Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=O)[CH:6]=[CH:5]2.CCCCCC.C([Li])CCC.[CH:26]1[N:30]=[CH:29][N:28]2[CH2:31][CH2:32][C:33](=[O:34])[C:27]=12.[Cl-].[NH4+:36]>C1COCC1.C(OCC)(=O)C>[OH:34][C:33]1([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[C:7]([C:12]([NH2:36])=[O:14])[CH:6]=[CH:5]3)[C:27]2[N:28]([CH:29]=[N:30][CH:26]=2)[CH2:31][CH2:32]1
Reactant: O=C(O)c1ccc2cc(Br)ccc2c1
Reactant: O=C1CCn2cncc21
Reactant: [NH4+]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NC(=O)c1ccc2cc(C3(O)CCn4cncc43)ccc2c1
Temperature: -100 °C

Procedure:
6-Bromo-2-naphthoic acid (1.51 g) was dissolved in dry THF (50 ml) and the mixture was cooled in a liquid nitrogen/diethyl ether bath to −100° C. With stirring the mixture, an n-butyl lithium hexane solution (1.6M; 7.88 ml) was added dropwise at not more than −95° C. over 5 min. The mixture was stirred at −100° C. for 30 min and at −80° C. for 10 min. Thereafter, the mixture was cooled again to −100° C. and a solution of 5,6-dihydro-7H-pyrrolo[1,2-c]imidazol-7-one (0.61 g) in dry THF (11 ml) was added dropwise at not more than −90° C. over 5 min. The mixture was stirred at same temperature for 30 min and warmed to −70° C. over 30 min. A saturated aqueous ammonium chloride solution (25 ml) was added to stop the reaction. After stirring the mixture for 10 min, ethyl acetate (50 ml) was added for partitioning. The organic layer was removed and the aqueous layer was concentrated to dryness. The resulting residue was purified by flash column chromatography and the objective fraction was dissolved in methanol. This solution was concentrated, ether was added to the precipitated powder for filtration and dried to give the title compound (180 mg) as a colorless powder. The mother liquid was concentrated to give a residue (449 mg) containing the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[C:13]1([CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:23]2[CH2:24][CH2:25][N:20]([CH:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:21][CH2:22]2)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: O=[N+]([O-])c1cc(CCl)ccc1Cl
Solvent: CCO
Product: O=[N+]([O-])c1cc(CN2CCN(C(c3ccccc3)c3ccccc3)CC2)ccc1Cl

Procedure:
A mixture of 10.3 parts of 1-chloro-4-(chloromethyl)-2-nitrobenzene, 25.2 parts of 1-(diphenylmethyl)piperazine and 120 parts of ethanol is stirred and refluxed for 4 hours. The reaction mixture is cooled and evaporated. The residue is taken up in about 100 parts of water and the products is extracted with methylbenzene. The extract is washed with water, dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using trichloromethane as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of 2,2'-oxybispropane and hexane (1:2 by volume). The product is filtered off, washed with hexane and dried, yielding 19.6 parts of 1-(4-chloro-3-nitrophenylmethyl)-4-(diphenylmethyl)piperazine; mp. 101.6° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][N:18]([S:21]([CH3:24])(=[O:23])=[O:22])[CH2:17][CH2:16]2)[C:10](O)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[Cl:47][C:48]1[CH:56]=[CH:55][C:51]([CH2:52][NH:53][CH3:54])=[CH:50][CH:49]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:47][C:48]1[CH:56]=[CH:55][C:51]([CH2:52][N:53]([CH3:54])[C:10](=[O:11])[CH:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][N:18]([S:21]([CH3:24])(=[O:23])=[O:22])[CH2:17][CH2:16]2)=[CH:50][CH:49]=1
Reactant: CS(=O)(=O)N1CCN(CCC(C(=O)O)c2ccc(Cl)c(Cl)c2)CC1
Reactant: CNCc1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1ccc(Cl)cc1)C(=O)C(CCN1CCN(S(C)(=O)=O)CC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 61.4 %

Procedure:
A mixture of 25 mg 2-(3,4-dichloro-phenyl)-4-(4-methanesulfonyl-piperazin-1-yl)-butyric acid (intermediate 1), 24.1 mg (0.075 mmol) TBTU, 11.67 mg (0.075 mmol) (4-chloro-benzyl)-methyl-amine (commercially available) and 0.06 mL N,N-diisopropyl ethylamine in 0.75 mL DMF was shaken at room temperature and subsequently subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3. The product containing fractions were evaporated to yield 20.7 mg (67%) of the title compound as yellow viscous oil. MS(m/e): 534.2 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](B(O)O)=[C:4]([O:12][C@H:13]([CH2:15][CH:16]=[CH2:17])[CH3:14])[CH:3]=1.[CH2:18]([O:21][C:22]1([CH3:55])[CH2:27][CH2:26][N:25]([C:28]2[N:33]3[CH:34]=[C:35]([C:37]4[CH:42]=[CH:41][CH:40]=[C:39](Br)[CH:38]=4)[N:36]=[C:32]3[CH:31]=[C:30]([CH3:44])[C:29]=2[C@H:45]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])[C:46]([O:48][CH3:49])=[O:47])[CH2:24][CH2:23]1)[CH:19]=[CH2:20].C(OC1(C)CCN(C2N3C=C(C4C=C(C5C=CC(F)=CC=5O[C@H](CC=C)C)C=CC=4)N=C3C=C(C)C=2[C@H](OC(C)(C)C)C(OC)=O)CC1)C=C>>[CH2:18]([O:21][C:22]1([CH3:55])[CH2:23][CH2:24][N:25]([C:28]2[N:33]3[CH:34]=[C:35]([C:37]4[CH:38]=[C:39]([C:5]5[CH:6]=[C:7]([CH3:8])[C:2]([CH3:1])=[CH:3][C:4]=5[O:12][C@H:13]([CH2:15][CH:16]=[CH2:17])[CH3:14])[CH:40]=[CH:41][CH:42]=4)[N:36]=[C:32]3[CH:31]=[C:30]([CH3:44])[C:29]=2[C@H:45]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])[C:46]([O:48][CH3:49])=[O:47])[CH2:26][CH2:27]1)[CH:19]=[CH2:20]
Reactant: C=CC[C@H](C)Oc1cc(C)c(C)cc1B(O)O
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(-c4cccc(Br)c4)cn23)CC1
Agent: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(-c4cccc(-c5ccc(F)cc5O[C@@H](C)CC=C)c4)cn23)CC1
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(-c4cccc(-c5cc(C)c(C)cc5O[C@@H](C)CC=C)c4)cn23)CC1
Yield: 77 %

Procedure:
Prepared in 77% yield from (S)-(4,5-dimethyl-2-(pent-4-en-2-yloxy)phenyl)boronic acid and (S)-methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3-bromophenyl)-7-methylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate following the procedure for (S)-methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(4′-fluoro-2′-((S)-pent-4-en-2-yloxy)-[1,1′-biphenyl]-3-yl)-7-methylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate. 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J=11.5 Hz, 2H), 7.92-7.87 (m, 1H), 7.58-7.52 (m, 1H), 7.43 (s, 1H), 7.32 (s, 1H), 7.22 (s, 1H), 6.81 (s, 1H), 6.11-5.99 (m, 2H), 5.82-5.68 (m, 1H), 5.48-5.38 (m, 1H), 5.10-4.94 (m, 3H), 4.27-4.19 (m, 1H), 4.07-3.92 (m, J=5.0 Hz, 3H), 3.87-3.76 (m, 1H), 3.69 (s, 3H), 3.06-2.97 (m, 1H), 2.79-2.68 (m, 1H), 2.47 (s, 3H), 2.42-2.34 (m, 1H), 2.30 (s, 3H), 2.26 (s, 3H), 2.25-2.18 (m, 1H), 2.02-1.95 (m, 2H), 1.86-1.75 (m, 2H), 1.29 (s, 3H), 1.27 (s, 9H), 1.16 (d, J=6.3 Hz, 3H); LCMS (ESI, M+1): 694.35.
Reaction SMILES: [CH3:1]O.C([O:7][CH2:8][CH2:9][CH2:10]C)CCC.[CH2:12]([OH:16])[CH:13]([CH3:15])[CH3:14]>>[C:12]([O:7][CH2:8][CH:9]([CH3:10])[CH3:1])(=[O:16])[C:13]([CH3:15])=[CH2:14]
Reactant: CO
Reactant: CCCCOCCCC
Reactant: CC(C)CO
Product: C=C(C)C(=O)OCC(C)C

Procedure:
The resulting reactor effluent of 6.9 kg/h had the following composition: 67.3% by weight of i-BuMA, 12.0% by weight of i-BuOH, 19.4% by weight of MMA, 0.8% by weight of MeOH and 0.5% by weight of by-products. The space-time yield of the reactor based on i-BuMA was therefore 516 kg/h/m3. Owing to virtually complete removal of low-boiling components relative to i-BuMA, the bottom effluent of the low boiler distillation column was a crude ester (5.0 kg/h) which already contained >99.5% by weight of i-BuMA and also all of the catalyst and the stabilizer. The yield of i-BuOH based on the overall process was therefore virtually 100%. The yield of MMA based on the overall process minus the MMA loss via the MMA/MeOH azeotrope calculated beforehand was likewise virtually 100%. At an evaporation ratio (ratio of vapour stream to feed stream) in the first, larger thin-film evaporator of about 90%, 4.5 kg/h of pure i-BuMA are finally obtained at the top of the high boiler distillation column and have the following composition: >99.9% by weight of i-BuMA, <150 ppm of i-BuOH, <10 ppm of MMA, 0 ppm of di-1-butyl ether, colour number (apha)<0.2. At an evaporation ratio in the second, smaller thin-film evaporator of about 90%, the overall discharge of the process (catalyst, stabilizer, high-boiling by-products, i-BuMA) is 0.05 kg/h and the yield loss of i-BuMA based on the pure i-BuMA produced is <0.5% by weight.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C@H:12]([C:14]([OH:16])=[O:15])[CH3:13])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.COC1C=C([CH:23]=[C:24](OC)[CH:25]=1)N.Cl[CH:29](C)C(O)=O.Cl[Si](C)(C)C>C(O)C(C)C>[CH2:29]([O:15][C:14](=[O:16])[C@H:12]([CH3:13])[NH:11][C:5]1[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH:24]([CH3:23])[CH3:25]
Reactant: COc1cc(N)cc(OC)c1
Reactant: COc1cc(N[C@@H](C)C(=O)O)cc(OC)c1
Reactant: CC(Cl)C(=O)O
Agent: C[Si](C)(C)Cl
Solvent: CC(C)CO
Product: COc1cc(N[C@@H](C)C(=O)OCC(C)C)cc(OC)c1

Procedure:
N-(3,5-dimethoxyphenyl)alanine (crude, 454 mg) (prepared according to the procedure described in U.S. Pat. No. 3,598,859 using 3,5-dimethoxyaniline (Aldrich) and 2-chloropropionic acid (Aldrich)) was treated in dry iso-butanol (10 mL) with 0.1 mL of chlorotrimethylsilane and the reaction mixture refluxed overnight. The excess alcohol was removed at reduced pressure and the residue dissolved in ethyl acetate. The ethyl acetate solution was washed with saturated aqueous NaHCO3, dried with Na2SO4 and the solvent removed to provide the title compound. The reaction was monitored by silica gel tlc (Rf=0.3 in 20% EtOAc/hexanes). Purification was by preparative thin layer chromatography using 20% EtOAc/hexanes as the eluant.
Reaction SMILES: [CH2:1]([N:5]=[C:6]=[O:7])[CH:2]([CH3:4])[CH3:3].Cl.Cl.C([O:13][C@@H:14]1[C@@H:55]([O:56]C(=O)C)[C@H:54]([O:60]C(=O)C)[C@@H:53]([CH2:64][O:65]C(=O)C)[O:52][C@H:15]1[O:16][C:17]1[C:21]([CH2:22][C:23]2[CH:28]=[CH:27][C:26](/[CH:29]=[CH:30]/[CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][CH2:36][C:35]4([CH2:43][CH2:42][N:41]([C:44](=[O:47])[CH2:45][NH2:46])[CH2:40][CH2:39]4)[CH2:34]3)=[CH:25][C:24]=2[CH3:48])=[C:20]([CH:49]([CH3:51])[CH3:50])[NH:19][N:18]=1)(=O)C.C(N(C(C)C)CC)(C)C>ClCCl>[C@@H:15]1([O:16][C:17]2[C:21]([CH2:22][C:23]3[CH:28]=[CH:27][C:26](/[CH:29]=[CH:30]/[CH2:31][CH2:32][N:33]4[CH2:38][CH2:37][CH2:36][C:35]5([CH2:43][CH2:42][N:41]([C:44](=[O:47])[CH2:45][NH:46][C:6]([NH:5][CH2:1][CH:2]([CH3:4])[CH3:3])=[O:7])[CH2:40][CH2:39]5)[CH2:34]4)=[CH:25][C:24]=3[CH3:48])=[C:20]([CH:49]([CH3:51])[CH3:50])[NH:19][N:18]=2)[O:52][C@H:53]([CH2:64][OH:65])[C@@H:54]([OH:60])[C@H:55]([OH:56])[C@H:14]1[OH:13]
Reactant: CC(C)CN=C=O
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/CCN3CCCC4(CCN(C(=O)CN)CC4)C3)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(/C=C/CCN2CCCC3(CCN(C(=O)CNC(=O)NCC(C)C)CC3)C2)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C
Reaction time: 0.5 h
Yield: 46.2 %

Procedure:
Add isobutyl isocyanate (77 mg, 0.78 mmol) to a solution of 4-(4-{(1E)-4-[9-(aminoacetyl)-2,9-diazaspiro[5.5]undec-2-yl]but-1-en-1-yl]-2-methylbenzyl}-5-(propan-2-yl)-1H-pyrazol-3-yl 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranoside dihydrochloride (350 mg, 0.39 mmol) and diisopropylethylamine (302 mg, 2.34 mmol) in dichloromethane (1.0 mL). After 30 min at room temperature, concentrate to dryness under the reduced pressure. Treat the residue with 2.0 M NH3/methanol (1.0 mL) for 3 hours at room temperature, remove the solvent under the reduced pressure. Purify the resulting residue by preparative HPLC method: high pH, 29% B for 4 min, 29-44% B for 5 min @ 85 mL/min using a 30×75 mm, 5 um C18XBridge ODB column, solvent A—H2O w NH4HCO3 @ pH 10, solvent B—acetonitrile to yield the title compound as solid (134 mg, 0.18 mmol). MS (m/z): 755.2 (M+1), 753.2 (M−1).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH2:26][OH:27].C(O)CC>O.C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][CH2:25][CH2:26][OH:27])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CCCO
Product: OCCCN1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1, 2benzisoxazole (10.0 g, 0.045 mol), K2CO3 (10.0 g), 3-bromo-1-propanol (7.3 g, propanol (7.3 g, 0.046 mol) and acetonitrile (200 ml) was refluxed for 3 hours. The reaction was poured into H2O and 7.1 g of a beige solid was collected. The filtrate was extracted with dichloromethane, and after concentration an additional 6.7 g of crude solid was harvested. The solids were combined and triturated with refluxing ethyl acetate to afford 8.0 g of 6-fluoro-3-[1-(3- hydroxypropyl)-4-piperidinyl]-1,2-benzisoxazole as an off-white solid. A sample (4.0 g) was recrystallized from ethanol-water (with charcoal treatment) to yield 2.4 g (40%) of the alcohol as a white solid, m.p.=140°-142° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([CH3:10])[CH:3]=1.C[C:12]1([CH3:20])[O:19][C:17](=[O:18])[CH2:16]C(=O)O1.N1CCCC1C(O)=O.[CH2:29]([S:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[C:37]2[C:41]=1[NH:40][CH:39]=[CH:38]2)[CH3:30]>C(#N)C.[Cu].C(O)C.N1C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([C:38]2[C:37]3[C:41](=[C:33]([CH2:32][S:31][CH2:29][CH3:30])[CH:34]=[CH:35][CH:36]=3)[NH:40][CH:39]=2)[CH2:16][C:17]([O:19][CH2:12][CH3:20])=[O:18])=[C:4]([CH3:10])[CH:3]=1
Reactant: CCSCc1cccc2cc[nH]c12
Reactant: Cc1cc(Cl)ccc1C=O
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: [Cu]
Agent: O=C(O)C1CCCN1
Solvent: CC#N
Solvent: c1ccncc1
Solvent: CCO
Product: CCOC(=O)CC(c1ccc(Cl)cc1C)c1c[nH]c2c(CSCC)cccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.5 %

Procedure:
849 mg (5.49 mmol) of 4-chloro-2-methylbenzaldehyde, 791 mg (5.49 mmol) of Meldrum's acid and 30.1 mg (0.26 mmol) of D,L-proline were added to a solution of 1.00 g (5.23 mmol) of the compound from Example 10A in 44 ml of acetonitrile. The reaction mixture was stirred at RT overnight. It was concentrated, the residue was taken up in diethyl ether, and a precipitate was separated off and discarded. Concentration resulted in 2.70 g of a crude product, of which 2.40 g were introduced into 9.5 ml of pyridine and 2.5 ml of ethanol, and 0.9 mg (14 μmol) of copper powder was added. The reaction mixture was heated under reflux for 1 h. It was concentrated, and the residue was taken up in ethyl acetate, washed with 1N hydrochloric acid, dried over magnesium sulfate, filtered through silica gel and concentrated. 950 mg of a crude product were obtained and were introduced into 14.2 ml of pyridine and 3.7 ml of ethanol, and 1.3 mg (21 μmol) of copper powder were added. The reaction mixture was heated under reflux for 1 h. It was concentrated, and the residue was taken up in ethyl acetate, washed with 1N hydrochloric acid, dried over magnesium sulfate, filtered through silica gel and concentrated. The crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient) to result in 620 mg of the title compound.
Reaction SMILES: [CH2:1]([C:8]1[NH:9][C:10](=[O:26])[N:11]([CH:13]2[CH2:18][CH2:17][N:16](CC3C=CC=CC=3)[CH2:15][CH2:14]2)[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd].CO.C(O)(=O)C>[CH2:1]([C:8]1[NH:9][C:10](=[O:26])[N:11]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1[nH]c(Cc2ccccc2)cn1C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: O=c1[nH]c(Cc2ccccc2)cn1C1CCNCC1
Reaction time: 16 h

Procedure:
10% Palladium on carbon (50 mg) was added to a solution of 4-benzyl-1-(1-benzylpiperidin-4-yl)-1,3-dihydro-2H-imidazol-2-one (100 mg, 0.287 mmol) in methanol (7.5 mL) and acetic acid (7.5 mL). The reaction vessel was evacuated and back-filled with nitrogen (3×), then back-filled with hydrogen (1 atm). After 16 h, the mixture was filtered and concentrated to give the title compound. MS 258.1 (M+1)
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=[O:4].[CH2:13](O)[CH2:14][OH:15].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1>[Br:1][CH2:2][C:3]1([C:5]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=2)[O:15][CH2:14][CH2:13][O:4]1
Reactant: OCCO
Reactant: COc1ccc(C(=O)CBr)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: COc1ccc(C2(CBr)OCCO2)cc1
Reaction time: 5 h
Yield: 98.9 %

Procedure:
2-bromo-1-(4'-methoxy-phenyl)-ethanone (20 g, 87 mmol), ethylene glycol (54 g, 870 mmol), para-toluenesulfonic acid hydrate (1.7 g, 8.7 mmol) and benzene (50 ml) are heated and stirred together for 5 h in a flask beneath a Dean-Stark trap. The reaction mixture is added dropwise to a well stirred saturated sodium carbonate solution (0.4 l) and extracted with ethyl ether (3×70 ml). The combined organic extract is washed with a 2% sodium hydrogen carbonate solution, dried (Na2CO3) and filtered. The solvent is evaporated under reduced pressure to give 2-bromomethyl-2-(4'-methoxy-phenyl)-1,3-dioxolane (23.5 g, 86 mmol; yield: 99%).
Reaction SMILES: Br[C:2]1[C:7]2[CH:8]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[O:10][C:6]=2[C:5]([O:15][CH3:16])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[O:43]1[CH2:47]CCC1.[OH2:48]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:14][S:11]([C:9]1[O:10][C:6]2[C:7](=[C:2]([C:47]([OH:43])=[O:48])[CH:3]=[CH:4][C:5]=2[O:15][CH3:16])[CH:8]=1)(=[O:13])=[O:12]
Reactant: O
Reactant: COc1ccc(Br)c2cc(S(C)(=O)=O)oc12
Reactant: C1CCOC1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)O)c2cc(S(C)(=O)=O)oc12

Procedure:
Prepared from 4-bromo-2-methanesulfonyl-7-methoxybenzofuran (1.64 g), triphenylphosphine (0.49 g), bis(triphenylphosphine)palladium (II) chloride (0.25 g) and triethylamine (7.2 ml) in tetrahydrofuran/water (68 ml/35 ml). The title compound was obtained as a white solid (1.23 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[C:11]1[CH:10]=[C:9]([C:17]([OH:19])=[O:18])[CH:8]=[CH:7][C:6]=1[O:5]2.S(=O)(=O)(O)O.[CH3:25]O>>[CH3:25][O:18][C:17]([C:9]1[CH:8]=[CH:7][C:6]2[O:5][C:4]3[C:13](=[CH:14][CH:15]=[C:2]([OH:1])[CH:3]=3)[C:12](=[O:16])[C:11]=2[CH:10]=1)=[O:19]
Reactant: O=C(O)c1ccc2oc3cc(O)ccc3c(=O)c2c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc2oc3cc(O)ccc3c(=O)c2c1
Temperature: 25 °C
Yield: 97 %

Procedure:
A mixture of 6-hydroxy-9-oxo-9H-xanthene-2-carboxylic acid (Gapinski, D. M. "Leukotriene Antagonists", U.S. Pat. No. 4,996,230, which is incorporated herein by reference, 1991; 10.6 g, 41.4 mmol) and concentrated sulfuric acid (1 mL) in methanol (100 mL) was refluxed for 48 hours. The mixture was cooled to room temperature and the resulting precipitate collected by vacuum filtration. The filtrate was concentrated in vacuo and diluted with water, which resulted in additional precipitate. This was collected and combined with the first fraction to provide 10.8 g (97%) of the title product: 1H-NMR (DMSO-d6) 11.03 (s, 1H, --OH), 8.56 (d, J=2 Hz, 1H), 8.18 (dd, J=9, 2 Hz, 1H), 7.96 (d, J=9 Hz, 1H), 7.59 (d, J=9 Hz, 1H), 6.88 (dd, J=9, 2 Hz, 1H), 6.81 (d, J=2 Hz, 1H), 3.86 (s, 3H); MS-FAB (m/e) 271 (p+1, 6); IR (KBr, cm-1) 3093 (b), 1727, 1604, 1459, 1282, 1120, 767. Anal. (C15H10O5 :
Reaction SMILES: Br[C:2]1[C:7]([N:8](COC)[S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:25])=[CH:4][N:3]=1.[C:26]1([OH:32])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([S:9]([NH:8][C:7]2[C:2]([O:32][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:3][CH:4]=[C:5]([Cl:25])[CH:6]=2)(=[O:11])=[O:10])=[CH:13][CH:14]=1)([CH3:20])([CH3:21])[CH3:19]
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(C(C)(C)C)cc1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(Cl)cnc2Oc2ccccc2)cc1
Temperature: 150 °C
Reaction time: 8 h

Procedure:
A 5 mL pear-shaped flask was charged with N-(2-bromo-5-chloro-pyridin-3-yl)-4-tert-butyl-N-methoxymethyl-benzenesulfonamide (134 mg, 0.30 mmol), phenol (85 mg, 0.90 mmol), potassium carbonate (250 mg, 18.0 mmol), and DMA (0.9 mL). The heterogeneous solution was heated to 150° C. and stirred overnight. The crude reaction mixture was subsequently purified via reverse phase HPLC (Column: Varian Dynamax 250×21.4 mm Microsorb100-8 C18, 0.1% TFA/H2O (Eluent A): 0.1% TFA/MeCN (Eluent B)): 1H NMR (400 MHz, CDCl3) δ 7.95 (d, 1H), 7.75 (d, 1H), 7.72 (d, 2H), 7.48 (d, 2H), 7.28-7.34 (m, 2H), 7.17-7.21 (m, 1H), 7.05 (bs, 1H), 6.71-6.76 (m, 2H), 1.34 (s, 9H); MS (ES) M+H expect 417.1, found 417.4.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>>[C:1]([N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)(=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: C1COCCN1
Product: CCCCCCC/C=C/C(=O)N1CCOCC1

Procedure:
The same procedures as in Example 1 were carried out using (E)-2-decenoic acid and morpholine as starting raw materials, to produce an intended compound.
Reaction SMILES: [O:1]([CH2:19][CH2:20][C:21]1([CH2:27][CH2:28]O)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[Si:2]([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CC(C)(O)[C:32]#[N:33].C(P(CCCC)CCCC)CCC>C1C=CC=CC=1>[O:1]([CH2:19][CH2:20][C:21]1([CH2:27][CH2:28][C:32]#[N:33])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[Si:2]([C:15]([CH3:18])([CH3:16])[CH3:17])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(O)C#N
Reactant: CC(C)(C)[Si](OCCC1(CCO)CCCCC1)(c1ccccc1)c1ccccc1
Agent: CCCCP(CCCC)CCCC
Solvent: c1ccccc1
Product: CC(C)(C)[Si](OCCC1(CCC#N)CCCCC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of [2-[1-[2-(tert-butyldiphenylsiloxy)ethyl]cyclohexyl]ethanol (1.25 g) dissolved in benzene (15 mL) were added acetone cyanohydrin (0.40 mL), tri-n-butylphosphine (1.08 mL) and 1,1-azobis(N,N-dimethylformamide) (754 mg). The solution was stirred at room temperature for 18 hours. The solvent was distilled off under reduced pressure, ethyl acetate was added and insolubles were filtered off. The solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography (silica gel, hexane:ethyl acetate=5:1) to give the title compound (1.07 g).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9](Cl)[N:8]=2)=[CH:4][CH:3]=1.[NH2:14][CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][NH:19][C:18]1=[O:22]>C(O)(C)C>[Br:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:14][CH2:15][CH2:16][N:17]3[CH2:21][CH2:20][NH:19][C:18]3=[O:22])[N:8]=2)=[CH:4][CH:3]=1
Reactant: NCCN1CCNC1=O
Reactant: Clc1nccc(-c2ccc(Br)s2)n1
Solvent: CC(C)O
Product: O=C1NCCN1CCNc1nccc(-c2ccc(Br)s2)n1
Temperature: 25 °C
Yield: 67.3 %

Procedure:
A mixture of 4-(5-bromothiophen-2-yl)-2-chloropyrimidine (1.0 g, 3.63 mmol), 1-(2-aminoethyl)imidazolidin-2-one (0.47 g, 3.63 mmol) and triethylame (0.44 g, 4.36 mmol) in isopropanol (25 mL) was refluxed for 30 h. After cooling down to rt the precipitate was filtered and washed with methanol (5 mL) and dried to give the title compound as a yellow solid (0.9 g, 68%). MS (M+H)+ 368/370.