Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5](=[O:12])[CH2:4][CH2:3][CH2:2]1.[N+:13]([O-])([O-:15])=[O:14].[Na+]>S(=O)(=O)(O)O>[N+:13]([C:10]1[CH:9]=[CH:8][C:7]2[O:1][CH2:2][CH2:3][CH2:4][C:5](=[O:12])[C:6]=2[CH:11]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])[O-]
Reactant: O=C1CCCOc2ccccc21
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C1CCCOc2ccc([N+](=O)[O-])cc21
Temperature: 0 °C

Procedure:
40.5 g (0.25 mole) of 2,3-dihydro-1-benzoxepin-5(4H)-one are introduced at -10° C. into 400 ml of concentrated sulfuric acid while stirring. Coarsely crystalline sodium nitrate is slowly introduced at -5° C. to 0° C. whilst stirring vigorously. The mixture is then stirred at 0° C. for about 1 hour, during which the sodium nitrate slowly dissolves. The mixture is stirred into ice/water and, after about 30 minutes, filtered with suction and washed thoroughly with water. The residue on the filter is taken up in ethyl acetate, and the solution is separated from the water, dried over sodium sulfate, filtered and evaporated in vacuo. The residue is crystallized in ethyl acetate/cyclohexane.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH2:13][CH:12]([CH2:16][N:17]3[C:23](=[O:24])[CH2:22][C:21]4[CH:25]=[C:26]([O:31][CH3:32])[C:27]([O:29][CH3:30])=[CH:28][C:20]=4[CH2:19][CH2:18]3)[CH2:11]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:40]([Cl:43])(=[O:42])[CH3:41].O>C(Cl)Cl>[ClH:43].[NH:1]([C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH2:13][CH:12]([CH2:16][N:17]3[C:23](=[O:24])[CH2:22][C:21]4[CH:25]=[C:26]([O:31][CH3:32])[C:27]([O:29][CH3:30])=[CH:28][C:20]=4[CH2:19][CH2:18]3)[CH2:11]2)=[CH:6][CH:7]=1)[C:40]([CH3:41])=[O:42]
Reactant: CC(=O)Cl
Reactant: COc1cc2c(cc1OC)CC(=O)N(CC1CCCN(CCc3ccc(N)cc3)C1)CC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1cc2c(cc1OC)CC(=O)N(CC1CCCN(CCc3ccc(NC(C)=O)cc3)C1)CC2
Product: Cl

Procedure:
0.88 g (0.002 mol) of 3-[(N-(2-(4-amino-phenyl)-ethyl)-piperidin-3-yl)-methyl]-7, 8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one and 0.3 ml (0.0022 mol) of triethylamine are dissolved in 10 ml of methylene chloride and 0.16 ml (0.0022 mol) of acetyl chloride are added dropwize with stirring. After 30 minutes water is added. The aqueous phase is extracted three times with methylene chloride. The organic phase is dried over magnesium sulphate and evaporated down in vacuo. The hydrochloride is precipitated from a solution of the residue in acetone using methanolic hydrochloric acid.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[F:5][C:6]1[CH:7]=[C:8]([C:22]2[N:23]=[C:24]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][C@@H:37]3[CH3:42])[C:25]3[CH2:30][N:29]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:28][C:26]=3[N:27]=2)[CH:9]=[CH:10][C:11]=1[NH:12][C:13](OC1C=CC=CC=1)=[O:14]>>[CH:1]1([NH:4][C:13](=[O:14])[NH:12][C:11]2[CH:10]=[CH:9][C:8]([C:22]3[N:23]=[C:24]([N:36]4[CH2:41][CH2:40][O:39][CH2:38][C@@H:37]4[CH3:42])[C:25]4[CH2:30][N:29]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:28][C:26]=4[N:27]=3)=[CH:7][C:6]=2[F:5])[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: CCOC(=O)N1Cc2nc(-c3ccc(NC(=O)Oc4ccccc4)c(F)c3)nc(N3CCOC[C@@H]3C)c2C1
Product: CCOC(=O)N1Cc2nc(-c3ccc(NC(=O)NC4CC4)c(F)c3)nc(N3CCOC[C@@H]3C)c2C1
Yield: 40 %

Procedure:
Method as described for example 51, using cyclopropylamine and (S)-ethyl 2-(3-fluoro-4-((phenoxycarbonyl)amino)phenyl)-4-(3-methylmorpholino)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate as starting materials. The mixture was reduced in vacuo and purified by flash SCX2 chromatography affording the title compound (11 mg, 0.023 mmol, 40%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[C:10]1[O:11][CH:12]=[CH:13][CH:14]=1.[CH2:15]1[C:20](=O)[CH2:19][C:17](=[O:18])[CH2:16]1.[NH2:22][C:23]1[N:27]([CH3:28])[NH:26][C:25](=[O:29])[CH:24]=1>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]2[C:24]3[C:25](=[O:29])[NH:26][N:27]([CH3:28])[C:23]=3[NH:22][C:20]3[CH2:15][CH2:16][C:17](=[O:18])[C:19]2=3)=[CH:4][C:3]=1[C:10]1[O:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=Cc1ccc(F)c(-c2ccco2)c1
Reactant: Cn1[nH]c(=O)cc1N
Reactant: O=C1CCC(=O)C1
Product: Cn1[nH]c(=O)c2c1NC1=C(C(=O)CC1)C2c1ccc(F)c(-c2ccco2)c1
Yield: 73.9 %

Procedure:
4-Fluoro-3-(2-furyl)-benzaldehyde (0.38 g, 2.0 mmol) from Example 14A, 1,3-cyclopentadione (0.2 g, 2.0 mmol), and 5-amino-1-methyl-1,2-dihydropyrazol-3-one (0.22 g, 2.0 mmol) were processed as described in Example 1 to provide 0.54 g of the title compound.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9](#[N:12])[CH:10]=[CH2:11].[CH3:13][O-:14].[Na+]>>[C:2]1([C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:10]([CH2:11][O:14][CH3:13])[C:9]#[N:12])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: C=CC#N
Reactant: C[O-]
Agent: [Na+]
Product: COCC(C#N)=C(c1ccccc1)c1ccccc1

Procedure:
In the procedure of Scheme C, benzaldehyde a is treated with acrylonitrile in the presence of sodium methoxide in step 1 to afford a phenyl methoxymethyl cinnamonitrile compound g, which in turn is reacted with guanidine in step 2 to yield the diaminopyrimidine r. Diamino pyrimidine r is a compound of formula (I) in which X is —CH2—, Y is —NH2 and R6, R7 and R8 are hydrogen.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH2:22][O:23][CH3:24])=[CH:18][CH:19]=2)[O:14][CH2:13][C:12]1([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][O:34][CH3:35])=[CH:28][CH:27]=1)[CH3:25].CS(C)=O.[N-:40]=[N+:41]=[N-:42].[Na+].CCCCCC>C(OCC)(=O)C>[N:40]([CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH2:22][O:23][CH3:24])=[CH:18][CH:19]=2)[O:14][CH2:13][C:12]1([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][O:34][CH3:35])=[CH:28][CH:27]=1)[CH3:25])=[N+:41]=[N-:42]
Reactant: [N-]=[N+]=[N-]
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCCOCCCCBr)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CS(C)=O
Product: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCCOCCCCN=[N+]=[N-])cc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To (3RS,4RS)-4-(9-bromo-5-oxanonyl)-7-methoxymethoxy-3-(4-(methoxymethoxy)phenyl)-3-methylchroman (276 mg, 0.5 mmol) in. DMSO was added sodium azide (65.1 mg, 1 mmol). The mixture was stirred at 80° C. for 3 h. After cooling, the mixture was extracted with ethyl acetate, dried over MgSO4, and filtered. The filtrate was evaporated under reduced pressure, and the concentrate thus obtained was subjected to silica gel column chromatography (n-hexane:ethyl acetate=10:1) to give 269 mg (yield. 100%) of a colorless oil.
Reaction SMILES: [C:1]1([CH2:7][O:8]C([NH:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][NH:24]C(OCC3C=CC=CC=3)=O)=[CH:17][CH:16]=2)=O)C=CC=CC=1.[H][H].[C:37]([OH:40])(=[O:39])[CH3:38]>[Pt]=O>[NH2:11][CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22][CH2:23][NH2:24])[CH2:17][CH2:16]1.[CH3:1][C:7]([CH2:38][C:37]([OH:40])=[O:39])=[O:8]
Reactant: [H][H]
Reactant: O=C(NCCCc1ccc(CCCNC(=O)OCc2ccccc2)cc1)OCc1ccccc1
Reactant: CC(=O)O
Agent: O=[Pt]
Product: CC(=O)CC(=O)O
Product: NCCCC1CCC(CCCN)CC1
Temperature: 25 °C

Procedure:
Into a 250 mL reduction vessel were placed (phenylmethoxy)-N-[3(4-{3-[(phenylmethoxy)carbonylamino]propyl}phenyl)propyl]carboxamide (0.93 g, 2.02 mmol), acetic acid (75 mL), and platinum oxide (0.5 g) and the mixture was heated at 60° C. under 60 psi (413.7 kPa) of hydrogen gas for 12 hours. The reaction was cooled to room temperature and filtered through a Celite® cake and the filtrate was concentrated under reduced vacuum to give the intermediate title compound, 3-[4-(3-aminoethyl)cyclohexyl]propyllamine, (0.64 g, 100%) as a diacetic acid salt. Electron spray M.S. 199 (M++1).
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[N:6][N:5]=[C:4]2[N:9]([CH3:18])[N:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:3]=12.[C:19]1(B2OC(C)(C)C(C)(C)O2)[CH2:23][CH2:22][CH2:21][CH:20]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O.C(Cl)Cl>[Cl:1][C:2]1[C:7]([C:19]2[CH2:23][CH2:22][CH2:21][CH:20]=2)=[N:6][N:5]=[C:4]2[N:9]([CH3:18])[N:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:3]=12
Reactant: Cn1nc(-c2ccccc2)c2c(Cl)c(I)nnc21
Reactant: CC1(C)OB(C2=CCCC2)OC1(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc(-c2ccccc2)c2c(Cl)c(C3=CCCC3)nnc21
Temperature: 30 °C
Yield: 20.1 %

Procedure:
Nitrogen was bubbled through a suspension of 4-chloro-5-iodo-1-methyl-3-phenyl-pyrazolo[3,4-c]pyridazine (60 mg, 0.16 mmol), 2-(cyclopenten-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (35 mg, 0.18 mmol) and K3PO4 (103 mg, 0.48 mmol) in DMF (1 mL) and water (0.3 mL) for 15 min. 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (13 mg, 0.016 mmol) was added and the tube sealed and heated to 30° C. for 16 h. The reaction mixture was diluted with CH2Cl2 and water. The aqueous phase was extracted with CH2Cl2 and the combined organic phases were dried (phase separator cartridge) and concentrated in vacuo. The resultant residue was purified using chromatography (silica gel, CH2Cl2/isohexane 1:1 to 1:0), to provide Compound IIIb as a solid (10 mg).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:12]=[C:11](N)[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=1.CC(C)CC[O:18]N=O.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl.ClCCl>[CH3:1][S:2][C:3]1[NH:12][C:11](=[O:18])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=1
Reactant: CSc1nc(N)c2c(n1)CCCC2
Reactant: CC(C)CCON=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CSc1nc2c(c(=O)[nH]1)CCCC2
Temperature: 60 °C
Reaction time: 2 h

Procedure:
2-Methylsulfanyl-5,6,7,8-tetrahydroquinazolin-4-ylamine (5.09 g; 23.145 mmol), 3-methyl-1-nitrosooxybutane (11.6 ml; 86.79 mmol) and trifluoroacetic acid (23.2 ml; 300.89 mmol) are dissolved in chloroform (300 ml), the pale-yellow solution is warmed to 60° C. and stirred for 2 h. The reaction mixture is diluted with dichloromethane and extracted with 10% K2CO3. The aqueous phase is separated off and back-extracted once with dichloromethane, NaCl is subsequently added, and the mixture is extracted again with ethyl acetate. The combined organic phases are dried over Na2SO4, filtered and evaporated. The crude product obtained in this way is adsorbed onto sorbent and purified by chromatography on a SI50 silica-gel column of a Combiflash Companion XL. After evaporation of the product fractions, the crystalline residue is triturated with diethyl ether, filtered off by suction and dried in vacuo; yield: 2.0 g (57%), crystals.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][O:41][C:42]([NH:44][C@@H:45]([C:49]([CH3:52])([CH3:51])[CH3:50])[C:46](O)=[O:47])=[O:43].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:30][O:29][C:28](=[O:31])[NH:27][C@@H:22]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:20](=[O:21])[NH:19][C@H:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)[CH2:4][C@H:3]([OH:32])[C@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[NH:1][C:46](=[O:47])[C@H:45]([C:49]([CH3:51])([CH3:50])[CH3:52])[NH:44][C:42](=[O:43])[O:41][CH3:40]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: COC(=O)N[C@H](C(=O)N[C@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N[C@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.8 %

Procedure:
A solution of the product of Example 1H (0.18 g, 0.33 mmol) in THF (3.3 mL) was treated with the product of Example 1F (0.11 g, 0.60 mmol), DEPBT (0.15 g, 0.50 mmol), and N,N-diisopropylethylamine (0.29 mL, 1.66 mmol), stirred at 25° C. for 16 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0%-75% ethyl acetate in chloroform to give the title product (0.19 g, 81% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.75 (s, 9 H), 0.78 (s, 9 H), 1.28 (m, 2 H), 1.55 (m, 1 H), 2.70 (m, 4 H), 3.55 (d, J=11.77 Hz, 6 H), 3.85 (m, 3 H), 4.15 (m, 1 H), 4.80 (d, J=5.15 Hz, 1 H), 6.75 (d, J=9.19 Hz, 1 H), 6.86 (d, J=9.56 Hz, 1 H), 7.13 (m, 5 H), 7.22 (d, J=8.46 Hz, 2 H), 7.32 (m, 1 H), 7.52 (d, *8.82 Hz, 1 H), 7.88 (m, 5 H), 8.64 (d, j=4.41 Hz, 1 H).
Reaction SMILES: [H-].[Na+].Cl.[S:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[NH:13][C@@H:14]1[CH2:17][C@H:16]([OH:18])[CH2:15]1.F[C:20]1[C:25]([C:26]2[CH2:31][CH2:30][N:29]([C:32](=[O:34])[CH3:33])[CH2:28][CH:27]=2)=[CH:24][CH:23]=[CH:22][N:21]=1>CN(C)C=O.CCOC(C)=O>[S:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[NH:13][C@@H:14]1[CH2:15][C@H:16]([O:18][C:20]2[C:25]([C:26]3[CH2:31][CH2:30][N:29]([C:32](=[O:34])[CH3:33])[CH2:28][CH:27]=3)=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:17]1
Reactant: CC(=O)N1CC=C(c2cccnc2F)CC1
Reactant: O[C@H]1C[C@@H](Nc2nc3ccccc3s2)C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)N1CC=C(c2cccnc2O[C@H]2C[C@@H](Nc3nc4ccccc4s3)C2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride, 60% dispersion in mineral oil (0.13 g, 3.18 mmol) was added to a solution of cis-3-(benzo[d]thiazol-2-ylamino)cyclobutanol hydrochloride (0.20 g, 0.795 mmol) in N,N-dimethylformamide (2.7 mL) under argon and the mixture was stirred for 30 min at RT. 1-(4-(2-Fluoropyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone (0.17 g, 0.79 mmol) was next added, and the resulting mixture was heated at 100° C. for 2 h. The cooled reaction was diluted with EtOAc and washed with water. The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. Flash column chromatography (20% to 80% EtOAc/Hexanes) afforded 1-(4-(2-(cis-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone as an off-white amorphous solid. [M+1]=421.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([OH:8])[CH:7]=1.C1(=O)O[CH2:14][CH2:13][O:12]1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([CH:7]=1)[O:8][CH2:14][CH2:13][OH:12]
Reactant: O=C1OCCO1
Reactant: COc1ccc(F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc(F)cc1OCCO
Yield: 79.8 %

Procedure:
A suspension of 8.75 g of 5-fluoro-2-methoxyphenol, 10.9 g of ethylene carbonate and 8.50 g of potassium carbonate in 12 ml of toluene was refluxed for 2.5 hours. The reaction mixture was diluted with benzene, washed with water, dried and evaporated. The residue was distilled to give 9.15 g of 2-(5-fluoro-2-methoxyphenoxy)ethanol as colorless oil, b.p. 138°-140° C. (8mmHg).
Reaction SMILES: F[B-](F)(F)F.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15](=[NH:19])OCC.C(N(CC)CC)C.[C:27]1([C:33]2([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C@H:41]3[C@H:37]([CH2:38][NH:39][CH2:40]3)[C@@H:36]([OH:42])[CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[C:43]1([C:33]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C@H:41]3[C@H:37]([CH2:38][N:39]([C:15](=[NH:19])[CH2:14][C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=4[O:7][CH3:6])[CH2:40]3)[C@@H:36]([OH:42])[CH2:35][CH2:34]2)[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: CCOC(=N)Cc1ccccc1OC
Reactant: O[C@H]1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@@H]21
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1CC(=N)N1C[C@H]2[C@@H](C1)C(c1ccccc1)(c1ccccc1)CC[C@@H]2O
Yield: 57 %

Procedure:
A solution of 1.56 g of ethyl (2-methoxyphenyl)-acetimidate tetrafluoroborate and 0.96 cm3 of triethylamine in 20 cm3 of dry dichloromethane is added to a solution of 2 g of (3aR,4S,7aR)-7,7-diphenyl-4-perhydroisoindolol in 30 cm3 of dry dichloromethane, and the reaction mixture is then refluxed for 2 hours. 10 cm3 of a 10% aqueous solution of potassium carbonate are then added, the mixture is decanted and then the organic phase is washed with 20 cm3 of water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on an alumina column (diameter 3.6 cm, height 31 cm), eluting under a nitrogen pressure of 0.1 bar with a dichloromethane and methanol mixture (95/5 by volume) and collecting fractions of 50 cm3. Fractions 5 to 30 are pooled and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is washed with isopropyl oxide, drained and dried. 1.4 g of (3aR,4S,7aR)-7,7-diphenyl-2-[1-imino-2-(2-methoxyphenyl)ethyl]-4-perhydroisoindolol are obtained in the form of white crystals; melting point 105° C., with decomposition.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([C:9](=[O:24])/[CH:10]=[CH:11]/[C:12]2[S:22][C:21]3[N:23]4[C:14](=[CH:15][N:16]=[C:17]4[CH:18]=[CH:19][CH:20]=3)[CH:13]=2)[CH2:5][CH2:4]1.Br[CH2:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C(#N)C>[C:29]1([CH2:28][CH2:27][CH2:26][N:3]2[CH2:8][CH2:7][CH:6]([C:9](=[O:24])/[CH:10]=[CH:11]/[C:12]3[S:22][C:21]4[N:23]5[C:14](=[CH:15][N:16]=[C:17]5[CH:18]=[CH:19][CH:20]=4)[CH:13]=3)[CH2:5][CH2:4]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(/C=C/C1=Cc2cnc3cccc(n23)S1)C1CCNCC1
Reactant: BrCCCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(/C=C/C1=Cc2cnc3cccc(n23)S1)C1CCN(CCCc2ccccc2)CC1

Procedure:
A solution of 0.675 g (1.756 mM) of (E)-1-(piperidin-4-yl)-3-(5-thia-1,8b-diazaacenaphthylen-4-yl)propen-1-one dihydrochloride, 0.52 g (2.63 mM) of 1-bromo-3-phenylpropane, and 0.86 ml (6.15 mM) of triethylamine in 30 ml of acetonitrile, and the mixture was refluxed for 1 day. This reaction mixture was poured in aqueous solution of sodium hydrogen carbonate and extracted with 3 portions of ethyl acetate. The organic layers were pooled and dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate˜ethyl acetate/methanol: 4/1) to provide the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].S(O[CH2:31][CH2:32][O:33][CH:34]([CH3:36])[CH3:35])(=O)(=O)C>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:16]([CH2:31][CH2:32][O:33][CH:34]([CH3:36])[CH3:35])[C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3[nH]2)CC1
Reactant: CC(C)OCCOS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)OCCn1c(N2CCCN(C(=O)OC(C)(C)C)CC2)nc2ccccc21
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Combine 1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepane (0.54 g, 1.71 mmol) and sodium hydride (0.87 g, 3.48 mmol) in dimethylformamide (10 mL). After 30 minutes, add 2-(isopropoxy)ethyl mesylate (0.51 g, 5.5 mmol). Heat to 80° C. After 2 hours, cool the reaction mixture to ambient temperature and partition between dichloromethane and a saturated aqueous sodium bicarbonate solution. Separate the layers and extract the organic layer with brine. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give 1-(t-butoxycarbonyl)-4-(1-(2-(isopropoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]([CH:24]=[O:25])=[C:11]([I:26])[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].I[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH:35]([CH3:37])[CH3:36])=[CH:30][CH:29]=1>>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:19])([CH3:20])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:22])[CH3:23])[C:12]([C@H:24]([C:28]3[CH:33]=[CH:32][C:31]([CH2:34][CH:35]([CH3:37])[CH3:36])=[CH:30][CH:29]=3)[OH:25])=[C:11]([I:26])[C:10]1=2)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)c1nc2c(c(I)c1C=O)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Reactant: CC(C)Cc1ccc(I)cc1
Product: CC(C)Cc1ccc([C@H](O)c2c(C(C)C)nc3c(c2I)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C3)cc1

Procedure:
Obtained by starting from (S)-5-(tert-butyldimethylsilyloxy)-4-iodo-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-3-carbaldehyde and 1-iodo-4-isobutylbenzene.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:24]=[CH:23][C:10]([O:11][CH2:12][C:13]2[N:14]([CH3:22])[C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:9][CH:8]=1.O.[OH-].[Na+].CN(C)[CH:30]=[O:31]>>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([O:11][CH2:12][C:13]2[N:14]([CH3:22])[C:15]3[C:20]([C:21]=2[CH:30]=[O:31])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:23][CH:24]=1
Reactant: CN(C)C=O
Reactant: Cn1c(COc2ccc(Cl)cc2)cc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cn1c(COc2ccc(Cl)cc2)c(C=O)c2ccccc21
Temperature: 55 °C

Procedure:
Under a nitrogen atmosphere a round bottom flask was charged with 0.63 ml of anhydrous N,N-dimethylformamide. The reaction vessel was placed in a −20° C. bath and then phosphorous oxychloride (0.187 ml, 0.310 g, 2.02 mmol) was carefully added. The resulting mixture was stirred in an ice bath for about twenty minutes and 2-[(4-chlorophenoxy)methyl]-1-methyl-1H-indole (0.50 g, 1.84 mmol) in 3.4 ml of N,N-dimethylformamide, was added. The resulting mixture was stirred at room temperature for about ninety minutes. The reaction mixture was then placed over an oil bath and heated to 55° C. and maintained at this temperature for about one hour. The reaction mixture was then permitted to cool to room temperature and was then poured into water. Sodium hydroxide (10 ml of a 5.0 N solution) was added and heated to reflux. The resulting mixture was cooled and the solids were then collected by filtration.
Reaction SMILES: CS(C)=O.[CH2:5]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([NH:16][S:17]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]([CH:30]([OH:32])[CH3:31])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:12][CH2:11]1)=[O:9])[CH3:6].C(N(CC)CC)C>C(Cl)Cl>[CH2:5]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([NH:16][S:17]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]([C:30](=[O:32])[CH3:31])=[CH:22][CH:21]=2)(=[O:18])=[O:19])[CH2:12][CH2:11]1)=[O:9])[CH3:6]
Reactant: CCOC(=O)N1CCC(NS(=O)(=O)c2ccc(C(C)O)c3ccccc23)CC1
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCC(NS(=O)(=O)c2ccc(C(C)=O)c3ccccc23)CC1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 25.1 %

Procedure:
To a −78° C. solution of oxalyl dihcloride (85 mg, 0.665 mmol) in CH2Cl2 (10 mL) was added DMSO (104 mg, 1.33 mmol). After stirred at -78° C. for 10 min, a solution of 4-[4-(1-hydroxy-ethyl)-naphthalene-1-sulfonylamino]-piperidine-1-carboxylic acid ethyl ester 38 (180 mg, 0.443 mmol) in CH2Cl2 was added into the mixture by dropwise. The resultant mixture was stirred at −78° C. for another 30 min, then was added triethyl amine (224 mg, 2.22 mmol). The reaction mixture was warmed up to room temperature and stirred for 2 h. The resultant mixture was quenched with saturated ammonium chloride solution and the aqueous layer was extracted with CH2Cl2. The organic extracts were combined, washed with brine and dried over MgSO4. The solution was filtered and concentrated in vacuo to give the crude product. The crude material was purified by Flash column chromatography (CH2Cl2: MeOH) to provide 45 mg of 4-(4-acetyl-naphthalene-1-sulfonylamino)-piperidine-1-carboxylic acid ethyl ester 39 in 25% yield. LC/MS showed m/z: 409 (M+H)+.