Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:42])[CH2:10][C@@H:11]([N:25]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:32][CH:31]=2)=[CH:26]1)[C:12]([NH:14][C@@H:15]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:16][OH:17])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:43](OC(=O)C[C@@H](NC(OC(C)(C)C)=O)C(N[C@@H](CC1C=CC=CC=1)COC)=O)C1C=CC=CC=1.C1(C2C=CC=CC=2)C=CC(C2CC(OC)OC2OC)=CC=1>CC(O)=O>[CH2:1]([O:8][C:9](=[O:42])[CH2:10][C@@H:11]([N:25]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)=[CH:32][CH:31]=2)=[CH:26]1)[C:12]([NH:14][C@@H:15]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:16][O:17][CH3:43])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(C[C@H](C(=O)N[C@H](CO)Cc1ccccc1)n1ccc(-c2ccc(-c3ccccc3)cc2)c1)OCc1ccccc1
Reactant: COC[C@H](Cc1ccccc1)NC(=O)[C@@H](CC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: COC1CC(c2ccc(-c3ccccc3)cc2)C(OC)O1
Solvent: CC(=O)O
Product: COC[C@H](Cc1ccccc1)NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccc(-c3ccccc3)cc2)c1
Yield: 54 %

Procedure:
According to the proecdure described in Example 1(a) for the preparation of N-(1(S)-benzyl-2-hydroxyethyl)-3(R)-[3-(biphenyl-4-yl)-1H-pyrrol-1-yl]succinamic acid benzyl ester, N-(1(S)-benzyl-2-methoxy-ethyl)-3(R)-(t-butoxycarbonylamino)succinamic acid benzyl ester was deprotected and the crude salt condensed in HOAc with 3-(biphenyl-4-yl)-2,5-dimethoxytetrahydrofuran (prepared as described in Example 1(a)) to provide in 54% yield N-(1(S)-benzyl-2-methoxyethyl)-3(R)-[3-(biphenyl-4-yl)-1H-pyrrol-1-yl]succinamic acid benzyl ester as an oil, which was used without further purification. 1H NMR (CDCl3): ∂ 7.65-7.62 (m, 6H), 7.57 (t, 2H, J=7.4Hz), 7.48-7.16 (m, 9H), 7.10 (d, 2H, J=7.7Hz), 6.98 (s, 1H), 6.69 (s, 1H), 6.57 (s, 1H), 5.78 (d, 1H, J=8.5 Hz), 5.10 (s, 2H), 5.01 (dd, 1H, J=5.5, 9.2 Hz), 4.20-4.16 (m, 1H), 3.43 (dd, 1H, J=5.3, 16.7 Hz), 3.28-3.15 (m, 5H), 3.02 (dd, 1H, J=9.2, 16.6 Hz), 2.76 (d, 2H, J=7.4 Hz); IR: 3315, 3063, 3030, 2930, 2891, 1738, 1682, 1526, 1495, 1204, 1167, 764, 737, 698 cm−1. HRFABMS: Calculated for C37H36N2O4 (M+H+): 572.2675. Found: 572.2674.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[C:19]([O:24][CH3:25])[CH:18]=3)[C:15]([S:26][CH2:27][C:28]3[CH:29]=[CH:30][C:31]([CH2:38][CH2:39][CH2:40]O)=[C:32]([CH:37]=3)[C:33]([O:35][CH3:36])=[O:34])=[N:14][CH:13]=2)([CH3:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:42][C:43](=[N:52]C(=O)OC(C)(C)C)[NH:44]C(OC(C)(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[C:19]([O:24][CH3:25])[CH:18]=3)[C:15]([S:26][CH2:27][C:28]3[CH:29]=[CH:30][C:31]([CH2:38][CH2:39][CH2:40][NH:44][C:43]([NH2:52])=[NH:42])=[C:32]([CH:37]=3)[C:33]([O:35][CH3:36])=[O:34])=[N:14][CH:13]=2)([CH3:10])[CH3:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)c1cc(CSc2ncc(C(C)(C)c3ccc(Cl)c(Cl)c3)n2-c2ccc(F)c(OC)c2)ccc1CCCO
Reactant: CC(C)(C)OC(=O)N=C(N)NC(=O)OC(C)(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(CSc2ncc(C(C)(C)c3ccc(Cl)c(Cl)c3)n2-c2ccc(F)c(OC)c2)ccc1CCCNC(=N)N
Reaction time: 16 h
Yield: 77.9 %

Procedure:
To a mixture of methyl 5-((5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluoro-3-methoxyphenyl)-1H-imidazol-2-ylthio)methyl)-2-(3-hydroxypropyl)benzoate (90 mg, 0.15 mmol, 1.0 eq), tert-butyl amino(tert-butoxycarbonylamino)methylenecarbamate (76 mg, 0.29 mmol, 2.0 eq) and triphenylphosphine (59 mg, 0.22 mmol, 1.5 eq) in tetrahydrofuran (0.7 mL) was added diisopropylazodicarboxylate (0.04 mL, 0.22 mmol, 1.5 eq). After stirring for 16 h, the reaction mixture was directly poured onto silica gel and purified (0 to 75% ethyl acetate/hexanes). This product was treated with 1:2 trifluoroacetic acid/dichloromethane (2 mL) at room temperature for 16 h. The reaction mixture was concentrated to provide 77 mg (70%) of methyl 5-((5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluoro-3-methoxyphenyl)-1H-imidazol-2-ylthio)methyl)-2-(3-guanidinopropyl)benzoate: MS (EI) m/z 759 [(M-Boc)H+].
Reaction SMILES: [C:1]([O:4][C:5]1[CH:22]=[CH:21][C:20]2[C@@H:19]3[C@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C:14](=[O:23])[CH2:13][CH2:12]4)[C@H:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30](=[O:32])[CH3:31])[CH2:8][C:7]=2[CH:6]=1)(=[O:3])[CH3:2].[CH2:33](O)[CH2:34][OH:35].C(OC)(OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[C:1]([O:4][C:5]1[CH:22]=[CH:21][C:20]2[C@@H:19]3[C@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C:14]3([O:35][CH2:34][CH2:33][O:23]3)[CH2:13][CH2:12]4)[C@H:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30](=[O:32])[CH3:31])[CH2:8][C:7]=2[CH:6]=1)(=[O:3])[CH3:2]
Reactant: OCCO
Reactant: CC(=O)OCCCCC[C@@H]1Cc2cc(OC(C)=O)ccc2[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(OC)OC
Solvent: ClCCl
Product: CC(=O)OCCCCC[C@@H]1Cc2cc(OC(C)=O)ccc2[C@H]2CC[C@@]3(C)[C@@H](CCC34OCCO4)[C@H]12

Procedure:
A solution of 63.9 g of 3-acetoxy-7α-(5-acetoxypentyl)-estra-1,3,5(10)-trien-17-one in 460 ml of dichloromethane is stirred with 460 ml of ethylene glycol, 155 ml of trimethyl orthoformate and 1.2 g of para-toluenesulfonic acid for 3 hours at a bath temperature of 50° C. Then, it is diluted with dichloromethane, washed with sodium bicarbonate and common salt solution and dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with hexane/ethyl acetate. 63.2 g of 3-acetoxy-7α-(5-acetoxypentyl)- 17,17-ethylenedioxy-estra- 1,3,5(10)-triene is obtained as oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7](O)=[O:8])[C:5]([NH:11][CH2:12][CH3:13])=[CH:4][CH:3]=1.[C:14]([OH:17])(=O)[CH3:15]>C(OC(=O)C)(=O)C>[Cl:1][C:2]1[CH:10]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:11]([CH2:12][CH3:13])[C:14](=[O:17])[CH:15]=[C:7]2[OH:8]
Reactant: CCNc1ccc(Cl)cc1C(=O)O
Reactant: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CCn1c(=O)cc(O)c2cc(Cl)ccc21
Temperature: 0 °C

Procedure:
5-Chloro-N-ethyl anthranilic acid (13.1g; 0.006 mole) in acetic acid (35 ml) and acetic anhydride (35 ml) was refluxed for 24 hours. The cooled mixture was poured into ice-water and basified to pH 14. The precipitated red oil was separated and the supernatant acidified to pH 5 to give the title compound as a white crystalline solid. m.p. (EtOH) 305°-8°C (Found C, 58.80; H, 4.64; N, 6.49; Cl, 15.95; C11H10CINO2 requires; C, 59.07; H, 4.51; N, 6.26; Cl, 15.85%).
Reaction SMILES: [F:1][C:2]([F:16])([C:12]([F:15])([F:14])[F:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11].N1C=CC=CC=1.[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>O>[S:29]([C:26]1[CH:27]=[CH:28][C:23]([CH3:33])=[CH:24][CH:25]=1)([O:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]([F:16])([F:1])[C:12]([F:13])([F:14])[F:15])(=[O:31])=[O:30]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCCCCCCCC(F)(F)C(F)(F)F
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCCCCCCC(F)(F)C(F)(F)F)cc1
Reaction time: 2 h

Procedure:
1.0 g of 9,9,10,10,10-pentafluorodecan-1-ol is dissolved in 8 ml of abs. pyridine, 985 mg of p-toluenesulphonyl chloride are added at 0° C. and the mixture is stirred in the cold for 2 hours. The reaction mixture is then added to water, extracted 3 times with ether, dried over magnesium sulphate and concentrated in vacuo. Preparative column chromatography on silica gel using a hexane-ethyl acetate gradient leads to 1.5 g of 9,9,10,10,10-penta-fluorodecyl tosylate as an oil.
Reaction SMILES: [C:1](OC)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([OH:18])[CH3:17]>C1(C)C=CC=CC=1>[C:1]([O:18][CH:16]([CH2:15][CH2:14][CH2:13][CH2:12][NH2:11])[CH3:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccccc1
Reactant: CC(O)CCCCN
Solvent: Cc1ccccc1
Product: CC(CCCCN)OC(=O)c1ccccc1
Yield: 66 %

Procedure:
In an argon atmosphere, a mixture of methyl benzoate (1.0 mmol), 6-aminohexan-2-ol (1.2 mmol), Zn4(OCOCF3)6O (1.25 mol % in terms of mole number) and toluene (1.7 ml) was heated to reflux for 46 hours, and as a result, 6-amino-2-hexyl benzoate was obtained at a yield of 66%. The yield of 6-benzoylamino-2-hexyl benzoate was 21%.
Reaction SMILES: [CH3:1][C@H:2]([CH2:8][CH2:9][CH3:10])[CH2:3][CH2:4][C:5]([OH:7])=O.C(N(CC)CC)C.CC(C)(C)C(Cl)=O.[Li+].[Cl-].[CH3:27][C@@H:28]1[C@H:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:31][C:30](=[O:39])[NH:29]1>C1COCC1>[CH3:27][C@@H:28]1[C@H:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:31][C:30](=[O:39])[N:29]1[C:5](=[O:7])[CH2:4][CH2:3][C@H:2]([CH3:1])[CH2:8][CH2:9][CH3:10]
Reactant: C[C@H]1NC(=O)O[C@H]1c1ccccc1
Reactant: CCC[C@@H](C)CCC(=O)O
Agent: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC[C@@H](C)CCC(=O)N1C(=O)O[C@@H](c2ccccc2)[C@H]1C
Temperature: 25 °C

Procedure:
To (R)-4-methyl-heptanoic acid (19 g, 0.132 mol) and triethylamine (49.9 g, 0.494 mol) in THF (500 mL) at 0° C. was added trimethylacetylchloride (20 g, 0.17 mol). After 1 hour LiCl (7.1 g, 0.17 mol) was added followed by (4R,5S)-(+)-4-methyl-5-phenyl-2-oxazolidinone) 3 (30 g, 0.17 mol). The mixture was warmed to room temperature and after 16 hours the filtrate was removed by filtration and the solution concentrated under reduced pressure. Flash chromatography (7:1 hexane/EtOAc) gave (4R,5S)-4-methyl-3-((R)-4-methyl-heptanoyl)-5-phenyl-oxazolidin-2-one as an oil. 31.5 g; 79%. [a]D=+5.5 (c 1 in CHCl3). MS, m/z (relative intensity): 304 [M+H, 100%].
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]3[O:14][CH2:13][O:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][C:3]=1C(O)=O.N1C2C(=CC=CC=2)C=CC=1>CCOCC>[CH2:13]1[O:14][C:8]2[CH:7]=[C:6]3[C:11]([C:2]([OH:1])=[CH:3][CH:4]=[N:5]3)=[CH:10][C:9]=2[O:12]1
Reactant: O=C(O)c1cnc2cc3c(cc2c1O)OCO3
Solvent: CCOCC
Solvent: c1ccc2ncccc2c1
Product: Oc1ccnc2cc3c(cc12)OCO3
Temperature: 25 °C

Procedure:
A suspension of 50 g. of 4-hydroxy-6,7-methylenedioxyquinoline-3-carboxylic acid in 500 ml. of freshly distilled quinoline was heated at 200° until the evolution of gas ceased. The reaction mixture was cooled to room temperature, diluted with an equal amount of ether and kept cool overnight. The precipitated brown solid (51.4 g., m.p. 254°-267°) was collected by filtration and dissolved in refluxing ethanol. The insoluble material was removed and the ethanol solution was reduced to one-third of its volume. The solution was diluted with an equal amount of ether. On cooling, 31.1 g. of 6,7-methylenedioxy-4-quinolinol separated, m.p. 280°-282°. Recrystallization (2x) from hot water yielded analytically pure 6,7-methylenedioxy-4-quinolinol as a pale yellow solid, m.p. 288°-289° .
Reaction SMILES: [CH3:1][N:2]([CH3:27])[S:3]([N:6]1[CH:10]=[C:9]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=2[F:19])[N:8]=[C:7]1[Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])(=[O:5])=[O:4].[CH:28]([N-]C(C)C)(C)C.[Li+].CI.O>O1CCCC1>[CH3:27][N:2]([CH3:1])[S:3]([N:6]1[CH:10]=[C:9]([CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=2[F:19])[CH3:28])[N:8]=[C:7]1[Si:20]([C:23]([CH3:24])([CH3:26])[CH3:25])([CH3:21])[CH3:22])(=[O:5])=[O:4]
Reactant: CC(C)[N-]C(C)C
Reactant: CN(C)S(=O)(=O)n1cc(Cc2cccc(F)c2F)nc1[Si](C)(C)C(C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: O
Solvent: C1CCOC1
Product: CC(c1cn(S(=O)(=O)N(C)C)c([Si](C)(C)C(C)(C)C)n1)c1cccc(F)c1F
Temperature: -75 °C
Reaction time: 1 h

Procedure:
An amount of 2.9 g (7.0 mmol) of 2-(tert-butyl-dimethyl-silanyl)-4-(2,3-difluoro-benzyl)-imidazole-1-sulfonic acid dimethylamide was dissolved in 30 ml tetrahydrofuran and added drop-wise to a freshly prepared solution of lithium diisopropylamide in tetrahydrofuran (from 6.54 ml 1.6M BuLi and 1.06 g diisopropylamine). After stirring for 1 h at −75° C., 1.14 g (8.0 mmol) methyl iodide was added, and stirring was continued overnight at ambient temperature. Water was added to quench the reaction. The aqueous phase was extracted with ethyl acetate (3 times) and the combined organic extracts were dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (silica gel, hexanes/ethyl acetate 4:1) to yield 2.47 g of rac-2-(tert-butyl-dimethyl-silanyl)-4-[1-(2,3-difluoro-phenyl)-ethyl]-imidazole-1-sulfonic acid dimethylamide (MS (ISP): 430.3 ((M+H)+.), light yellow oil). This material was separated by chiral column chromatography (Chiral OD, isopropanol/heptane=2:98) to yield 0.785 g (26%) of (+)-2-(tert-butyl-dimethyl-silanyl)-4-[1-(2,3-difluoro-phenyl)-ethyl]-imidazole-1-sulfonic acid dimethylamide and 0.946 g (32%) of (+)-2-(tert-butyl-dimethyl-silanyl)-4-[1-(2,3-difluoro-phenyl)-ethyl]-imidazole-1-sulfonic acid dimethylamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:16][C:10]3([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[CH2:9][C:8](=[O:17])[C:7]=2[CH:18]=1.C(=O)(O)[O-].[Na+].Cl.Cl[CH2:26][CH2:27][NH2:28].Cl[C:30]1[N:35]([CH3:36])[C:34](=[O:37])[N:33]([CH3:38])[C:32](=[O:39])[CH:31]=1>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:16][C:10]3([CH2:11][CH2:12][N:13]([NH:28][CH2:27][CH2:26][C:30]4[N:35]([CH3:36])[C:34](=[O:37])[N:33]([CH3:38])[C:32](=[O:39])[CH:31]=4)[CH2:14][CH2:15]3)[CH2:9][C:8](=[O:17])[C:7]=2[CH:18]=1
Reactant: NCCCl
Reactant: COc1ccc2c(c1)C(=O)CC1(CCNCC1)O2
Reactant: Cn1c(Cl)cc(=O)n(C)c1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc2c(c1)C(=O)CC1(CCN(NCCc3cc(=O)n(C)c(=O)n3C)CC1)O2
Reaction time: 28 h
Yield: 10.5 %

Procedure:
A suspension of 3,4-dihydro-6-methoxyspiro[(2H)-1-benzopyran-2,4'-piperidin]-4-one (0.284 g, 1 mmol) and sodium bicarbonate (0.42 g, 5 mmol) in acetonitrile was heated at reflux for 1 hour, 2-chloro ethylamine hydrochloride (0.116 g, 1 mmol) was added the solution was heated at reflux for 17 hours, 6-chloro-1,3-dimethyluracil (0.175 g, 1 mmol) and sodium bicarbonate (0.16 g, 2 mmol) were added. Refluxing was continued for 28 hours. After cooling, the reaction mixture was concentrated in vacuo to dryness. The residue was partitioned between chloroform and water. The chloroform solution was washed with water and dried over sodium sulfate. The resulting residue was chromatographed through a pressure column (silica gel) eluting with 5% methanol/chloroform to give the title compound (45 mg, 10.5% yield), mp 235°-238° C. dec.
Reaction SMILES: C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:15]1[CH:32]=[CH:31][C:18]([O:19][CH2:20][CH:21]([OH:30])[CH2:22][CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[CH:17][CH:16]=1.[Cl:33][C:34]1[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:35]=1B(O)O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[Cl:33][C:34]1[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:35]=1[C:15]1[CH:32]=[CH:31][C:18]([O:19][CH2:20][CH:21]([OH:30])[CH2:22][CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[CH:17][CH:16]=1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: OC(CCc1cccnc1)COc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: OC(CCc1cccnc1)COc1ccc(-c2ccc(Cl)cc2Cl)cc1
Temperature: 120 °C
Yield: 78.1 %

Procedure:
Prepared according to the method described in Example 33a) from toluene (3 ml), aqueous sodium carbonate (2 M, 1.4 ml), (±)-1-(4-bromophenoxy)-4-(3-pyridyl)-2-butanol (0.51 g), ethanol (0.8 ml), 2,4-dichlorobenzeneboronic acid (0.32 g) and tetrakis(triphenylphosphine)palladium(0) (75 mg) with heating at 120° C. for 4 hours. The residue obtained after work up was purified by column chromatography over silica eluting with dichloromethane then ether then ethyl acetate to give (±)-1-(2',4'-dichlorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butanol (0.48 g). A sample that had been purified by reverse phase HPLC was converted to the oxalate salt by treatment of the parent compound in ether with a saturated ethereal solution of oxalic acid. The precipitated salt was filtered to give the title compound (0.23 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]3[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.C(OCC)(=O)C.O>C(OCC)(=O)C>[CH:21]1([C:18]2[CH:19]=[CH:20][C:15]([O:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:16][CH:17]=2)[CH2:22][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C3CC3)cc2)CC1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: c1cc(C2CC2)ccc1OC1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 1-Boc-4-(4-bromophenoxy)piperidine (5 g), dichlorobis(tricyclohexylphosphine)palladium(II) (725 mg), tripotassium phosphate (14.9 g) and cyclopropylboronic acid (1.81 g) was added toluene (70 mL), and the mixture was stirred with heating under reflux for 7 hr. The reaction mixture was cooled, water was added, and the insoluble material was collected by filtration. The filtrate was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography to give 4-(4-cyclopropylphenoxy)piperidine-1-carboxylic acid tert-butyl ester. The obtained 4-(4-cyclopropylphenoxy)piperidine-1-carboxylic acid tert-butyl ester was dissolved in ethyl acetate (3 mL), 4N hydrogen chloride/ethyl acetate (7 mL) was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was washed with ethyl acetate. To the obtained aqueous layer was added 1N aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated to give 4-(4-cyclopropylphenoxy)piperidine (2.49 g). Using the obtained 4-(4-cyclopropylphenoxy)piperidine (1.4 g) and 6-bromonicotinic acid (1.2 g) and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (2.4 g) was obtained.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:27][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][C:14]3[C:15]([O:20][C@@H:21]4[CH2:26][CH2:25][CH2:24][O:23][CH2:22]4)=[N:16][CH:17]=[CH:18][CH:19]=3)[C:7]=2[C:6]=1[CH3:28])=[O:4].CO.[OH-].[Na+].Cl>O.C1COCC1>[CH3:28][C:6]1[C:7]2[C:12]([NH:13][C:14]3[C:15]([O:20][C@@H:21]4[CH2:26][CH2:25][CH2:24][O:23][CH2:22]4)=[N:16][CH:17]=[CH:18][CH:19]=3)=[N:11][CH:10]=[N:9][C:8]=2[S:27][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1sc2ncnc(Nc3cccnc3O[C@@H]3CCCOC3)c2c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1c(C(=O)O)sc2ncnc(Nc3cccnc3O[C@@H]3CCCOC3)c12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 1.4 g (3.14 mmol) 5-methyl-4-{2-[(R)-(tetrahydro-pyran-3-yl)oxy]-pyridin-3-ylamino}-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester, 20 ml methanol, 7 ml THF and 6.29 ml sodium hydroxid solution (1 M) was stirred at room temperature for 48 hours. Then 6.3 ml hydrochloric acid solution (1M) were added followed by addition of water. The mixture was filtered. The solid was washed with water and diisopropylether and dried in an oven (vacuo).
Reaction SMILES: [CH2:1]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].F[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1>CS(C)=O>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([NH:9][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(N)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: CS(C)=O
Product: CCCCc1ccc(Nc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 100 °C
Yield: 63 %

Procedure:
To a flask equipped with a magnetic stirrer, reflux condenser, and a nitrogen inlet was added 4-n-butylaniline (48.5 grams, 0.325 moles), 1-fluoro-4-nitrobenzene (15.3 grams, 0.108 moles) and anhydrous methyl sulfoxide (120 ml). The contents of the flask were heated at 100° C. for 3 days; cooled to room temperature; partitioned between diethyl ether (300 ml) and water (100 ml). The ether extract was washed with water (4×100 ml) followed by brine (2×50 ml). The ether extract was dried over anhydrous magnesium sulfate, filtered and concentrated m vacuo to yield a brown oily residue. The residue was re-crystallized from hexane (300 ml) to yield 18.4 grams of product as a yellow solid. 1H NMR (CDCl3) δ 8.1(d, 2H), 7.2(d, 2H), 7.15(d, 2H), 6.9(d, 2H), 6.3(bs, 1H), 2.6(t 2H), 1.6(pent, 2H), 1.4(hextet, 2H), 0.9(t, 3H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.[NH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[N:13][C:14](Cl)=[CH:15][CH:16]=2)[N:11]=1.[CH3:21][OH:22]>O>[O:22]([C:14]1[N:13]=[C:12]2[C:17]([CH:18]=[CH:19][C:10]([NH:9][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[O:8])=[N:11]2)=[CH:16][CH:15]=1)[C:21]1[CH:5]=[CH:4][CH:3]=[CH:2][CH:6]=1
Reactant: CO
Reactant: Nc1ccc2ccc(Cl)nc2n1
Reactant: O=C(O)c1cccs1
Solvent: O
Product: O=C(Nc1ccc2ccc(Oc3ccccc3)nc2n1)c1cccs1
Temperature: 4 °C

Procedure:
The procedure is similar to that described in Example 1, but starting with 2-thiophenecarboxylic acid (4 g), N,N'-carbonyldiimidazole (5.1 g) and 2-amino-7-chloro-1,8-naphthyridine (7 g). The product produced by precipitation in water (8.8 g; m.p. 175° C.) is dissolved in boiling methanol (150 cc). After 3 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with methanol (3×10 cc) and dried at 40° C. under reduced pressure (0.067 kPa). N-(7-phenoxy-1,8-naphthyridin-2-yl)-2-thiophenecarboxamide (6 g) is produced, m.p. 176° C.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[N:9]=[N:8][C:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[N:6][CH:5]=1)[CH3:3].[Br:19][C:20]1[S:24][C:23]([C:25](O)=[O:26])=[CH:22][CH:21]=1.C(N(CC)CC)C>CN(C)C=O>[NH3:1].[Br:19][C:20]1[S:24][C:23]([C:25]([NH:1][CH:2]([C:4]2[N:9]=[N:8][C:7]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[N:6][CH:5]=2)[CH3:3])=[O:26])=[CH:22][CH:21]=1
Reactant: COc1ccc(Nc2ncc(C(C)N)nn2)cc1
Reactant: O=C(O)c1ccc(Br)s1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(Nc2ncc(C(C)NC(=O)c3ccc(Br)s3)nn2)cc1
Product: N
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 122.4 %

Procedure:
To a stirred solution of 6-(1-aminoethyl)-N-[4-(methyloxy)phenyl]-1,2,4-triazin-3-amine (Intermediate 47) (100 mg, 0.41 mmol), 5-bromothiophene-2-carboxylic acid (93 mg, 0.45 mmol) and O-(7-azabenzotriazol-1-yl-N,N,N′N′-tetramethyluronium hexafluorophospahte (186 mg, 0.49 mmol) in N,N-dimethylformamide (5 mL) was added triethylamine (0.170 mL, 1.22 mmol) and the resulting mixture stirred at room temperature, under nitrogen, for 2 h 50 min. The mixture was then reduced under vacuum and the residue purified by SPE (Si, 10 g cartridge) eluting with hexane/ethyl acetate (10:1 to 0:1) and then methanol. The appropriate fractions containing product were combined and then purified further by SPE (SCX, 5 g cartridge) eluting with methanol then ammonia in methanol (0.5 N to 2.0 N) to afford 5-bromo-N-[1-(3-{[4-(methyloxy)phenyl]amino}-1,2,4-triazin-6-yl)ethyl]-2-thiophenecarboxamide (109 mg) as a yellow solid. MS m/z 434/436 (M+1).