Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH2:2][C:3]([OH:5])=O.C1(N=C=NC2CCCCC2)CCCCC1.[CH2:21]([NH2:29])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>ClCCl>[C:23]1([CH2:22][CH2:21][NH:29][C:3](=[O:5])[CH2:2][F:1])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCCc1ccccc1
Reactant: O=C(O)CF
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(CF)NCCc1ccccc1
Reaction time: 12 h

Procedure:
To a mixture containing 11.7 g of fluoroacetic acid (0.15M), 27.3 ml of dicyclohexylcarbodiimide(0.17M) and 200 ml of dichloromethane was dropwise added 17 ml of phenethylamine(0.17M), which was stirred for 12 hours. The solids produced were filtered and the filtrate was washed with water, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give 11.9 g of the title compound as white solids.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)=[C:8]2[N:13]([C:14]=1[Br:15])[N:12]=[CH:11][N:10]=[C:9]2[NH2:16])=[O:5])[CH3:2].C(N(CC)CC)C.C1([O:37][C:38](=O)[NH:39][C:40]2[CH:45]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:43]=[CH:42][N:41]=2)C=CC=CC=1>C1COCC1>[NH2:16][C:9]1[C:8]2=[C:7]([C:17]3[CH:18]=[CH:19][C:20]([NH:23][C:38]([NH:39][C:40]4[CH:45]=[C:44]([C:46]([F:48])([F:47])[F:49])[CH:43]=[CH:42][N:41]=4)=[O:37])=[CH:21][CH:22]=3)[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:14]([Br:15])[N:13]2[N:12]=[CH:11][N:10]=1
Reactant: CCOC(=O)c1c(-c2ccc(N)cc2)c2c(N)ncnn2c1Br
Reactant: O=C(Nc1cc(C(F)(F)F)ccn1)Oc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccn3)cc2)c2c(N)ncnn2c1Br
Temperature: 70 °C
Yield: 88.8 %

Procedure:
Ethyl-4-amino-5-(4-aminophenyl)-7-bromopyrrolo[2,1-f][1,2,4]triazine-6-carboxylate (1.5 g, 3.99 mmol) was suspended in THF (20 mL) and treated with triethylamine (0.56 mL, 3.99 mmol) and phenyl[4-(trifluoromethyl)pyridin-2-yl]carbamate (1.13 g, 3.99 mmol). The mixture was heated to 70° C. for 18 h. After cooling to rt, he mixture was concentrated then suspended in EtOAc. The product was collected by filtration to give 2.0 g of a tan solid (89%). 1H-NMR (DMSO-d6) δ 9.91 (s, 1H) 9.75 (s, 1H), 8.53 (d, J=5.4, 1H), 8.06 (s, 1H), 8.04 (s, 1H), 7.60 (d, J=11, 2H), 7.37-7.31 (m, 3H), 5.15 (bs, 2H), 4.04 (q, J=7.1, 2H), 0.99 (t, J=7.2, 3H); MS [M+H]+=563.9, 565.9; LCMS RT=3.22.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[C:13]12([CH2:23][CH2:24]O)[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>O1CCCC1>[CH2:9]([O:8][C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:24][CH2:23][C:13]23[CH2:22][CH:17]4[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]4)[CH2:14]2)[CH2:20]3)=[CH:12][CH:11]=1)[CH3:10]
Reactant: OCCC12CC3CC(CC(C3)C1)C2
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(OCCC23CC4CC(CC(C4)C2)C3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 4-hydroxybenzoate (83 mg) and 1-adamantaneethanol (90 mg) were combined in tetrahydrofuran (2 mL). Polymer-supported triphenylphospine (250 mg of 3 mmol/g) and di-tert-butyl azodicarboxylate (173 mg) were added. The reaction was stirred at room temperature overnight. The resin was removed by filtration through celite. The filtrate was concentrated under vacuum, and the residue was triturated with 95/5 hexanes/ether to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[CH:15]=[C:16]([C:30]2[CH:35]=[CH:34][C:33]([CH2:36][N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[CH:32][CH:31]=2)[CH:17]=[C:18]([N:21]([CH2:28][CH3:29])[CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[C:19]=1[CH3:20])=[O:13].C(N(CC)CC)C.[S:50](Cl)([CH3:53])(=[O:52])=[O:51].[OH-].[Na+]>C(Cl)Cl.CO.O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[CH:15]=[C:16]([C:30]2[CH:35]=[CH:34][C:33]([CH2:36][N:37]3[CH2:38][CH2:39][O:40][CH2:41][CH2:42]3)=[CH:32][CH:31]=2)[CH:17]=[C:18]([N:21]([CH2:28][CH3:29])[CH:22]2[CH2:23][CH2:24][N:25]([S:50]([CH3:53])(=[O:52])=[O:51])[CH2:26][CH2:27]2)[C:19]=1[CH3:20])=[O:13]
Reactant: CCN(c1cc(-c2ccc(CN3CCOCC3)cc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCNCC1
Reactant: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: CCN(c1cc(-c2ccc(CN3CCOCC3)cc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCN(S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
To stirred solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(piperidin-4-yl)amino)-4-methyl-4′-(morpholinomethyl)-[1,1′-biphenyl]-3-carboxamide (0.2 g, 0.35 mmol) in DCM (8 mL) was added triethyl amine (0.106 g, 1.04 mmol) and mesyl chloride (0.08 g, 0.69 mmol) at 0° C. The resulting reaction mixture was stirred at room temperature for 2 h. After completion, water was added to the reaction mixture and extracted with 10% MeOH/DCM. Combined organic layers were dried over sodium sulphate and concentrated under reduced pressure giving crude material which was then dissolved in methanol (10 mL) and added NaOH (0.021 g, 0.52 mmol). This mixture was stirred at room temperature for 15 h. After completion, extraction was carried out using 20% MeOH/DCM. Combined organic layers were dried over sodium sulfate, concentrated and crude material was purified by solvent washing giving the title compound (0.1 g, 45.45%).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[C:18]([CH2:20][O:21][C:22](=[O:24])[NH2:23])[O:17][N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:25](=O)[CH2:26][CH3:27]>>[CH2:1]([N:8]([CH2:25][CH2:26][CH3:27])[C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:19]=[C:18]([CH2:20][O:21][C:22](=[O:24])[NH2:23])[O:17][N:16]=2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)OCc1cc(-c2ccc(NCc3ccccc3)cc2)no1
Reactant: CCC=O
Product: CCCN(Cc1ccccc1)c1ccc(-c2cc(COC(N)=O)on2)cc1

Procedure:
An experiment was performed using the compound carbamic acid 3-(4-benzylamino-phenyl)-isoxazol-5-ylmethyl ester in Example 74 as a starting material and propionaldehyde in the same manner as in Example 74.4 to obtain carbamic acid 3-[4-(benzyl-propyl-amino)-phenyl]-isoxazol-5-ylmethyl ester.
Reaction SMILES: [CH2:1]([N:8]([CH2:32][CH3:33])[C:9](=[O:31])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][O:20][C:21]2[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=2[C:23]([O:25]C)=[O:24])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+]>C1COCC1.O>[CH2:1]([N:8]([CH2:32][CH3:33])[C:9](=[O:31])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][O:20][C:21]2[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=2[C:23]([OH:25])=[O:24])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(Cc1ccccc1)C(=O)COc1ccc(CCOc2ccccc2C(=O)OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCN(Cc1ccccc1)C(=O)COc1ccc(CCOc2ccccc2C(=O)O)cc1
Yield: 109.3 %

Procedure:
Methyl 2-[2-(4-{2-[benzyl(ethyl)amino]-2-oxoethoxy}phenyl)ethoxy]benzoate (0.138 g, 0.308 mmol) was dissolved in a mixture of THF/water (1/1, 4 ml). Lithium hydroxide (0.015 g, 0.617 mmol) was added. The reaction was performed in an single node microwave oven (14 min, 150 deg). Workup by removing the solvent by evaporation and addition of HCl (2 ml, 1 M). The waterphase was extracted with two portions of EtOAc (20 ml), the organic phase was dried (MgSO4) and the solvent was removed by evaporation to give 0.146 g of 2-[2-(4-{2-[benzyl(ethyl)amino]-2-oxoethoxy}phenyl)ethoxy]benzoic acid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([N:9]([CH2:21][CH:22]([CH3:24])[CH3:23])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]([NH2:20])[CH:14]=1)(=[O:12])=[O:11])[CH2:7][OH:8].S(Cl)(Cl)(=O)=O.[C:30]([O:34][C:35]([NH:37][C@@H:38]([CH2:42][C:43]1[CH:52]=[CH:51][C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:44]=1)[C:39](O)=[O:40])=[O:36])([CH3:33])([CH3:32])[CH3:31]>>[C:30]([O:34][C:35](=[O:36])[NH:37][C@H:38]([C:39](=[O:40])[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([N:9]([S:10]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]([NH2:20])[CH:14]=1)(=[O:12])=[O:11])[CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:7][OH:8])[CH2:42][C:43]1[CH:52]=[CH:51][C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:44]=1)([CH3:31])([CH3:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Reactant: CC(C)CN([C@H](CO)CCCCN)S(=O)(=O)c1ccc(F)c(N)c1
Solvent: O=S(=O)(Cl)Cl
Product: CC(C)CN([C@H](CO)CCCCNC(=O)[C@H](Cc1ccc2ccccc2c1)NC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(F)c(N)c1
Yield: 38 %

Procedure:
The title compound was prepared from the crude amine mixture of (1S)-N-(5-amino-1-hydroxymethyl-pentyl)-N-isobutyl-3-amino-4-fluoro-benzenesulfonamide which is described earlier (example 53, step C, which was made from a batch of sulfonyl chloride containing the two regioisomers) and (2S)-2-tert-butoxycarbonylamino-3-naphthalen-2-yl-propionic acid using general procedure A. The crude residue was purified by semi-preparative HPLC in several batches of 80 mg using a gradient of 35 to 90% of acetonitrile over 30 min and a flow rate of 15 mL/min, retention time=23.9 min. All the pure fractions were combined to provide 460 mg (38% yield) of the title compound.
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([N:12]2[CH2:16][CH2:15][CH2:14][CH:13]2[C:17]2[O:21][N:20]=[C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[CH:18]=2)[N:3]=1.[NH2:28][C:29]1[CH:33]=[C:32]([CH3:34])[NH:31][N:30]=1>>[CH3:34][C:32]1[NH:31][N:30]=[C:29]([NH:28][C:2]2[CH:7]=[C:6]([C:8]([F:9])([F:11])[F:10])[N:5]=[C:4]([N:12]3[CH2:16][CH2:15][CH2:14][CH:13]3[C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)[CH:18]=3)[N:3]=2)[CH:33]=1
Reactant: Oc1cc(C(F)(F)F)nc(N2CCCC2c2cc(-c3ccccn3)no2)n1
Reactant: Cc1cc(N)n[nH]1
Product: Cc1cc(Nc2cc(C(F)(F)F)nc(N3CCCC3c3cc(-c4ccccn4)no3)n2)n[nH]1

Procedure:
Starting materials: 4-hydroxy-6-trifluoromethyl-2-[2-{3-(pyrid-2-yl)isoxazol-5-yl}pyrrolidin-1-yl]pyrimidine (Method 37) and 3-amino-5-methyl-1H-pyrazole.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.Br[C:30]1[CH:35]=[CH:34][C:33]([N:36]2[C:40]([C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([O:49][C@@H:50]4[CH2:54][CH2:53][O:52][CH2:51]4)[CH:42]=3)=[CH:39][CH:38]=[N:37]2)=[CH:32][CH:31]=1.[N:55]1([C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[NH4+].[Cl-]>O1CCCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:48][O:47][C:44]1[CH:45]=[CH:46][C:41]([C:40]2[N:36]([C:33]3[CH:34]=[CH:35][C:30]([N:58]4[CH2:57][CH2:56][N:55]([C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[CH2:60][CH2:59]4)=[CH:31][CH:32]=3)[N:37]=[CH:38][CH:39]=2)=[CH:42][C:43]=1[O:49][C@@H:50]1[CH2:54][CH2:53][O:52][CH2:51]1
Reactant: COc1ccc(-c2ccnn2-c2ccc(Br)cc2)cc1O[C@@H]1CCOC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: C1CCOC1
Product: COc1ccc(-c2ccnn2-c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc1O[C@@H]1CCOC1
Temperature: 65 °C
Yield: 33.6 %

Procedure:
Into a 1-neck round-bottom flask was added 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (4.74 mg, 0.0120 mmol), 1-(4-bromophenyl)-5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazole (50.0 mg, 0.120 mmol), tert-butyl 1-piperazinecarboxylate (26.9 mg, 0.144 mmol) and tris(dibenzylideneacetone)dipalladium(0) (11.0 mg, 0.0120 mmol). The reaction was placed under an atmosphere of argon, 0.4 mL of 1.00 M lithium bis(trimethylsilyl)amide in tetrahydrofuran was added and the mixture was heated to 65° C. for 16 hours. After cooling to room temperature, 30 mL of saturated aqueous NH4Cl solution was added and the aqueous layer was extracted with 30 mL ethyl acetate. The separated organic layer was dried over sodium sulfate, filtered, and approximately 1 g silica gel was added and the mixture was evaporated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 20% ethyl acetate in hexanes to yield tert-butyl 4-[4-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)phenyl]piperazine-1-carboxylate (21 mg, 34%) as a yellow oil. LC/MS (EI) tR 4.62 (Method C), m/z 521.3 (M++1). 1H NMR (CDCl3 300 MHz) δ 1.5 (s, 9H); 1.9 (m, 2H); 3.1 (m, 4H); 3.6 (m, 4H); 3.7-3.9 (m, 4H); 3.9 (s, 3H); 4.6 (m, 1H); 6.4 (s, 1H); 6.6 (s, 1H); 6.9-7.1 (m, 4H); 7.2 (d, 2H); 7.6 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C:11]2([CH2:23][C:22](=[O:24])[C:21]3[C:16](=[CH:17][CH:18]=[C:19](Br)[CH:20]=3)[O:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:26]([O:30][CH3:31])(=[O:29])[CH:27]=[CH2:28]>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:31][O:30][C:26](=[O:29])/[CH:27]=[CH:28]/[C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[O:15][C:11]1([CH2:12][CH2:13][CH2:14][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]1)[CH2:23][C:22]2=[O:24]
Reactant: C=CC(=O)OC
Reactant: CC(C)(C)OC(=O)N1CCCC2(CC1)CC(=O)c1cc(Br)ccc1O2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(C(=O)OC(C)(C)C)CC1)O2
Temperature: 100 °C
Yield: 97.1 %

Procedure:
A mixture of (±)-6-bromo-4-oxo-spiro(chromane-2,4′-azepane)-1′-carboxylic acid tert-butyl ester (7.20 g, 17.6 mmol), Pd(OAc)2 (78 mg, 0.35 mmol), P(o-tol)3 (213 mg, 0.70 mmol), TEA (7.32 ml, 52.7 mmol), methyl acrylate (4.74 ml, 52.7 mmol) in dry DMF (20 ml) was heated under N2 atmosphere to 100° C. for 3 h. After cooling down to RT, the solution was filtered on a celite pad and washed with EtOAc (100 ml). The filtrate was washed with water and brine. The organic phase was dried over Na2SO4 and evaporated under vacuum. The crude residue was purified by column chromatography (eluent: petroleum ether/EtOAc 8:2 to 7:3) to give (±)-(E)-3-[1′-tert-butoxycarbonyl-4-oxo-spiro(chromane-2,4′-azepane)-6-yl]-acrylic acid methyl ester (7.1 g) as a light yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[F:10].C1C(=O)N([I:18])C(=O)C1.O>C(O)(=O)C>[Br:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[C:4]([I:18])[C:3]=1[F:10]
Reactant: Nc1cc(F)c(Br)c(F)c1
Reactant: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Solvent: O
Product: Nc1cc(F)c(Br)c(F)c1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 109.9 %

Procedure:
To a solution of the 4-bromo-3,5-difluoroaniline (5 g, 20 mmol) in acetic acid (60 mL) was added NIS (5.68 g). The reaction mixture was stirred at room temperature for two hours, and poured into water (300 mL). The product was extracted with ethyl acetate (2×200 mL), and the combined organic layers were washed with 1 N aqueous NaOH (200 mL) and saturated aqueous sodium thiosulfate (100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The oily residue was filtered through a plug of silica gel, eluting with heptane/ethyl acetate (4:1). The filtrate was concentrated in vacuo to give the title compound (7.34 g) as a white solid. 1H NMR (500 MHz, CDCl3) δ 6.44 (dd, J=10.00, 1.95 Hz, 1 H) 4.46 (br. s., 2 H).
Reaction SMILES: [CH2:1]([Li])CCC.[I-].C[S+](C)C.[CH2:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:12]1[O:14][CH2:13]1.O>CCCCCC.O1CCCC1>[CH2:16]([O:15][CH2:11][CH:12]([OH:14])[CH:13]=[CH2:1])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: [Li]CCCC
Reactant: c1ccc(COCC2CO2)cc1
Agent: C[S+](C)C
Agent: [I-]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: C=CC(O)COCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 2.64 M solution of n-butyllithium in hexane (35.7 mL) was added to a solution of trimethylsulfonium iodide (19.9 g) in tetrahydrofuran (300 mL) at −25° C. The mixture was stirred at the same temperature for 30 minutes. Benzyl glycidyl ether (5.00 mL) was added to the reaction solution at the same temperature, and then the mixture was warmed to room temperature over two hours and 50 minutes. Water was added to the reaction solution, followed by extraction with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (6.98 g).
Reaction SMILES: [Cl:1][C:2]([Cl:10])([Cl:9])[CH:3]([OH:8])[CH2:4][C:5]([CH3:7])=[CH2:6].[C:11](OC(=O)C)(=[O:13])[CH3:12]>S(=O)(=O)(O)O>[Cl:1][C:2]([Cl:10])([Cl:9])[CH:3]([O:8][C:11](=[O:13])[CH3:12])[CH2:4][C:5]([CH3:7])=[CH2:6]
Reactant: CC(=O)OC(C)=O
Reactant: C=C(C)CC(O)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)O
Product: C=C(C)CC(OC(C)=O)C(Cl)(Cl)Cl
Reaction time: 0.17 h

Procedure:
50.0 g. (0.246 moles) of 1,1,1-trichloro-2-hydroxy-4-methyl-4-pentene are admixed with 30.1 g. (0.295 moles) of acetic anhydride, whereupon 3 drops of a concentrated sulfuric acid solution are added to the mixture, which is then stirred for 10 minutes. 1,1,1-trichloro-2-acetoxy-4-methyl-4-pentene is obtained in the reaction which can be detected by t.l.c. measurement (Merck Art. No. 5715 analytical sheet, benzene; Rf for the starting material: 0.34, Rf for the acetylated product: 0.66). The reaction mixture obtained and 123 ml. of a 2 N aqueous sodium hydrogensulfate solution are simultaneously added to a suspension of 32.2 g. (0.492 moles) of zinc powder in 200 ml. of methanol in 10 minutes, under vigorous stirring, while keeping the reaction vessel on a water bath of 10°-15°C. When the addition is complete, the mixture is stirred for another 5 minutes, whereupon the solids are filtered off.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:11]2[O:12][C:13]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21]CC=C)[C:14]=3[C:15]=2[CH3:16])[S:9][CH:10]=1)=[O:5])[CH3:2].C1N2CCN(CC2)C1.Cl>C(O)C.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.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:11]2[O:12][C:13]3[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[C:14]=3[C:15]=2[CH3:16])[S:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: C=CCOc1cccc2oc(-c3nc(C(=O)OCC)cs3)c(C)c12
Agent: [Rh]
Agent: C1CN2CCN1CC2
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1csc(-c2oc3cccc(O)c3c2C)n1
Yield: 84.9 %

Procedure:
2-(4-Allyloxy-3-methyl-benzofuran-2-yl)-thiazole-4-carboxylic acid ethyl ester (28 mg) in 80% aqueous ethanol (6 ml) was stirred in the presence of chlorotris(triphenylphosphine)rhodium (3 mg) and triethylenediamine (2 mg) at 90° C. for 6 hours. The reaction mixture was poured into 1N aqueous hydrochloric acid and extracted with ethyl acetate. The combined organic extracts were washed with brine and dried over magnesium sulfate. Evaporation of the solvent under reduced pressure gave 2-(4-hydroxy-3-methyl-benzofuran-2-yl)-thiazole-4-carboxylic acid ethyl ester as a white solid (21 mg). FAB-MS: m/z 304 (MH+).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1Cl)=[O:13])[CH2:8]2.[CH2:26]([NH2:32])[CH:27]1[O:31][CH2:30][CH2:29][CH2:28]1>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1[NH:32][CH2:26][CH:27]1[CH2:28][CH2:29][CH2:30][O:31]1)=[O:13])[CH2:8]2
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)c1cnn(-c2ccccc2)c1Cl
Reactant: NCC1CCCO1
Product: O=C(NC1C2CC3CC(C2)CC1C3)c1cnn(-c2ccccc2)c1NCC1CCCO1

Procedure:
Phenyl-5-[(tetrahydro-furan-2-ylmethyl)-amino]-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide was prepared using Procedure A from 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Intermediate 3) and tetrahydrofurfurylamine. Mass spectrum (ES) MH+=421.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C1N2CN3CN(C2)CN1C3.Cl.FC(F)(F)[C:25](O)=[O:26]>>[OH:11][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[CH:7][C:6]=1[CH:25]=[O:26]
Reactant: COc1ccc(O)cc1OC
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Product: COc1cc(O)c(C=O)cc1OC
Reaction time: 0.25 h

Procedure:
In a 500 mL recovery flask, 5.0 g (32.4 mmol) of 3,4-dimethoxyphenol (manufactured by Tokyo Chemical Industry Co., Ltd.) and 18.2 g (130 mmol, 4.0 eq) of hexamethylenetetramine (manufactured by Tokyo Chemical Industry Co., Ltd.) were dissolved in 100 ml of trifluoroacetic acid (manufactured by Kanto Chemical Co., Inc.) and reacted at 100° C. for 24 hours. After the reaction was completed, in an ice bath, 200 ml of 1 N hydrochloric acid was added thereto and the resultant was stirred for 15 minutes. After the stirring was completed, the resultant was extracted with chloroform to obtain an extract. The extract was washed with hydrochloric acid and saturated saline, thereby obtaining 2.17 g (11.0 mmol) of 2-hydroxy-4,5-dimethoxybenzaldehyde.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][N:50]=1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([NH:47][CH2:48][C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][N:50]=4)=[O:43])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: NCc1ccccn1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)NCc2ccccn2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-Butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with 2-(aminomethyl)pyridine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C42H49Cl2N6O3 [(M+H)+] 755.3238, observed 755.3238.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][N:19]=2)[C:13]([NH:15][NH2:16])=[O:14])=[CH:5][CH:4]=1.[C:20]([O:23][C:24]([CH3:29])([CH3:28])[C:25](Cl)=[O:26])(=[O:22])[CH3:21]>CN(C)C(=O)C.C(OCC)(=O)C>[C:20]([O:23][C:24]([CH3:29])([CH3:28])[C:25]([NH:16][NH:15][C:13](=[O:14])[C:12]1[CH:17]=[CH:18][N:19]=[C:10]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=2)[CH:11]=1)=[O:26])(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Reactant: CSc1ccc(Nc2cc(C(=O)NN)ccn2)cc1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CSc1ccc(Nc2cc(C(=O)NNC(=O)C(C)(C)OC(C)=O)ccn2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.9 %

Procedure:
To a solution of 2-[[4-(methylthio)phenyl]amino]isonicotinohydrazide (513 mg, 1.87 mmol) in N,N-dimethylacetamide (5 mL) was added dropwise 2-chloro-1,1-dimethyl-2-oxoethyl acetate (0.294 mL, 2.06 mmol) under ice-cooling, and the resulting mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from hexane/ethyl acetate to give the title compound (624 mg, yield 83%) as colorless crystals.