Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:15]1([C:20](=[O:26])[CH2:21][CH2:22][C:23](O)=[O:24])[CH2:19][CH2:18][CH2:17][CH2:16]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:23](=[O:24])[CH2:22][CH2:21][C:20]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:26])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=C(O)CCC(=O)C1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)CCC(=O)C2CCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
To a stirred solution of 4-Amino-piperidine-1-carboxylic acid tert-butyl ester (0.3 g, 1.49 mmol) in anhydrous CH2Cl2 under argon and cooled to 0° C., were added 4-Cyclopentyl-4-oxo-butyric acid (0.31 g, 1.79 mmol), EDC.HCl (0.35 g, 1.79 mmol), HOBt (0.24 g, 1.79 mmol), and TEA (0.25 mL, 1.79 mmol). The resulting solution was stirred at 25° C. overnight. CH2Cl2 was evaporate and the residue was partitioned between EtOAc and 1N HCl. The organic layer was washed with H2O, brine and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by flash column chromatography (80% EtOAc in hexanes) to provide the desired product (0.37 g, 71%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 1.24-1.32 (m, 2H), 1.45 (s, 9H), 1.60-1.85 (m, 11H), 2.41 (t, J=6.4 Hz, 2H), 2.79-3.04 (m, 5H), 3.85-4.13 (m, 2H), 5.65 (s, 1H). MS(ESI):351 (MH−).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5]N1C2=C3C(=CC=C2)CCCN3S1.[NH:18]1[C:28]2=[C:29]3[C:24](=[CH:25][CH:26]=[CH:27]2)[CH2:23][CH2:22][CH2:21][N:20]3[S:19]1(=[O:31])=[O:30].[H-].[Na+].BrCCCCCl>CN(C)C=O.O.C(OCC)(=O)C>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:18]1[C:28]2=[C:29]3[C:24](=[CH:25][CH:26]=[CH:27]2)[CH2:23][CH2:22][CH2:21][N:20]3[S:19]1(=[O:30])=[O:31]
Reactant: ClCCCCN1SN2CCCc3cccc1c32
Reactant: O=S1(=O)Nc2cccc3c2N1CCC3
Agent: ClCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=S1(=O)N(CCCCCl)c2cccc3c2N1CCC3
Reaction time: 0.5 h

Procedure:
1-(4-Chlorobutyl)-5,6-dihydro(1H,4H)-1,2,5-thiadiazolo[4,3,2-ij]quinoline can be prepared as follows: a solution of 5,6-dihydro(1H,4H)-1,2,5-thiadiazolo[4,3,2-ij]quinoline 2,2-dioxide (4 g) in dry N,N-dimethylformamide (20 cc) is added dropwise to a suspension of sodium hydride (0.69 g, 80% suspension in oil) in N,N-dimethylformamide (20 cc). After 30 minutes' stirring, a solution of 1-bromo-4-chlorobutane (3.93 g) in N,N-dimethylformamide (20 cc) is added. The reaction mixture is stirred at 20° C. for 2 hours and then diluted in a mixture of water (200 cc) and ethyl acetate (200 cc). The organic phase is washed with water (3×200 cc), is dried over magnesium sulphate and is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (0.2-0.063-mm particle size, 4-cm diameter, 50-cm height) and eluted at a pressure of 0.7 bars of nitrogen with a mixture of cyclohexane and ethyl acetate (80-20 by volume), 125-cc fractions being collected. Fractions 3 to 9 are combined and concentrated to dryness under reduced pressure (2.7 kPa) to give 1-(4-chlorobutyl)-5,6-dihydro-(1H,4H)-1,2,5-thiadiazolo[4,3,2-ij]quinoline 2,2-dioxide (4.5 g).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](Cl)=[O:9])(=[O:4])=[O:3].[CH2:14]([NH:21][C:22]([C:24]1[S:28][C:27]([NH2:29])=[N:26][C:25]=1[CH3:30])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([NH:21][C:22]([C:24]1[S:28][C:27]([NH:29][C:8](=[O:9])[C:7]2[CH:11]=[CH:12][CH:13]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=2)=[N:26][C:25]=1[CH3:30])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Reactant: CS(=O)(=O)c1cccc(C(=O)Cl)c1
Product: Cc1nc(NC(=O)c2cccc(S(C)(=O)=O)c2)sc1C(=O)NCc1ccccc1
Yield: 15 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use 3-methanesulfonylbenzoyl chloride in place of benzoyl chloride to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 15% yield; m.p. 111-113° C.; 1H NMR (CD3OD, 300 MHz) δ 8.55 (t, J=5.8 Hz, 1H), 8.09 (dd, J=1.2, 7.6 Hz, 1H), 7.36-7.19 (m, 2H), 7.68 (dd, J=1.2, 7.6 Hz, 1H), 7.27 (m, 5H), 4.50 (d, J=1.9 Hz, 2H), 3.33 (s, 3H), 2.52 (s, 3H); MS (ES+) m/z 430.1 (M+1).
Reaction SMILES: [CH2:1]([C:8]1[C:13](=[O:14])[CH:12]=[C:11]([CH3:15])O[C:9]=1[CH3:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].Cl.[NH2:18][OH:19].C([O-])(=O)C.[Na+].O>C(O)C>[CH2:1]([C:8]1[C:13](=[O:14])[CH:12]=[C:11]([CH3:15])[N:18]([OH:19])[C:9]=1[CH3:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCc1c(C)oc(C)cc1=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCCCCc1c(C)n(O)c(C)cc1=O
Temperature: 25 °C

Procedure:
A mixture of trimethyl pyrone 1 (113 mg, 0.51 mmol), hydroxylamine hydrochloride (707 mg, 10.2 mmol), sodium acetate (835 mg, 10.2 mmol), water (1 mL), and ethanol (2 mL) was heated to reflux for 8 hr. After the reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column. Elution with 5:1 ethyl acetate/methanol gave 3-heptyl-1-hydroxy-2,6-dimethylpyridin-4(1H)-one (CPD-6): yield 63 mg (51%); silica gel TLC Rf 0.35 (3:1 ethyl acetate/methanol); 1H NMR (400 MHz, CDCl3) δ 0.84-0.88 (m, 3H), 1.24-1.45 (m, 10H), 2.36 (s, 3H), 2.47 (s, 3H), 2.60 (t, 2H, J=7.6 Hz) and 6.73 (s, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[CH2:16]([O:23][C:24](=[O:42])[CH:25]([NH:31][C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[CH2:26][S:27](Cl)(=[O:29])=[O:28])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(#N)C.C(Cl)Cl>[CH2:16]([O:23][C:24](=[O:42])[C@@H:25]([NH:31][C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[CH2:26][S:27]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)(=[O:29])=[O:28])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: C1COCCN1
Reactant: O=C(NC(CS(=O)(=O)Cl)C(=O)OCc1ccccc1)OCc1ccccc1
Solvent: ClCCl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H](CS(=O)(=O)N1CCOCC1)C(=O)OCc1ccccc1)OCc1ccccc1
Reaction time: 0.17 h
Yield: 99.2 %

Procedure:
To a solution of morpholine (Aldrich, 1.27 mL, 14.6 mmol) and N,N-diisopropyl-N-ethylamine (DIPEA, Aldrich, 2.5 mL, 14.6 mmol) in acetonitrile (25 mL) at rt is added solid 2-benzyloxycarbonylamino-3-chlorosulfonylpropionic acid benzyl ester (3.0 g, 7.3 mmol), (prepared as described in Ross, D. L.; Skinner, C. G.; Shive, W. J. Org. Chem. 1959, 24, 1372-1374; and b) Byrnes, S.; Burckart, G. J.; Mokotoff, M. J. Med. Chem. 1978, 21, 45-49], in small portions over 10 min. A clear colorless solution resulted from which white solid began to precipitate within minutes. After 10 min, a thick white suspension was formed. The reaction was diluted in CH2Cl2 to redissolve all solids and the solution washed with 1M HCl. The aqueous layer was separated and extracted with additional CH2Cl2. The organic layer was washed with brine and dried over anhydrous Na2SO4. Following concentration in vacuo, 3.35 g (99%) of 2(R)-benzyloxycarbonylamino-3-(morpholin-4-sulfonyl)propionic acid benzyl ester was obtained as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:13]3[CH2:14][CH2:15][NH:16][CH2:17][CH:18]=3)=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C([SiH](CC)CC)C.[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29]>>[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29].[N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH:13]3[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]3)=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2c(C3=CCNCC3)c[nH]c2c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1ccc2c(C3CCNCC3)c[nH]c2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
6-nitro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (2.4 g, 9.9 mmol) was stirred in trifluoroacetic acid (10 mL) at room temperature under an atmosphere of nitrogen. Triethylsilane (1.65 mL, 10.4 mmol) was slowly added. After an initial exotherm, the mixture was stirred at room temperature for 12 hours. The mixture was concentrated under reduced pressure to yield a dark residue. The crude product was crystallized from ethanol to yield the title compound as a yellow crystalline solid. Yield 2.4 g (67%). mp 215°-217° C. FDMS m/e=245 (M+ of free base).
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH:27]2[CH2:29][CH2:28]2)[CH2:25]O)[C:5]1=[O:30])[CH:2]=[CH2:3].[CH2:32]([SH:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(#N)C>>[CH2:1]([C@@:4]1([CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@@H:24]([CH:27]2[CH2:29][CH2:28]2)[CH2:25][S:39][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:5]1=[O:30])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CO)C2CC2)C1=O
Reactant: SCc1ccccc1
Solvent: CC#N
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CSCc2ccccc2)C2CC2)C1=O
Temperature: 100 °C

Procedure:
A mixture of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-hydroxyethyl)-3-methylpiperidin-2-one (1.35 g, 2.94 mmol; Example 252, Step A), benzyl mercaptan (0.691 ml, 5.89 mmol) and 2-(tributylphosphoranylidene) in acetonitrile (1.579 ml, 5.89 mmol) was heated to 100° C. for 2 h. The reaction mixture was cooled to RT, and extracted with 80 mL of EtOAc. The combined organics were washed with sat. aq. NH4Cl solution and brine, dried over Na2SO4, filtered and the filtrate was concentrated. The crude product was purified by chromatography on silica gel eluting with 0 to 50% EtOAc/hexane to give the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=4[F:32])[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[Cl:34][C:35]1[CH:36]=[C:37]([CH:39]=[CH:40][C:41]=1[O:42][CH2:43][CH2:44][O:45][CH3:46])[NH2:38].COCCOC>Cl.CCOC(C)=O.O>[Cl:34][C:35]1[CH:36]=[C:37]([NH:38][C:2]2[N:7]=[C:6]([C:8]3[C:9]([C:17]4[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]5[C:26]([F:32])=[CH:27][CH:28]=[CH:29][C:30]=5[F:31])[CH:20]=[CH:21][CH:22]=4)=[N:10][N:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=34)[CH:5]=[CH:4][N:3]=2)[CH:39]=[CH:40][C:41]=1[O:42][CH2:43][CH2:44][O:45][CH3:46]
Reactant: COCCOc1ccc(N)cc1Cl
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COCCOc1ccc(Nc2nccc(-c3c(-c4cccc(NC(=O)c5c(F)cccc5F)c4)nn4ccccc34)n2)cc1Cl
Temperature: 160 °C
Yield: 40.2 %

Procedure:
N-{3-[3-(2-Chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide (0.1 g, 0.218 mmol) and 3-chloro-4-{[2-(methyloxy)ethyl]oxy}aniline (0.057 g, 0.283 mmol) were combined in a microwave safe reaction vessel. Ethylene glycol dimethyl ether (1.5 mL) and HCl (˜½ drop) were then added and the resulting mixture was heated in a microwave to 160° C. for 8 min. The reaction was then cooled to rt diluted with EtOAc (100 mL) and water (50 mL). The organic layer was separated, washed with brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo onto silica gel. This was then purified via silica gel chromatography (EtOAc/Hexanes) to provide 55 mg of the title compound. 1H NMR (400 MHz, DMSO-d6): δ 10.92 (s, 1H), 9.53 (s, 1H), 8.83 (d, 1H), 8.42 (br m, 1H), 8.25 (d, 1H), 8.00 (s, 1H), 7.93 (s, 1H), 7.80 (d, 1H), 7.62-7.42 (m, 4H), 7.33 (d, 1H), 7.24 (m, 2H), 7.12 (m, 1H), 7.03 (d, 1H), 6.52 (d, 1H), 4.11 (m, 2H), 3.65 (m, 2H), 3.30 (s, 3H); HRMS: calc. C33H26N6O3F2 (M+H)+ 627.1723 found 627.1732.
Reaction SMILES: [CH3:1][C:2]12[CH:11]([CH:12]=[O:13])[CH2:10][CH2:9][CH:8]=[C:7]1[CH2:6][C:5]1([S:17][CH2:16][CH2:15][S:14]1)[CH2:4][CH2:3]2.[C:18]1([Mg]Br)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[CH3:1][C:2]12[CH:11]([CH:12]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[OH:13])[CH2:10][CH2:9][CH:8]=[C:7]1[CH2:6][C:5]1([S:14][CH2:15][CH2:16][S:17]1)[CH2:4][CH2:3]2
Reactant: CC12CCC3(CC1=CCCC2C=O)SCCS3
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: CC12CCC3(CC1=CCCC2C(O)c1ccccc1)SCCS3
Temperature: -78 °C
Yield: 92.8 %

Procedure:
Aldehyde 241 (200 mg, 0.746 mmol) was dissolved in 10 mL THF and cooled to −78° C. Phenylmagnesium bromide (1M in THF, 1.12 mL, 1.12 mmol) was added to the solution dropwise and the mixture was allowed to warm to room temperature over 2 hours. The reaction mixture was then cooled to 0° C. and quenched with 10 mL of water. The layers were separated and the aqueous layer was extracted with (3×10 mL) ether. The pooled organic extracts was washed with brine, dried (MgSO4), filtered, and concentrated under vacuum. Purification by flash chromatography over silica gel (10% ethyl acetate-hexanes) afforded alcohol 247 (240 mg, 93%) as a white solid.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:34][C:35]1[CH:42]=[C:41]([OH:43])[CH:40]=[CH:39][C:36]=1[C:37]#[N:38].O[CH2:45][C:46]1[CH:47]=[C:48]([CH2:52][CH2:53][C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH:49]=[CH:50][CH:51]=1>O1CCCC1>[C:37]([C:36]1[CH:39]=[CH:40][C:41]([O:43][CH2:45][C:46]2[CH:47]=[C:48]([CH2:52][CH2:53][C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH:49]=[CH:50][CH:51]=2)=[CH:42][C:35]=1[F:34])#[N:38]
Reactant: N#Cc1ccc(O)cc1F
Reactant: CC(C)(C)OC(=O)CCc1cccc(CO)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCc1cccc(COc2ccc(C#N)c(F)c2)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 13.3 %

Procedure:
Diisopropyl azodicarboxylate (2.6 g) is added portionwise to a stirred solution of triphenylphosphine (3.4 g) in dry tetrahydrofuran (40 mL) at 0° C. under nitrogen. The reaction mixture is stirred at 0° C. for 15 minutes then treated with a solution of 2-fluoro-4-hydroxybenzonitrile (0.87 g) and t-butyl 3-(3-hydroxymethylphenyl)propionate (1.5 g) in dry tetrahydrofuran (10 mL) whilst maintaining the temperature at 0-5° C. Stirring is continued at this temperature for 1 hour when the reaction mixture is allowed to warm up to room temperature. The reaction mixture is evaporated to low bulk and partitioned between ethyl acetate (100 mL) and water (100 mL). The organic phase is washed with water (50 mL), dried over magnesium sulphate and evaporated. The residue is purified by flash chromatography on silica eluting with a mixture of cyclohexane and ethyl acetate (4:1 v/v). Fractions homogeneous in the required product are combined and evaporated to give tert-butyl 3-[3-(4-cyano-3-fluoro-phenoxymethyl)phenyl]propionate (0.3 g).
Reaction SMILES: [CH3:1][N:2]([C:7]1[CH:8]=[C:9]([CH:22]=[C:23]([CH2:25]Br)[CH:24]=1)[C:10]([NH:12][C@@H:13]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[CH3:14])=[O:11])[S:3]([CH3:6])(=[O:5])=[O:4].[NH2:27][C:28]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:29][OH:30].NC(CC1C=CC=CC=1)(CCCC)COCC1C=C(C=C(N(C)S(C)(=O)=O)C=1)C(N[C@@H](C1C=CC(F)=CC=1)C)=O>>[NH2:27][C:28]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:29][O:30][CH2:25][C:23]1[CH:22]=[C:9]([CH:8]=[C:7]([N:2]([CH3:1])[S:3]([CH3:6])(=[O:5])=[O:4])[CH:24]=1)[C:10]([NH:12][C@@H:13]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[CH3:14])=[O:11]
Reactant: NC(CO)(Cc1ccccc1)Cc1ccccc1
Reactant: C[C@@H](NC(=O)c1cc(CBr)cc(N(C)S(C)(=O)=O)c1)c1ccc(F)cc1
Agent: CCCCC(N)(COCc1cc(C(=O)N[C@H](C)c2ccc(F)cc2)cc(N(C)S(C)(=O)=O)c1)Cc1ccccc1
Product: C[C@@H](NC(=O)c1cc(COCC(N)(Cc2ccccc2)Cc2ccccc2)cc(N(C)S(C)(=O)=O)c1)c1ccc(F)cc1

Procedure:
Prepared from 3-(N-methyl-N-(methylsulfonyl)amino)-5-(bromomethyl)-N-((R)-1-(4-fluorophenyl)ethyl)benzamide and 2-amino-2-benzyl-3-phenylpropan-1-ol using a similar procedure as described for the preparation of 3-{[(2-amino-2-benzylhexyl)oxy]methyl}-N-[(1R)-1-(4-fluorophenyl)ethyl]-5-[methyl(methyl sulfonyl)amino]benzamide (Example 4). HRMS ES calculated for C34H38FN3O4S: 604.2640, found: 604.2641.
Reaction SMILES: C(OC(=O)[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]([CH2:27][C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)=[N:19][N:18]=3)[CH2:13][CH2:12]2)=[N:7][CH:6]=1)C.[CH3:36][Mg]I.[CH2:39]1[CH2:43][O:42]CC1>>[F:34][C:31]1[CH:32]=[CH:33][C:28]([CH2:27][C:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:17]([N:14]3[CH2:13][CH2:12][N:11]([C:8]4[N:7]=[CH:6][C:5]([C:43]([OH:42])([CH3:39])[CH3:36])=[CH:10][CH:9]=4)[CH2:16][CH2:15]3)=[N:18][N:19]=2)=[CH:29][CH:30]=1
Reactant: CCOC(=O)c1ccc(N2CCN(c3nnc(Cc4ccc(F)cc4)c4ccccc34)CC2)nc1
Reactant: C1CCOC1
Reactant: C[Mg]I
Product: CC(C)(O)c1ccc(N2CCN(c3nnc(Cc4ccc(F)cc4)c4ccccc34)CC2)nc1
Yield: 10 %

Procedure:
6-{4-[4-(4-Fluoro-benzyl)-phthalazin-1-yl]-piperazin-1-yl}-nicotinic acid ethyl ester (85 mg, 0.180 mmol) is dissolved in THF (1 mL). Methyl magnesium iodide (240 μL, 3M in diethyl ether, 0.72 mmol) is added dropwise. Stir reaction for 2 h at room temperature. Concentrate in vacuo. The residue is purified by flash chromatography on silica gel (MeOH/CH2Cl2) to afford the title compound (8 mg, 10%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Cl:12])=[N:4][N:3]=1.[CH2:13]1[CH:22]2[CH:17]([CH2:18][CH2:19][CH2:20][CH2:21]2)[CH2:16][CH2:15][NH:14]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([N:14]2[CH2:15][CH2:16][CH:17]3[CH:22]([CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:13]2)=[N:3][N:4]=1
Reactant: Clc1nnc(Cl)c2ccccc12
Reactant: C1CCC2CNCCC2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Clc1nnc(N2CCC3CCCCC3C2)c2ccccc12
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A resealable pressure bottle was charged with 1,4-dichlorophthalazine (1258 mg, 6.28 mmol), decahydroisoquinoline (588 μl, 3.95 mmol), potassium carbonate (546 mg, 3.95 mmol) and DMSO (20 mL, 0.2 M). Reaction was stirred at 80° C. for 16 h, then cooled to RT and diluted with 5 mL of DMSO. The solution was purified by Gilson HPLC (10% to 90% CH3CN/H2O/0.1% TFA) to afford 1-chloro-4-(octahydroisoquinolin-2(1H)-yl)phthalazine. MS [M+H]=302.1. Calcd for C17H20ClN3: 301.8.
Reaction SMILES: [OH:1][CH:2]1[C:11]2[CH:10]=[N:9][CH:8]=[C:7]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)[C:6]=2[CH2:5][CH2:4][CH2:3]1.[H-].[Na+].CI.[C:24]([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:24][O:1][CH:2]1[C:11]2[CH:10]=[N:9][CH:8]=[C:7]([C:12]3[CH:13]=[CH:14][C:15]([C:16]#[N:17])=[CH:18][CH:19]=3)[C:6]=2[CH2:5][CH2:4][CH2:3]1
Reactant: N#Cc1ccc(-c2cncc3c2CCCC3O)cc1
Reactant: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC1CCCc2c(-c3ccc(C#N)cc3)cncc21
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 32 %

Procedure:
A cooled (0° C.) solution of (rac)-4-(8-hydroxy-5,6,7,8-tetrahydroisoquinolin-4-yl)benzonitrile (example 11) (50 mg, 200 μmol) in DMF (1.4 mL) was treated with NaH (55% in oil, 9.6 mg, 220 μmol) and after ½ h with methyl iodide (13.7 μL, 220 μmol) in DMF (0.2 mL). After stirring 1 h at 0° C. and 1.5 h at room temperature, the reaction mixture was poured on aq. sat. NaHCO3 solution followed by extraction with AcOEt (3×). The organic phases were washed once with aq. sat. NaCl solution. The combined organic phases were dried (Na2SO4), filtered and purified by flash chromatography (50 g SiO2, Telos-cartridge, CH2Cl2/MeOH 1%). Precipitation from CH2Cl2 with n-pentane gave the title compound (17 mg, 32%) as off-white powder. MS: 265.1 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]3[CH:11]=[C:10]([CH2:12][OH:13])[N:9]=[C:7]3[S:8][C:4]=2[CH:3]=1>C(Cl)Cl.CN(C=O)C.O=[Mn]=O>[CH:12]([C:10]1[N:9]=[C:7]2[N:6]([CH:11]=1)[C:5]1[CH:14]=[CH:15][C:2]([F:1])=[CH:3][C:4]=1[S:8]2)=[O:13]
Reactant: OCc1cn2c(n1)sc1cc(F)ccc12
Agent: O=[Mn]=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=Cc1cn2c(n1)sc1cc(F)ccc12

Procedure:
2-Formyl-7-fluoro-imidazo[2,1-b]-benzthiazole was prepared according to the procedure outlined in Example 1, (Step 3). Starting from 7-fluoro-imidazo[2,1-b]-benzthiazole-2-methanol (1.5 g 6.7 mmol) in methylene chloride/DMF (300 mL: 50 mL) and active MnO2 (12 g, excess), 1.1 g (78% Yield) of the aldehyde derivative was isolated as brown solid. (M+H) 221.
Reaction SMILES: [OH-].[Li+].[CH2:3]([O:5][C:6]([C:8]1[NH:9][C:10]([CH2:14][CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])=[CH:11][C:12]=1[CH3:13])=[O:7])[CH3:4].C(O)C>CO.O>[CH2:3]([O:5][C:6]([C:8]1[NH:9][C:10]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:11][C:12]=1[CH3:13])=[O:7])[CH3:4]
Reactant: CCOC(=O)c1[nH]c(CCC(=O)OC(C)(C)C)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CO
Product: CCOC(=O)c1[nH]c(CCC(=O)O)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
Lithium hydroxide (1.02 g, 42.65 mmol) was added to a suspension of 5-(2-tert-butoxycarbonyl-ethyl)-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (2.4 g, 8.53 mmol) in methanol (50 mL) and water (12 mL). Ethanol (4 mL) was added to the mixture (to aid solvation of the starting material) and it was stirred at room temperature for overnight. The reaction was diluted with water (20 mL), concentrated (to remove most of the alcohol) and extracted with ether. The aqueous layer was the acidified to pH=2 using 1N HCl (43 mL) and extracted with ethyl acetate (2×). The combined extract was then washed with brine, dried and concentrated to give 1.89 g of 5-(2-carboxy-ethyl)-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester as a white solid.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]=1[CH3:13].[O:14]=[C:15]1[CH2:20][O:19][C:18]2[CH:21]=[C:22]([CH:25]=[CH:26][C:27](O)=[O:28])[CH:23]=[N:24][C:17]=2[NH:16]1.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.CN(C)CCCN=C=NCC>CN(C=O)C.O>[CH3:1][N:2]([CH2:3][C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]=1[CH3:13])[C:27](=[O:28])/[CH:26]=[CH:25]/[C:22]1[CH:23]=[N:24][C:17]2[NH:16][C:15](=[O:14])[CH2:20][O:19][C:18]=2[CH:21]=1
Reactant: O=C(O)C=Cc1cnc2c(c1)OCC(=O)N2
Reactant: CNCc1c(C)oc2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1oc2ccccc2c1CN(C)C(=O)/C=C/c1cnc2c(c1)OCC(=O)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.9 %

Procedure:
To a solution of methyl-(2-methyl-benzofuran-3-ylmethyl)-amine (152 mg, 0.87 mmol) in DMF (5 mL) were added in sequential order 3-(3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-acrylic acid (175 mg, 0.79 mmol), 1-hydroxybenzotriazole (121 mg, 0.87 mmol), diisopropylethylamine (412 uL, 2.37 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (174 mg, 0.87 mmol). The mixture was stirred at room temperature overnight, cooled in an ice bath and treated with water under rapid stirring. The precipitated product was filtered and dried, triturated with diethyl ether to yield the title compound (125 mg, 42%) as a light brown solid and as a mixture of amide rotamers. 1H NMR (400 MHz, DMSO-d6) δ 11.46 (s, 1H), 8.21 (s, 1H), 7.89 (s, 1H), 7.50-7.59 (m, 3H), 7.19-7.26 (m, 3H), 4.74 (s, 2H), 4.70 (s, 2H), 3.06 (s, 3H), 2.52 (s, 3H); MS (ESI) m/e 378 (C21H19N3O4+H)+.