Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH2:29][CH2:30][O:31][CH3:32])[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:34]([C@@H:36]([O:38]C(=O)C)[CH3:37])=[O:35]>>[OH:38][C@@H:36]([CH3:37])[C:34]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH2:29][CH2:30][O:31][CH3:32])[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)=[O:35]
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: COCCOc1cc(OC)ccc1-c1ncnc2c(C(=O)N[C@H]3CC[C@H](N)CC3)c[nH]c12
Product: COCCOc1cc(OC)ccc1-c1ncnc2c(C(=O)N[C@H]3CC[C@H](NC(=O)[C@H](C)O)CC3)c[nH]c12

Procedure:
Starting from trans-4-[4-methoxy-2-(2-methoxy-ethoxy)-phenyl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A182) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound was obtained as colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[C:7]2[NH:12][NH2:13].[C:14](Cl)(=O)[CH2:15][CH2:16][CH3:17].C(N(CC)CC)C>ClCCl>[CH2:15]([C:14]1[N:6]2[CH:5]=[CH:4][C:3]3[C:8]([C:7]2=[N:12][N:13]=1)=[CH:9][CH:10]=[CH:11][C:2]=3[Br:1])[CH2:16][CH3:17]
Reactant: NNc1nccc2c(Br)cccc12
Reactant: CCCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCc1nnc2c3cccc(Br)c3ccn12

Procedure:
A mixture of 5-bromo-1-hydrazinoisoquinoline (4.76 g., 0.02 mol.) and butyryl chloride (2.1 ml., 0.02 mol.) in dichloromethane (100 ml.) was allowed to reflux overnight. The solvent was removed in vacuo and the residue was heated at reflux for three hours in xylene (100 ml.) and triethylamine (2.8 ml., 0.02 mol.). The mixture was filtered and the xylene removed in vacuo to provide the crude product. Recrystallization from ethanol (≈100 ml.) gave the pure product, 4.4 g. (76%); m.p. 197°-199°C., m.p. (hydrochloride salt) 200°-201°C.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:26])=[C:11]([N:19]4[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]4)[C:12]=3[CH2:14][O:15]C(=O)C)[C:7](=[O:27])[C:6]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:5]2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:26])=[C:11]([N:19]4[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]4)[C:12]=3[CH2:14][OH:15])[C:7](=[O:27])[C:6]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(COC(C)=O)c(N3CCN(C)CC3)c(F)cc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1cn(C2CC2)c2c(CO)c(N3CCN(C)CC3)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 78.5 %

Procedure:
To a solution of ethyl 1-cyclopropyl-7-(4-methyl-1-piperazinyl)-6-fluoro-8-acetoxymethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (142 mg) in ethanol (10 ml) is added 2N aqueous potassium carbonate (1 ml), and the mixture is stirred at room temperature for 2.5 hours. The reaction mixture is extracted with chloroform. The extract is dried over magnesium sulfate and the solvent is distilled off. The residue is crystallized by adding thereto diethyl ether to give ethyl 1-cyclopropyl-7-(4-methyl-1-piperazinyl)-6-fluoro-8-hydroxymethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (101 mg), as pale yellow powder, m.p. 216°-218° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[F:9].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:16][O:17][C:18](=[O:30])[C:19]1[CH:24]=[C:23]([OH:25])[CH:22]=[C:21]([O:26][CH2:27][O:28][CH3:29])[CH:20]=1>N1C=CC=CC=1.[Cu]=O>[CH3:16][O:17][C:18](=[O:30])[C:19]1[CH:20]=[C:21]([O:26][CH2:27][O:28][CH3:29])[CH:22]=[C:23]([O:25][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([F:9])[CH:4]=2)[CH:24]=1
Reactant: Fc1cc(I)ccc1Br
Reactant: COCOc1cc(O)cc(C(=O)OC)c1
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: c1ccncc1
Product: COCOc1cc(Oc2ccc(Br)c(F)c2)cc(C(=O)OC)c1
Temperature: 130 °C
Reaction time: 8 h
Yield: 6.4 %

Procedure:
After adding 20.4 g (0.68 mol) of 1-bromo-2-fluoro-4-iodobenzene, 20.8 g (0.64 mol) of cesium carbonate and 5.07 g (0.64 mol) of copper (II) oxide to a solution of 9.00 g (0.43 mol) of 5-hydroxy-3-methoxymethoxybenzoic acid methyl ester in pyridine (50.0 ml), the mixture was stirred at 130° C. for 8 hours under a nitrogen atmosphere. The reaction mixture was filtered and then concentrated under reduced pressure, acetic acid ethyl ester and saturated aqueous ammonium chloride were added to the obtained residue, and the organic layer was washed with brine, dried and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:acetic acid ethyl ester=9:1) to obtain 10.6 g of 3-(4-bromo-3-fluoro-phenoxy)-5-methoxymethoxybenzoic acid methyl ester (yield: 65%) as a yellow oil.
Reaction SMILES: [OH:1][C:2]1([CH:13]2[CH2:18][NH:17][CH2:16][CH2:15][NH:14]2)[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.C(N(CC)C(C)C)(C)C.[N+:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37](Cl)(=[O:39])=[O:38])([O-:30])=[O:29]>C1COCC1>[OH:1][C:2]1([CH:13]2[CH2:18][N:17]([S:37]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[N+:28]([O-:30])=[O:29])(=[O:38])=[O:39])[CH2:16][CH2:15][NH:14]2)[CH2:3][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:5]1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC(O)(C2CNCCN2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(O)(C2CN(S(=O)(=O)c3ccccc3[N+](=O)[O-])CCN2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.5 %

Procedure:
To a solution of 1,1-dimethylethyl 3-hydroxy-3-piperazin-2-ylazetidine-1-carboxylate (227 mg, 0.88 mmol) and N,N-diisopropylethylamine (436 μL, 2.64 mmol) in THF (5 mL) was added 2-nitrobenzenesulfonyl chloride (195 mg, 0.88 mmol). The mixture was stirred at room temperature for 2 hours. The solution was concentrated and the residue was purified by column chromatography (95% dichloromethane:5% methanol) to provide 1,1-dimethylethyl 3-hydroxy-3-{4-[(2-nitrophenyl)sulfonyl]piperazin-2-yl}azetidine-1-carboxylate as a white foam (308 mg, 0.70 mmol, 79% yield). 1H NMR, (400 MHz, CDCl3): 7.98 (m, 1H), 7.72 (m, 2H), 7.64 (m, 1H), 3.96 (d, 1H), 3.94 (d, 1H), 3.85 (d, 1H), 3.79 (d, 1H), 3.79-3.73 (m, 2H), 3.11 (m, 1H), 3.05 (dd, 1H), 3.00 (br s, 1H), 2.94 (dt, 1H), 2.78 (dt, 1H), 2.68 (dd, 1H), 1.45 (s, 9H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:12]([F:15])([F:14])[F:13])[CH:6]=[C:7]([N+:9]([O-:11])=[O:10])[CH:8]=1.Cl.[NH+]1C=CC=CC=1>>[OH:2][C:3]1[CH:4]=[C:5]([C:12]([F:13])([F:14])[F:15])[CH:6]=[C:7]([N+:9]([O-:11])=[O:10])[CH:8]=1
Reactant: COc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Agent: Cl
Agent: c1cc[nH+]cc1
Product: O=[N+]([O-])c1cc(O)cc(C(F)(F)F)c1
Reaction time: 168 h

Procedure:
3-Methoxy-5-nitrobenzotrifluoride (40 g, 181 mmol, 1 eq) and pyridinium hydrochloride (167 g, 1448 mmol, 8 eq) were heated together to 210° C. in an open vessel for 2.5 h. The dark mixture was cooled and partitioned between EtOAc and 2 N HCl. The EtOAc layer was washed (6×) with 2 N HCl, and once with brine. After drying over Na2SO4 the solution was filtered and stripped. The crude material was placed under vacuum for 7 days to provide a brownish solid which was used without further purification.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[C:11]1([S:17][CH2:18][C:19](Cl)=[O:20])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl.O>[OH-].[Na+]>[C:11]1([S:17][CH2:18][C:19]([NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1]([OH:10])=[O:9])=[O:20])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccccc1C(=O)O
Reactant: O=C(Cl)CSc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(CSc1ccccc1)Nc1ccccc1C(=O)O
Reaction time: 1 h

Procedure:
To a solution of 6.3 g of anthranilic acid in aqueous NaOH (4 g of NaOH in 40 mL of water) which was cooled using an ice-bath was added 8.6 g (0.046 mol) of phenylmercaptoacetylchloride from Example 46. The reaction mixture was stirred for 1 h. The reaction mixture was neutralized with 5% HCl, water (50 mL) was added, and then the mixture was extracted with EtOAc (3×100 mL). The EtOAc solution was dried, filtered, and then concentrated to give after drying under high vacuum, 7.0 g (53%) of the title compound, mp 166°-167° C. (lit. 164°-166° C. (Gorlitzer, K.; Weber, J. Arch. Pharm (Weinheim) 1980, 314, 76)); 1H NMR (DMSO-d6) δ11.82 (s, 1H, COOH), 8.51 (s, 1H, J=8.4),7.96 (dd, 1H, J=1.2, J=8), 7.58 (t, 1H, J=8), 7.38 (d,1H, J=7.2), 7.13 (m, 5H), 4.01 (s, 2H); 13C NMR (DMSO-d6) δ169.17, 167.42, 140.31, 135.00, 134.07, 133.72, 131.12, 129.18, 128.07, 126.33, 123.01, 119.77, 116.58, 116.31, 114.54; MS (EI, m/z) 287 (M+). HRMS (EI) calcd for C15H13N2 O3S 287.0616, found 287.0617.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([CH2:19][O:20][NH2:21])=[CH:17][CH:16]=1.O=[C:25]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].C(O)(=O)C.C([O-])(=O)C.[Na+]>C(OCC)(=O)C.CCCCCC.O.C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][O:20]/[N:21]=[C:25](/[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)\[CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:22][CH:23]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CON)cc1
Reactant: CCOC(=O)CCCCC(=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)CCCC/C(=N\OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1ccccc1
Temperature: 25 °C
Yield: 73.1 %

Procedure:
After a mixture of 4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyamine (500 mg), ethyl 6-oxo-6-phenylhexanoate (415 mg), acetic acid (0.276 ml), sodium acetate (264 mg) and ethanol (20 ml) was heated to reflux for 13 hours, the mixture was cooled to room temperature. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography to obtain ethyl E-6-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-6-phenylhexanoate (620 mg, yield 73%) as a colorless oil from an ethyl acetate-hexane (1:4, v/v)-eluted fraction.
Reaction SMILES: COC(=O)C1C=CC=C(N[C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:14]2=[O:37])C=1.[CH2:40]([O:42]C(=O)CN1CCC2C(=CC(N)=CC=2)C1)[CH3:41]>>[CH2:40]([O:42][C:11](=[O:38])[CH2:12][N:13]1[N:19]=[C:18]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=2[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:34])([CH3:33])[CH3:35])[C:14]1=[O:37])[CH3:41]
Reactant: COC(=O)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Reactant: CCOC(=O)CN1CCc2ccc(N)cc2C1
Product: CCOC(=O)CN1N=C(C2CCCCC2)c2ccccc2N(CC(=O)C(C)(C)C)C1=O

Procedure:
The title compound was obtained by the method used in the preparation of 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzoic acid methyl ester (Example 1) except that (7-amino-3,4-dihydro-1H-isoquinolin-2-yl)-acetic acid ethyl ester was used instead of 3-amino-benzoic acid methyl ester in step e, followed by reaction of the product obtained, in place of [5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid ethyl ester (Example 1, step c), according to the method of Example 1, step d. 1H NMR (DMSO-d6) 9.90 (1H, brs), 7.54-7.42 (3H, m), 7.28-7.11 (4H, m), 4.78 (2H, m), 4.33 (2H, m), 4.09 (2H, m), 3.39 (3H, m), 3.00 (3H, m), 1.65-1.21 (6H, m), 1.12-1.04 (13H, m). The product was further characterised as the hydrochloride salt. Found: C, 47.05; H, 5.34; N, 7.72%; C33H41N5O5.HCl.3.4CH2Cl2 requires: C, 47.14; H, 5.48; N, 7.55%.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH:16]1[CH2:20][CH:19]([CH3:21])[C:18](=[O:22])[O:17]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][C@H:8]([C@H:16]1[O:17][C:18](=[O:22])[C@H:19]([CH3:21])[CH2:20]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC1CC([C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)OC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1C[C@@H]([C@@H](N)Cc2ccccc2)OC1=O

Procedure:
A solution of [(S)-1-(4-methyl-5-oxo-tetrahydrofuran-2-yl)-2-phenylethyl]-carbamic acid t-butyl ester (synthesis described in Journal of Organic Chemistry (1986) 51(21), 3921) (2 g, 6.27 mmol) in DCM (40 ml) was treated with trifluoroacetic acid (5 ml) for 2 h. The solvent was evaporated under reduced pressure, the residue dissolved in DCM, washed with aqueous sodium bicarbonate and dried (Na2SO4). The solvent was evaporated to afford the title compound (D48) as a pale yellow solid (1.25 g)
Reaction SMILES: [O-]CC.[Na+].[Na].[C:6]([O:14]CC)(=O)[CH2:7][C:8]([O:10]CC)=O.[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([NH2:22])=[NH:21]>C(O)C>[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]1[N:22]=[C:6]([OH:14])[CH:7]=[C:8]([OH:10])[N:21]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: N=C(N)c1ccccc1Cl
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: Oc1cc(O)nc(-c2ccccc2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
A solution of sodium ethoxide (19.83 g, 291 mmol) in ethanol [previously prepared by dissolving sodium (6.7 g, 291 mmol) in ethanol (200 mL)] was treated with diethyl malonate (14.73 mL, 97 mmol) with stirring at ambient temperature. A solution of 2-chlorobenzamidine (15 g, 97 mmol) in ethanol (100 mL) was then added dropwise with stirring at room temperature. On completion of addition the reaction mixture was then heated at reflux for 5 h and allowed to stand overnight. The reaction mixture was concentrated in vacuo, water added and the pH adjusted to pH 3-4 using 2N HCl. The resulting solid formed was filtered and washed with water and diethyl ether to give the title compound as a solid (17.12 g, 79%). MS (ES+) m/e=223. 1H NMR: (DMSO) 5.33 (1H, s), 7.43-7.70 (4H, m), 12.00 (2H, brs).
Reaction SMILES: C1(COC(=O)[NH:10][C@@H:11]([C:13]2[NH:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[N:14]=2)[CH3:12])C=CC=CC=1>[Pd].CO>[CH3:12][C@H:11]([C:13]1[NH:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)[NH2:10]
Reactant: C[C@@H](NC(=O)OCc1ccccc1)c1nc2ccccc2[nH]1
Agent: [Pd]
Solvent: CO
Product: C[C@@H](N)c1nc2ccccc2[nH]1
Yield: 82.2 %

Procedure:
The title compound is prepared by the procedure of Example 15, in a Parr apparatus, using 1.07 g of product from Example 44, 90 ml of methyl alcohol and 2.45 g of 10% palladium on carbon to give 0.48 g of the desired product after recrystallization from carbon tetrachloride.
Reaction SMILES: [CH3:1][C@:2]1([NH:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@@H:9]2[C@@H:5]([CH2:6][NH:7][CH2:8]2)[CH2:4][CH2:3]1.Br[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[N:21]=1.C(N(CC)CC)C>C(O)C>[CH3:1][C@:2]1([NH:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@@H:9]2[C@@H:5]([CH2:6][N:7]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[N:21]=3)[CH2:8]2)[CH2:4][CH2:3]1
Reactant: C[C@@]1(NC(=O)c2ccccc2)CC[C@@H]2CNC[C@@H]21
Reactant: FC(F)(F)c1cccc(Br)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: C[C@@]1(NC(=O)c2ccccc2)CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Temperature: 75 °C

Procedure:
N-[(3aR,4R,6aS)-4-methyloctahydrocyclopenta[c]pyrrol-4-yl]benzamide (118 mg, 0.483 mmol, Example 8) was combined with 2-bromo-6-(trifluoromethyl)pyridine (131 mg, 0.580 mmol) and triethylamine (0.202 mL, 1.449 mmol) in ethanol (0.2 mL). The reaction was heated at 75° C. for 72 hours. The reaction mixture was partitioned between water (1 mL) and dichloromethane. The crude brown material was purified by silica gel chromatography using 1-10% methanol (2 N ammonia)/dichloromethane as eluent to give the title compound: 1H NMR (400 MHz, pyridine-d5) δ ppm 8.71 (s, 1H), 8.16 (dd, J=5.3, 3.3, 2H), 7.47 (t, J=7.9, 1H), 7.43-7.30 (m, 3H), 6.96 (d, J=7.2, 1H), 6.46 (d, J=8.6, 1H), 3.79-3.64 (m, 2H), 3.60 (dd, J=11.1, 7.3, 1H), 3.56-3.45 (m, 2H), 2.80-2.69 (m, 1H), 2.25 (dd, J=21.5, 9.6, 1H), 2.00-1.78 (m, 2H), 1.64 (s, 3H), 1.45-1.33 (m, 1H); MS (ESI+) m/z 390 (M+H)+.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([O:14][CH2:15][C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(Cl)Cl.[OH-].[Na+]>C(OCC)C>[CH2:7]([O:14][CH2:15][CH2:16][NH:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(COCc1ccccc1)Nc1ccc(F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClCCl
Solvent: CCOCC
Product: Fc1ccc(NCCOCc2ccccc2)cc1
Temperature: 0 °C
Yield: 83 %

Procedure:
To a suspension of LAH (1.25 g, 27 mmol) in dry diethyl ether (100 mL) was added dropwise a solution of 2-benzyloxy-N-(4-fluoro-phenyl)-acetamide (33) (6.9 g, 27 mmol) in dry diethyl ether (100 mL). The addition was such as a reflux was maintained. Once the addition was completed, the reaction mixture was heated to reflux for 4 h, then poured into ice-water and DCM was added. In order to break down the aluminium salt, 2M aqueous sodium hydroxide solution was added until strong basic pH was obtained. The layers were separated and the aqueous layer was washed with DCM, dried and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with petrol (A) and ethyl acetate (B) (5-50% B, 100 g, 12 CV, 60 mL/min) to afford 5.5 g (84%) of (2-benzyloxy-ethyl)-(4-fluoro-phenyl)-amine (34) as a yellow oil. The structure was confirmed by 13C NMR (75 MHz, CDCl3) δC 44.0, 68.3, 72.8, 113.7 (d, JCF=7 Hz), 115.3 (d, JCF=22 Hz), 127.5, 127.6 (d, JCF=3 Hz), 128.3, 137.8, 144.5, 154.1, and 157.2.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][OH:5].C(=O)([O-])[O-].[K+].[K+].OC(C(F)(F)F)=O.OC(C(F)(F)F)=O.[F:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>C(#N)C>[F:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:2][CH2:3][CH2:4][OH:5])[CH2:31][CH2:30]1
Reactant: OCCCBr
Reactant: FCCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: OCCCN1CCN(CCF)CC1
Temperature: 85 °C
Reaction time: 4 h
Yield: 90.7 %

Procedure:
3-Bromopropan-1-ol (581 mg, 4.18 mmol) and potassium carbonate (2.88 g, 20.9 mmol) were added to a solution of 1-(2-fluoroethyl)-piperazine diTFA salt (1.5 g, 4.18 mmol) in acetonitrile (11 ml). The reaction mixture was stirred at 85° C. for 4 hours and then loaded directly onto a column and eluted with a mixture of methanol in methylene chloride (7/93) to give 3-[4-(2-fluoroethyl)piperazin-1-yl]propan-1-ol (721 mg, 91%).
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][C:11]([NH2:13])=[CH:12][C:7]=2[N:6]=[CH:5]1)([CH3:3])[CH3:2].[I:14]I.N>CC(O)=O.[Hg](OC(C)=O)OC(C)=O>[CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][C:11]([NH2:13])=[C:12]([I:14])[C:7]=2[N:6]=[CH:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1cnc2cc(N)ccc21
Reactant: II
Agent: CC(=O)O[Hg]OC(C)=O
Agent: N
Solvent: CC(=O)O
Product: CC(C)n1cnc2c(I)c(N)ccc21
Yield: 35 %

Procedure:
To a solution of 1-isopropyl-5-aminobenzimidazole (0.70 g, 3.7 mmol) and Hg(OAc)2 (2.1 g, 5.6 mmol) in 10 ml of AcOH was added solution of I2 in AcOH until it produces a precipitation; The reaction mixture was concentrated in vacuo to provide a brown solid which was subjected to column chromatography (5% NH3 sat'd MeOR/CH2Cl2) to provide 0.40 g (1.3 mmol, 35%) of the product.
Reaction SMILES: [CH2:1]([PH:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)(Cl)(Cl)[Cl:11]>P(Cl)(Cl)Cl>[CH2:1]([P:5]([CH2:6][CH2:7][CH2:8][CH3:9])[Cl:11])[CH2:2][CH2:3][CH3:4]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CCCCPCCCC
Solvent: ClP(Cl)Cl
Product: CCCCP(Cl)CCCC
Yield: 55.9 %

Procedure:
148 g (1 mol) di-n-butylphosphine was dropped at a maximum reaction temperature of 30° C. into a suspension of 232 g (1.1 mol) PCl5 in 500 ml toluene. HCl and PCl3 formed during the reaction were removed under a vacuum of 130 mbar and condensed in a cooling trap. After the reaction was complete, the reaction mixture was found to comprise two liquid phases. The upper phase contained PCl3 in toluene. The bulk quantity of chlorophosphine was in the lower phase (31P-NMR). It was worked up distillatively and 101 g product was obtained (55% of the theoretical). bp 92° C./16 mbar.
Reaction SMILES: [CH2:1]([N:3]1[CH2:20][C@H:19]([CH3:21])[N:18]2[C:5](=[C:6]([O:22][CH3:23])[C:7]3[C:12](=[O:13])[NH:11][N:10]=[C:9]([C:14]([NH:16][CH3:17])=[O:15])[C:8]=32)[C:4]1=[O:24])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:35][C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][C:43]=1[F:44])[CH2:39]Br>CN(C=O)C>[Cl:35][C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][C:43]=1[F:44])[CH2:39][N:11]1[C:12](=[O:13])[C:7]2[C:6]([O:22][CH3:23])=[C:5]3[C:4](=[O:24])[N:3]([CH2:1][CH3:2])[CH2:20][C@H:19]([CH3:21])[N:18]3[C:8]=2[C:9]([C:14]([NH:16][CH3:17])=[O:15])=[N:10]1
Reactant: Fc1ccc(CBr)cc1Cl
Reactant: CCN1C[C@H](C)n2c(c(OC)c3c(=O)[nH]nc(C(=O)NC)c32)C1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCN1C[C@H](C)n2c(c(OC)c3c(=O)n(Cc4ccc(F)c(Cl)c4)nc(C(=O)NC)c32)C1=O
Reaction time: 0.42 h

Procedure:
To a cold (0° C.) solution of (6S)-8-ethyl-10-methoxy-N,6-dimethyl-1,9-dioxo-1,2,6,7,8,9-hexahydropyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyridazine-4-carboxamide (1.58 g, 4.73 mmol) in anhydrous DMF (50 mL), a solution of lithium bis(trimethylsilyl)amide (4.97 mL, 4.97 mmol, 1 M in THF) was added. After stirring at the same temperature for 25 minutes, 3-chloro-4-fluorobenzyl bromide (1.27 g, 5.68 mmol) was added. The reaction mixture was stirred at room temperature for 10 minutes and concentrated under vacuum. The residue was partitioned between chloroform and brine. The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with a 1-5% methanol in ethyl acetate gradient. Collection and concentration of appropriate fractions provided the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[S:11][C:12]([C:15]#[N:16])=[CH:13][N:14]=2)[CH:4]=1.[CH3:17][N:18]([CH3:27])[C:19]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:20]>CS(C)=O.O>[C:15]([C:12]1[S:11][C:10]([NH:9][C:5]2[CH:4]=[C:3]([CH2:2][N:24]3[CH2:23][CH2:22][N:21]([C:19]([N:18]([CH3:27])[CH3:17])=[O:20])[CH2:26][CH2:25]3)[CH:8]=[CH:7][N:6]=2)=[N:14][CH:13]=1)#[N:16]
Reactant: CN(C)C(=O)N1CCNCC1
Reactant: N#Cc1cnc(Nc2cc(CCl)ccn2)s1
Solvent: CS(C)=O
Solvent: O
Product: CN(C)C(=O)N1CCN(Cc2ccnc(Nc3ncc(C#N)s3)c2)CC1
Reaction time: 3.5 h

Procedure:
2-(4-Chloromethyl-pyridin-2-ylamino)-thiazole-5-carbonitrile (0.119 g, 0.47 mmol) was dissolved in 1 mL DMSO. N,N-Dimethyl-1-piperazinecarboxamide (0.149 g, 0.95 mmol) was added and the solution was stirred for 3.5 hr. Additional N,N-dimethyl-1-piperazinecarboxamide (0.149 g, 0.95 mmol) was added and the solution was stirred for 1.5 hr. The reaction was diluted with water and the resulting precipitate collected by filtration. The solid was washed with water and hexanes then air dried overnight to afford the free base. Free base: 1H NMR (CD3OD) δ 8.33 (d, 1H, J=5.0 Hz), 8.03 (s, 1H), 7.08 (s, 1H), 7.04 (d, 1H, J=5.0 Hz), 3.58 (s, 1H), 3.29 (t, 4H, J=6.0 Hz), 2.84 (s, 6H), 2.49 (t, 4H, J=Hz). MS [M+H]+=372.1611.