)C(C)(C)N
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)NC(C)(C)C(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.1 %

Procedure:
To a solution of 1.2 g (0.012 mole) 2,3-dimethyl-2-butylamine in 20 mL pyridine, a solution of 1.9 g (0.010 mole) tosylchloride in 20 mL pyridine was added dropwise in a glacial water bath, stirred for 3 hours in that bath and 1 hour at room temperature, then heated for 2 hours in a bath at temperature of 95-100° C. The solvent was distilled off in vacuum. Toluene was added to the residue, then distilled off the solvent in vacuum. The residue was dissolved in water and extracted with toluene (×4). The toluene extract was washed with water once, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled off the solvent. The residue was recrystallized from isopropanol to give a colorless columnar crystal 1.1 g, mp 80-89° C., recrystallized from isopropanol once again to give a white crystal 0.8 g, mp 88-89° C. Elemental analysis for C13H21NO2S (%): Calculated C, 61.14; H, 8.29; N, 5.48. Found C, 61.11;, H, 8.37;, N, 5.55. 1H-NMR(CDCl3; ppm) 0.91(d, J=6.8 Hz, 6H, 2CH3), 1.17(s, 6H, 2CH3), 1.82(M, 1H, CH), 2.47(s, 3H, CH3), 7.32(d,J=8.0, 2H,2Ar—H), 7.82(d, J=8.0, 2H, 2Ar—H′). MS(M/z) 255 (M+), 172(B).
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[CH:12][C:13]3[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=3)=[CH:8][CH:9]=2)[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:3]1.[OH-].[Na+]>O1CCCC1.CO>[CH3:1][C:2]1([CH3:29])[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[CH:12][C:13]3[CH:22]=[CH:21][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=3)=[CH:8][CH:9]=2)[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:3]1
Reactant: COC(=O)c1ccc(C=Cc2ccc3c(c2)C(c2ccccc2)=CC3(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)C=C(c2ccccc2)c2cc(C=Cc3ccc(C(=O)O)cc3)ccc21
Yield: 97.8 %

Procedure:
Methyl 4-[2-(1,1-dimethyl-3-phenyl-1H-inden-5-yl)-vinyl]benzoate (294 mg, 0.77 mmol) and 0.77 mL of 10N NaOH in 7 mL of tetrahydrofuran and 5 mL of methanol were stirred at reflux for 1 hour. The mixture was concentrated and acidified with 1N HCl (10 mL), extracted with ethyl acetate (30 mL×2). The combined extracts were washed with water (10 mL), dried over magnesium sulfate, and evaporated. The residue was triturated in hot methanol to give 276 mg (90% yield) of the title compound which contained a molecule of methanol; 1H-NMR (DMSO-d6) δ 1.34 (s, 6H), 3.14 (s, 3H), 6.58 (s, 1H), 7.25 (d, J=16.4 Hz, 1H), 7.37-7.71 (m, 11H), 7.90 (d, J=8.3 Hz, 2H); MS m/e 367 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[CH2:20]([NH2:22])[CH3:21]>CO>[C:8]1([C:5]2[N:6]=[CH:7][C:2]([NH:22][CH2:20][CH3:21])=[N:3][C:4]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCN
Reactant: Clc1cnc(-c2ccccc2)c(-c2ccccc2)n1
Solvent: CO
Product: CCNc1cnc(-c2ccccc2)c(-c2ccccc2)n1
Temperature: 90 °C
Reaction time: 17.5 h

Procedure:
1.00 g of 2-chloro-5,6-diphenylpyrazine was added to 18.7 ml of 2M ethylamine in methanol and the mixture was reacted in a sealed tube at 80° C. for 16 hours. After cooling, 12 ml of a 2M ethylaminemethanol solution was further added, followed by continuous stirring in the sealed tube at 90° C. for 17.5 hours and further stirring at room temperature for 46 hours. After the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography to obtain 531 mg of the desired compound as a pale yellow crystal having a melting point of 121 to 123° C.
Reaction SMILES: COC1C=C(C=CC=1OC)C(CCC(=O)C1C=CC(OC)=C(OC)C=1)=O.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([C:37](=O)[CH2:38][CH2:39][C:40]([C:42]2[CH:51]=[CH:50][C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[CH:43]=2)=[O:41])[CH:32]=[CH:33][C:34]=1[O:35][CH3:36]>>[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:37]2[CH2:38][CH2:39][CH:40]([C:42]3[CH:51]=[CH:50][C:49]4[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=4)[CH:43]=3)[O:41]2)[CH:32]=[CH:33][C:34]=1[O:35][CH3:36]
Reactant: COc1ccc(C(=O)CCC(=O)c2ccc3ccccc3c2)cc1OC
Agent: COc1ccc(C(=O)CCC(=O)c2ccc(OC)c(OC)c2)cc1OC
Product: COc1ccc(C2CCC(c3ccc4ccccc4c3)O2)cc1OC

Procedure:
Following the same procedure as described in Example 1, Step B, but substituting for the 1,2-bis-(3,4-dimethoxybenzoyl)ethane used therein, the 1-(3,4-dimethoxyphenyl)- 4-(2-naphthyl)butan-1,4-dione prepared above in Step A, there was obtained 370 mg of 2-(3,4-dimethoxyphenyl)-5-(2-naphthyl)tetrahydrofuran as a trans and cis mixture. This mixture was separated by HPLC to the cis-isomer (m.p. 74°-77° C.) and the trans-isomer (m.p. 112°-113° C.). PG,38 What is claimed is:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].F[C:8]1[CH:9]=[CH:10][C:11]2[N:12]([C:14]([C:17]3[S:21][C:20]([C:22](=[O:24])[CH3:23])=[CH:19][CH:18]=3)=[CH:15][N:16]=2)[N:13]=1.[C:25]([O:29][C:30](=[O:37])[N:31]([CH2:33][CH2:34][CH2:35][NH2:36])[CH3:32])([CH3:28])([CH3:27])[CH3:26]>CN(C)C=O>[C:25]([O:29][C:30](=[O:37])[N:31]([CH2:33][CH2:34][CH2:35][NH:36][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([C:14]([C:17]3[S:21][C:20]([C:22](=[O:24])[CH3:23])=[CH:19][CH:18]=3)=[CH:15][N:16]=2)[N:13]=1)[CH3:32])([CH3:28])([CH3:26])[CH3:27]
Reactant: CN(CCCN)C(=O)OC(C)(C)C
Reactant: CC(=O)c1ccc(-c2cnc3ccc(F)nn23)s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(-c2cnc3ccc(NCCCN(C)C(=O)OC(C)(C)C)nn23)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cesium carbonate [534-17-8] (125 mg, 0.4 mmol) was added to a solution of 1-[5-(6-fluoro-imidazo[1,2-b]pyridazin-3-yl)-thiophen-2-yl]-ethanone (50 mg, 0.2 mmol) and N-(3-aminopropyl)-N-methylcarbamic acid tert-butyl ester [150349-36-3] (72 mg, 0.4 mmol) in N,N-dimethylformamide (1.5 mL) and stirred overnight at ambient temperature then partitioned between ethyl acetate and water. The organic extract was evaporated and product isolated by preparative RP-HPLC to provide {3-[3-(5-acetyl-thiophen-2-yl)-imidazo[1,2-b]pyridazin-6-ylamino]-propyl}-methyl-carbamic acid tert-butyl ester as a yellow oil. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.33-1.49 (m, 9H) 2.04 (d, J=11.87 Hz, 2H) 2.59 (s, 3H) 2.91 (s, 3H) 3.35-3.53 (m, 4H) 4.62 (s, 1H) 6.75 (d, J=9.60 Hz, 1H) 7.64-7.75 (m, 2H) 7.87 (d, J=4.04 Hz, 1H) 7.98 (s, 1H). LRMS (ESI) m/z 430.2 [(M+H)]+, calc'd for C21H27N5O3S: 429.55.
Reaction SMILES: [F:1][C:2]([F:27])([C:23]([F:26])([F:25])[F:24])/[CH:3]=[CH:4]/[C:5]([NH:7][CH2:8][CH2:9][NH:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([C:17]2([CH3:22])OCC[O:18]2)[CH:12]=1)=[O:6].Cl>CC(C)=O.O>[C:17]([C:13]1[CH:12]=[C:11]([NH:10][CH2:9][CH2:8][NH:7][C:5](=[O:6])/[CH:4]=[CH:3]/[C:2]([F:1])([F:27])[C:23]([F:26])([F:24])[F:25])[CH:16]=[CH:15][N:14]=1)(=[O:18])[CH3:22]
Reactant: CC1(c2cc(NCCNC(=O)/C=C/C(F)(F)C(F)(F)F)ccn2)OCCO1
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)c1cc(NCCNC(=O)/C=C/C(F)(F)C(F)(F)F)ccn1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
(E)-4,4,5,5,5-Pentafluoro-N-[2-[[2-(2-methyl-1,3-dioxolan-2-yl)-4-pyridyl]amino]ethyl]pent-2-enamide (35 mg, 0.09 mmol) was dissolved in aceton (1 ml), 4M hydrochloric acid (0.5 ml) was added and the mixture was stirred in a closed vessel at 100° C. for 15 minutes with microwave heating. The mixture was diluted with water, extracted with ethyl acetate and the organic phase was washed with brine, dried over magnesium sulfate and evaporated to dryness. The resulting residue was purified by preparative HPLC (gradient of water containing 0.1% NH3 and acetonitrile) to yield 2.5 mg (0.0071 mmol, 7.9%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)=[C:7]([CH:10]=1)[C:8]#[N:9].Cl[C:23]1[CH:24]=[C:25]2[N:32]([CH:33]3[CH2:35][CH2:34]3)[CH2:31][CH2:30][N:26]2[C:27](=[O:29])[N:28]=1>>[CH:33]1([N:32]2[C:25]3[N:26]([C:27](=[O:29])[N:28]=[C:23]([O:1][CH2:2][C:3]4[CH:4]=[CH:5][C:6]([O:11][C:12]5[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:20])[F:21])[CH:13]=5)=[C:7]([CH:10]=4)[C:8]#[N:9])[CH:24]=3)[CH2:30][CH2:31]2)[CH2:35][CH2:34]1
Reactant: N#Cc1cc(CO)ccc1Oc1cccc(C(F)(F)F)c1
Reactant: O=c1nc(Cl)cc2n1CCN2C1CC1
Product: N#Cc1cc(COc2cc3n(c(=O)n2)CCN3C2CC2)ccc1Oc1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from 5-(hydroxymethyl)-2-(3-(trifluoromethyl)phenoxy)benzonitrile and 7-chloro-1-cyclopropyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:18][C:17]([NH:19][C:20](=[O:22])[CH3:21])=[N:16][C:15]=2[C:23]2[O:24][CH:25]=[CH:26][CH:27]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H].[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34]>CO.C(O)C.[C].[Pd]>[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34].[O:24]1[CH:25]=[CH:26][CH:27]=[C:23]1[C:15]1[N:16]=[C:17]([NH:19][C:20](=[O:22])[CH3:21])[S:18][C:14]=1[N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(=O)Nc1nc(-c2ccco2)c(N2CCN(Cc3ccccc3)CC2)s1
Reactant: [H][H]
Agent: [Pd]
Agent: O=C(O)/C=C/C(=O)O
Solvent: CO
Solvent: CCO
Product: CC(=O)Nc1nc(-c2ccco2)c(N2CCNCC2)s1
Yield: 19.3 %

Procedure:
Compound 79 (274 mg, 0.72 mmol) was dissolved in methanol (7 mL), and 10% palladium-carbon (274 mg) was added thereto, followed by stirring in an atmosphere of hydrogen at 50° C. for 24 hours. The reaction mixture was filtered through Celite, and the resulting filtrate was concentrated to afford a free form of the entitled Compound. The resulting free form was dissolved in ethanol (5 mL), fumaric acid (83.0 mg, 0.51 mmol) was added thereto, and the precipitated solid was collected by filtration to afford the entitled Compound 80 (40.1 mg, 14%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[CH:19]([C:20]([O:22][CH3:23])=[O:21])[CH:18](O)[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[O:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.C(N(CC)CC)C.CS(Cl)(=O)=O.N12CCCN=C1CCCCC2>ClCCl.C1C=CC=CC=1.C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[O:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COC(=O)C1C(O)c2ccccc2OC1c1ccc2c(c1)OCO2
Agent: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccccc1
Product: COC(=O)C1=Cc2ccccc2OC1c1ccc2c(c1)OCO2
Temperature: 25 °C
Yield: 58.4 %

Procedure:
A suspension of racemic methyl 2-(benzo[d][1,3]dioxol-5-yl)-4-hydroxychroman-3-carboxylate (49 mg, 149 μmol) in dichloromethane (2.0 mL) was stirred on an ice bath and treated with triethylamine (31 μL, 224 μmol), then dropwise with methanesulfonyl chloride (13 μL, 164 μmol). The cooling bath was removed after 90 min and the solution was stirred at rt for 23 h. At the conclusion of this period, the solution was diluted with additional dichloromethane, washed with 1.0 M aqueous HCl, dried over sodium sulfate and concentrated under vacuum to yield a residue. The residue was dissolved in benzene (2.0 mL), treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (30 μL, 224 μmol) and stirred at 60° C. for 3.75 h. After this time, the mixture was cooled to rt and then diluted with ethyl acetate, washed with 1.0 M aqueous HCl, water, and saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under vacuum. The resulting residue was purified by column chromatography (silica gel, 2-10% ethyl acetate/hexane) to provide racemic methyl 2-(benzo[d][1,3]dioxol-5-yl)-2H-chromene-3-carboxylate as a white solid (27 mg, 58%). 1H NMR (400 MHz, CDCl3) δ ppm 3.77 (s, 3 H) 5.91 (m, 2 H) 6.18 (s, 1 H) 6.71 (d, J=8.6 Hz, 1 H) 6.78 (d, J=8.1 Hz, 1 H) 6.85 (m, 2 H) 6.90 (t, J=7.4 Hz, 1 H) 7.19 (m, 2 H) 7.67 (s, 1 H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Br:19]Br>C(Cl)(Cl)Cl>[C:1]([N:4]1[CH2:9][CH2:8][C:7]([Br:19])([C:10](=[O:18])[C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: BrBr
Reactant: CC(=O)N1CCC(C(=O)c2ccc(F)cc2)CC1
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCC(Br)(C(=O)c2ccc(F)cc2)CC1
Reaction time: 8 h

Procedure:
A solution of 36 g (0.145 mole) of 1-acetyl-4-(p-fluorobenzoyl)piperidine in 175 ml of chloroform was treated with fifteen ml of bromine. The mixture was heated at reflux for one hour and then allowed to stand overnight at room temperature. 1-Acetyl-4-bromo-4-(p-fluorobenzoyl)piperidine precipitated and was collected by filtration and recrystallized from ethanol. Yield 40.6 g, melting point 156°-159° C. In the same manner, additional intermediates of this type are produced by substituting the selected starting materials from Preparation 2 or 11 in the procedure of Preparation 4.
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][S:8][CH2:9][C@H:10]2[O:14][C@@H:13]([N:15]3[C:34]4[N:33]=[CH:32][N:31]=[C:19]([NH:20][CH2:21][C:22]5[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=5)[C:18]=4[N:17]=[CH:16]3)[C@H:12]([OH:35])[C@@H:11]2[OH:36])C(=O)C2=CC=CC=C12.NN>C(O)C>[NH2:5][CH2:6][CH2:7][S:8][CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[C:34]3[N:33]=[CH:32][N:31]=[C:19]([NH:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=4)[C:18]=3[N:17]=[CH:16]2)[C@H:12]([OH:35])[C@@H:11]1[OH:36]
Reactant: O=C1c2ccccc2C(=O)N1CCSC[C@H]1O[C@@H](n2cnc3c(NCc4ccc([N+](=O)[O-])cc4)ncnc32)[C@H](O)[C@@H]1O
Agent: NN
Solvent: CCO
Product: NCCSC[C@H]1O[C@@H](n2cnc3c(NCc4ccc([N+](=O)[O-])cc4)ncnc32)[C@H](O)[C@@H]1O

Procedure:
deprotection of the product of step (b) by heating with hydrazine in ethanol to give the phthaloyl hydrazide salt of 5'-S-(2-aminoethyl)-N6 -(4-nitrobenzyl)-5'-thioadenosine; and
Reaction SMILES: Br.[CH:2]1([CH2:8][C@H:9]2[CH2:14][C@@H:13]([C:15]3[O:19][NH:18][C:17](=[O:20])[CH:16]=3)[CH2:12][CH2:11][N:10]2C(OC)=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1>>[CH:2]1([CH2:8][C@H:9]2[CH2:14][C@@H:13]([C:15]3[O:19][NH:18][C:17](=[O:20])[CH:16]=3)[CH2:12][CH2:11][NH:10]2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1CC1CCCCC1
Agent: Br
Product: O=c1cc([C@H]2CCN[C@@H](CC3CCCCC3)C2)o[nH]1
Reaction time: 8 h
Yield: 33 %

Procedure:
HBr (33% in acetic acid) (5 mL) was added to (2S,4S)-methyl 2-(cyclohexylmethyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate, from a preparation of example 21, step 1 (0.27 g, 0.85 mmol). The reaction was stirred vigorously overnight. The solvent was evaporated. Purification using PrepLC (pH=11, small column, sample dissolved in acetonitrile/water (40/60), gradient 15-55, 20 minutes) gave the title compound (75 mg, 33%). 1H NMR (600 MHz, cd3od) δ 0.80-0.95 (m, 2H), 1.03-1.27 (m, 3H), 1.29-1.47 (m, 4H), 1.53-1.72 (m, 6H), 2.05 (d, 1H), 2.13 (d, 1H), 2.82-2.90 (m, 1H), 2.97 (td, 1H), 3.13 (s, 1H), 3.31 (d, 1H), 5.40 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[S:13][C:12]([C:14]([N:16]2[CH2:21][CH2:20][C:19]([C:30]([NH2:32])=[O:31])([N:22]3[CH2:27][CH2:26][C:25]([F:29])([F:28])[CH2:24][CH2:23]3)[CH2:18][CH2:17]2)=[O:15])=[CH:11][C:10]=1[C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][CH2:42][O:43]C2CCCCO2)=[CH:35][CH:34]=1.Cl>CO>[ClH:1].[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[S:13][C:12]([C:14]([N:16]2[CH2:21][CH2:20][C:19]([C:30]([NH2:32])=[O:31])([N:22]3[CH2:23][CH2:24][C:25]([F:28])([F:29])[CH2:26][CH2:27]3)[CH2:18][CH2:17]2)=[O:15])=[CH:11][C:10]=1[C:33]1[CH:34]=[CH:35][C:36]([O:39][CH2:40][CH2:41][CH2:42][OH:43])=[CH:37][CH:38]=1
Reactant: NC(=O)C1(N2CCC(F)(F)CC2)CCN(C(=O)c2cc(-c3ccc(OCCCOC4CCCCO4)cc3)c(-c3ccc(F)cc3Cl)s2)CC1
Agent: Cl
Solvent: CO
Product: NC(=O)C1(N2CCC(F)(F)CC2)CCN(C(=O)c2cc(-c3ccc(OCCCO)cc3)c(-c3ccc(F)cc3Cl)s2)CC1
Reaction time: 1 h
Yield: 208.1 %

Procedure:
0.63 g of the compound obtained in stage 17A) and 2 ml of 2N ethereal hydrochloric acid are added to 15 ml of methanol. After 1 hour at AT, concentrating to dryness and then crystallizing from AcOEt, 0.612 g of the expected compound is obtained.
Reaction SMILES: [ClH:1].[CH3:2][S:3]([NH:6][C:7]1[CH:20]=[CH:19][C:10]([C:11]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=1)(=[O:5])=[O:4].C(=O)([O-])[O-].[K+].[K+].Cl.[Cl:28][CH2:29][CH2:30][C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1.[I-].[K+]>CN(C)C=O>[ClH:28].[ClH:1].[CH3:2][S:3]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:11]([CH:13]2[CH2:18][CH2:17][N:16]([CH2:29][CH2:30][C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)[CH2:15][CH2:14]2)=[O:12])=[CH:19][CH:20]=1)(=[O:4])=[O:5]
Reactant: ClCCc1cccnc1
Reactant: CS(=O)(=O)Nc1ccc(C(=O)C2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1ccc(C(=O)C2CCN(CCc3cccnc3)CC2)cc1
Temperature: 40 °C
Reaction time: 0.33 h
Yield: 28.8 %

Procedure:
35 g (0.101 mol) of 4-(4-methylsulfonylaminobenzoyl)piperidine hydrochloride and 55 g of potassium carbonate were suspended in 700 ml of dimethylformamide and the suspension was stirred at 40° C. for 20 min. 19.6 g (0.101 mol) of 3-(2-chloroethyl)pyridine hydrochloride and 6.0 g (0.036 mol) of potassium iodide were added to the suspension and the mixture was stirred at 90° C. for 3.5 h. The liquid reaction mixture was filtered and the filtrate was concentrated, while the residue was purified according to silica gel chromatography (chloroform:methanol=93.7). The purified product was converted into its hydrochloride with ethanolic hydrogen chloride and recrystallized from methanol/ispropanol to obtain 13.4 g of the intended compound.