Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.[OH:7][C@H:8]1[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:10]([C:20]([O:22][CH3:23])=[O:21])[CH2:9]1>C(Cl)Cl>[O:7]=[C:8]1[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[C@H:10]([C:20]([O:22][CH3:23])=[O:21])[CH2:9]1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)[C@@H]1CC(=O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 81.1 %

Procedure:
CrO3 (194 g, 1.94 mol) was added slowly with stirring over 30 min to a solution of pyridine (340 mL) in DCM (900 mL) at 0° C. The mixture was warmed to rt and (2S,4R)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (56 g, 0.216 mol) in DCM (700 mL) was added. The reaction was stirred vigorously for 4 hs at rt. The formed dark solid was decanted and washed with DCM. The organic phases were washed with aq. NaHCO3, 10% aqueous critic acid, and brine, and dried over anhydrous Na2SO4. The solvent was removed in vacuo and purified by silica gel column chromatography (PE: EtOAc=50:1 to 10:1) to afford (S)-1-tert-butyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate (42.6 g, 81%) as yellow oil.
Reaction SMILES: [Na].[SH:2][C:3]1[S:4][CH2:5][CH2:6][N:7]=1.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[C:16]([NH:18][C:19](=[O:21])[CH:20]=1)=[O:17].Cl>O1CCCC1>[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]1[CH:20]([S:2][C:3]2[S:4][CH2:5][CH2:6][N:7]=2)[C:19](=[O:21])[NH:18][C:16]1=[O:17]
Reactant: SC1=NCCS1
Reactant: O=C1C=C(c2ccccc2Cl)C(=O)N1
Agent: Cl
Agent: [Na]
Solvent: C1CCOC1
Product: O=C1NC(=O)C(c2ccccc2Cl)C1SC1=NCCS1
Yield: 29.6 %

Procedure:
A solution of mercaptothiazoline sodium (4.50 g) in tetrahydrofuran (30 ml) is added to a refluxed solution of 2-(2-chlorophenyl)maleimide (3.00 g) in tetrahydrofuran (40 ml) and the mixture is refluxed for 10 minutes. After cooling, the reaction mixture is diluted using diluted hydrochloric acid and the solvent is distilled off. The residue is extracted with ethyl acetate and the extract is washed with water and dried over magnesium sulfate. The ethyl acetate is distilled off and the residue is subjected to silica gel chromatography, elution being carried out with dichloromethanemethanol (50:1). The eluate is recrystallized from ethanol to give 2-(2-chlorophenyl)-3-(2-thiazolin-2-ylthio)succinimide (1.40 g), m.p. 195°-200° C.
Reaction SMILES: C(OC([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[C:16]([N:26]([C:28](=[O:43])[C:29]2[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[C:31]([C:39]([F:42])([F:41])[F:40])[CH:30]=2)[CH3:27])=[CH:15][N:14]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:27][N:26]([C:16]1[CH:15]=[N:14][C:13]([C:9]2[NH:8][CH:12]=[CH:11][CH:10]=2)=[CH:18][C:17]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH3:25])[C:28](=[O:43])[C:29]1[CH:30]=[C:31]([C:39]([F:41])([F:42])[F:40])[CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1
Reactant: Cc1ccccc1-c1cc(-c2cccn2C(=O)OC(C)(C)C)ncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccccc1-c1cc(-c2ccc[nH]2)ncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-{5-[(3,5-bis-trifluoromethyl-benzoyl)-methyl-amino]-4-o-tolyl-pyridin-2-yl}-pyrrole-1-carboxylic acid tert-butyl ester (39 mg, 64.6 μmol) in CH2Cl2 (2 mL) was added TFA (2 mL) at 0° C. The reaction mixture was stirred for at room temperature for 1 hour and then concentrated under vacuum. The residue was poured on 30 mL aqueous NaHCO3 solution and 30 mL EtOAc and the layers were separated. The aqueous layer was extracted a second time with 30 mL EtOAc. The organic layers were washed with 30 mL brine, dried over MgSO4, filtered and concentrated under vacuum. Light yellow solid (32 mg, 98%). MS (ESI): m/z=504.151 [M+H]+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH2:21])=O)=[CH:17][CH:16]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>C1COCC1>[CH2:7]([O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][NH2:21])=[CH:22][CH:23]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCOc1ccc(C(N)=O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCCOc1ccc(CN)cc1
Reaction time: 3 h
Yield: 84.3 %

Procedure:
To a stirred suspension of lithium aluminum hydride (1.928 g, 52.23 mmol) in THF (150 ml) at room temperature under nitrogen was added a suspension of 4-(heptyloxy)benzamide (6.146 g, 26.117 mmol). After refluxing for 22 h, reaction was cooled in an ice bath and quenched in the following order: water (2.09 ml), 15% NaOH (2.09 ml) and water (6.26 ml). The mixture was stirred for 3 h followed by the addition of Na2SO4. The mixture was filtered and concentrated in vac. The residue was taken up in Et2O, filtered, concentrated, and the resulting residue taken up in hexane, filtered, concentrated, and dried to give the desired product as a hazy yellow oil (4.872 g, 84%); 1H NMR (400 MHz, DMSO-d6) δ 0.86 (t, J=7 Hz, 3H), 1.22–1.42 (m, 8H), 1.64–1.72 (m, 2H), 1.82 (broad s, 2H), 3.13 (s, 2H), 3.89 (t, J=6.6 Hz, 2H), 6.80–6.84 (m, 2H), 7.17–7.21 (m, 2H); IR (film) 2940, 2850, 1510, 1250 cm−1; mass spectrum [(+)ESI], m/z 222 (M+H)+.
Reaction SMILES: [NH:1]([C:3]1[N:4]=[C:5]([C:12]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[O:13])[C:6]2[S:11][CH:10]=[CH:9][C:7]=2[N:8]=1)[NH2:2].[CH2:19]([N:22]=[C:23]=[O:24])[CH:20]=[CH2:21]>C1COCC1>[CH2:19]([NH:22][C:23]([NH:2][NH:1][C:3]1[N:4]=[C:5]([C:12]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[O:13])[C:6]2[S:11][CH:10]=[CH:9][C:7]=2[N:8]=1)=[O:24])[CH:20]=[CH2:21]
Reactant: NNc1nc(C(=O)c2cccs2)c2sccc2n1
Reactant: C=CCN=C=O
Solvent: C1CCOC1
Product: C=CCNC(=O)NNc1nc(C(=O)c2cccs2)c2sccc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
A mixture of 2-hydrazinothieno[3,2-d]pyrimidin-4-yl 2-thienylmethanone (100 mg, 0.36 mmol) and THF (5 mL) was treated with allyl isocyanate (32 μl, 0.36 mmol), stirred at room temperature for 1 h and filtered to give the title compound (88 mg, 68%) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:7]([CH2:20][CH2:21][CH2:22]Cl)[C:6]=2[C:5]([C:24]([O:26][CH3:27])=[O:25])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:24]([O:26][CH3:27])=[O:25])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[CH2:22][CH2:21][CH2:20][N:7]21
Reactant: COC(=O)c1ccc(Br)c2nc(Nc3ccc(Cl)cc3Cl)n(CCCCl)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Br)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 92 %

Procedure:
A mixture of above crude methyl 4-bromo-1-(3-chloropropyl)-2-[(2,4-dichlorophenyl)amino]-1H-benzimidazole-7-carboxylate and potassium carbonate (205 mg, 1.49 mmol) in N,N-dimethylformamide (10 mL) was stirred at 80° C. for 15 min. After ethyl acetate was added, the resultant mixture was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-40% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (414 mg, 0.910 mmol, 92%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5](Cl)[C:6]([CH3:12])=[N:7]2.[CH:14]1([NH2:21])[CH2:19][CH2:18][CH2:17][CH:16]([NH2:20])[CH2:15]1>CS(C)=O.O>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([NH:20][CH:16]1[CH2:17][CH2:18][CH2:19][CH:14]([NH2:21])[CH2:15]1)[C:6]([CH3:12])=[N:7]2
Reactant: Cc1nc2cccc(Br)c2nc1Cl
Reactant: NC1CCCC(N)C1
Solvent: CS(C)=O
Solvent: O
Product: Cc1nc2cccc(Br)c2nc1NC1CCCC(N)C1
Temperature: 100 °C
Yield: 150.7 %

Procedure:
A mixture of 5-bromo-3-chloro-2-methylquinoxaline (126e, 7.25 g, 28.2 mmol) and (rac)-1,3-cyclohexanediamine (TCI America, Inc., Portland, Oreg.; 23.69 m, 197 mmol) in DMSO (28.2 mL) was heated to 100° C. for 16 h. The reaction was cooled to RT and diluted with water. It was extracted with EtOAc (3×), dried over MgSO4, filtered, and concentrated to give (N1-(8-bromo-3-methylquinoxalin-2-yl)cyclohexane-1,3-diamine (483a, 14.25 g, 151% yield) a dark orange-brown oil. MS (ESI, pos. ion) m/z: 335.0/337.0 (M+1). Separation of (1S,3R)—N1-(8-bromo-3-methylquinoxalin-2-yl)cyclohexane-1,3-diamine. The racemic mixture was separated using chiral SFC via two purifications. 1st Purification: Preparative SFC: AY-H (5 μm, 21 mm×25 cm) with 20% organic modifier: 80% carbon dioxide. Organic modifier: methanol with 0.2% diethylamine. F=70 ml/min, T=40° C., BPR=100 bar, P=179 bar, 256 nm. (N1-(8-bromo-3-methylquinoxalin-2-yl)cyclohexane-1,3-diamine (483a, 14.25 g) dissolved in methanol (250 mL, 60 mg/mL). 0.5 mL injection. Two peaks were collected. 2nd Purification: Preparative SFC: Repurification of peak 2. OJ-H (5 μm, 21 mm×25 cm, S/N=0131) with 20% organic modifier modifier: 80% carbon dioxide. Organic modifier: methanol with 0.2% diethylamine. F=70 mL/min, T=40° C., BPR=100 bar, P=172 bar, 256 nm. Peak 2 from the 1st purification was dissolved in methanol (60 mL). 0.6 mL injection. A single peak was collected to give (1S,3R)—N1-(8-bromo-3-methylquinoxalin-2-yl)cyclohexane-1,3-diamine (483b, 2.81 g, 30% recovery) as a light orange solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.80 (1H, d, J=7.63 Hz) 7.70 (1H, d, J=8.02 Hz) 7.15-7.26 (2H, m) 4.17 (1H, br. s.) 2.76 (1H, t, J=10.17 Hz) 2.52 (3H, br. s.) 2.08 (1H, d, J=12.13 Hz) 1.95 (1H, br. s.) 1.76 (2H, d, J=9.19 Hz) 1.26-1.41 (3H, m) 1.02-1.17 (1H, m). MS (ESI, pos. ion) m/z: 335.0/337.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]=1[S:14]([NH2:17])(=[O:16])=[O:15].[CH2:18]([N:22]=[C:23]=[O:24])[CH2:19][CH2:20][CH3:21].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:18]([NH:22][C:23]([NH:17][S:14]([C:3]1[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])(=[O:16])=[O:15])=[O:24])[CH2:19][CH2:20][CH3:21]
Reactant: CCCCN=C=O
Reactant: NS(=O)(=O)c1c(Cl)cccc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCNC(=O)NS(=O)(=O)c1c(Cl)cccc1-c1ccccc1
Yield: 94 %

Procedure:
A mixture of 7.7 g (0.029 mol) 2-chloro-6-phenylbenzenesulfonamide, 3.6 ml (0.032 mol) n-butylisocyanate and 4.1 g (0.03 mol) potassium carbonate was heated in 80 ml dry acetonitrile for 18 hours at reflux. The solvent was evaporated and the residue treated with 1N HCl and ethyl acetate and the insoluble solids were collected, washed with water and then ether. Additional material was obtained from the organic phase of the filtrate to afford a total of 10 g of the title compound, m.p. 184°-186°. NMR (90 MHz, CDCl3), 0.9 (CH3, t, br), 1.4 (4H, m), 3.05 (q, J=7 Hz, 2H), 5.9 (t, br, NH), 7.2-7.6 (m, 8H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:26](OC)=[O:27])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[C:16]([O:24][CH3:25])=[N:17][C:18]([CH3:23])=[N:19][C:20]=3[O:21][CH3:22])[CH2:12][CH2:13][CH2:14][N:7]21.[BH4-].[Li+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:26]=[O:27])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[C:16]([O:24][CH3:25])=[N:17][C:18]([CH3:23])=[N:19][C:20]=3[O:21][CH3:22])[CH2:12][CH2:13][CH2:14][N:7]21
Reactant: COC(=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(OC)nc(C)nc1OC
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1nc(C)nc(OC)c1N1CCCn2c1nc1c(Cl)ccc(C=O)c12
Reaction time: 15 h
Yield: 75.5 %

Procedure:
To a stirred solution of methyl 9-chloro-1-(4,6-dimethoxy-2-methylpyrimidin-5-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carboxylate (627 mg, 1.50 mmol) in tetrahydrofuran (15 mL) was added lithium borohydride (131 mg, 6.00 mmol) at room temperature. After being stirred for 15 h at ° C., the reaction mixture was quenched with aqueous ammonium chloride, extracted with ethyl acetate, and concentrated in vacuo. The resulting solid was washed with ethyl acetate and dissolved in dimethyl sulfoxide (15 mL). To the solution was added Dess-Martin reagent (1.27 g, 3.00 mmol) at room temperature, and the mixture was stirred for 15 h. The reaction mixture was diluted with ethyl acetate, quenched with aqueous sodium hydrogen carbonate, washed with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 20-80% ethyl acetate/hexane gradient mixture to give the title compound as a pale yellow solid (439 mg, 75%).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH:6]1[CH2:10][CH2:9][CH:8]([OH:11])[C:7]1([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][C:13]#[C:14][CH2:15][CH3:16])=[O:4].[H][H]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].CCCCCC.CC(C)=O>[C:20]([O:19][C:17]([C:7]1([CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH3:16])[CH:6]([CH2:5][C:3]([O:2][CH3:1])=[O:4])[CH2:10][CH2:9][CH:8]1[OH:11])=[O:18])([CH3:21])([CH3:23])[CH3:22]
Reactant: CCC#CCC1(C(=O)OC(C)(C)C)C(O)CCC1CC(=O)OC
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCCCCC
Solvent: CC(C)=O
Product: CC/C=C\CC1(C(=O)OC(C)(C)C)C(O)CCC1CC(=O)OC

Procedure:
A 1.4 g quantity of 3-methoxycarbonylmethyl-2-methoxycarbonyl-2-(2-pentynyl)-cyclopentanol (compound (1-a)) and 2.2 g of Lindlar catalyst are dissolved in a mixture of 50 ml of n-hexane and 5 ml of acetone. The starting compound is thus reduced at room temperature and atmospheric pressure with use of hydrogen gas. The reaction is completed when the solution has absorbed the theoretical amount of the gas, whereupon the catalyst is filtered off. The filtrate is concentrated in vacuo, and the residue dissolved in benzene-ethyl acetate and purified with a silica gel column. The product is distilled in a vacuum, giving 2-methoxycarbonyl-3-methoxycarbonylmethyl-2-(cis-2-pentenyl)-cyclopentanol (compound (1-b), R1 =R2 =CH3) in a yield of 87%, b.p. 74°-78° C./0.01 mm Hg.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[C:9]([O:13][C:14](=[O:29])[NH:15][C:16]1[C:20]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:19][S:18][CH:17]=1)([CH3:12])([CH3:11])[CH3:10]>C(Cl)(Cl)(Cl)Cl>[C:9]([O:13][C:14](=[O:29])[NH:15][C:16]1[C:20]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:19][S:18][C:17]=1[Br:8])([CH3:12])([CH3:11])[CH3:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)Nc1cscc1NC(=O)OC(C)(C)C
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)Nc1csc(Br)c1NC(=O)OC(C)(C)C
Reaction time: 16 h
Yield: 71.1 %

Procedure:
NBS (1.22 g, 6.87 mmol) was added to a solution of compound 57 (2.16 g, 6.87 mmol) in CCl4 (137 mL) at r.t. The mixture was stirred for 16 h. The solid material was filtered off and the filtrate was collected and washed with water. The organic layer was dried over MgSO4 and concentrated in vacuum. The residue was purified by flash chromatography with DCM as an eluent affording the title compound 58 (1.92 g, 71% yield). 1H NMR: (CDCl3) δ(ppm): 7.30 (bs, 1H), 6.00 (s, 1H), 1.45 (s, 9H), 1.43 (s, 9H). m/z: 415.4/417.4 (M+Na/M+2+Na). This procedure is essentially as described in Brugier et al., Tetrahedron, 56: 2985-2993 (2000), which is incorporated by reference in its entirety.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH2:9]([C:13]1[N:14]=[C:15]([Cl:22])[C:16]2[NH:21][CH:20]=[CH:19][C:17]=2[N:18]=1)[CH2:10][CH2:11][CH3:12]>C1COCC1.CC(OC)(C)C>[CH2:9]([C:13]1[N:14]=[C:15]([Cl:22])[C:16]2[NH:21][CH:20]=[C:19]([I:1])[C:17]=2[N:18]=1)[CH2:10][CH2:11][CH3:12]
Reactant: O=C1CCC(=O)N1I
Reactant: CCCCc1nc(Cl)c2[nH]ccc2n1
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: CCCCc1nc(Cl)c2[nH]cc(I)c2n1
Reaction time: 0.25 h
Yield: 81.3 %

Procedure:
N-Iodosuccinimide (2.09 g, 9.29 mmol) was added portionwise to a stirred solution of 2-butyl-4-chloro-5H-pyrrolo[3,2-d]pyrimidine (1.69 g, 8.06 mmol) in THF (35 mL). The resultant mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with TBME (50 mL) then washed with aqueous sodium thiosulphate solution (50 mL) then saturated aqueous sodium chloride solution (20 mL). The organic phase was dried (Na2SO4), filtered and evaporated. The sample was dissolved in dichloromethane and purified by chromatography on silica using a gradient of 0-100% dichloromethane-cyclohexane over 30 minutes followed by a gradient of 0-100% TBME-cyclohexane followed by 0-20% methanol over 15 minutes. The appropriate fractions were identified by LC-MS then combined and evaporated in vacuo to give the title compound as a yellow solid (2.2 g).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:28][C:29]1[CH:30]=[C:31]([CH2:35][O:36][CH2:37][CH2:38]O)[CH:32]=[CH:33][CH:34]=1>C(Cl)Cl.[Al]>[Br:1][CH2:38][CH2:37][O:36][CH2:35][C:31]1[CH:32]=[CH:33][CH:34]=[C:29]([F:28])[CH:30]=1
Reactant: OCCOCc1cccc(F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: [Al]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Fc1cccc(COCCBr)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 78.3 %

Procedure:
N-bromosuccinimide (146 mg, 0.820 mmol) was added to resin-bound triphenylphosphine (274 mg, 0.822 mequiv, Fluka) and 2-{[(3-fluorophenyl)methyl]oxy}ethanol (70 mg, 0.411 mmol) in DCM (4 mL). The reaction vial was sealed with a Teflon-lined cap, wrapped in aluminum foil, and shaken at rt for 17 h. The reaction was filtered through a SPE cartridge (5 g silica) eluting with the following 10 mL fractions: DCM (fraction 1), 30% EtOAc/hexanes (fraction 2), and 50% EtOAc/hexanes (fraction 3) to give the title compound (75 mg, 78%). The product was characterized by 1H NMR (400 MHz) in CDCl3.
Reaction SMILES: S(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)(=O)(=O)C.Cl.[NH:20]1[CH2:24][CH2:23][C@H:22]([OH:25])[CH2:21]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[OH:25][C@H:22]1[CH2:23][CH2:24][N:20]([CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[CH2:21]1
Reactant: CS(=O)(=O)OCCc1ccc(N2CCCC2)cc1
Reactant: O[C@H]1CCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O[C@H]1CCN(CCc2ccc(N3CCCC3)cc2)C1
Temperature: 90 °C

Procedure:
4-Pyrrolidinophenethyl mesylate (13.45 g, 50.0 mmol), (S)-3-pyrrolidinol hydrochloride (5.56 g, 45.0 mmol) and potassium carbonate (18.63 g, 135 mmol) were added to acetonitrile (200 ml), and they were heated at 90° C. for 3 hours. The reaction mixture was cooled and then filtered. The filtrate was evaporated to dryness under reduced pressure, and the residue was distributed into water and ethyl acetate. The intended product was extracted from the ethyl acetate layer with 1 M hydrochloric acid. The aqueous layer was neutralized and then the product was again extracted with ethyl acetate. The organic layer was dried and the solvent was evaporated under reduced pressure to obtain (S)-3-hydroxy-1-(4-pyrrolidinophenethyl)pyrrolidine in the form of a light yellow solid (6.30 g, 52%).
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][C@@H:3]([CH2:7][NH:8][C:9]([C:11]1[N:18]3[C:14]([S:15][CH:16]=[CH:17]3)=[N:13][C:12]=1[CH3:19])=[O:10])[NH:2]2.[Cl:20][C:21]1[CH:22]=[C:23]([C:27]2[C:28]([C:33](O)=[O:34])=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:24]=[CH:25][CH:26]=1>>[Cl:20][C:21]1[CH:22]=[C:23]([C:27]2[C:28]([C:33]([N:2]3[C@H:3]([CH2:7][NH:8][C:9]([C:11]4[N:18]5[C:14]([S:15][CH:16]=[CH:17]5)=[N:13][C:12]=4[CH3:19])=[O:10])[CH2:4][C@H:5]4[C@@H:1]3[CH2:6]4)=[O:34])=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@@H]1C[C@@H]2C[C@@H]2N1
Reactant: O=C(O)c1ccccc1-c1cccc(Cl)c1
Product: Cc1nc2sccn2c1C(=O)NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1ccccc1-c1cccc(Cl)c1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid [(1S,3S,5S)-2-aza-bicyclo[3.1.0]hex-3-ylmethyl]-amide with 3′-chloro-biphenyl-2-carboxylic acid. LC-MS (basic): tR=1.38 min; [M+H]+=490.9.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[Cl:12][C:13]1[C:21]([Cl:22])=[CH:20][C:16]2[N:17]=[CH:18][NH:19][C:15]=2[CH:14]=1>C(O)CCC>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:17]2[C:16]3[CH:20]=[C:21]([Cl:22])[C:13]([Cl:12])=[CH:14][C:15]=3[N:19]=[CH:18]2)[N:3]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: Clc1cc2nc[nH]c2cc1Cl
Solvent: CCCCO
Product: Clc1nc(-n2cnc3cc(Cl)c(Cl)cc32)c2nc[nH]c2n1
Reaction time: 24 h
Yield: 53.8 %

Procedure:
567 mg of 2,6-dichloropurine, 6 ml of butanol and 617 mg of 5,6-dichlorobenzimidazole are mixed and brought to a temperature of 100° C. for approximately 24 hours. The mixture is allowed to return to ambient temperature. Partial drying, washing with isopropanol and drying under vacuum at 50° C. are carried out, and 548 mg of expected product are obtained, in the form of gray/black-colored crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][PH:12](=[O:14])[OH:13])=[CH:4][CH:3]=1.[C:15]1([CH2:21][O:22][C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][C@H:30](O)[C:31]([N:33]2[CH2:47][CH2:46][CH2:45][C@H:34]2[C:35]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:36])=[O:32])=[O:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(N=C=NC2CCCCC2)CCCCC1.CN(C1C=CC=CN=1)C>O1CCCC1.C(OCC)(=O)C>[C:15]1([CH2:21][O:22][C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][C@H:30]([O:14][PH:12]([CH2:11][CH2:10][CH2:9][CH2:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[O:13])[C:31]([N:33]2[CH2:47][CH2:46][CH2:45][C@H:34]2[C:35]([O:37][CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)=[O:36])=[O:32])=[O:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(NCCCC[C@H](O)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)OCc1ccccc1
Reactant: O=[PH](O)CCCCc1ccc(F)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(NCCCC[C@H](O[PH](=O)CCCCc1ccc(F)cc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
[4-(4-Fluorophenyl)butyl]phosphinic acid, 1-adamantanamine salt (1.18 g.) is partitioned between 1.0N hydrochloric acid and ethyl acetate. The organic phase is washed with brine and dried over anhydrous sodium sulfate. The mixture is evaporated to give 696 mg. of [4-(4-fluorophenyl)butyl]phosphinic acid. This acid (696 mg., 3.22 mmole, 1.5 eq.) is dissolved in dry tetrahydrofuran (15 ml.), combined with 1-[(S)-6-[[(phenylmethoxy)carbonyl]amino]-2-hydroxy-1-oxohexyl]-L-proline, phenylmethyl ester (1.01 g., 2.15 mmole, 1 eq.) and treated with dicyclohexylcarbodiimide (664 mg., 3.22 mmole, 1.5 eq.) and dimethylaminopyridine (39 mg., 0.15 eq.). The white suspension is stirred under argon for 1 hour at room temperature, then diluted with ethyl acetate, and filtered to remove dicyclohexyl urea. The filtrate is washed with 5% potassium bisulfate, saturated sodium bicarbonate, and brine, then dried over anhydrous sodium sulfate, and evaporated to an oily residue. Chromatography on a 3/4 inch pad of SiliCAR CC-7 silica gel eluting with ethyl ether:acetone (8:2) removes impurities. Product containing fractions are pooled and evaporated to give crude 1-[(S)-6-[[(phenylmethoxy)carbonyl]amino]-2-[[[4-(4-fluorophenyl)butyl]phosphinyl]oxy]-1-oxohexyl]-L-proline, phenylmethyl ester as an oil. TLC (silica gel; ethyl ether:acetone, 8:2) Rf =0.09.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH2:10]([OH:14])[CH2:11][CH2:12][CH3:13]>F[B-](F)(F)F.C[N+](C)(C)C>[C:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[O:14][CH2:10][CH2:11][CH2:12][CH3:13])(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCCCC1
Reactant: CCCCO
Agent: C[N+](C)(C)C
Agent: F[B-](F)(F)F
Product: CCCCOC1CCCCN1C(C)=O
Yield: 57.1 %

Procedure:
In the same manner as indicated in Example 6 there are electrolyzed 8.5 g of N-acetylpiperidine and 49.7 g of n-butanol in the presence of 0.3 g of tetramethylammonium tetrafluoroborate as conducting salt. After throughput of 2.5 Faraday per mol of N-acetylpiperidine the current is switched off. The calculated mean cell voltage is 91 volts. Work-up of the electrolysis solution gives 7.6 g of 1-acetyl-2-n-butoxypiperidine (boiling point 70° C./0.1 mbar; nD25 = 1.4656), which corresponds to a product yield of 56.8% and a current efficiency of 45.5%.