Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[CH2:15][CH2:14][C@@H:13]([N:17]([CH3:19])[CH3:18])[CH2:12][C:11]=2[CH:10]=[CH:9][CH:8]=1)(=O)=O.[CH3:22][N:23]1[C:27]([CH3:28])=[C:26](B2OC(C)(C)C(C)(C)O2)[C:25]([CH3:38])=[N:24]1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.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>[CH3:18][N:17]([CH3:19])[C@@H:13]1[CH2:14][CH2:15][C:16]2[C:11](=[CH:10][CH:9]=[CH:8][C:7]=2[C:26]2[C:25]([CH3:38])=[N:24][N:23]([CH3:22])[C:27]=2[CH3:28])[CH2:12]1
Reactant: CN(C)[C@@H]1CCc2c(cccc2OS(=O)(=O)C(F)(F)F)C1
Reactant: Cc1nn(C)c(C)c1B1OC(C)(C)C(C)(C)O1
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: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1nn(C)c(C)c1-c1cccc2c1CC[C@@H](N(C)C)C2
Reaction time: 2 h

Procedure:
(6R)-6-(Dimethylamino)-5,6,7,8-tetrahydronaphthalen-1-yl trifluoromethanesulfonate (2.5 g, 7.731 mmol), 1,3,5-trimethyl-1H-pyrazole-4-boronic acid pinacol ester (2.10 g, 8.893 mmol) and Pd(PPh3)4 (1.2 g, 1.038 mmol) were added to a solution of K2CO3 (2.15 g, 15.556 mmol) in a mixture of 1,2-dimethoxyethane (60 mL) and H2O (8 mL). The reaction mixture was purged with N2 (g) for 10 min, and warmed up to reflux. The reaction was completed in 2 h. It was allowed to reach room temperature, diluted with H2O (200 mL) and extracted with AcOEt (1×400 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (0-10-20% Et3N/AcOEt) to afford the desired product as a brown-colored oil. The material was dissolved in CH2Cl2 (200 mL) and acidified with HCl aqueous solution (6 N). The organic layer was discarded, and the aqueous layer was taken to pH>13 with NaOH aqueous solution (6 N). It was extracted with CH2Cl2 (3×300 mL), and the organic layer was dried over anhydrous Na2SO4, filtered and concentrated, to give 1.45 g of the coupling product (Rf=0.2 (10% Et3N/AcOEt), colorless oil, 66% yield).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([CH3:21])([CH3:20])[CH2:9]1)C1C=CC=CC=1>CO.[H][H].[OH-].[OH-].[Pd+2]>[C:15]([NH:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][C:10]1([CH3:20])[CH3:21])([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)NC1CCN(Cc2ccccc2)CC1(C)C
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCOC(=O)NC1CCNCC1(C)C

Procedure:
A mixture of 20% Pd(OH)2 on carbon (0.3 g) and 1-benzyl-4-carbethoxyamino-3,3-dimethylpiperidine (1.3 g, 4.48 mmol) in methanol (15 ml) was stirred in hydrogen atmosphere (1 atm.) at 30° C. for 3 hr. The catalyst was filtered off, washed with methanol and filtrate concentrated to dryness to afford 4-carbethoxyamino-3,3-dimethylpiperidine. Yield 0.8 g (90%), C10H20N2O2, m/z 201 (M+1).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:11]=[CH:12][N:13]=2)[CH:10]=1)[NH2:4].[F:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([CH:23]=1)[C:20](O)=O.N>>[F:14][C:15]1[CH:23]=[C:19]([C:20]2[O:1][N:2]=[C:3]([C:5]3[CH:6]=[CH:7][C:8]4[N:9]([CH:11]=[CH:12][N:13]=4)[CH:10]=3)[N:4]=2)[CH:18]=[N:17][CH:16]=1
Reactant: NC(=NO)c1ccc2nccn2c1
Reactant: O=C(O)c1cncc(F)c1
Agent: N
Product: Fc1cncc(-c2nc(-c3ccc4nccn4c3)no2)c1

Procedure:
The title compound was prepared according to method C using N′-hydroxyimidazo[1,2-a]pyridine-6-carboximidamide (Bionet) and 5-fluoronicotinic acid (Frontier). 1H NMR (300 MHz, DMSO-d6) δ 7.71 (d, J=1.4 Hz, 1H), 7.74-7.88 (m, 2H), 8.20 (s, 1H), 8.51 (ddd, J=9.0, 2.9, 1.7 Hz, 1H), 8.97 (d, J=3.1 Hz, 1H), 9.24 (t, J=1.5 Hz, 1H), 9.47 (t, J=1.4 Hz, 1H) ppm; MS (DCI/NH3) m/z 282 (M+H)+.
Reaction SMILES: Cl.C(O[C:5](=[O:9])[CH2:6][NH:7][CH3:8])C.[C:10]([C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[S:22])=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11].C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:10]([C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:5](=[O:9])[CH2:6][N:7]([CH3:8])[C:21]2=[S:22])=[CH:16][CH:15]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)c1ccc(N=C=S)cc1
Reactant: CCOC(=O)CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CN1CC(=O)N(c2ccc(C(C)(C)C)cc2)C1=S
Temperature: 25 °C
Yield: 75.5 %

Procedure:
A mixture of sarcosine ethyl ester hydrochloride (7.68 g), 4-t-butylphenylisothiocyanate (9.6 g), triethyl amine (10.1 g) and chloroform (250 mL) was heated at reflux for 3 hours. The mixture was cooled to ambient temperature, washed with 2N HCl (2×200 mL), then with water (200 mL). The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was crystallized from ethanol to give the title compound (9.9 g), m.p. 156°-158° C. Anal. Calcd. for C14H18N2O S: C, 64.09; H, 6.91; N,10.68. Found: C, 63.83; H, 7.15; N, 10.53. Mass spectrum (EI, M.+) m/z 262.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[C:11]=1[NH2:12]>C(#N)C.C(O)(=O)C>[Br:1][C:15]1[CH:14]=[C:13]([C:17]([F:19])([F:18])[F:20])[C:11]([NH2:12])=[C:10]([Cl:9])[CH:16]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1c(Cl)cccc1C(F)(F)F
Solvent: CC(=O)O
Solvent: CC#N
Product: Nc1c(Cl)cc(Br)cc1C(F)(F)F

Procedure:
N-bromosuccinimide (910 mg, 5.1 mmol) was added to a solution of 2-chloro-6-(trifluoromethyl)aniline (1.0 g, 5.1 mmol) in acetonitrile (10 mL) and acetic acid (3 mL) at room temperature. The mixture was stirred at reflux to 18 h. The reaction mixture was then filtered through Celite and concentrated to give the title compound which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24]([OH:26])=O)[CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]([O:31][C:32](=[O:41])[NH:33][C@H:34]([CH2:39][OH:40])[CH2:35][CH2:36][CH2:37][NH2:38])([CH3:30])([CH3:29])[CH3:28].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C@H:12]([C:24]([NH:38][CH2:37][CH2:36][CH2:35][C@H:34]([NH:33][C:32]([O:31][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:41])[CH2:39][OH:40])=[O:26])[CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CCCN
Reactant: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)NCCC[C@@H](CO)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Under argon, 0.155 g (0.42 mmol) of N2-[(benzyloxy)carbonyl]-N5-(tert-butoxycarbonyl)-L-ornithine and 0.12 g (0.55 mmol) of tert-butyl[(1S)-4-amino-1-(hydroxymethyl)butyl]carbamate (Example 247A) are dissolved in 6 ml of dimethylformamide. Then, at 0° C. (ice bath), 0.105 g (0.55 mmol) of EDC and 0.017 g (0.13 mmol) of HOBt are added. The mixture is slowly warmed to RT and stirred at RT for 12 h. The solution is concentrated in vacuo and the residue is taken up with ethyl acetate. The organic phase is washed successively with saturated sodium bicarbonate and sodium chloride solutions, dried over magnesium sulfate and evaporated in vacuo. The remaining solid is purified by preparative HPLC (Kromasil, mobile phase acetonitrile/0.25% aqueous trifluoroacetic acid 5:95→95:5).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([O:35][CH2:36][CH2:37][CH2:38][OH:39])(=[O:34])[CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].[C:40]1([CH2:46][CH2:47][CH2:48][C:49](O)=[O:50])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:16]([O:35][CH2:36][CH2:37][CH2:38][O:39][C:49](=[O:50])[CH2:48][CH2:47][CH2:46][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)(=[O:34])[CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)OCCCO
Reactant: O=C(O)CCCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)OCCCOC(=O)CCCc1ccccc1

Procedure:
A solution of 1,3-dicyclohexylcarbodiimide (710 mg, 3.45 mmol) and 4-(N,N-dimethylamino)pyridine (475 mg, 3.9 mmol) in methylene chloride (10 ml) was added to a solution of 1-(z,z,z-octadeca-6,9,12-trienoyloxy)-3-hydroxypropane (1 g, 3 mmol) and 4-phenylbutanoic acid (520 mg, 3.15 mmol) in methylene chloride (15 ml). The resultant mixture was stirred at room temperature under nitrogen until it was complete as indicated by tlc. The mixture was filtered, concentrated and purified by flash chromatography to yield 1-(z,z,z-octadeca-6,9,12-trienoyloxy)-3-(4-phenylbutanoyloxy)propane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[CH:10]=[C:9]([O:13][CH3:14])[C:8](=[O:15])[NH:7][C:6]=2[CH:16]=1.C([O-])(=O)C.[Na+].[I:22]Cl>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]([I:22])=[C:9]([O:13][CH3:14])[C:8](=[O:15])[NH:7][C:6]=2[CH:16]=1
Reactant: ClI
Reactant: COc1cc(=O)c2ccc(Cl)cc2[nH]c1=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1c(I)c(=O)c2ccc(Cl)cc2[nH]c1=O
Reaction time: 0.25 h

Procedure:
To a suspension of 8-chloro-3-methoxy-2,5-dioxo-2,5-dihydro-1H-benz[b]azepine (3.00 g) in glacial acetic acid (250 mL) was added sodium acetate (2.07 g) followed by iodine monochloride (15.2 mL). The mixture was heated to reflux for 1.5 hours, was allowed to cool, and the acetic acid was evaporated from the reaction mixture. The solid residue was suspended in tetrahydrofuran and stirred for 15 minutes. The solution was filtered and the resulting filtrate evaporated. The yellowish solid was recrystallized from refluxing toluene (700 mL) to afford the title compound (3.8 g); 250 MHz NMR: 11.60 (broad s, 1), 7.59 (d,1, J=7.1), 7.30 (d,1, J=1.4), 7.23 (dd,1, J=7.1, 1.6), 3.90 (s,3). Analysis for C11H7ClINO3 : Calculated: C, 36.34; H, 1.94; N, 3.85; Found: C, 36.35, H, 1.87; N, 3.82.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.C(P(=O)(OCC)OCC)#N.CN1CCOCC1.[NH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:33]1[C:37]2=[C:38]([S:42]([NH:45][C:46]([CH3:49])([CH3:48])[CH3:47])(=[O:44])=[O:43])[CH:39]=[CH:40][CH:41]=[C:36]2[S:35][N:34]=1>C(Cl)Cl>[C:46]([NH:45][S:42]([C:38]1[C:37]2[C:33]([NH:32][CH2:31][CH2:30][CH2:29][NH:28][C:6](=[O:8])[C:5]3[CH:4]=[CH:3][C:2]([I:1])=[CH:10][CH:9]=3)=[N:34][S:35][C:36]=2[CH:41]=[CH:40][CH:39]=1)(=[O:44])=[O:43])([CH3:49])([CH3:48])[CH3:47]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc2snc(NCCCN)c12
Reactant: O=C(O)c1ccc(I)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)NS(=O)(=O)c1cccc2snc(NCCCNC(=O)c3ccc(I)cc3)c12
Reaction time: 0.25 h
Yield: 91.1 %

Procedure:
To a solution of 4-iodobenzoic acid (210 mg, 0.8 mmol) in methylene chloride (2 mL), diethyl cyanophosphonate (120 μL, 0.8 mmol) and 4-methylmorpholine (172 μL, 1.6 mmol) were added at room temperature and allowed to stir for 15 min. A solution of 3-(3-aminopropylamino)-N-tert-butylbenzo[d]isothiazole-4-sulfonamide (243 mg, 0.7 mmol) in methylene chloride (4 mL) was then added and the resulting reaction mixture was allowed to stir overnight. The reaction mixture with diluted with methylene chloride (20 mL), washed with 10% HCl aqueous solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography, on silica gel, eluting with 1:1 ethyl acetate:hexanes, followed by 7:3 ethyl acetate:hexanes provided N-(3-(4-(N-tert-butylsulfamoyl)benzo[d]isothiazol-3-ylamino)propyl)-4-iodobenzamide (365 mg) as a yellow foam. 1H NMR (300 MHz, CDCl3): 8.01 (dd, 1H), 7.96 (dd, 1H), 7.80 (d, 2H), 7.59 (d, 2H), 7.43-7.49 (m, 2H), 6.10 (t, 1H), 4.98 (s, 1H), 3.71 (dd, 2H), 3.59 (dd, 2H), 1.92-2.00 (m, 2H), 1.25 ppm (s, 9H). MW=572 confirmed by LC-MS, tr=13.85 min (Method Y) MH+=573.
Reaction SMILES: [Br:1][C:2]1[C:3]2[C:8]([C:9]([C:16]3[CH:21]=[CH:20][C:19]([CH:22]=O)=[CH:18][CH:17]=3)=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[CH2:24](P(=O)(OCC)OCC)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CS(C)=O.CC(C)([O-])C.[K+]>O>[Br:1][C:2]1[C:3]2[C:8]([C:9]([C:16]3[CH:21]=[CH:20][C:19]([CH:22]=[CH:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:18][CH:17]=3)=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: CCOP(=O)(Cc1ccccc1)OCC
Reactant: O=Cc1ccc(-c2c3ccccc3c(Br)c3ccccc23)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Brc1c2ccccc2c(-c2ccc(C=Cc3ccccc3)cc2)c2ccccc12
Temperature: 25 °C
Reaction time: 10 h
Yield: 85.6 %

Procedure:
Under an atmosphere of argon, 9-bromo-10-(4-formylphenyl)-anthracene (3.9 g, 11 mmole) and diethyl benzylphosphonate (3 g, 13 mmole, 1.2 eq) were suspended into DMSO (25 ml). To the resultant suspension, potassium t-butoxide (1.6 g, 14 mmole, 1.1 eq) was added and the obtained mixture was stirred at the room temperature for 10 hours and left standing for one night. The reaction mixture was diluted with water (50 ml) and subjected to extraction with toluene (300 ml). The organic layer was washed with water (50 ml) and a saturated aqueous solution of sodium chloride (50 ml) and dried with magnesium sulfate. Then, the solvent was removed by distillation and a yellow solid was obtained. The obtained solid was purified by recrystallization from toluene (40 ml) and yellow needle crystals (4.1 g, 86%) were obtained.
Reaction SMILES: C=O.[C:3]([BH3-])#N.[Na+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH2:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[N:15]=[CH:14][N:13]([CH2:27][O:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[C:12]2=[O:35]>C1COCC1.CO>[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH2:20][CH:21]1[CH2:22][CH2:23][N:24]([CH3:3])[CH2:25][CH2:26]1)[N:15]=[CH:14][N:13]([CH2:27][O:28][C:29](=[O:34])[C:30]([CH3:31])([CH3:32])[CH3:33])[C:12]2=[O:35]
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCC1CCNCC1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCC1CCN(C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
A 37% aqueous solution of formaldehyde (501 μl, 6 mmol) followed by sodium cyanoborohydride (228 mg, 3.6 mmol) were added in portions to a solution of 6-methoxy-7-(piperidin-4-ylmethoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (1.21 g, 3 mmol) in a mixture of THF/methanol (10 ml/10 ml). After stirring for 30 minutes at ambient temperature, the organic solvents were removed under vacuum and the residue was partitioned between methylene chloride and water. The organic layer was separated, washed with water and brine, dried (MgSO4) and the volatiles were removed by evaporation. The residue was triturated with ether and the resulting solid was collected by filtration, washed with ether and dried under vacuum to give 6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (1.02 g, 82%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([O:10][CH2:11][O:12][CH3:13])[CH:7]=[CH:8][CH:9]=1)([O-])=O>CCOCC>[CH3:13][O:12][CH2:11][O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([NH2:1])[CH:5]=1
Reactant: COCOc1cccc([N+](=O)[O-])c1
Solvent: CCOCC
Product: COCOc1cccc(N)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
A solution of 11 (5.68 g, 31 mmol) in 310 mL moist ether (8:2:1 Et2O/EtOH/H2O) was cooled to 0° C., and treated with freshly prepared Al—Hg (5.2 g Al, 217 mmol) in small 1×1 cm pieces. The reaction mixture was stirred vigorously for 0.5 h at 0° C., and 1 h at 25° C. The reaction mixture was filtered through Celite, and the Celite was washed thoroughly with Et2O (5×50 mL). The filtrate was washed with saturated aqueous NaCl (300 mL), dried (Na2SO4), and concentrated under reduced pressure to afford 12 (4.23 g, 89%) as a golden oil, which was immediately carried on to the next step without further purification. For 12: 1H NMR (CDCl3, 250 MHz) δ7.05 (t, J=8.0 Hz, 1H), 6.38 (m, 3H), 5.12 (s, 2H), 3.70 (br s, 2H), 3.46 (s, 3H); 13C NMR (CDCl3, 250MHz) 158.2, 147.7, 129.9, 108.7, 106.0, 102.9, 94.0, 55.7;IR (film) νmax 3452, 3367, 2955, 2900, 1623, 1601, 1494, 1287, 1147, 1074, 1009 cm−1; FABHRMS (NBA/NaI) m/z 153.0786 (C8H11NO2 requires 153.0790).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:16]([C:18]12[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:26][CH:20]([CH2:21]3)[CH2:19]1)[CH2:25]2)#[CH:17].C(N(CC)CC)C>[Cu](I)I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CC=CC=1>[CH3:10][O:9][C:7]([C:6]1[CH:11]=[C:2]([C:17]#[C:16][C:18]23[CH2:27][CH:22]4[CH2:23][CH:24]([CH2:26][CH:20]([CH2:21]4)[CH2:19]2)[CH2:25]3)[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=1)=[O:8]
Reactant: C#CC12CC3CC(CC(C3)C1)C2
Reactant: COC(=O)c1cc(Br)cc(C(=O)OC)c1
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C#CC23CC4CC(CC(C4)C2)C3)cc(C(=O)OC)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
Next, 125 g of dimethyl 5-bromoisophthalate (458 mmol), 1.1 g of triphenylphosphine (4.19 mmol), 0.275 g of copper iodide (1.44 mmol), 64.26 g of 1-ethynyladamantane (401 mmol), 375 mL of dehydrated triethylamine, 200 mL of dehydrated pyridine, 0.3 g of dichlorobis (triphenylphosphine) palladium (0.427 mmol) and a stirrer were charged in a 1 L recovery flask and agitated at 100° C. for one hour. After reaction solution was filtered, solvent was removed from the reaction solution under reduced pressure. Solid thus obtained was washed with 1 L of ion-exchange water and then with 1 L of 2 mol/L hydrochloric acid aqueous solution, followed by drying under reduced pressure, thus obtaining 121.5 g of 1-(3,5-bis(methoxycarbonyl)phenyl)-2-(1-adamantyl)ethyne (344.9 mmol; yield: 86.0%).
Reaction SMILES: CC1(C)CCC2C(=CC([N+:12]([O-:14])=[O:13])=CC=2)N1.[CH2:16]([C:18]1([CH2:28][CH3:29])[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19]1)[CH3:17].[N+]([O-])(O)=O.CCOC(C)=O>S(=O)(=O)(O)O>[CH2:28]([C:18]1([CH2:16][CH3:17])[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][C:22]([N+:12]([O-:14])=[O:13])=[CH:23][CH:24]=2)[NH:19]1)[CH3:29]
Reactant: CC1(C)CCc2ccc([N+](=O)[O-])cc2N1
Reactant: CCC1(CC)CCc2ccccc2N1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: O=[N+]([O-])O
Product: CCC1(CC)CCc2ccc([N+](=O)[O-])cc2N1
Yield: 69 %

Procedure:
This compound was prepared in a manner similar to that described for 1,2,3,4-tetrahydro-2,2-dimethyl-7-nitroquinoline (Scheme III) from for 2,2-diethyl-1,2,3,4-tetrahydroquinoline (0.955 g, 5.04 mmol) and fuming HNO3 (0.32 g, 5.0 mmol) in concentrated sulfuric acid (10 mL) to afford 0.811 g (69%) of 2,2-diethyl-1,2,3,4-tetrahydro-7-nitroquinoline after chromatography (hexanes:EtOAc, 24:1). Data for 2,2-diethyl-1,2,3,4-tetrahydro-7-nitroquinoline: Rf 0.43 (24:1 hexanes:ethyl acetate); 1H NMR (400 MHz, CDCl3) 7.38 (dd, J=8.3, 2.3, 1H), 7.29 (d, J=2.3, 1H), 7.04 (d, J=8.3, 1H), 4.00 (broad s, 1H), 2.78 (t, J=6.7 2H), 1.71 (t, J=6.7, 2H), 1.38-1.58 (m, 4H), 0.88 (t, J=7.4, 6H).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:12][C:13]1[N:14]([CH3:29])[C:15]2[C:20]([N:21]=1)=[C:19]([N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)[N:18]=[C:17]([Cl:28])[N:16]=2>>[C:1]([CH:5]1[CH2:10][CH2:9][N:8]([CH2:12][C:13]2[N:14]([CH3:29])[C:15]3[C:20]([N:21]=2)=[C:19]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[N:18]=[C:17]([Cl:28])[N:16]=3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C1CCNCC1
Reactant: Cn1c(CBr)nc2c(N3CCOCC3)nc(Cl)nc21
Product: Cn1c(CN2CCC(C(C)(C)C)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Yield: 68.1 %

Procedure:
4-tert-butylpiperidine (0.45 g) was reacted with 4-(8-(bromomethyl)-2-chloro-9-methyl-9H-purin-6-yl)morpholine (1.0 g) via General Procedure C to yield 4-(8-((4-tert-butylpiperidin-1-yl)methyl)-2-chloro-9-methyl-9H-purin-6-yl)morpholine (0.80 g) as a white solid.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:14]1([CH:20]([CH3:25])[CH2:21][C:22](Cl)=[O:23])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[C:14]1([CH:20]([CH3:25])[CH2:21][C:22]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:23])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Oc1ccccc1
Reactant: CC(CC(=O)Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(CC(=O)Oc1ccccc1)c1ccccc1
Temperature: 10 °C
Reaction time: 24 h
Yield: 83.8 %

Procedure:
To the solution of phenol (8.62 g, 92 mmol) and 4-dimethylaminopyridine (400 mg) in toluene (110 ml) was added pyridine (18.1 g, 229 mmol) and the resulting solution was cooled to 10° C. Then a solution of 3-phenylbutanoyl chloride (20.1 g, 110 mmol) was added dropwise. The resulting mixture was stirred at room temperature for 24 h, and then cooled to 5° C. before the careful addition of 2N aq. HCl-solution (225 ml). The mixture was stirred intensely for 15 min, then diluted with toluene and transferred into a separatory funnel. The aqueous layer was separated and the organic layer washed 4 times with water, then brine and dried over MgSO4. The solvent was removed in a rotary evaporator and the residue short-path distilled at 125-128° C./0.07 mbar to yield 18.52 g (70%) of colourless oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:9]2[N:10]=[C:11]([C:13]3[NH:22][C:16]4[CH2:17][CH2:18][NH:19][CH2:20][CH2:21][C:15]=4[N:14]=3)[S:12][C:8]=2[C:7]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:6][CH:5]=1.C(N(C(C)C)C(C)C)C.[CH:38]1([C:41](Cl)=[O:42])[CH2:40][CH2:39]1>O1CCCC1>[CH:38]1([C:41]([N:19]2[CH2:20][CH2:21][C:15]3[N:14]=[C:13]([C:11]4[S:12][C:8]5[C:7]([N:23]6[CH2:24][CH2:25][O:26][CH2:27][CH2:28]6)=[CH:6][CH:5]=[C:4]([O:3][CH3:2])[C:9]=5[N:10]=4)[NH:22][C:16]=3[CH2:17][CH2:18]2)=[O:42])[CH2:40][CH2:39]1
Reactant: O=C(Cl)C1CC1
Reactant: COc1ccc(N2CCOCC2)c2sc(-c3nc4c([nH]3)CCNCC4)nc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(N2CCOCC2)c2sc(-c3nc4c([nH]3)CCN(C(=O)C3CC3)CC4)nc12
Yield: 93 %

Procedure:
To a suspension of 0.04 g 2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1,4,5,6,7,8-hexahydro-imidazo[4,5-d]azepine hydrochloride in 3.4 ml tetrahydrofurane were added at 0–4° C. 0.07 ml N-ethyldiisopropylamine and 0.012 g cyclopropanecarbonyl chloride. The mixture was refluxed for 17 hours, silicagel was added and the solvent was distilled off. The residue was transferred to a column prefilled with silicagel and was chromatographed with dichloromethane/methanol 96:4 to yield 0.04 g (90%) cyclopropyl-[2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4,5,7,8-tetrahydro-1H-imidazo[4,5-d]azepin-6-yl]-methanone as yellow solid; MS (ISP): m/e=454 (M+H+).
Reaction SMILES: [CH3:1][N:2]([CH2:14][C:15]([OH:17])=O)[NH:3][C:4](=[O:13])[NH:5][CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1.[NH2:18][C@@H:19]([CH2:43][C:44]1[CH:49]=[CH:48][C:47]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:46][CH:45]=1)[C:20]([N:22]([C@@H:34]([CH3:42])[CH:35]([O:39][CH2:40][CH3:41])[O:36][CH2:37][CH3:38])[CH2:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1)=[O:21]>>[C:51]([O:50][C:47]1[CH:46]=[CH:45][C:44]([CH2:43][C@H:19]([NH:18][C:15](=[O:17])[CH2:14][N:2]([CH3:1])[NH:3][C:4]([NH:5][CH2:6][C:7]2[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=2)=[O:13])[C:20]([N:22]([C@@H:34]([CH3:42])[CH:35]([O:39][CH2:40][CH3:41])[O:36][CH2:37][CH3:38])[CH2:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][CH:25]=2)=[O:21])=[CH:49][CH:48]=1)([CH3:54])([CH3:52])[CH3:53]
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Reactant: CN(CC(=O)O)NC(=O)NCc1ccncc1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)CN(C)NC(=O)NCc1ccncc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(1-methyl-2-(pyridin-4-ylmethylcarbamoyl)hydrazinyl)acetic acid (Compound VI-6) 71 mg (0.30 mmol) was coupled with (S)-2-amino-3-(4-tert-butoxyphenyl)-N—((S)-1,1-diethoxy-propan-2-yl)-N-(naphthalen-1-ylmethyl)propanamide (Compound IV-2) 100 mg (0.20 mmol) to obtain the title compound.