Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH2:4][OH:5].Cl.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18]Cl.Cl[C:21]([N:23]1[C@H:28]([CH3:29])[CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][C@@H:24]1[CH3:37])=[O:22]>>[CH3:37][C@H:24]1[CH2:25][NH:26][CH2:27][C@@H:28]([CH3:29])[N:23]1[C:21]([O:5][CH2:4][C:3]1[CH:6]=[C:7]([O:10][CH2:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=2)[CH:8]=[CH:9][C:2]=1[F:1])=[O:22]
Reactant: OCc1cc(O)ccc1F
Reactant: ClCc1ccccn1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1C(=O)Cl
Agent: Cl
Product: C[C@@H]1CNC[C@H](C)N1C(=O)OCc1cc(OCc2ccccn2)ccc1F

Procedure:
2-Fluoro-5-(2-pyridylmethyl)oxybenzyl cis-2,6-dimethylpiperazine-1-carboxylate was prepared from 2-fluoro-5-hydroxybenzyl alcohol, 2-pyridylmethyl chloride hydrochloride and 1-chlorocarbonyl-cis-2,6-dimethyl-4-tert-butoxycarbonylpiperazine according to the methods described for Examples 54 and 121 to give the product as a yellow oil (10.4%); HPLC (XTERRA, 50/80, 220 nm) 91.1% (2.02 min); NMR δH (400 MHz, DMSO-d6) 1.174 (6H, d, J 6.5 Hz), 2.676 (4H, m), 3.902 (2H, m), 5.069 (2H, s), 5.165 (2H, s), 7.018 (2H, m), 7.161 (1H, t, J 9.0 Hz), 7.350 (1H, m), 7.493 (1H, d, J 7.0 Hz), 7.825 (1H, m) and 8.575 (1H, m).
Reaction SMILES: [N:1]1([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]2[C:18]([O:19][CH3:20])=[N:17][C:16]3[C:11]2=[N:12][C:13]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[N:14][C:15]=3[NH2:21])[CH2:4][CH2:3][CH2:2]1.[CH2:27](OC1N=C2C(N=C(OC)N2CCCCCCl)=C(N)N=1)[CH2:28][CH2:29]C.N1CCCCCC1>>[CH2:23]([O:22][C:13]1[N:12]=[C:11]2[C:16]([N:17]=[C:18]([O:19][CH3:20])[N:10]2[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][N:1]2[CH2:2][CH2:3][CH2:29][CH2:28][CH2:27][CH2:4]2)=[C:15]([NH2:21])[N:14]=1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCCCl)c2n1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCCN3CCC3)c2n1
Agent: C1CCCNCC1
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCCN3CCCCCC3)c2n1

Procedure:
Prepared similarly to Intermediate 27 from 2-(butyloxy)-9-(5-chloropentyl)-8-(methyloxy)-9H-purin-6-amine and hexahydro-1H-azepine but with sequential purifications by MDAPs using Method A followed by Method E.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][C:5]=1[CH3:10].C1C=C(Cl)C=C(C(OO)=[O:20])C=1>C(Cl)Cl>[CH3:1][O:2][C:3]([C:4]1[C:5]([CH3:10])=[N+:6]([O-:20])[CH:7]=[CH:8][CH:9]=1)=[O:11]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1cccnc1C
Solvent: ClCCl
Product: COC(=O)c1ccc[n+]([O-])c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.1 %

Procedure:
To a stirred solution of methyl-2-methylnicotinate (95 g, 629 mmol) in DCM (1.5 L) was added m-CPBA (119 g, 692 mmol) at 0° C. After the reaction mixture was stirred at room temperature for 16 hours, it was washed with a mixture of satd. aq. Na2SO3 and NaHCO3 solution. The organic layer was then dried over anhy. Na2SO4, filtered, and concentrated in vacuo to give a crude product (60 g, yield 57%), which was used in the next step reaction without further purification.
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]=[C:9]1[CH:13]=[CH:12][C:11](=[O:14])[N:10]1[CH2:15][CH2:16][CH2:17][C:18]([NH:20][NH2:21])=[O:19].[C:22]([C:25]1[CH:80]=[CH:79][C:28]([O:29][CH2:30][CH2:31][O:32][C:33]2[CH:34]=[C:35]([CH2:59][O:60][C:61]3[C:62]([O:77][CH3:78])=[CH:63][C:64]4[C:70](=[O:71])[N:69]5[CH2:72][CH2:73][CH2:74][CH2:75][C@@H:68]5[CH:67]=[N:66][C:65]=4[CH:76]=3)[CH:36]=[C:37]([CH2:39][O:40][C:41]3[C:42]([O:57][CH3:58])=[CH:43][C:44]4[C:50](=[O:51])[N:49]5[CH2:52][CH2:53][CH2:54][CH2:55][C@@H:48]5[CH:47]=[N:46][C:45]=4[CH:56]=3)[CH:38]=2)=[CH:27][CH:26]=1)(=O)[CH3:23].C(Cl)(=O)C>C(Cl)Cl>[CH3:78][O:77][C:62]1[C:61]([O:60][CH2:59][C:35]2[CH:34]=[C:33]([CH:38]=[C:37]([CH2:39][O:40][C:41]3[C:42]([O:57][CH3:58])=[CH:43][C:44]4[C:50](=[O:51])[N:49]5[CH2:52][CH2:53][CH2:54][CH2:55][C@H:48]5[CH:47]=[N:46][C:45]=4[CH:56]=3)[CH:36]=2)[O:32][CH2:31][CH2:30][O:29][C:28]2[CH:79]=[CH:80][C:25](/[C:22](=[N:21]/[NH:20][C:18](=[O:19])[CH2:17][CH2:16][CH2:15][N:10]3[C:9](=[O:8])[CH:13]=[CH:12][C:11]3=[O:14])/[CH3:23])=[CH:26][CH:27]=2)=[CH:76][C:65]2[N:66]=[CH:67][C@@H:68]3[CH2:75][CH2:74][CH2:73][CH2:72][N:69]3[C:70](=[O:71])[C:64]=2[CH:63]=1
Reactant: COc1cc2c(cc1OCc1cc(COc3cc4c(cc3OC)C(=O)N3CCCC[C@@H]3C=N4)cc(OCCOc3ccc(C(C)=O)cc3)c1)N=C[C@H]1CCCCN1C2=O
Reactant: NNC(=O)CCCN1C(=O)C=CC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)Cl
Solvent: ClCCl
Product: COc1cc2c(cc1OCc1cc(COc3cc4c(cc3OC)C(=O)N3CCCC[C@H]3C=N4)cc(OCCOc3ccc(/C(C)=N/NC(=O)CCCN4C(=O)C=CC4=O)cc3)c1)N=C[C@@H]1CCCCN1C2=O
Reaction time: 0.25 h
Yield: 61.4 %

Procedure:
4-(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)butanehydrazide trifluoroacetic acid salt (246) (3 mg, 0.0096 mmol), (5Z,5′Z,6aR,6a′R)-3,3′-(5-(2-(4-Acetylphenoxy)ethoxy)-1,3-phenylene)bis(methylene)bis(oxy)bis(2-methoxy-7,8,9,10-tetrahydrobenzo[e]pyrido[1,2-a][1,4]diazepin-12(6aH)-one) (243) (7.5 mg, 0.0093 mmol) and 50 mg 4 A molecular sieves was stirred in 2 ml of dry 5% HAc in DCM (one day earlier dried by 4 A molecular sieves) for 2 h, neutralized with 0.5 ml of DIPEA, evaporated and purified on HPLC preparative C-18 column (Φ10 mm×200 mm column, flow rate 9 mL/min and a gradient solvent system going from 80:20 solvent A:B at time 0-5 min to 50:50 A:B at 15 min then to 30:70 A:B at 25 min until to 10:90 A:B at 30 min. Solvent A—water, solvent B—methanol/dioxane (2:1)) and lyophilized to afford a white solid 5.6 mg (61%) of the title compound. MS m/z+1066.3 (M+2CH3OH+Na).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:29]=[CH:30][N:31]=3)[N:17]=[C:18]([C:20]3[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][CH:21]=3)[CH:19]=2)[CH:10]=[CH:9][CH:8]=1.[N:32]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][NH2:40])=[CH:34][CH:33]=1.CCN=C=NCCCN(C)C.CN1C=CN=C1>CN(C=O)C.ClCCl>[CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:29]=[CH:30][N:31]=3)[N:17]=[C:18]([C:20]3[CH:21]=[CH:22][C:23]([C:24]([NH:40][CH2:39][CH2:38][C:35]4[CH:36]=[CH:37][N:32]=[CH:33][CH:34]=4)=[O:26])=[CH:27][CH:28]=3)[CH:19]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: CC1CCCN1c1cccc(Nc2cc(-c3ccc(C(=O)O)cc3)nn3ccnc23)n1
Reactant: NCCc1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: Cn1ccnc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1CCCN1c1cccc(Nc2cc(-c3ccc(C(=O)NCCc4ccncc4)cc3)nn3ccnc23)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 23.1 %

Procedure:
A mixture of 4-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid (41 mg, 0.1 mmol), 2-(pyridin-4-yl)ethanamine (15 mg, 0.12 mmol), EDCI (77 mg, 0.4 mmol), N-methyl-imidazole (33 mg, 0.4 mmol), dichloromethane (3 mL) and DMF (0.5 mL) was stirred at room temperature for 16 h. The solution was concentrated in vacuo, triturated with water (10 mL×3), and the residue purified by chromatography (silica gel, 200-300 mesh, CH2Cl2:MeOH=30:1) to give 4-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)-N-(2-(pyridin-4-yl)ethyl)benzamide (12 mg, 24%) as a yellow oil. 1H NMR (300 MHz, DMSO): δ 9.68 (s, 1H), 8.81 (s, 1H), 8.74-8.70 (m, 1H), 8.49-8.47 (m, 2H), 8.23 (s, 1H), 8.03-7.95 (m, 4 h), 7.68 (s, 1H), 7.46 (t, 1H, J=8.4 Hz), 7.30 (s, 1H), 7.29 (s, 1H), 6.75 (d, 1H, J=7.5 Hz), 6.09 (d, 1H, J=8.1 Hz), 4.25-4.21 (m, 1H), 3.61-3.56 (m, 2H), 3.47-3.40 (m, 2H), 2.92 (t, 2H, J=6.6 Hz), 2.11-1.99 (m, 3H), 1.71 (s, 1H), 0.85 (d, 3H, J=6.6 Hz). LC-MS: [M+H]+, 519, tR=1.333 min, HPLC: 100% at 214 nm, 100% at 254 nm, tR=5.008 min.
Reaction SMILES: [OH-:1].[Na+].OO.O.[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C@:14]1([CH2:33][I:34])[O:18][CH2:17][C@@H:16]([C:19](N2[C@H](C3C=CC=CC=3)COC2=O)=[O:20])[CH2:15]1>O1CCCC1>[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C@:14]1([CH2:33][I:34])[O:18][CH2:17][C@@H:16]([C:19]([OH:20])=[O:1])[CH2:15]1
Reactant: O=C1OC[C@@H](c2ccccc2)N1C(=O)[C@@H]1CO[C@@](CI)(c2ccc(F)cc2F)C1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1CO[C@@](CI)(c2ccc(F)cc2F)C1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
Sodium hydroxide solution (prepared from 17.7 g of sodium hydroxide and 390 ml of water) was added to a pre-cooled solution of hydrogen peroxide (30 ml), water (65 ml) and tetrahydrofuran (390 ml) at 0-10° C., followed by a solution of (R)-3-((3S,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-carbonyl)-4-phenyloxazolidin-2-one compound of formula-6 (130 g) in tetrahydrofuran (390 ml) at 0-10° C. and the reaction mixture was stirred for 30 minutes at 0-10° C. Further temperature of the reaction mixture was raised to 25-30° C. and then stirred for 2 hours at 25-30° C. After completion of the reaction, the reaction mixture was quenched with 10% sodium sulphite solution and the reaction mixture was washed with toluene. The pH of aqueous layer was adjusted to 10.5 using 50% HCl and then washed with dichloromethane. Further pH of aqueous layer was again adjusted to 4.5 using 50% HCl. The aqueous layer was extracted with methyl tertiary butyl ether and distilled off the solvent from methyl tert.butyl ether layer and then co-distilled with cyclohexane. Cyclohexane (190 ml) was added to the obtained compound and stirred for 2 hours at 25-30° C. Filtered the solid, washed with cyclohexane and then dried to get title compound. Yield: 65 g; MR: 80-87° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].S(Cl)(Cl)=O.[CH3:18]O>>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([O:8][CH3:18])=[O:7]
Reactant: CO
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc(C(F)(F)F)c1
Temperature: 75 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
To a solution of 3-(trifluoromethyl)benzoic acid (5 g, 26.30 mmol, 1.00 equiv) in methanol (25 mL) was added dropwise thionyl chloride (9.39 g, 78.93 mmol, 3.00 equiv) and the resulting solution was stirred for 2 h at 75° C. in an oil bath. The mixture was concentrated under vacuum, diluted with 100 mL of ethyl acetate and then washed with 2×30 mL of sodium carbonate and 2×30 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to yield 4.6 g (86%) of methyl 3-(trifluoromethyl)benzoate as yellow oil
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:6][C:5]2[CH:7]=[C:8]([N:16]3[CH:20]=[N:19][N:18]=[N:17]3)[CH:9]=[C:10]([C:11]([O:13]CC)=[O:12])[C:4]=2[O:3]1.[OH-].[Li+].CO.O1CCCC1>O>[CH3:1][C:2]1([CH3:21])[CH2:6][C:5]2[CH:7]=[C:8]([N:16]3[CH:20]=[N:19][N:18]=[N:17]3)[CH:9]=[C:10]([C:11]([OH:13])=[O:12])[C:4]=2[O:3]1
Reactant: CCOC(=O)c1cc(-n2cnnn2)cc2c1OC(C)(C)C2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC1(C)Cc2cc(-n3cnnn3)cc(C(=O)O)c2O1
Yield: 82.8 %

Procedure:
A solution of ethyl 2,2-dimethyl-5-(1H-tetrazol-1-yl)-2,3-dihydrobenzofuran-7-carboxylate (676) (182 mg, 0.631 mmol), lithium hydroxide (106 mg, 2.53 mmol), methanol (1 mL), tetrahydrofuran (1 mL), and water (4 mL) was heated at 50° C. for 1 hour. The volatiles were removed in vacuo and 2N HCl was added. The white solid was collected by filtration washing with water to provide 2,2-dimethyl-5-(1H-tetrazol-1-yl)-2,3-dihydrobenzofuran-7-carboxylic acid (677) (136 mg, 83%).
Reaction SMILES: Br[C:2]1[C:3]([CH3:11])=[C:4]([CH2:8][O:9][CH3:10])[S:5][C:6]=1[CH3:7].[CH2:12]([O:14]CC)C.C([Li])CCC>CN(C)C=O>[CH3:7][C:6]1[S:5][C:4]([CH2:8][O:9][CH3:10])=[C:3]([CH3:11])[C:2]=1[CH:12]=[O:14]
Reactant: CCOCC
Reactant: COCc1sc(C)c(Br)c1C
Agent: [Li]CCCC
Solvent: CN(C)C=O
Product: COCc1sc(C)c(C=O)c1C
Temperature: -70 °C
Reaction time: 0.25 h

Procedure:
15.5 G. of 4-bromo-3,5-dimethyl-2-methoxymethylthiophene was dissolved in 200 ml. of anhydrous ethyl ether under argon. The resulting solution was cooled to -70° C. and 22 ml. of a 2.4 M solution of n-butyl lithium was slowly added. The reaction mixture was warmed to -30° C. for 10 minutes and then cooled to -70° C. 7.3 G. of dimethylformamide was slowly added and reaction was warmed to room temperature for 14 hours. The resulting reaction mixture was poured into ice water, stirred for 15 minutes and extracted with ethyl ether. The combined ether extracts were washed with a solution of 5% sodium carbonate, a saturated solution of sodium chloride, drive over sodium sulfate, filtered and evaporated to yield 2,4-dimethyl-5-methoxymethylthiophene-3-carboxaldehyde.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.CO[CH:13](OC)[CH2:14][NH2:15].Cl.[S-:19][C:20]#[N:21].[K+]>C(O)C.[Pd].CO>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:15]2[CH:14]=[CH:13][NH:21][C:20]2=[S:19])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=O)cc1
Reactant: N#C[S-]
Reactant: COC(CN)OC
Agent: [Pd]
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: CCO
Product: COc1ccc(Cn2cc[nH]c2=S)cc1
Temperature: 95 °C
Yield: 65 %

Procedure:
A mixture of 4-methoxybenzaldehye (13.6 g, 0.1 mol), aminoacetaldehyde dimethyl acetal (10.5 g, 0.1 mol), and methanol (1 ml) was heated at 95° C. for 10 minutes. The resulting mixture was dissolved in ethanol (150 ml) and hydrogenated over 10% Pd on carbon (1 g) until H2 uptake slowed (about 2 hours). The catalyst was filtered and the filtrate was treated with 1.5N hydrochloric acid (80 ml) and potassium thiocyanate (10.4 g, 0.11 mol). The resulting mixture was boiled until the volume was reduced to 100 ml, then it was heated at reflux an additional 1 hour and cooled to 5° C. The crystalline precipitate was filtered, washed with water, and dried. Recrystallization from ethanol gave 1-(4'-methoxybenzyl)-1,3-dihydro-2H-imidazole-2-thione, 65% yield, m.p. 140° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=NC2CCCCC2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[O:26]([CH2:34][CH:35]=[O:36])[Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].[Cl-].[NH4+].[O:39]1CCCC1>CCCCCC>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11](=[O:39])[CH:12]([CH:35]([OH:36])[CH2:34][O:26][Si:27]([C:30]([CH3:32])([CH3:33])[CH3:31])([CH3:29])[CH3:28])[CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Reactant: c1ccc(CN2CCC(=NC3CCCCC3)CC2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)OCC(O)C1CN(Cc2ccccc2)CCC1=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
The above N-(1-benzyl-4-piperidylidene)cyclohexylamine (4.81 g (17.69 mmol)) was dissolved in 150 ml of tetrahydrofuran. After this solution was cooled to -78° C., 13.3 ml (21.2 mmol) of 1.6 M n-butyl lithium in hexane was added dropwise. After the reaction mixture was stirred for 30 minutes under ice-cooling, a solution of 4.01 g (23.0 mmol) of tert-butyldimethylsiloxyacetaldehyde in 50 ml of tetrahydrofuran was added, followed by stirring for 1 hour under ice-cooling. To the reaction mixture, aqueous ammonium chloride was added, followed by stirring for 10 minutes and 3 extractions with ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1) to yield 1-benzyl-3-(2-tert-butyldimethylsiloxy-1-hydroxyethyl)-4-piperidinone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[Cl:12][CH:13](Br)[CH2:14][CH3:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:12][CH2:13][CH2:14][CH2:15][O:11][C:5]1[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cc(O)cc(OC)c1
Reactant: CCC(Cl)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(OC)cc(OCCCCl)c1
Temperature: 25 °C
Yield: 53.2 %

Procedure:
A mixture of 3,5-dimethoxyphenol 100.0 g (0.6486 mole), chlorobromopropane 148.0 g (0.96 mole) and potassium carbonate 89.6 g (0.96 mole) was heated overnight at gentle reflux in 600 ml of acetone. The reaction mixture was cooled at room temperature, filtered, and stripped to dryness via a rotary evaporator. The resulting oil was dissolved in chloroform and the solution extracted with 5% aqueous sodium hydroxide; removal of chloroform gave a dark brown oil. A 5-g sample of the oil was pumped in vacuo overnight at 80° C. This produced 3.23 g (53.2% yield based on the aliquot taken) of dark brown oil. H1 (CDCl3): δ 2-2.14 (quintuplet, center methylene protons, 2H), 3.6-4.2 (m, aliphatic protons, 4H), 3.8 (s, OCH3, 6H), 6.1 (s,aromatic protons, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]1([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH2:8][CH2:7][CH:6]([N:28]2[CH2:27][CH2:26][N:25]([C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:24])[CH2:30][CH2:29]2)[CH2:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COC1(Cc2ccccc2C)CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: COC1(Cc2ccccc2C)CCC(N2CCN(C(=O)OC(C)(C)C)CC2)CC1
Reaction time: 8 h
Yield: 70.4 %

Procedure:
A solution of EXAMPLE 15C (0.42 g, 1.80 mmol) and 1-tert-butoxycarbonylpiperazine (0.391 g, 2.10 mmol) in dichloroethane (10 mL) at room temperature was treated with acetic acid (500 μL) and sodium triacetoxyborohydride (10.89 g, 4.2 mmol), stirred overnight, diluted with ethyl acetate (300 mL), washed sequentially with 1N NaOH, water, and brine, dried (Na2SO4), filtered, and concentrated to provide the desired product (0.51 g, 70%); MS (ESI) m/e 403 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@@H:9]1[CH2:40][CH2:39][C:12]2[N:13]=[C:14]([NH:16][C:17]([C:19]3[CH:20]=[C:21]([CH:36]=[CH:37][CH:38]=3)[CH2:22][NH:23][C:24](=[O:35])[C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=3)=[O:18])[S:15][C:11]=2[CH2:10]1.CCN(C(C)C)C(C)C.Br[CH2:51][CH2:52][O:53][CH2:54][CH2:55]Br>CN(C=O)C>[CH3:34][O:33][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][C:28]=1[O:31][CH3:32])[C:24]([NH:23][CH2:22][C:21]1[CH:36]=[CH:37][CH:38]=[C:19]([C:17](=[O:18])[NH:16][C:14]2[S:15][C:11]3[CH2:10][C@H:9]([N:8]4[CH2:55][CH2:54][O:53][CH2:52][CH2:51]4)[CH2:40][CH2:39][C:12]=3[N:13]=2)[CH:20]=1)=[O:35]
Reactant: BrCCOCCBr
Reactant: COc1ccc(C(=O)NCc2cccc(C(=O)Nc3nc4c(s3)C[C@H](N)CC4)c2)cc1OC
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(=O)NCc2cccc(C(=O)Nc3nc4c(s3)C[C@H](N3CCOCC3)CC4)c2)cc1OC
Temperature: 70 °C

Procedure:
Dissolved N-[3-((R)-6-Amino-4,5,6,7-tetrahydro-benzothiazol-2-ylcarbamoyl)-benzyl]-3,4-dimethoxy-benzamide trifluoroacetate (50.0 mg, 0.09 mmol) in 1.5 mL of dry DMF. To this was added DIPEA (0.05 mL, 0.26 mmol) and the 1-bromo-2-(2-bromo-ethoxy)-ethane (0.02 mL, 0.12 mmol). The mixture was heated at 70° C. overnight. LC-MS analysis indicted the desired material. Dissolved in 5 mL of DMF and purified via prep HPLC (5%-95% CH3CN/H2O) to give the desired product with one major impurity. Applied to a SiO2 prep plate. Eluted with (10% MeOH/1% NH3/CH2Cl2) to give 18.9 mg of N-[3-((R)-6-Amino-4,5,6,7-tetrahydro-benzothiazol-2-ylcarbamoyl)-benzyl]-3,4-dimethoxy-benzamide. MS, electrospray 537.6 (M+H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.Br.[OH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]3[N:26]([CH:27]=2)[CH:25]=[CH:24][S:23]3)=[CH:16][C:15]=1[O:28][CH3:29].[Cl:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35]Br)=[CH:33][CH:32]=1>O.CO>[Cl:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:21]=[C:22]4[N:26]([CH:27]=3)[CH:25]=[CH:24][S:23]4)=[CH:16][C:15]=2[O:28][CH3:29])=[CH:33][CH:32]=1
Reactant: COc1cc(-c2cn3ccsc3n2)ccc1O
Reactant: Clc1ccc(CBr)cc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: COc1cc(-c2cn3ccsc3n2)ccc1OCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
Potassium carbonate (106 g) was added to 490 ml of an anhydrous DMF suspension of 120 g of the compound obtained in Step 1. After stirring for 2 hours, to the mixture was added 82.9 g of p-chlorobenzyl bromide at 0° C., and stirred for 3 hours at 0° C. and for 42 hours at room temperature. The reaction mixture was mixed with 500 ml of methanol and 450 ml of water, and stirred at 70° C. for 30 minutes. After cooling the mixture to room temperature, the precipitated crystals were suction filtered, rinsed with 50% methanol and water, and dried under reduced pressure, thereby yielding 102 g of transparent crystals of the desired compound (“Example Compound 23”).
Reaction SMILES: C([O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([CH3:16])=[CH:10][C:11](=[O:15])[O:12]2)=[CH:7][CH:6]=1)C=C.C(N(CC)[C:20]1[CH:25]=CC=C[CH:21]=1)C>>[CH2:25]([C:14]1[C:5]([OH:4])=[CH:6][CH:7]=[C:8]2[C:13]=1[O:12][C:11](=[O:15])[CH:10]=[C:9]2[CH3:16])[CH:20]=[CH2:21]
Reactant: CCN(CC)c1ccccc1
Reactant: C=CCOc1ccc2c(C)cc(=O)oc2c1
Product: C=CCc1c(O)ccc2c(C)cc(=O)oc12
Temperature: 250 °C
Yield: 88 %

Procedure:
7-Allyloxy-4-methylcoumarin 2 (1.0 g, 4.62 mmol) was dissolved in N,N-diethylaniline (8 mL) in a sealed vial and heated to 250° C. for 25 min under microwave. The reaction mixture was then cooled, during which some of the product precipitated. Hexane (10 mL) was added in order to precipitate out the remaining product. The precipitate was filtered, washed with hexane, and dried under vacuum to yield 3 as a pale-yellow solid (0.88 g, 88%). TLC (hexane/ethyl acetate, 1:3): Rf=0.5. mp 204° C. 1H NMR (CDCl3/CD3OD, 500 MHz) δ 2.43 (s, 3H, CH3), 3.57 (d, J=6.0 Hz, 2H, CH2), 4.95 (d, J=10.0 Hz, 1H), 5.04 (d, J=17.0 Hz, 1H), 5.97 (m, 1H), 6.10 (s, 1H), 6.86 (d, J=9.0 Hz, 1H), 7.46 (d, J=9.0 Hz, 1H). 13C NMR (CDCl3/CD3OD, 125 MHz) δ 18.85, 27.66, 110.78, 113.20, 113.73, 114.93, 115.41, 124.38, 136.16, 153.89, 155.88, 160.18, 163.92. ESIMS calcd for C13H13O3 [M+H]+ 217.1. Found 217.2.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:7]([N:9]1[CH2:23][CH2:22][CH2:21][C@H:10]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].Cl.CCOC(C)=O>O1CCOCC1>[NH2:1][C@H:2]([C:7]([N:9]1[CH2:23][CH2:22][CH2:21][C@H:10]1[C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])=[O:8])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 5 h

Procedure:
To a flask containing Boc-Leu-Pro-OBn (113.8 g, 272 mmol) a solution of hydrogen chloride in dioxane (209 ml, 5.3 N) was added and the stirring was continued for 5 h or until total conversion by TLC (disappearance of starting material: Rf=0.47 (hex-EtOAc 2:1, silica). The solution was concentrated under reduced pressure and the resulting oil was chased with CHCl3 (3×50 ml), CHCl3-MTBE (30 ml-50 ml), MTBE (50 ml) and hex (50 ml). The residue was dried under vacuum (16 h) to remove residual HCl, to give the title compound as a white solid. A5 (96.4 g, 100%) was used directly without further purification in the next step. [α]D22 −85.21 (c=1, CHCl3).