Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:23][C:20]1[CH:21]=[CH:22][C:17]([NH2:16])=[CH:18][CH:19]=1
Reactant: Nc1ccc(O)cc1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Temperature: 100 °C
Reaction time: 18 h
Yield: 61.1 %

Procedure:
A suspension of 4-chloro-6,7-dimethoxyquinoline (1566 mg, 7.00 mmol), 4-aminophenol (917 mg, 8.40 mmol) and cesium carbonate (4561 mg, 14.0 mmol) in dimethyl sulfoxide (14 ml) was stirred at 100° C. for 18 hr. Water was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate/tetrahydrofuran (=1/1). The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate→ethyl acetate/methanol=60/40). Ethyl acetate was added to the obtained residue and the mixture was filtrated to give the title compound (1267 mg, 61%) as a white powder.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:14]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:13][C:9]1[CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(-c2ccccc2)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cccc(-c2ccccc2)c1
Temperature: 70 °C

Procedure:
To a solution of 3-phenyltoluene (1.80 mL, 10.9 mmol) in carbon tetrachloride (50 mL) was added N-bromosuccinimide (2.124 g, 11.93 mmol) and the mixture heated to 70° C. AIBN (50 mg, 0.30 mmol) was added and the mixture refluxed for 30 mins. Additional AIBN was added (50 mg, 0.30 mmol) and the mixture refluxed for 16 hours. The reaction was cooled, filtered, and the solvent evaporated in vacuo. The residue was chromatographed (Silica gel, 5% EtOAc in hexanes) to afford the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22](O)=[O:23])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6].[CH3:25][CH:26]1[CH2:30][CH2:29][CH:28]([CH3:31])[NH:27]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([N:27]1[CH:28]([CH3:31])[CH2:29][CH2:30][CH:26]1[CH3:25])=[O:23])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6]
Reactant: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)O)c(Cl)c1
Reactant: CC1CCC(C)N1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC1CCC(C)N1C(=O)c1ccc(C(=O)NCc2nc3cc(Cl)ccc3[nH]2)cc1Cl

Procedure:
Prepared analogously to Example 1d from 3-chloro-N-(5-chloro-1H-benzimidazol-2-ylmethyl)-4-carboxybenzamide, 2,5-dimethylpyrrolidine, TBTU, and triethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.77 minutes; C22H22Cl2N4O2 (445.35); mass spectrum: (M+H)+=445.2.
Reaction SMILES: O[CH2:2][C@H:3]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH:12]([CH3:16])[CH2:13][CH2:14][CH3:15])=[CH:6][CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:45]>O1CCCC1>[Br:45][CH2:2][C@H:3]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH:12]([CH3:16])[CH2:13][CH2:14][CH3:15])=[CH:6][CH:5]=1
Reactant: CCCC(C)COc1ccc([C@H](CO)NC(=O)OC(C)(C)C)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCC(C)COc1ccc([C@H](CBr)NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
To a solution of t-butyl (1R)-2-hydroxy-1-(4-(2-methylpentyloxy)phenyl)ethylcarbamate (15 g, 44.5 mmol), prepared according to the procedure described in example 1, in anhydrous tetrahydrofuran (200 mL) was added triphenylphosphine (17.49 g, 66.7 mmol) and carbon tetrabromide (22.11 g, 66.7 mmol). The reaction mixture was stirred at room temperature for 2 h. The mixture was filtered through a pad of diatomaceous earth (Celite®) and the filtrate was concentrated to afford yellow residue which was purified by column chromatography on silica gel (20→30% ethyl acetate in hexanes) to afford t-butyl (1R)-2-bromo-1-(4-(2-methylpentyloxy)phenyl)ethylcarbamate (17.8 g, 100% yield) as a colorless solid: 1H NMR (400 MHz, CDCl3) δ 7.18 (d, J=8.8 Hz, 2H), 6.86 (d, J=8.6 Hz, 2H), 5.05 (br. s., 1H), 4.91 (br. s., 1H), 3.78 (dd, J=8.8, 5.8 Hz, 1H), 3.68 (dd, J=9.1, 6.8 Hz, 1H), 3.65 (d, J=5.0 Hz, 1H), 1.86-1.97 (m, 1H), 1.60 (d, J=7.3 Hz, 1H), 1.42 (s, 9H), 1.14-1.51 (m, 4H), 0.99 (d, J=6.5 Hz, 3H), 0.90 (t, J=7.3 Hz, 3H); LRMS (ESI) m/e 400.2 [(M+H)+, calcd for C19H31NO3Br 400.1].
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[CH3:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][NH2:44]>C1COCC1.CCOC(C)=O>[CH3:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][NH:44][S:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:10]2[N:9]=[C:8]([C:6]3[CH:5]=[C:4]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:32])([F:31])[F:33])=[CH:26][CH:25]=4)[CH:3]=[C:2]([CH3:1])[N:7]=3)[CH:13]=[CH:12][CH:11]=2)[CH:15]=1)(=[O:22])=[O:21]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)Cl)c3)n2)n1
Reactant: COCCOCCOCCN
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCCOCCOCCNS(=O)(=O)c1cccc(-c2cccc(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C)n3)n2)c1
Yield: 71.5 %

Procedure:
The title compound was prepared from 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonyl chloride (example I.2) (0.200 g, 0.409 mmol) by treatment with 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethylamine [CAS-no. 74654-07-2] (0.334 mg, 2.04 mmol) in THF (5 mL) at 23° C. for 16 h. Diluted with EtOAc, washed with 5% citric acid, sat. NaHCO3-sol. and brine, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with EtOAc followed by trituration with diethyl ether/heptane to give the title compound (0.180 g, 71%) as a light yellow oil. MS (ISP) 616.2 [(M+H)+].
Reaction SMILES: I[C:2]1[CH:16]=[CH:15][C:5]([O:6][CH:7]2[CH:12]3[CH2:13][CH2:14][N:9]([CH2:10][CH2:11]3)[CH2:8]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][C:23]=1[CH3:24].[ClH:28].O1CCOCC1>C(OCC)(=O)C>[ClH:28].[N:9]12[CH2:14][CH2:13][CH:12]([CH2:11][CH2:10]1)[CH:7]([O:6][C:5]1[CH:15]=[CH:16][C:2]([C:20]3[CH:21]=[CH:22][C:23]([CH3:24])=[C:18]([NH2:17])[CH:19]=3)=[CH:3][CH:4]=1)[CH2:8]2
Reactant: Cc1ccc(B(O)O)cc1N
Reactant: Ic1ccc(OC2CN3CCC2CC3)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1ccc(-c2ccc(OC3CN4CCC3CC4)cc2)cc1N

Procedure:
The product of Example 1A (330 mg, 1 mmol) was treated with 3-amino-4-methyl-phenylboronic acid (Lancaster, 302 mg, 2 mmol) according to the procedure of Example 1B. The free base of the title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3H2O, 90:10:2, Rf. 0.10) as oil (230 mg, yield, 75%). The free base of the title compound (230 mg, 0.75 mmol) in ethyl acetate (5 mL) was treated with 4M HCl in 1,4-dioxane (0.5 mL, 2 mmol). The title compound was obtained as solid (180 mg, yield, 74%): 1H NMR (MeOH-d4, 300 MHz) δ 1.85-2.19 (m, 3H), 2.28-2.38 (m, 1H), 2.43 (s, 3H), 2.51-2.57 (m, 1H), 3.31-3.45 (m, 5H), 3.82-3.89 (m, 1H), 4.93-4.99 (m, 1H), 7.13 (dt, J=8.8, 3.0 Hz, 2H), 7.44 (d, J=8.8 Hz, 1H), 7.56-7.66 (m, 4H) ppm. MS (DCl/NH3) m/z 309 (M+H)+. Anal. Calculated for C19H22N2O.2.0HCl.0.1H2O: C, 62.70; H, 6.89; N, 7.31. Found: C, 62.52; H, 6.59; N, 7.35.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(=O)(O)[O-].[Na+].Cl.[CH3:17][NH:18][O:19][CH3:20].Cl>C1COCC1.O>[Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:18]([O:19][CH3:20])[CH3:17])=[O:5]
Reactant: CNOC
Reactant: O=C(Cl)c1cccnc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CON(C)C(=O)c1cccnc1Cl
Yield: 87.2 %

Procedure:
To a solution of 2-chloro-nicotinoyl chloride (7.00 g, 39.8 mmol) and sodium bicarbonate (10.0 g, 119 mmol) in 1:1 THF/H2O (110 mL) at 0° C. was added N,O-dimethyl hydroxylamine hydrochloride (4.68 g, 47.7 mmol). The resultant solution was stirred 2 h at 0° C., neutralized with 10% HCl to pH ˜7, and the aqueous layer was extracted two times with EtOAc. The combined organics were dried with sodium sulfate and concentrated in vacuo to produce 6.96 g (87%) of the crude nicotinamide, which was used without further purification.
Reaction SMILES: [CH3:1]/[C:2](/[CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])=[CH:3]/[CH2:4]O.N1C(C)=CC(C)=CC=1C.[Cl-].[Li+].CS([Cl:27])(=O)=O>CN(C=O)C>[Cl:27][CH2:4]/[CH:3]=[C:2](/[CH3:1])\[CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)=CCC/C(C)=C\CO
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1cc(C)nc(C)c1
Solvent: CN(C)C=O
Product: CC(C)=CCC/C(C)=C\CCl
Temperature: 0 °C
Reaction time: 4 h
Yield: 84.7 %

Procedure:
To a stirred solution of 10.0 g (64.83 mmol) of (Z)-3,7-dimethyl-2,6-octadien-1-ol and 9.42 mL (71.31 mmol) of 2,4,6-collidine under argon at room temperature was added dropwise 2.74 g (64.83 mmol) of lithium chloride in 30 mL of DMF. The mixture was cooled to 0° C. and treated with 5.52 mL (71.31 mmol) of methanesulfonyl chloride dropwise over 10 minutes. The reaction was stirred at 0° C. for 4 hours (solid present), then was poured into 300 mL of ice/water. The aqueous solution was washed three times with 200 mL portions of hexane. The organic layers were combined and washed with 5% KHSO4, water, saturated NaHCO3, brine, dried (MgSO4) and evaporated to provide 9.48 g (85%) of title chloride as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:6]=[C:5]([C:20]([NH:22][NH2:23])=[O:21])[CH:4]=1.[C:24]1(=O)[CH2:28][CH2:27][CH2:26][CH2:25]1>C(OCC)C>[C:24]1(=[N:23][NH:22][C:20](=[O:21])[C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[CH:11]=3)[N:6]=2)[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C1CCCC1
Reactant: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)NN)c1
Solvent: CCOCC
Product: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)NN=C2CCCC2)c1

Procedure:
4-methoxy-6-[3-(trifluoromethyl)phenoxy] picolinic acid hydrazide (0.40 g, 0.0012 mol) was mixed cyclopentanone (1.0 g, 0.0012×10 mol) and then with diethyl ether (about 10 ml). The resultant mixture was stirred at room temperature for about one hour. The obtained reaction solution was concentrated, thereby obtaining an aimed product.
Reaction SMILES: Br[CH2:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[S:9]2(=[O:25])=[O:24])=[CH:5][CH:4]=1.[CH3:28][NH2:29]>>[F:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[N:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:8]([CH2:7][C:6]2[CH:26]=[CH:27][C:3]([CH2:2][NH:29][CH3:28])=[CH:4][CH:5]=2)[S:9]1(=[O:24])=[O:25]
Reactant: O=S1(=O)N(Cc2ccc(CBr)cc2)c2ccccc2N1c1ccccc1F
Reactant: CN
Product: CNCc1ccc(CN2c3ccccc3N(c3ccccc3F)S2(=O)=O)cc1
Yield: 100 %

Procedure:
In an analogous manner to general procedure V, 1-[4-(bromomethyl)benzyl]-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide (0.11 g, 0.24 mmol) was treated with methylamine (10 mL) to provide 0.09 g, (100%) of 1-(4-{[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]methyl}phenyl)-N-methylmethanamine. MS (ES) m/z 397.0. HPLC purity 100.0% at 210-370 nm, 7.7 min.; Xterra RP18, 3.5 u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH:4]=[CH2:5].[NH2:7][CH2:8][CH2:9][CH:10]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([F:20])[CH:17]=2)[O:12][C:11]1([CH3:22])[CH3:21]>CO>[CH3:21][C:11]1([CH3:22])[CH:10]([CH2:9][CH2:8][NH:7][CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:6])[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([F:20])[CH:17]=2)[O:12]1
Reactant: C=CC(=O)OC
Reactant: CC1(C)Oc2ccc(F)cc2CC1CCN
Solvent: CO
Product: COC(=O)CCNCCC1Cc2cc(F)ccc2OC1(C)C

Procedure:
While stirring at a temperature of from 0° to 5°, a solution of 0.86 g (9.9 mmol) of acrylic acid methyl ester in 10 ml of methanol is added dropwise within a period of 15 minutes to a solution of 2.23 g (10 mmol) of 3-(2-aminoethyl)-2,2-dimethyl-6-fluoro-chroman in 50 ml of methanol. The reaction mixture is then stirred for 16 hours at from 0° to 5° and then concentrated by evaporation in vacuo. The oily residue is chromatographed on 200 g of silica gel (0.040-0.063 mm) with ethyl acetate as eluant, yielding 1.9 g (61.4% of the theoretical yield) of N-[2-(2,2-dimethyl-6-fluoro-chroman-3-yl)-ethyl]-N-(2-methoxycarbonylethyl)-amine in the form of a light-yellow oil. The N-[2-(2,2-dimethyl-6-fluoro-chroman-3-yl)-ethyl]-N-(2-methoxycarbonylethyl)-amine hydrochloride, prepared therefrom with hydrochloric acid in diethyl ether, crystallises from acetone/diethyl ether and melts at 129°-131°.
Reaction SMILES: [F:1][C@H:2]1[C@H:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=2[C:18]([F:21])([F:20])[F:19])[CH2:6][CH2:5][NH:4][CH2:3]1.[O:22]1[CH2:25][C:24](=O)[CH2:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:1][C@H:2]1[C@H:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=2[C:18]([F:21])([F:19])[F:20])[CH2:6][CH2:5][N:4]([CH:24]2[CH2:25][O:22][CH2:23]2)[CH2:3]1
Reactant: O=C1COC1
Reactant: O=[N+]([O-])c1ccc(O[C@@H]2CCNC[C@H]2F)c(C(F)(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: O=[N+]([O-])c1ccc(O[C@@H]2CCN(C3COC3)C[C@H]2F)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
A solution of (3R,4R)-3-fluoro-4-(4-nitro-2-(trifluoromethyl)phenoxy)piperidine (1.3 g, 1.0 eq, 4.3 mmol) and oxetan-3-one (0.43 g, 1.4 eq, 6.0 mmol) in 1,2-dichloroethane (50 mL) was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (1.6 g, 1.8 eq, 7.7 mmol) was added in portions to the above solution and the heterogeneous mixture was stirred at room temperature overnight. Work-up and purification of the crude mixture used the same conditions as Example 88 above for Compound 120, and gave the product in 66% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:3]=1[C:4]([NH:6][C:7]([CH3:34])([C:9]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[CH2:14][CH2:13][N:12]([S:15]([NH:18][CH2:19][CH2:20]C(OC(C)(C)C)=O)(=[O:17])=[O:16])[CH2:11][CH2:10]1)[CH3:8])=[O:5].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:3]=1[C:4]([NH:6][C:7]([CH3:34])([C:9]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[CH2:10][CH2:11][N:12]([S:15]([NH:18][CH2:19][CH3:20])(=[O:17])=[O:16])[CH2:13][CH2:14]1)[CH3:8])=[O:5]
Reactant: CC(C)(C)OC(=O)CCNS(=O)(=O)N1CCC(c2ccccn2)(C(C)(C)NC(=O)c2ccc(Cl)cc2Cl)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCNS(=O)(=O)N1CCC(c2ccccn2)(C(C)(C)NC(=O)c2ccc(Cl)cc2Cl)CC1
Reaction time: 0.5 h

Procedure:
2,4-Dichloro-N-{1-methyl-1-[1-((tert-butoxycarbony)ethylaminosulfonyl)-4-pyridin-2-ylpiperidin-4-yl]ethyl}benzamide (VI-2, 35 mg, 0.061 mmol) was dissolved in DCM (1.6 mL) and cooled in an ice bath. TFA (0.4 mL) was added dropwise and upon completion of the addition the reaction mixture was stirred in a nice bath for 0.5 h then allowed to warm to roomtemperature and stirred at room temperature for 12 h. The volatile components of the reaction mixture were removed in vacuo then saturated aqueous sodium hydrogen carbonate solution added dropwise. The mixture was extracted three times with EtOAc. The combined organic phase was dried (Na2SO4) and the solvent removed in vacuo to give 2,4-dichloro-N-{1-methyl-1-[1-(ethylaminosulfonyl)-4-pyridin-2-ylpiperidin-4-yl]ethyl}benzamide (VI-3). 1H NMR (CD3OD, 500 MHz), δ 8.62 (d, J=4.1 Hz, 1H), 7.93 (m, 1H), 7.65 (d, J=8.0 Hz, 1H), 7.48 (d, J=1.8 Hz, 1H), 7.37 (m, 1H), 7.30 (d, J=8.0 Hz, 1H), 3.66 (s, 2H), 3.48 (m, 2H), 3.00 (q, J=7.0 Hz, 2H), 2.94 (m, 2H), 2.50 (m, 2H), 2.04 (m, 2H), 1.12 (t, J=7.0 Hz, 3H); MS 472 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:19]=[C:18]([CH2:20][C:21]([NH:23][CH:24]([C:37]([O:39][CH2:40][CH2:41][CH3:42])=[O:38])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[O:22])[CH:17]=[CH:16][C:5]=1[C:6]([O:8]CC1C=CC=CC=1)=[O:7])[CH3:2]>C(O)CC>[CH2:1]([O:3][C:4]1[CH:19]=[C:18]([CH2:20][C:21]([NH:23][CH:24]([C:37]([O:39][CH2:40][CH2:41][CH3:42])=[O:38])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[O:22])[CH:17]=[CH:16][C:5]=1[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCCOC(=O)C(NC(=O)Cc1ccc(C(=O)OCc2ccccc2)c(OCC)c1)c1ccccc1N1CCCCC1
Solvent: CCCO
Product: CCCOC(=O)C(NC(=O)Cc1ccc(C(=O)O)c(OCC)c1)c1ccccc1N1CCCCC1

Procedure:
Prepared analogously to Example 68 by catalytic hydrogenation of benzyl 2-ethoxy-4-[N-(α-n-propoxycarbonyl-2-piperidino-benzyl)-aminocarbonyl methyl]-benzoate in n-propanol.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:12][CH2:13][CH:14]2OCC[O:15]2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:26])[N:6]2[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])O.[Na+]>Cl.O1CCCC1>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:12][CH2:13][CH:14]=[O:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:26])[N:6]2[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1nc(SCCC2OCCO2)nc2c1nc(O)n2Cc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1nc(SCCC=O)nc2c1nc(O)n2Cc1ccccc1
Temperature: 70 °C
Reaction time: 7 h
Yield: 25.8 %

Procedure:
6-Amino-9-benzyl-2-[2-(1,3-dioxolan-2-yl)ethyl)thio-8-hydroxypurine (74 mg, 0.20 mmol) was dissolved in a mixture of 3.3N hydrochloric acid (1 ml) and tetrahydrofuran (4 ml). The solution was stirred at 70° C. for 7 hours and then neutralized with aqueous sodium hydrogen carbonate. After removal of tetrahydrofuran in vacuo, the resulting crystals were filtered, purified by silica gel chromatography (5% methanol/chloroform) to give the subject compound (17 mg, yield 44%).
Reaction SMILES: [N:1]#[N:2].[CH2:3]([O:10][C:11]([C@@:13]1([C:23]([NH2:25])=[O:24])[CH2:17][C@H:16]([OH:18])[CH2:15][N:14]1[C:19]([CH3:22])([CH3:21])[CH3:20])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28].O>N1C=CC=CC=1>[N:1]#[N:2].[CH2:3]([O:10][C:11]([C@@:13]1([C:23]([NH2:25])=[O:24])[CH2:17][C@H:16]([O:18][S:27]([CH3:26])(=[O:29])=[O:28])[CH2:15][N:14]1[C:19]([CH3:21])([CH3:22])[CH3:20])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)N1C[C@@H](O)C[C@]1(C(N)=O)C(=O)OCc1ccccc1
Agent: N#N
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)N1C[C@@H](OS(C)(=O)=O)C[C@]1(C(N)=O)C(=O)OCc1ccccc1
Temperature: 0 °C

Procedure:
0.32 g of N2 -(benzyloxycarbonyl)-N1 -tert.butyl-4(S)-hydroxy-L-prolinamide was dissolved in 5 ml of dry pyridine while stirring, cooled to 0° C. and treated dropwise with 0.82 ml of methanesulphonyl chloride. The solution was stirred at 0° C. for a further 2 hours. The mixture was poured into a mixture of ice and water which was then extracted with ethyl acetate. The combined organic extracts were washed with 2M hydrochloric acid and then with saturated sodium bicarbonate solution and subsequently dried over anhydrous sodium sulphate. After evaporation there was obtained 0.5 g of N2 -(benzyloxycarbonyl)-N1 -tert.butyl-4(S)-(methanesulphonyloxy)-L-prolinamide as an oil which was used without further purification.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([O:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][CH2:21][CH3:22])=[CH:7][CH:6]=[CH:5][C:4]=1[OH:23])[CH3:2].[C:24]([C:30]([O:32][CH3:33])=[O:31])#[C:25][C:26]([O:28][CH3:29])=[O:27].[OH-].C([N+](C)(C)C)C1C=CC=CC=1.[OH-].[Na+]>>[CH2:1]([C:3]1[C:8]([O:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][CH2:21][CH3:22])=[CH:7][CH:6]=[CH:5][C:4]=1[O:23]/[C:25](=[CH:24]\[C:30]([O:32][CH3:33])=[O:31])/[C:26]([O:28][CH3:29])=[O:27])[CH3:2]
Reactant: COC(=O)C#CC(=O)OC
Reactant: CCCc1ccccc1OCCCOc1cccc(O)c1CC
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: CCCc1ccccc1OCCCOc1cccc(O/C(=C\C(=O)OC)C(=O)OC)c1CC

Procedure:
A mixture of 73.9 parts of 2-ethyl-3-(3-[2-propylphenoxy]propoxy)phenol, 35.0 parts of acetylene dicarboxylic acid, dimethyl ester and 4 parts of benzyl trimethyl ammonium hydroxide was warmed, with stirring, to 70° when an exothermic reaction occurred. The reaction mixture was maintained at 100°-120° for a further fifteen minutes, cooled, and 1000 parts of 1N sodium hydroxide solution was added. The mixture was extracted with chloroform and the chloroform extract washed with water and saturated sodium chloride solution and dried. Evaporation of the chloroform gave an oil which on trituration with 40/60 petrol gave a solid that crystallised from methanol to give 43.4 parts of dimethyl 2-ethyl-3-(3-[2-propylphenoxy]propoxy)phenoxy fumarate, m.pt. 63.5°-66° (raised to 71°-72.5° by recrystallisation).
Reaction SMILES: [CH3:1][C:2]1([CH3:6])[CH2:5][NH:4][CH2:3]1.Cl[CH2:8][CH:9]([N:11]1[CH:15]([CH3:16])[CH2:14][N:13]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[C:12]1=[O:24])[CH3:10].Cl>>[Cl:23][C:19]1[CH:18]=[C:17]([N:13]2[CH2:14][CH:15]([CH3:16])[N:11]([CH:9]([CH3:10])[CH2:8][N:4]3[CH2:5][C:2]([CH3:6])([CH3:1])[CH2:3]3)[C:12]2=[O:24])[CH:22]=[CH:21][CH:20]=1
Reactant: CC1(C)CNC1
Reactant: CC(CCl)N1C(=O)N(c2cccc(Cl)c2)CC1C
Agent: Cl
Product: CC(CN1CC(C)(C)C1)N1C(=O)N(c2cccc(Cl)c2)CC1C

Procedure:
The title compound is prepared pursuant to the procedure of Example 4 from 3,3-dimethylazetidine and 3-(2-chloro-1-methylethyl)-1-(m-chlorophenyl)-4-methyl-2-imidazolidinone. B.p. 200° C./0.6 mm Hg. The corresponding hydrochloride melts at 162°-164° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]=[O:7])[N:3]=[CH:2]1.[H-].[Na+].[CH3:10][Si:11]([CH3:18])([CH3:17])[CH2:12][CH2:13][O:14][CH2:15]Cl>CN(C)C=O>[CH3:10][Si:11]([CH3:18])([CH3:17])[CH2:12][CH2:13][O:14][CH2:15][N:1]1[CH:5]=[C:4]([CH:6]=[O:7])[N:3]=[CH:2]1
Reactant: O=Cc1c[nH]cn1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cnc(C=O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
Imidazole-4-carboxaldehyde (1 g, 10.4 mmol) was added portionwise to a solution of sodium hydride (463 mg, 60% dispersion in mineral oil, 11.4 mmol) in N,N-dimethylformamide (15 ml), and the solution stirred for 30 minutes at room temperature. 2-(Trimethylsilyl)ethoxymethyl chloride (2.03 ml, 11.4 mmol) was added and the reaction stirred at room temperature for 18 hours. The reaction was quenched by the addition of aqueous ammonium chloride solution, and the mixture extracted with ethyl acetate (2×). The combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with methanol:ethyl acetate (3:97), to give the title compound, 1.8 g, 77% yield.