Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[C:6]1([S:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][CH:23]=[C:18]3C=C2)(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.ICC.[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[CH2:3]([C:2]1[N:15]([S:12]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)(=[O:14])=[O:13])[C:19]2=[N:20][CH:21]=[CH:22][CH:23]=[C:18]2[CH:1]=1)[CH3:4]
Reactant: [Li]CCCC
Reactant: O=S(=O)(c1ccccc1)n1ccc2cccnc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCI
Product: CCc1cc2cccnc2n1S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 37.6 %

Procedure:
n-Butyllithium (2.03 mL, 3.25 mmol, 1.6M in hexanes) was added to a solution of 1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.60 g, 2.32 mmol) in THF (9.0 mL) at −78° C. The reaction mixture was stirred at −78° C. for 30 minutes, and then iodoethane (0.557 mL, 6.97 mmol) was added. The reaction mixture was warmed up to 0° C. and stirred for 2 hours, after which more iodoethane (0.278 mL, 3.48 mmol) was added. The reaction mixture was warmed up to room temperature and stirred overnight. Saturated aqueous ammonium chloride and ethyl acetate were then added, and the layers were separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried with sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography to afford 2-ethyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.25 g, 23% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][N:15]=[C:16]2[C:19]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])[CH2:21][CH2:20]2)=[CH:11][C:10]=1[O:29][CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)COC(N1CCC[C@H]1C(O[BH-](OC(=O)[C@@H]1CCCN1C(OCC(C)C)=O)OC(=O)[C@@H]1CCCN1C(OCC(C)C)=O)=O)=O.[Na+].S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][NH:15][CH:16]2[C:19]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])[CH2:20][CH2:21]2)=[CH:11][C:10]=1[O:29][CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(cc1OCc1ccccc1)C(C1(c3ccccc3Cl)CC1)=NCC2
Agent: CC(C)COC(=O)N1CCC[C@H]1C(=O)O[BH-](OC(=O)[C@@H]1CCCN1C(=O)OCC(C)C)OC(=O)[C@@H]1CCCN1C(=O)OCC(C)C
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: COc1cc2c(cc1OCc1ccccc1)C(C1(c3ccccc3Cl)CC1)NCC2
Reaction time: 49 h

Procedure:
A solution of 7-benzyloxy-1-[1-(2-chlorophenyl)cyclopropyl]-6-methoxy-3,4-dihydroisoquinoline (0.5 g, prepared in a similar manner to that described in Example CA281) in dichloromethane (10 ml) was added dropwise at -40° C. to a stirred solution of sodium tris[N-(2-methylpropyloxycarbonyl)prolyloxy]borohydride (2.43 g) in dichloromethane (10 ml). The mixture was allowed to reach ambient temperature and was stirred for 49 hours. Dilute sulphuric acid (10 ml, 10% v/v) was added, and stirring continued for 1 hour. The mixture was basified by addition of saturated aqueous sodium carbonate solution. The organic layer was washed with brine, dried over magnesium sulphate and the solvent removed in vacuo to yield 7-benzyloxy-1-[1-(2-chlorophenyl)cyclopropyl]-6-methoxy-1,2,3,4-tetrahydroisoquinoline as a gum (0.42 g). This product was shown to have a 92% enantiomeric excess of one of the enantiomers.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([NH2:12])[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[F:13][C:14]([F:26])([F:25])[C:15]1[N:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.N1C=CC=CC=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([NH:12][S:21]([C:18]3[CH:19]=[N:20][C:15]([C:14]([F:26])([F:13])[F:25])=[CH:16][CH:17]=3)(=[O:23])=[O:22])[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: Nc1cc(F)cc2cccnc12
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)nc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1cc(F)cc2cccnc12)c1ccc(C(F)(F)F)nc1
Yield: 26.3 %

Procedure:
In a similar fashion using route 14 general procedure 27, 6-fluoroquinolin-8-ylamine (Intermediate 48) (150 mg, 0.92 mmol), 6-(trifluoromethyl)pyridine-3-sulfonyl chloride (250 mg, 1.01 mmol) in DCM (2 ml), DMAP (cat), pyridine (146 mg, 1.84 mmol) and DCM (5 ml) gave the title compound (90 mg, 26%) after purification by column chromatography with n-hexane/EtOAc (90:10) as the eluent.
Reaction SMILES: N1CCCCC1.C(O)(=O)C.[C:11]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:12][C:13]([CH3:15])=[O:14].[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1>C1(C)C=CC=CC=1.O>[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[C:12]([C:13](=[O:14])[CH3:15])[C:11]([O:17][CH2:18][CH3:19])=[O:16])=[CH:23][CH:22]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CCOC(=O)CC(C)=O
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C(=Cc1ccc(F)cc1)C(C)=O
Temperature: 25 °C
Yield: 78.8 %

Procedure:
Piperidine (4.0 mL) and glacial acetic acid (12 mL) were added to a stirred solution of ethyl acetoacetate (127.5 mL, 1.0 mol) and 4-fluorobenzaldehyde (136.52 g, 1.1 mol) in 200 mL of toluene. This mixture was heated under reflux for four hours with azeotropic removal of water. The reaction mixture was cooled to room temperature and concentrated. The residue was flash chromatographed on silica gel, eluting with toluene, to produce 226.0 g of crude product which was then distilled to yield 186.2 g of a mixture of cis- and trans-ethyl 2-[(4-fluorophenyl)methylene]-3-oxobutanoate, bp 160°-170° C. at 5 mm Hg.
Reaction SMILES: [C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17](O)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1>>[C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17]([NH:33][C:32]4[CH:34]=[CH:35][C:29]([N:26]5[CH2:25][CH2:24][N:23]([CH3:22])[CH2:28][CH2:27]5)=[CH:30][CH:31]=4)=[O:18])=[CH:13][CH:12]=3)[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: O=C(O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Product: CN1CCN(c2ccc(NC(=O)COc3ccc(C45CC6CC(CC(C6)C4)C5)cc3)cc2)CC1
Yield: 94.6 %

Procedure:
The title compound was prepared from 2-(4-(adamantan-1-yl)phenoxy)acetic acid (0.2 g, 0.69 mmol) and 4-(4-methylpiperazin-1-yl)aniline (0.133 g, 0.69 mmol) according to the example 1, which was given 2-(4-(adamantan-1-yl)phenoxy)-N-(4-(4-methylpiperazin-1-yl)phenyl)acetamide as a white solid (0.30 g, 93.4% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([CH2:20][CH2:21][NH2:22])=[CH:18][CH:17]=1>N1C=CC=CC=1>[CH3:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([CH2:20][CH2:21][NH:22][S:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)(=[O:12])=[O:11])=[CH:18][CH:17]=1
Reactant: COc1ccc(CCN)cc1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: COc1ccc(CCNS(=O)(=O)c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.1 %

Procedure:
4-Nitrobenzenesulphonyl chloride (10 g) was added portionwise to a stirred solution of 4-methoxyphenethylamine (6.8 g) in pyridine (40 ml) and the resulting solution stirred at room temperature for 30 min. The solution was partitioned between hydrochloric acid (5 N, 400 ml) and ethyl acetate (2×250 ml). The combined extracts were washed with hydrochloric acid (5 N, 100 ml), sodium bicarbonate (8%, 100 ml) dried --MgSO4) and evaporated in vacuo to give an oil. The oil was purified by column chromatography eluted with hexane:ethyl acetate (2:1) to give the title compound as a solid (4.7 g) m.p. 92°-93°.
Reaction SMILES: [O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][NH:12][CH2:13][CH:14]3[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]3)[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1.[F:27][C:28]([F:35])([F:34])[C:29](OCC)=[O:30]>CO>[O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][N:12]([CH2:13][CH:14]3[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]3)[C:29](=[O:30])[C:28]([F:35])([F:34])[F:27])[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCCC(CNCc2cc3c(cn2)OCCO3)C1
Reactant: CCOC(=O)C(F)(F)F
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCC(CN(Cc2cc3c(cn2)OCCO3)C(=O)C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1.3 g of tert-butyl 3-(((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)methyl)piperidine-1-carboxylate in 10 mL of methanol, 0.54 mL of ethyl trifluoroacetate was added, and a mixture was stirred at room temperature for 2 hours, and then stirred at 40 to 45° C. for 3 hours. Thereto was added 0.54 mL of ethyl trifluoroacetate, and the mixture was heated under reflux while stirring for 3 hours. The mixture was cooled to room temperature, and the solvent was then distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using an eluent of hexane:ethyl acetate=1:1 to obtain 0.47 g of tert-butyl 3-(((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(trifluoroacetyl)amino)-methyl)piperidine-1-carboxylate as a colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13]C)=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:25][CH2:24][CH2:23][C:22]2=[O:26])=[CH:17][CH:16]=1.[OH-].[Na+].Cl>CO.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:16]=[CH:17][C:18]([N:21]2[CH2:25][CH2:24][CH2:23][C:22]2=[O:26])=[CH:19][CH:20]=1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(N4CCCC4=O)cc3)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1c[nH]c2cc(Cl)c(-c3ccc(N4CCCC4=O)cc3)cc12
Temperature: 75 °C
Reaction time: 48 h
Yield: 37.6 %

Procedure:
To a mixture of methyl 6-chloro-5-[4-(2-oxopyrrolidin-1-yl)phenyl]-1H-indole-3-carboxylate (112 mg, 0.30 mmol) in methanol (3 mL) and water (3 mL) was added sodium hydroxide (36 mg, 0.94 mmol). The reaction mixture was heated at 75° C. and stirred for 48 hours. The mixture was acidified to pH=4 using 1 N hydrochloric acid and concentrated to give a brown solid. It was purified by reverse phase HPLC to give the title compound (40 mg, 37% yield) as a pale solid. MS (ES+) 355.1 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 12.11 (br. s, 1 H), 11.95 (br. s, 1 H), 8.07 (s, 1 H), 7.95 (s, 1 H), 7.75 (d, 2 H), 7.62 (s, 1 H), 7.43 (d, 2 H), 3.89 (t, 2 H), 2.53 (m, 2 H), 2.09 (m, 2 H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH:13]([F:16])[CH:14]=[CH2:15])[CH2:11][O:10][C:9]1([CH3:18])[CH3:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:19]=[CH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]CC.CCOCC.CCCCCC>C(Cl)Cl.Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1>[C:1]([O:5][C:6]([N:8]1[C@H:12]([CH:13]([F:16])[CH:14]=[CH:15][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH3:19])[CH2:11][O:10][C:9]1([CH3:18])[CH3:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC(F)[C@@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Reactant: C=CCCCCCCCCCCCCC
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCCCCC
Product: CCCCCCCCCCCCCC=CC(F)[C@@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 36 h

Procedure:
tert-Butyl-(4S)-4-(1-fluoroprop-2-en-1-yl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (0.036 g, 0.14 mmol) and 1-pentadecene (0.2 ml, 5 eq) were solubilised in anhydrous CH2Cl2 (2.5 ml) under an atmosphere of nitrogen, in a sealed tube. Grubbs 2nd Generation catalyst (0.006 g, 2 mol %) was added as a solid, and the reaction mixture was allowed to stir for 36 hours at 100° C., with the reaction monitored by t.l.c. (ether:hexane, 1:19). The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. Purification by flash chromatography (ether:hexane, 1:19) afforded the product (0.062 g, quantitative yield) and a mixture of compounds of varying alkyl chain length. Tentative analysis of this compound describes a mixture of products. m/z: HRMS required for C26H48FNO3 mass is 441.3600, found 441.3618 as major compound, also found 413.3164, 427.3433, 455.3875 and 469.3886 as minor products; IR (film) νmax (cm−1) 2926, 1704, 1386; 1H NMR (CDCl3, 400 Mhz) δ=5.81 (m, 1H, H8), 5.51 (m, 1H, H7), 5.10 and 4.94 (2 m, H6erythreo, threo), 4.08 (m, 1H, H4), 3.94 (m, 2H, H5,5′), 2.04 (m, 2H, H9,9′), 1.48 (m, 15H, NCOOC(CH3)3 and —OC(CH3)2N—), 1.25 (br s, 22H, (CH2)11), 0.88 (t, J=7.0, 3H, CH3, H21); 13C-NMR (CDCl3, 100.6 MHz) δ=152.4 (—NCOO—), 136.9 (CH, C8), 125.2 (CH, C7), 94.4 (CH, C6), 93.9 (OC(CH3)2N), 80.4 (OC(CH3)3), 63.4 (CH, C4), 60.4 (CH2, C5), 31.6, 31.9, 29.7, 22.7, 21.0 (12C, CH2, (CH2)12), 28.4 (CH3, OC(CH3)3), 26.9 and 24.7 (CH3, —OC(CH3)2N—), 14.1 (CH3, (CH2)12CH3)); 19F-NMR (CDCl3, 400 MHz) δ=major compounds −183.0, −186.0, minor compounds −175.6, −177.7, −192.6, −194.6;
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]([O:12]C)=O)[CH2:4][CH2:3]1.[CH2:14]([NH2:26])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C(Cl)(Cl)Cl.CO>[CH2:14]([NH:26][C:10](=[O:12])[CH2:9][CH2:8][N:5]1[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCCN
Reactant: COC(=O)CCN1CCN(C)CC1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCNC(=O)CCN1CCN(C)CC1
Temperature: 185 °C

Procedure:
Methyl 3-(4-methylpiperazin-1-yl)propanoate 40.0 g (0.21 moles) and dodecylamine 39.7 g (0.21 moles) are charged into a 3-neck 250-mL round bottom flask equipped with a Dean-Stark trap, thermocouple, and reflux condenser. The mixture is agitated using a magnetic stirring bar and heated to 185° C. for five hours. The volume of methanol that is distilled from the reaction is used to monitor the progress of the reaction. Evidence of the chemical transformation is observed by thin layer chromatography (TLC) analysis using a 4:1 CHCl3/MeOH as mobile phase. The final product is a light yellow solid at ambient temperature. 1H-NMR (300 MHz, CDCl3): δ 2.98 (m, 2H), 2.07 (m, 1511), 1.27 (m, 2H), 1.0 (m, 18H), 0.65 (t, 6.7 Hz, 3H). 13C-NMR (75 MHz, CDCl3): δ 171.70, 54.60, 54.39, 54.34, 53.45, 51.86, 45.39, 38.45, 31.60, 31.38, 29.14, 29.11, 28.93, 28.85, 28.83, 26.65, 22.15, 13.61.
Reaction SMILES: [H-].[K+].[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH:13]1[O:19][C:18]2[CH:20]=[CH:21][CH:22]=[N:23][C:17]=2[N:16]2[CH:24]=[CH:25][CH:26]=[C:15]2[C:14]1=[O:27].[CH3:28][N:29]([CH3:33])[C:30](Cl)=[O:31]>C1COCC1>[CH3:28][N:29]([CH3:33])[C:30]([O:27][C:14]1[C:15]2[N:16]([CH:24]=[CH:25][CH:26]=2)[C:17]2[N:23]=[CH:22][CH:21]=[CH:20][C:18]=2[O:19][C:13]=1[C:4]1[CH:5]=[CH:6][C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:3]=1)=[O:31]
Reactant: CN(C)C(=O)Cl
Reactant: O=C1c2cccn2-c2ncccc2OC1c1ccc2ccccc2c1
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN(C)C(=O)OC1=C(c2ccc3ccccc3c2)Oc2cccnc2-n2cccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
To a suspension of potassium hydride (0.211 g, 1.84 mmol, 35% in oil) in anhydrous TBF (5.0 mL) was added the the (±)-6-(2-naphthyl)pyrrolo[1,2-d]pyrido[3,2-b][1,4]oxazepin-7(6H)-one (600 mg, 1.84 mmol) dissolved in anhydrous THF (5 mL). The reaction mixture was stirred at rt for 2 h, and then dimethylcarbamoyl chloride (0.228 g, 2.12 mmol) was slowly added. After stirring for 12 h at 30° C., the solvent was removed in vacuo and the residue was dissolved in EtOAc. The organic layer was washed with brine, dried and concentrated. The residue was chromatographed (dichloromethane and hexane 1:3) to give the PBOX-43 in 76% yield. IR (neat) 1730 cm−1; 1HNMR (CDCl3) δ 2.92 (s, 3 H), 3.12 (s, 3 H), 6.44 (m, 2 H), 7.12 (m, 1 H), 7.47-7.55 (m, 3 H), 7.73-7.87 (m, 5 H), 8.24(m, 2H).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([SH:10])=[CH:8][CH:7]=[CH:6][C:5]=12.C(N(CC)CC)C.Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(O)C>[N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: Sc1cccc2nccn12
Reactant: CCOC(=O)CBr
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)CSc1cccc2nccn12
Reaction time: 2 h

Procedure:
To a solution of 120.02 g (0.7991 mol) of imidazo-[1,2-a]pyridine-5-thiol and 134 ml (0.959 mol) of triethylamine in 500 ml of ethanol was added 88.6 ml (0.799 mol) of ethyl bromoacetate dropwise at room temperature, and the mixture was stirred at the same temperature for 2 hours. The solvent was then distilled off under reduced pressure and ethyl acetate was added to the residue. The resulting precipitate (for the most part, triethylamine hydrochloride) was filtered off and washed with ethyl acetate. The filtrate and washes were pooled and the solvent was distilled off under reduced pressure to provide ethyl (imidazo[1,2-a]pyridin-5-ylthio)acetate as crude product. This crude product was not purified but used as it was in the next reaction.
Reaction SMILES: C([N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:9][CH2:10][NH2:11])C1C=CC=CC=1>O>[CH:16]1[CH:17]=[CH:18][C:13]([CH2:12][NH:11][CH2:10][CH2:9][NH:8][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:14][CH:15]=1
Reactant: NCCN(Cc1ccccc1)Cc1ccccc1
Solvent: O
Product: c1ccc(CNCCNCc2ccccc2)cc1

Procedure:
HPLC analysis shows there to be 19.7% N,N dibenzylethylenediamine and 80% compound of Example 42 to be present by total area analysis. Water is present at 0.3%. This gives a stoichiometric ratio of compound to base of 1:0:5.
Reaction SMILES: C(O[CH2:5][CH2:6][CH2:7][CH2:8][C@@H:9](O)[C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)(=S)C.C(N(CC)CC)C.C[S:25](Cl)(=O)=O.C[O-].[Na+]>ClCCl.CO>[N:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C@@H:9]2[CH2:8][CH2:7][CH2:6][CH2:5][S:25]2)[CH:11]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(=S)OCCCC[C@@H](O)c1cccnc1
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: c1cncc([C@@H]2CCCCS2)c1
Temperature: 25 °C

Procedure:
A solution of (R)-5-hydroxy-5-(3-pyridyl)pentyl thioacetate (10.0 g) in dichloromethane (200 ml) under nitrogen is cooled to 0° C. and treated with triethylamine (7 ml), followed by methanesulphonyl chloride (3.8 ml), dropwise between -5° C. and 0° C., during 5 minutes. The reaction mixture is then warmed to room temperature. After 60 minutes the mixture is cooled to 10° C. and treated, dropwise during 10 minutes, with a solution of sodium methoxide in methanol (20 ml; 25% w/v). The mixture is allowed to warm to room temperature. After 30 minutes the mixture is washed with water until the pH is between 9 and 10, dried over magnesium sulphate, evaporated and chromatographed, to give (S)-2-(3-pyridyl)tetrahydro-2H-thiopyran (7.5 g; 91% ee), in the form of an amber oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CC([O-])=O.CC([O-])=O.[Pd+2].O>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:3]=[CH:4][C:5]([N:8]3[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]3)=[N:6][CH:7]=2)=[CH:20][CH:19]=1
Reactant: OCCC1CCN(c2ccc(Br)cn2)CC1
Reactant: OB(O)c1ccc(F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Product: OCCC1CCN(c2ccc(-c3ccc(F)cc3)cn2)CC1

Procedure:
Under an inert atmosphere, 3.60 g (12.62 mmol) of 2-(5′-bromo-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)ethanol, prepared in step 1.1., 3.53 g (25.25 mmol) of 4-fluorophenylboronic acid, 5.23 g (37.87 mmol) of potassium carbonate and 4.88 g (15.15 mmol) of tetrabutylammonium bromide in suspension are introduced into 20 mL of water. 0.142 g (0.63 mmol) of Pd(OAc)2 is then added. The reaction mixture is refluxed for 24 hours.
Reaction SMILES: [CH3:1][C:2]1([C:13]([OH:15])=[O:14])[CH2:6][S:5]C(C2C=CC=CC=2)=[N:3]1.[ClH:16]>O>[ClH:16].[CH3:1][C@:2]([C:13]([OH:15])=[O:14])([CH2:6][SH:5])[NH2:3]
Reactant: CC1(C(=O)O)CSC(c2ccccc2)=N1
Agent: Cl
Solvent: O
Product: C[C@@](N)(CS)C(=O)O
Temperature: 20 °C

Procedure:
18.6 g of 4-methyl-2-phenylthiazoline-4-carboxylic acid were dissolved in 186 ml of 6 N HCl under a nitrogen atmosphere and the solution was then heated under reflux for 16 hours. After cooling to 20° C., the precipitated benzoic acid was filtered off and washed with 2×10 ml of completely demineralized water. The filtrate was extracted three times with 95 ml each of MTBE, then residual MTBE was stripped off by evacuation at room temperature and only then was the water removed by distillation at reduced pressure and at most 40° C. The oil obtained was dissolved in 110 ml of water and again concentrated down to an about 50% strength solution. 300 ml of 2-butanol were added to this concentrated solution and the residual water was entrained by distilling off the azeotrope of 2-butanol and water (total: 250 ml). In the course of this, a water content of 0.6 gg % was achieved in the last distillate fraction. The concentrated solution obtained was further concentrated under reduced pressure, cooled to room temperature and then treated with 200 ml of MTBE. The precipitated crystals were filtered off with suction, washed 2× with 20 ml each of MTBE and dried at 45° C./30 mbar.
Reaction SMILES: I[CH2:2][CH3:3].[CH3:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[N:12]([CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[C:13](=[O:21])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>C1C=CC=CC=1>[CH3:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[N:12]([CH:22]1[CH2:27][CH2:26][N:25]([CH2:2][CH3:3])[CH2:24][CH2:23]1)[C:13](=[O:21])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1cccc(C)c1N(C(=O)Cc1ccccc1)C1CCNCC1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: c1ccccc1
Product: CCN1CCC(N(C(=O)Cc2ccccc2)c2c(C)cccc2C)CC1

Procedure:
A mixture of 4 parts of iodoethane, 5 parts of N-(2,6-dimethylphenyl)-N-(4-piperidinyl)benzeneacetamide, 5 parts of sodium carbonate, a few crystals of potassium iodide in 200 parts of benzene is stirred and refluxed for 23 hours. The reaction mixture is filtered hot and the filtrate is evaporated in vacuo. The solid residue is crystallized from 1,1'-oxybisethane, yielding 2 parts of N-(2,6-dimethylphenyl)-N-(1-ethyl-4-piperidinyl)-benzeneacetamide; mp. 86.5° C.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH2:5]([O:12][CH2:13][C@@H:14]1[CH2:18][C@H:17](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:16][N:15]1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(O)C.CN(C)C=O>[N:1]([C@H:17]1[CH2:16][N:15]([C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31])[C@H:14]([CH2:13][O:12][CH2:5][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:18]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2C[C@@H](COCc3ccccc3)N(C(=O)OC(C)(C)C)C2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1C[C@H](N=[N+]=[N-])C[C@H]1COCc1ccccc1
Temperature: 80 °C
Yield: 99 %

Procedure:
Sodium azide (0.32 g) was added to a solution of tert-Butyl (2S,4S)-2-[(benzyloxy)methyl]-4-[(4-methylphenyl)sulfonyl]oxypyrrolidine-1-carboxylate (1.15 g) [see Preparation 32] in ethanol (20 ml) and dimethylformamide (5 ml). The reaction mixture was heated to 80° C. for 4 hours, after which time the cooled mixture was partitioned between diethyl ether and water. The organic layer was separated and the aqueous extracted twice with diethyl ether, the combined organic layers were dried over magnesium sulphate and the solvent removed under reduced pressure. The residue was azeotroped with dichloromethane to afford tert-butyl (2S,4R)-4-azido-2-[(benzyloxy)methyl]pyrrolidine-1-carboxylate (820 mg) as an oil.