Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1I.[CH2:14]([O:21][CH2:22][C@@H:23]1[O:31][CH2:30][C:26]2=[N:27][O:28][CH2:29][C@@H:25]2[CH2:24]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.B(F)(F)F.CCOCC>O1CCCC1.C1(C)C=CC=CC=1>[CH2:14]([O:21][CH2:22][C@@H:23]1[O:31][CH2:30][C@:26]2([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[F:6])[NH:27][O:28][CH2:29][C@@H:25]2[CH2:24]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: c1ccc(COC[C@H]2C[C@H]3CON=C3CO2)cc1
Reactant: Fc1ccccc1I
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: Fc1ccccc1[C@]12CO[C@@H](COCc3ccccc3)C[C@H]1CON2
Reaction time: 0.5 h

Procedure:
n-Butyllithium (2.5 M solution in hexanes, 11.3 mL, 28.3 mmol) was added in a drop-wise manner to a solution of 1-fluoro-2-iodobenzene (3.30 mL, 28.3 mmol) in a mixture of tetrahydrofuran (26 mL) and toluene (116 mL) at −78° C., and the reaction mixture was stirred at this temperature for 30 minutes. In a separate flask, a solution of (3aR,5R)-5-[(benzyloxy)methyl]-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazole (P1) (3.50 g, 14.2 mmol) in toluene (116 mL) was cooled to −78° C. and treated with boron trifluoride diethyl etherate (3.49 mL, 28.3 mmol); this mixture was also allowed to stir at −78° C. for 30 minutes, and then added via cannula over three to four minutes to the aryllithium solution. The reaction mixture was stirred at −78° C. for approximately 30 minutes and was then quenched with saturated aqueous ammonium chloride solution. The mixture was extracted three times with ethyl acetate, and the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatography on silica gel (Gradient: 0% to 20% ethyl acetate in heptane) provided the product as a yellow oil. Yield: 4.39 g, 12.8 mmol, 90%. The stereochemical outcome of this reaction (cis ring fusion) was established via single crystal X-ray analysis of intermediate C17 (see data below). LCMS m/z 344.5 (M+1). 1H NMR (400 MHz, CDCl3) δ 1.50-1.61 (m, 1H), 1.82-1.90 (m, 1H), 3.10-3.18 (m, 1H), 3.50 (dd, half of ABX pattern, J=10.3, 4.1 Hz, 1H), 3.55-3.60 (m, 2H), 3.72 (br d, J=7.2 Hz, 1H), 3.85-3.93 (m, 2H), 4.20 (dd, J=12.7, 1.8 Hz, 1H), 4.61 (AB quartet, JAB=12.1 Hz, ΔνAB=22.5 Hz, 2H), 7.04 (ddd, J=12.1, 8.2, 1.2 Hz, 1H), 7.17 (ddd, J=7.8, 7.4, 1.4 Hz, 1H), 7.26-7.40 (m, 6H), 7.95 (ddd, J=8.1, 8.0, 1.8 Hz, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:7][CH2:8][NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16]([NH:19][C:20]1[CH:29]=[CH:28][C:27]2[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=2[C:21]=1[C:30]([OH:32])=[O:31])(=[O:18])=[O:17].C(O)(=O)C.[C:37]1(=O)[CH2:41][CH2:40][CH2:39][CH2:38]1.C([BH3-])#N>CN(C=O)C>[CH:37]1([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]2[CH2:7][CH2:8][NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[S:16]([NH:19][C:20]2[CH:29]=[CH:28][C:27]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=3[C:21]=2[C:30]([OH:32])=[O:31])(=[O:18])=[O:17])[CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: O=C1CCCC1
Reactant: O=C(O)c1c(NS(=O)(=O)c2ccccc2NCC[C@@H]2CCCCN2)ccc2c1CCCC2
Agent: [BH3-]C#N
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C(O)c1c(NS(=O)(=O)c2ccccc2NCCC2CCCCN2C2CCCC2)ccc2c1CCCC2
Temperature: 50 °C
Reaction time: 0.33 h

Procedure:
A solution of Example 401A (0.022 g, 0.044 mmol) in DMF (1.0 mL) was treated with acetic acid (0.05 mL) and cyclopentanone (0.005 mL, 0.06 mmol). The mixture was shaken at 50° C. for 20 minutes, treated with macroporous polystyrene bound cyanoborohydride resin (47 mg, 0.13 mmol), shaken at 70° C. for 15 hours, concentrated, and purified by C18 reverse-phase HPLC using acetonitrile/water/0.1% TFA to provide the desired product. MS (DCI) m/e 526 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 13.21 (br s, 1H), 7.54 (d, 1H), 7.40 (t, 1H), 6.93 (br s, 1H), 6.84 (d, 1H), 6.65 (t, 2H), 6.03 (br s, 1H), 4.02 (br s, 1H), 3.63 (br s, 1H), 3.35 (br s, 3H), 2.99 (br s, 1H), 2.70 (br s, 2H), 2.63 (br s, 2H), 2.00 (br s, 4H), 1.83 (br s, 3H), 1.65-1.54 (m, 13H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11]2[C:17]([CH2:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1[CH2:28]Br>>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1[CH2:28][N:13]1[C:12]2[CH:14]=[CH:15][CH:16]=[C:17]([CH2:18][CH3:19])[C:11]=2[N:10]=[C:9]1[C:3]1[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=1[F:1]
Reactant: CCc1cccc2nc(-c3c(F)cccc3F)[nH]c12
Reactant: Fc1cccc(F)c1CBr
Product: CCc1cccc2c1nc(-c1c(F)cccc1F)n2Cc1c(F)cccc1F
Yield: 76 %

Procedure:
2-(2,6-Difluorophenyl)-4-ethylbenzimidazole (4010) (0.70 g, 2.71 mmol) was reacted with 2,6-difluoro-a-bromo-toluene (0.72 g, 3.48 mmol, 130 M%). The crude product was purified by flash chromatography eluting with 2% MeOH/CH2Cl2 and recrystallization from diethylether/hexane (3:1), yielding white crystals of 1-(2,6-Difluorobenzyl)-2-(2,6-difluorophenyl)-4-ethylbenzimidazole (4011) (0.79 g, 2.06 mmol, 76% yield). M.p. 165-166° C. 1H-NMR (200 MHz, CD2Cl2): δ7.53 (m, 1H, H4′), 7.32 (d, J=8.2 Hz, 1H, H5), 7.29-7.16 (m, 2H, H6,4″), 7.14-7.01 (m, 1H, H7), 7.07 (m, 2H, H3′,5′), 6.81 (m, 2H, H3″,5″), 5.33 (s, 2H, CH2), 3.07 (q, J=7.6 Hz, 2H, CH2), 1.35 (t, J=7.6 Hz, 3H, CH3).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[CH2:15][C:16]1[O:17][C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:15][C:16]3[O:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(N2CCNCC2)cc1
Reactant: ClCc1nc2ccccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Oc1ccc(N2CCN(Cc3nc4ccccc4o3)CC2)cc1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 71.7 %

Procedure:
A mixture of 6.06 g (34 mmol) of 1-(4-hydroxyphenyl)piperazine and 5.36 g (32 mmol) of 2-chloromethylbenzoxazole in 100 ml of absolute DMF was warmed to 80° C., and 737 mg of powdered K2CO3 were added with stirring (under a nitrogen atmosphere) in each case after 10 minutes, after a further 25 minutes and after a further 60 minutes (total addition of 2.21 g (16 mmol) of K2CO3). The mixture was stirred for a further 3 hours at 80° C., the DMF was substantially removed by distillation in vacuo, and the residue was taken up in 200 ml of ether and 100 ml of water. After separating the phases, the aqueous phase was extracted a further twice with ether. The combined ether extracts were dried, filtered and evaporated in vacuo. The residue was taken up in diisopropyl ether, whereafter crystallization occurred. The crystalline substance was filtered off under suction. 7.10 g (71.7% of theory) of 1-(4-hydroxyphenyl)-4-(benzoxazol-2-ylmethyl)piperazine, melting point 155°-56° C., were obtained,
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH3:17])=[C:7]2[C:12](Cl)=[C:11]([C:14]#[N:15])[CH:10]=[N:9][N:8]2[CH:16]=1)=[O:4].[C:18]([O:22][C:23](=[O:42])[C:24]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][C:35]1[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=1)([CH3:26])[CH3:25])([CH3:21])([CH3:20])[CH3:19].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[C:6]([CH3:17])=[C:7]2[C:12]([NH:41][C:38]3[CH:39]=[CH:40][C:35]([O:34][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[O:27][C:24]([C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:42])([CH3:26])[CH3:25])=[CH:36][CH:37]=3)=[C:11]([C:14]#[N:15])[CH:10]=[N:9][N:8]2[CH:16]=1)=[O:4]
Reactant: COC(=O)c1cn2ncc(C#N)c(Cl)c2c1C
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1ccccc1Oc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4OC(C)(C)C(=O)OC(C)(C)C)cc3)c2c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 91 %

Procedure:
A mixture of 4-chloro-3-cyano-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylic acid methyl ester (prepared using the procedure of Example 1D) (320 mg, 1.28 mmol), aniline 388C (440 mg, 1.28 mmol) and K2CO3 (1.77 g, 12.8 mmol) in anhydrous DMF (8 ml) was stirred at rt for 16 h. After regular workup, the residue was purified by silica gel flash column chromatography to afford 388D (651 mg, 91%) as a faintly yellow solid (0%-4% EtOAc—CH2Cl2). LCMS Found: (M+H)+=556.8; (M−tBu+2H)+=500.9
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@@H:4]([NH:13][C:14](=[O:23])[C:15]1[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=1[Cl:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1.[C:25]1([CH:35]=O)[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(Cl)Cl>ClCCCl.C1COCC1>[CH3:1][O:2][C:3](=[O:24])[C@@H:4]([NH:13][C:14](=[O:23])[C:15]1[CH:20]=[C:19]([NH:21][CH2:35][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=[CH:27][CH:26]=2)[CH:18]=[CH:17][C:16]=1[Cl:22])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([Br:12])=[CH:10][CH:11]=1
Reactant: O=Cc1cccc2ccccc12
Reactant: COC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)c1cc(N)ccc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)c1cc(NCc2cccc3ccccc23)ccc1Cl
Yield: 62.1 %

Procedure:
(S)-3-(4-Bromo-phenyl)-2-{2-chloro-5-[(naphthalen-1-ylmethyl)-amino]-benzoylamino}-propionic acid methyl ester (264 mg) was prepared from (S)-2-(5-amino-2-chloro-benzoylamino)-3-(4-bromo-phenyl)-propionic acid methyl ester (316 mg, 0.77 mmol) and 1-naphthaldehyde (0.231 mL, 1.7 mmol) according to Procedure G, except for the following: the reaction was done in 15 mL DCE and 2 mL THF, two additional equiv. NaBH(OAc)3 were added after 2 h and an adapted work-up. After reaction completion, 100 mL of DCM was added and the organic washed with saturated sodium bicarbonate, dried over sodium sulfate, and evaporated. The crude material was purified over silica gel (8:2, DCM-hexanes).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:14]([OH:16])=[O:15])[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCC(N=C=NC2CCCCC2)CC1.[C:32]12(O)[CH2:41][CH:36]3[CH2:37][CH:38]([CH2:40][CH:34]([CH2:35]3)[CH2:33]1)[CH2:39]2>C1COCC1.CN(C)C1C=CN=CC=1.CC(O)=O.CCOC(C)=O>[C:32]12([O:15][C:14](=[O:16])[C@@H:12]([CH3:13])[NH:11][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:10])[CH2:41][CH:36]3[CH2:37][CH:38]([CH2:40][CH:34]([CH2:35]3)[CH2:33]1)[CH2:39]2
Reactant: OC12CC3CC(CC(C3)C1)C2
Reactant: C[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: C[C@@H](NC(=O)OCc1ccccc1)C(=O)OC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-Benzyloxycarbonyl-D-alanine (11.15 g, 50 mmol) was dissolved in 250 mL THF and treated with DCC (10.3 g, 50 mmol), 1-adamantanol (7.7 g, 51 mmol) and 1.45 g of 4-dimethylaminopyridine. The reaction mixture was stirred at room temperature. At the end of 24 hours, a few drops of HOAc was added and the reaction mixture was stirred for an additional 15 minutes. DCU was filtered off, the filtrate was evaporated to dryness under reduced pressure. The oily residue so obtained was dissolved in EtOAc and the solution was refrigerated overnight. More DCU was filtered off. The filtrate was then washed with 0.1N HCl (3×), H2O (3×), 0.1N NaOH (3×), H2O (3×) and dried over anhydrous Na2SO4. The solution was evaporated to dryness to give a clear oil. The oil was subjected to sublimation at 100°/0.1 mm for 5 hours. The oily residue was crystallized from hexane: mp 72°-74°, yield 11.6 g (75%), 250 MHz nmr (CDCl3, ppm) 1.37 (d, 3H, J=7.35 Hz, β--CH3 of Ala), 1.65 (s, 6H, adamantyl aliphatic protons of C's 4, 6 and 10), 2.09 (s, 6H, 1-adamantyl aliphatic protons of C's 2, 8 and 9), 2.16 (s, 3H, 1-adamantyl aliphatic protons of C's 3, 5 and 7), 4.23 (m, 1H, α--H of Ala), 5.09 (s, 2H, Ar--CH2 --O--), 5.32 (br.d, amide proton), 7.33 (s, 5H, ArH5).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([Cl:14])[C:5]2[NH:6]C(=O)O[C:9](=[O:10])[C:4]=2[CH:3]=1.CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[CH:28]([S+:31]([CH:33]([CH3:35])[CH3:34])[NH2:32])([CH3:30])[CH3:29].C([O-])(C)(C)C.[K+].O>C(Cl)Cl>[NH2:6][C:5]1[C:12]([Cl:14])=[CH:13][C:2]([Cl:1])=[CH:3][C:4]=1[C:9]([N:32]=[S:31]([CH:33]([CH3:35])[CH3:34])[CH:28]([CH3:30])[CH3:29])=[O:10]
Reactant: CC(C)[S+](N)C(C)C
Reactant: O=c1[nH]c2c(Cl)cc(Cl)cc2c(=O)o1
Agent: CC(C)(C)[O-]
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CC(C)S(=NC(=O)c1cc(Cl)cc(Cl)c1N)C(C)C
Temperature: 0 °C
Reaction time: 16 h
Yield: 276.5 %

Procedure:
To a suspension of 6,8-dichloro-1H-benzo[d][1,3]oxazine-2,4-dione (45.0 g, 70.7 mmol) in methylene chloride (500 mL) was added S,S-Diisopropyl-S-aminosulfonium 2,4,6-trimethyl-phenylsulfonate (77.6 g, 234 mmol). The reaction mixture was cooled to 0° C. and potassium tert-butanolate (8.73 g, 77.8 mmol) was added after which the reaction was allowed to come to room temperature and stirred for 16 h. Water (200 mL) and methylene chloride (50 mL) were then added, the organic phase was separated and the aqueous phase further extracted with methylene chloride (2×100 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo to afford the title compound (62.8 g, quant.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[NH2:11])[CH3:2].[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[C:15]=1[CH2:22][C:23](Cl)=[O:24]>C1(C)C=CC=CC=1.C(OCC)C>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[NH:11][C:23](=[O:24])[CH2:22][C:15]1[C:16]([F:21])=[CH:17][C:18]([F:20])=[CH:19][C:14]=1[F:13])[CH3:2]
Reactant: O=C(Cl)Cc1c(F)cc(F)cc1F
Reactant: CCOC(=O)c1cccnc1N
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCOC(=O)c1cccnc1NC(=O)Cc1c(F)cc(F)cc1F
Temperature: 25 °C
Yield: 92.5 %

Procedure:
2-Aminonicotinic acid ethyl ester (2.4 g) was suspended in dry toluene (50 ml). To the stirred suspension, 2,4,6-trifluorophenylacetyl chloride (3.0 g) in dry toluene (20 ml) was added. The resulting suspension was heated to reflux for 8 hours. The reaction mixture was cooled to ambient temperature, diluted with diethyl ether (100 ml), washed with water and brine, and the organic layer was dried over magnesium sulphate. The solvent was evaporated to give 2-[2-(2,4,6-trifluorophenyl)-acetylamino]-nicotinic acid ethyl ester as a yellow solid (4.5 g, 93%).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][CH2:8][C:7](=[O:11])[N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:4].[F:19][C:20]1[CH:21]=[C:22]([Mg]Br)[CH:23]=[CH:24][C:25]=1[F:26].[Cl-].[NH4+].C(OCC)(=O)C>C1COCC1>[C:15]([O:14][C:12]([NH:6][C@H:5]([CH2:10][CH2:9][CH2:8][C:7]([C:23]1[CH:22]=[CH:21][C:20]([F:19])=[C:25]([F:26])[CH:24]=1)=[O:11])[C:3]([O:2][CH3:1])=[O:4])=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: Fc1ccc([Mg]Br)cc1F
Reactant: COC(=O)[C@H]1CCCC(=O)N1C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)[C@@H](CCCC(=O)c1ccc(F)c(F)c1)NC(=O)OC(C)(C)C
Temperature: -40 °C
Reaction time: 7 h

Procedure:
To a solution of (R)-6-oxopiperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (CAS No. 183890-36-0, 5.8 g) in THF (200 mL), 3,4-difluorophenylmagnesium bromide (0.5 M solution in THF, 50 mL) was added dropwise at −40° C., and the reaction solution was stirred at −40° C. for seven hours. A saturated ammonium chloride solution and ethyl acetate were added to the reaction solution, and the mixture was heated to room temperature. Thereafter, the organic layer was separated, and the resulting organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane->heptane:ethyl acetate=1:1) to obtain 3.8 g of the title compound. The property value of the compound is as follows.
Reaction SMILES: N1([C:7]2[CH:30]=[CH:29][C:10]([C:11]([NH:13][CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:18][CH:17]=3)=[O:12])=[CH:9][N:8]=2)CCOCC1.[OH:31][CH:32]1[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]1.[OH-].[K+]>CS(C)=O.C(Cl)Cl.O>[CH3:38][N:35]1[CH2:36][CH2:37][CH:32]([O:31][C:7]2[CH:30]=[CH:29][C:10]([C:11]([NH:13][CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:18][CH:17]=3)=[O:12])=[CH:9][N:8]=2)[CH2:33][CH2:34]1
Reactant: O=C(NCCc1ccc(Oc2ccccc2)cc1)c1ccc(N2CCOCC2)nc1
Reactant: CN1CCC(O)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Solvent: ClCCl
Product: CN1CCC(Oc2ccc(C(=O)NCCc3ccc(Oc4ccccc4)cc3)cn2)CC1
Temperature: 100 °C
Yield: 20.9 %

Procedure:
A solution of 6-chloro-N-[2-(4-phenoxy-phenyl)-ethyl]-nicotinamide (130 mg, intermediate from example 23) in DMSO (1.4 ml) was treated with 4-hydroxy-N-methylpiperidine (68 mg) and KOH (93 mg). The reaction mixture was heated for 20 min at 100° C. in the microwave oven. Then it was cooled to r.t. and diluted with CH2Cl2 and water. The aqueous layer was washed with CH2Cl2. The combined organic layers were dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (silica gel; gradient: CH2Cl2→CH2Cl2/MeOH 98:2) to give 6-(1-methyl-piperidin-4-yloxy)-N-[2-(4-phenoxy-phenyl)-ethyl]-nicotinamide (29 mg) as off-white solid. MS (ISP): 432.2 ([M+H]+)
Reaction SMILES: COCC(O)C.[OH-].[Na+].[C:9](OC)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:19]1(=[O:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.S(=O)(=O)(O)O>>[C:9]([CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24][C:19]1=[O:25])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1CCCCC1
Reactant: COC(=O)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: COCC(C)O
Product: O=C1CCCCC1C(=O)c1ccccc1
Yield: 65 %

Procedure:
1-Methoxy-2-propanol (61.3 g; 0.68 mol), sodium hydroxide (16.0 g; 0.40 mol), and xylenes (300 mL) were placed into a four-necked, round bottom, half-liter flask equipped with a stirrer, a thermometer, and an Oldershaw column with a Dean-Stark trap and a condenser. The mixture was heated to boiling with stirring under a blanket of nitrogen and the water was azeotroped out (temperature of reflux 106-116° C.). When no more water was collected (23 mL of lower phase) some solvent was distilled off (215 mL), while xylenes (432.2 g, dry) were replaced, until no more alcohol was detected in the distillate (temperature of reflux 137° C.). The mixture in the flask was cooled down to and kept at 80° C. and the fractionation column and trap were replaced with a reflux condenser while maintaining the nitrogen stream. Methyl benzoate (68.1 g; 0.50 mol) was added, and slow addition over a period of 10 minutes of cyclohexanone (24.5 g, 0.250 mol) by means of a syringe pump was begun. After 19 minutes from the beginning of the addition of the ketone, the mixture was cooled down (an ice bath was used), and acidified by slow addition of 98% sulfuric acid (slightly over 24.5 g) with stirring. The mixture was transferred to a 1 L separatory funnel, washed with aqueous sodium bicarbonate, and then with water. Evaporation of the organic layer under vacuum and recrystallization from heptane afforded 32.86 g of BCH (65% yield based on cyclohexanone), with a purity of 99% (GC).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)O)=[CH:4][CH:3]=1.[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.C(=O)([O-])O.[Na+]>S(Cl)(Cl)=O.C(#N)C.CO>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(O)c2ccc(C)cc2)cc1
Reactant: C1CCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Solvent: O=S(Cl)Cl
Product: Cc1ccc(C(c2ccc(C)cc2)N2CCCC2)cc1
Temperature: 25 °C
Yield: 85.5 %

Procedure:
Compound 14 (0.30 g, 1.41 mmol) was dissolved in thionyl chloride (1 mL) (Wako Pure Chemical Industries, Ltd.), and the mixture was refluxed for 2 hours. The reaction solution was concentrated under reduced pressure, to thereby obtain a residue. The residue was dissolved in acetonitrile (5 mL) (Wako Pure Chemical Industries, Ltd.), and pyrrolidine (0.50 g, 7.03 mmol) was added thereto, and the mixture was refluxed for 2 hours and then allowed to cool to room temperature. A saturated aqueous solution of sodium hydrogen carbonate (Wako Pure Chemical Industries, Ltd.) was added to the reaction solution, and then mixture was extracted with ethyl acetate. The organic layer was dried with anhydrous sodium sulfate (Wako Pure Chemical Industries, Ltd.), and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform (Wako Pure Chemical Industries, Ltd.):methanol (Wako Pure Chemical Industries, Ltd.)=99:1 as an eluent), to thereby obtain the title compound (0.32 g, 84% yield).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[NH2:15][C:16](N)=[O:17]>>[C:16](=[O:17])([O:14][C:11]1[CH:10]=[CH:9][C:8]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[CH:13][CH:12]=1)[NH2:15]
Reactant: CCCCCCCc1ccc(O)cc1
Reactant: NC(N)=O
Product: CCCCCCCc1ccc(OC(N)=O)cc1
Yield: 78 %

Procedure:
The same method as step (6-1) of Example 6 was carried out with the exception of using 14629 g of p-heptyl phenol instead of 4-phenyl phenol, using 959 g of urea and carrying out the reaction for 17 hours. When a portion of the reaction liquid was removed and analyzed by liquid chromatography, the formation of (p-heptylphenyl) carbamate was confirmed. The yield was about 78% based on the charged amount of urea.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.I[C:36]1[C:45]([CH3:46])=[CH:44][C:39]([C:40]([NH:42][CH3:43])=[O:41])=[CH:38][C:37]=1[CH3:47].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>C1(C)C=CC=CC=1>[CH3:47][C:37]1[CH:38]=[C:39]([C:40](=[O:41])[NH:42][CH3:43])[CH:44]=[C:45]([CH3:46])[C:36]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:10]2[C:6]=1[CH2:7][CH2:8][C@H:9]2[O:11][C:12]1[CH:25]=[CH:24][C:15]2[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=2[CH:13]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: CNC(=O)c1cc(C)c(I)c(C)c1
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CNC(=O)c1cc(C)c(-c2ccc(F)c3c2CC[C@H]3Oc2ccc3c(c2)OC[C@H]3CC(=O)OC)c(C)c1
Temperature: 120 °C
Reaction time: 5 h

Procedure:
In a microwave vial, methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (75 mg), 4-iodo-N,3,5-trimethylbenzamide (93 mg), K3PO4 (102 mg) and dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (S-Phos) (7 mg) are suspended in toluene (1.8 mL) and water (0.2 mL) and purged for 10 minutes with argon. Palladium-(II)-acetate (4 mg) is added, the vial is sealed and the mixture is stirred at 120° C. for 5 hours. After cooling to ambient temperature the mixture is partitioned between ethyl acetate and water. The organic phase is dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 100:0→80:20) to give the title compound. Yield: 16 mg; LC (method 25): tR=1.32 min; Mass spectrum (ESI+): m/z=504 [M+H]+.