Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](C1C=C(C=CC=1)COC1C=CC(C[C@]2(S(C3C=CC4OCOC=4C=3)(=O)=O)[C@@H](CC(C)C)OC(C)(C)N2CN)=CC=1)#[N:2].[CH2:43]([O:50][C:51]1[CH:89]=[CH:88][C:54]([CH2:55][C@H:56]([NH:76][C:77](=[O:87])[O:78][C@@H:79]2[C@H:86]3[C@H:82]([O:83][CH2:84][CH2:85]3)[O:81][CH2:80]2)[C@H:57]([OH:75])[CH2:58][N:59]([S:64]([C:67]2[CH:72]=[CH:71][C:70]([OH:73])=[C:69]([CH3:74])[CH:68]=2)(=[O:66])=[O:65])[CH2:60][CH:61]([CH3:63])[CH3:62])=[CH:53][CH:52]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>>[C:1]([C:48]1[CH:49]=[C:44]([CH:45]=[CH:46][CH:47]=1)[CH2:43][O:50][C:51]1[CH:52]=[CH:53][C:54]([CH2:55][C@H:56]([NH:76][C:77](=[O:87])[O:78][CH:79]2[CH:86]3[CH:82]([O:83][CH2:84][CH2:85]3)[O:81][CH2:80]2)[C@H:57]([OH:75])[CH2:58][N:59]([S:64]([C:67]2[CH:72]=[CH:71][C:70]([OH:73])=[C:69]([CH3:74])[CH:68]=2)(=[O:65])=[O:66])[CH2:60][CH:61]([CH3:62])[CH3:63])=[CH:88][CH:89]=1)#[N:2]
Reactant: Cc1cc(S(=O)(=O)N(CC(C)C)C[C@@H](O)[C@H](Cc2ccc(OCc3ccccc3)cc2)NC(=O)O[C@H]2CO[C@H]3OCC[C@H]32)ccc1O
Reactant: CC(C)C[C@H]1OC(C)(C)N(CN)[C@@]1(Cc1ccc(OCc2cccc(C#N)c2)cc1)S(=O)(=O)c1ccc2c(c1)OCO2
Product: Cc1cc(S(=O)(=O)N(CC(C)C)C[C@@H](O)[C@H](Cc2ccc(OCc3cccc(C#N)c3)cc2)NC(=O)OC2COC3OCCC23)ccc1O

Procedure:
The alkylation step was carried out as described for N-(3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl-oxycarbonyl-, (4S,5R)-4-[4-(3-cyanobenzyloxy)-benzyl]-5-i-butyl-[(3,4-methylenedioxyphenyl)sulfonyl]-aminomethyl-2,2-dimethyl-oxazolidine. The deacetylation step was carried out as described previously for (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-[4-(benzyloxy)benzyl]-2-hydroxy-3-[[(4-hydroxy-3-methylphenyl)sulfonyl](isobutyl)amino]propylcarbamate. The final product was isolated by preparative HPLC. (Column: Luna C18, Solvent: 75% to 100% MeOH/0.1% formic acid, tret: 4.08 min.) (Y=6%, 2 steps, overall.)
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:45])([CH3:44])[C:13]([NH:15][C@@H:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:19]=2[N:18]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[CH2:41][NH2:42])=[CH:31][CH:30]=2)[C:17]1=[O:43])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C([O-])=O.[CH3:53][N:54]=[C:55]=[O:56]>>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:45])([CH3:44])[C:13]([NH:15][C@@H:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:19]=2[N:18]([CH2:28][C:29]2[CH:30]=[CH:31][C:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[CH2:41][NH:42][C:55]([NH:54][CH3:53])=[O:56])=[CH:33][CH:34]=2)[C:17]1=[O:43])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)N[C@@H]1CCc2cc(F)ccc2N(Cc2ccc(-c3ccccc3CN)cc2)C1=O
Reactant: CN=C=O
Agent: O=C([O-])C(F)(F)F
Product: CNC(=O)NCc1ccccc1-c1ccc(CN2C(=O)[C@H](NC(=O)C(C)(C)NC(=O)OCc3ccccc3)CCc3cc(F)ccc32)cc1

Procedure:
Prepared from 2-benzyloxycarbonylamino-2-methyl-N-[7-fluoro-2,3,4,5-tetrahydro-2-oxo-1-[[2'-(aminomethyl) [1,1'-biphenyl ]-4-yl]methyl]-1H-benzazepin-3(R)-yl]propanamide, trifluoroacetate (Step G) and methyl isocyanate according to the procedure described in Example 35, Step I. 1H NMR (400 MHz, CDCl3): δ 1.44 (s, 3H), 1.45 (s, 3H), 1.78 (m, 1H), 1.85 (s, 1H), 2.30-2.60 (m,3H), 2.57 (d, 4 Hz, 3H), 4.18 (d, 5 Hz, 2H), 4.40 (m, 1H), 4.62 (m, 1H), 4.80 (m, 2H), 5.00 (s, 2H), 5.17 (d, 15 Hz, 1H), 540 (s, 1H), 6.85 (m, 1H), 6.96 (m, 1H), 7.08-7.35 (m, 13H), 7.39 (m, 1H). FAB-MS: calculated for C38H40FN5O5 665; found 666 (M+H, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH:11][CH3:12])[C:5](O)=[O:6].C(C1NC=CN=1)([C:15]1[NH:16][CH:17]=CN=1)=O.C(N(CC)CC)C>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH:11][CH3:12])[C:5]([N:16]([CH3:17])[CH3:15])=[O:6]
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: CNc1ccc(C(=O)O)cc1Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CNc1ccc(C(=O)N(C)C)cc1Cl
Reaction time: 1 h

Procedure:
To 3-chloro-4-methylamino-benzoic acid (387 mg) in dry N. N-dimethylformamide (10 mL) was added carbonyl diimidazole (440 mg). After one hour, dimethylamine. HCl (221 mg) and triethylamine (0.38 mL) were added. The reaction mixture was stirred overnight, then diluted with ethyl acetate, washed with brine, dried (MgSO4) and the solvent removed in vacuo. Purification using flash chromatography yielded 3-chloro-N,N-dimethyl-4-methylamino-benzamide.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]=[C:9]=[O:10])=O)=[CH:4][C:3]=1[C:13]([F:16])([F:15])[F:14].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:20][C:19]=1[NH:32][NH:33]C(OC(C)(C)C)=O.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:20][C:19]=1[N:32]1[C:9](=[O:10])[NH:8][C:6]([C:5]2[CH:11]=[CH:12][C:2]([F:1])=[C:3]([C:13]([F:16])([F:15])[F:14])[CH:4]=2)=[N:33]1
Reactant: CC(C)(C)OC(=O)NNc1cc(CNC(=O)C(C)(C)C)ccc1Cl
Reactant: O=C=NC(=O)c1ccc(F)c(C(F)(F)F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(-n2nc(-c3ccc(F)c(C(F)(F)F)c3)[nH]c2=O)c1
Yield: 45.5 %

Procedure:
The title compound was prepared according to the procedure described in Example-83 by using 4-fluoro-3-(trifluoromethyl)benzoyl isocyanate (Intermediate-101, 0.196 g, 0.84 mmol), tert-butyl 2-(2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}phenyl)hydrazinecarboxylate (Intermediate-94, 0.150 g, 0.420 mmol), DCM (15 mL), and trifluoro acetic acid (3.0 mL) to afford 0.090 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 1.12 (s, 9H), 4.29 (d, J=5.7 Hz, 2H), 7.35 (d, J=8.4 Hz, 1H), 7.43 (s, 1H), 7.60 (d, J=8.7 Hz, 1H), 7.70-7.76 (m, 1H), 8.19-8.23 (m, 3H), 12.76 (s, 1H); MS (m/z): 471.32 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[CH:12](OCC)(OCC)OCC>>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[O:7][CH:12]=[N:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(OCC)OCC
Reactant: NNC(=O)c1ccc(Cl)cc1
Product: Clc1ccc(-c2nnco2)cc1

Procedure:
A stirred solution of 8.1 grams (0.048 mole) of 4-chlorobenzoic acid hydrazide in 300 ml of triethyl orthoformate was heated under reflux for 16 hours. The excess triethyl orthoformate was removed by distillation and the residual solid was stirred with petroleum ether to yield 7.7 grams of 2-(4-chlorophenyl)-1,3,4-oxadiazole; m.p. 129° C. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:9]=[C:8]2[N:10]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([CH:22]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH:23]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:18][CH:17]=3)[C:11]([CH2:13][CH3:14])=[N:12][C:7]2=[C:6]([CH3:40])[CH:5]=1.[CH3:41]I.O>CN(C)C=O>[CH3:3][C:4]1[N:9]=[C:8]2[N:10]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([CH:22]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:23]([C:29]([O:31][CH2:32][CH3:33])=[O:30])([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:41])=[CH:20][CH:21]=3)[C:11]([CH2:13][CH3:14])=[N:12][C:7]2=[C:6]([CH3:40])[CH:5]=1
Reactant: CI
Reactant: CCOC(=O)C(C(=O)OCC)C(c1ccccc1)c1ccc(Cn2c(CC)nc3c(C)cc(C)nc32)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)(C(=O)OCC)C(c1ccccc1)c1ccc(Cn2c(CC)nc3c(C)cc(C)nc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.4 %

Procedure:
To a suspension of 55% sodium hydride in 103 mL of dimethylformamide, cooled with an ice bath, was added dropwise 13 g (25.3 mmol) of the compound obtained in example 59 dissolved in 51 mL of dimethylformamide, followed by 4.6 mL (75.9 mmol) of methyl iodide. After the addition was complete, the reaction mixture was stirred at room temperature overnight. Then, water was added and the solvent was removed. The residue was taken up in ethyl acetate and washed with brine. The organic phase was dried and the solvent was removed to yield 13 g of a crude product. This was chromatographed on silica gel (ethyl acetate-hexane mixtures of increasing polarity) to afford 10.2 g of the title compound of the example (yield: 76%).
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([C:9]([N:11]2[CH2:16][C:15]3([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[O:14][CH2:13][CH2:12]2)=[O:10])[S:7][CH:8]=1)([CH3:3])[CH3:2].Br[CH2:23][C:24]1[CH:25]=[C:26]([CH2:30][CH2:31][OH:32])[CH:27]=[CH:28][CH:29]=1.C(N(CC)CC)C>C(#N)C>[OH:32][CH2:31][CH2:30][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[CH2:23][N:19]1[CH2:18][CH2:17][C:15]2([O:14][CH2:13][CH2:12][N:11]([C:9]([C:6]3[S:7][CH:8]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:5]=3)=[O:10])[CH2:16]2)[CH2:21][CH2:20]1
Reactant: CC(C)c1csc(C(=O)N2CCOC3(CCNCC3)C2)n1
Reactant: OCCc1cccc(CBr)c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)c1csc(C(=O)N2CCOC3(CCN(Cc4cccc(CCO)c4)CC3)C2)n1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
A solution of (4-isopropylthiazol-2-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone (example 66, step b) (0.28 g) and 2-(3-(bromomethyl)phenyl)ethanol (example 6, step a) (0.171 g) in acetonitrile (20 mL) was treated with triethylamine (0.276 mL) and the reaction mixture stirred for 2 hours at 20° C. The solvent was evaporated under reduced pressure and the residue partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was dried over sodium sulphate, filtered and the solvent removed under reduced pressure. The crude product was purified by flash silica chromatography using 2.5% methanol in dichloromethane with 1% triethylamine as solvent to afford the subtitled compound. Yield 0.25 g.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][NH2:14])[CH:8]=1.[N:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1>CO>[CH3:2][O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][NH:14][CH2:26][C:25]2[CH:24]=[CH:23][C:22]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][N:16]=3)=[CH:29][CH:28]=2)[CH:8]=1
Reactant: COC(=O)CCc1cccc(CN)c1
Reactant: O=Cc1ccc(-c2cnccn2)cc1
Agent: Cl
Solvent: CO
Product: COC(=O)CCc1cccc(CNCc2ccc(-c3cnccn3)cc2)c1

Procedure:
The title compound of Step A was prepared from 3-(3-aminomethyl-phenyl)-propionic acid methyl ester hydrochloride salt, of Preparation 44, and 4-pyrazin-2-yl-benzaldehyde, of Preparation 27, using the method described in Example 1, Step A except the imine was formed in MeOH at reflux over 2 h. 1H NMR (400 MHz, CDCl3) δ 9.02 (d, 1H), 8.61 (m, 1H), 8.48 (d, 1H), 7.98 (d, 2H), 7.49 (d, 2H), 7.25 (m, 1H), 7.19 (m, 2H), 7.09 (d,1H), 3.87 (s, 2H), 3.79 (s, 2H), 3.66 (s, 3H), 2.94 (t, 2H), 2.63 (t, 2H); MS 362 (M+1).
Reaction SMILES: S(Cl)(Cl)=O.[OH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]([CH3:15])[CH:7]=1.[CH3:16]O>>[OH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:12][CH3:16])=[O:11])=[C:8]([CH3:15])[CH:7]=1
Reactant: Cc1cc(O)ccc1C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(O)cc1C
Temperature: 60 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To methanol (10 ml) was added dropwise thionyl chloride (1.92 ml, 26.3 mmol) at 0° C., 4-hydroxy-2-methylbenzoic acid (2.00 g, 13.1 mmol) was added, and the mixture was stirred at 60° C. overnight. After completion of the reaction, the solvent was evaporated, and the residue was dissolved in ethyl acetate (20 ml). The mixture was washed twice with 5% aqueous sodium hydrogen carbonate solution (10 ml), once with 1N hydrochloric acid (10 ml), and once with water (10 ml), and the solvent was evaporated to give methyl 4-hydroxy-2-methylbenzoate (2.24 g, yield 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[N:9]=[CH:8][N:7]=[C:6]2[O:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26].[F:30][C:31]([C:34]1[CH:38]=[C:37]([NH:39][C:40](=O)[O:41]C2C=CC=CC=2)[O:36][N:35]=1)([CH3:33])[CH3:32]>CN(C)C1C=CN=CC=1>[F:30][C:31]([C:34]1[CH:38]=[C:37]([NH:39][C:40]([NH:26][C:25]2[CH:27]=[CH:28][CH:29]=[C:23]([O:22][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][N:16]5[CH2:21][CH2:20][O:19][CH2:18][CH2:17]5)=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH:24]=2)=[O:41])[O:36][N:35]=1)([CH3:32])[CH3:33]
Reactant: COc1cc2c(Oc3cccc(N)c3)ncnc2cc1OCCN1CCOCC1
Reactant: CC(C)(F)c1cc(NC(=O)Oc2ccccc2)on1
Agent: CN(C)c1ccncc1
Product: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)F)no4)c3)ncnc2cc1OCCN1CCOCC1
Yield: 49 %

Procedure:
Using the procedure described in Example 229B by using 3-(6-methoxy-7-(2-morpholinoethoxy)quinazolin-4-yloxy)aniline described in Example 251A Step 3 (146 mg, 0.37 mmol) was reacted with phenyl 3-(2-fluoropropan-2-yl)isoxazol-5-ylcarbamate from Example 42A (117 mg, 0.44 mmol) and 4-(dimethylamino)pyridine (45 mg, 0.37 mmol) to give 1-(3-(2-fluoropropan-2-yl)isoxazol-5-yl)-3-(3-(6-methoxy-7-(2-morpholinoethoxy)quinazolin-4-yloxy)phenyl)urea (101.6 mg, 49%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 10.41 (s, 1H), 9.11 (s, 1H), 8.56 (s, 1H), 7.57 (s, 2H), 7.44-7.40 (m, 2H), 7.32 (d, 1H), 7.00 (d, 1H), 6.15 (s, 1H), 4.35-4.33 (m, 2H), 3.98 (s, 3H), 3.62-3.60 (m, 4H), 2.85-2.70 (m, 2H), 2.52-2.50 (m, 4H), 1.70 (s, 3H), 1.63 (s, 3H); LC-MS (ESI) m/z 567 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:16][CH2:15][C:14](O)([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:25])=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(Cl)Cl.C(=O)([O-])[O-].[K+].[K+]>[C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:12][CH:13]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]([NH:23][C:24]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:25])=[CH:21][CH:22]=3)[CH2:15][CH2:16]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Nc1ccc(C2(O)CCN(C(=O)OCc3ccccc3)CC2)cc1)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(C2=CCN(C(=O)OCc3ccccc3)CC2)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 4-hydroxy-4-[4-[[(phenylmethoxy)carbonyl]amino]phenyl]-1-piperidinecarboxylic acid phenylmethyl ester (EXAMPLE 17, Step 1, 2.50 g) in dry methylene chloride under N2 is treated with trifluoroacetic acid (0.84 mL), stirred at ambient temperature for three hours, diluted with saturated aqueous potassium carbonate (25 mL) to neutralize excess trifluoroacetic acid, and the layers are separated. The organic phase is washed with water (20 mL) and saline (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue is chromatographed on silica gel (230-400 mesh, 300 g), eluting with a gradient of ethyl acetate/hexane (20/80-50/50). Pooling of fractions with an Rf =0.69 by TLC (ethyl acetate/hexane, 50/50) and removal of solvent under reduced pressure gives the title compound, mp 146-148° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][C:13](OCC3C=CC4C(=CC=CC=4)N=3)=[CH:12][CH:11]=2)=[O:9])=[CH:3][CH:2]=1.CON(C)C(=O)C1C=CC([CH2:38][CH2:39][C:40]2[CH:49]=[CH:48][C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[N:41]=2)=CC=1>>[N:1]1[CH:2]=[CH:3][C:4]([CH2:7][C:8]([C:10]2[CH:11]=[CH:12][C:13]([CH2:38][CH2:39][C:40]3[CH:49]=[CH:48][C:47]4[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=4)[N:41]=3)=[CH:14][CH:15]=2)=[O:9])=[CH:5][CH:6]=1
Reactant: O=C(Cc1ccncc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: CON(C)C(=O)c1ccc(CCc2ccc3ccccc3n2)cc1
Product: O=C(Cc1ccncc1)c1ccc(CCc2ccc3ccccc3n2)cc1

Procedure:
Following the procedure for the preparation of 2-pyridin-4-yl-1-[4-(quinolin-2-ylmethoxy)-phenyl]-ethanone but substituting N-Methoxy-N-methyl-4-(2-quinolin-2-yl-ethyl)-benzamide provided the title compound. MS: (M+H m/z=353.1).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]2[O:22][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=[CH:5][CH:4]=1.[CH2:34]([O:41][CH2:42][CH2:43]I)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH2:34]([O:41][CH2:42][CH2:43][O:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])[CH2:11][CH:10]2[O:22][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=[CH:5][CH:4]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: ICCOCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CO)cc2)C(OCc2ccc3ccccc3c2)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(COCCOCc3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 1(g), by alkylating tert-butyl (3RS,4RS)-4-(4-hydroxymethyl-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate [Example 22(j)] with 2-(benzyloxy)-ethyl iodide [Helv.Chim.Acta Vol.71, (1988),2039] there was obtained tert-butyl (3RS,4RS)-4-[4-(2-benzyloxy-ethoxymethyl)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless foam; MS: 599 (M+NH4)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:18]([F:19])=[C:17]([F:20])[CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=O)=[C:5]([F:21])[CH:4]=1)[CH3:2].[CH3:22][C:23]1([CH3:32])[O:28][C@@H:27]([CH2:29][O:30][NH2:31])[CH2:26]C[O:24]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>ClCCl>[CH3:32][C:23]1([CH3:22])[O:28][C@@H:27]([CH2:29][O:30][NH:31][C:12](=[O:14])[C:11]2[CH:15]=[CH:16][C:17]([F:20])=[C:18]([F:19])[C:10]=2[NH:9][C:6]2[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][C:5]=2[F:21])[CH2:26][O:24]1
Reactant: CCc1ccc(Nc2c(C(=O)O)ccc(F)c2F)c(F)c1
Reactant: CC1(C)OCC[C@H](CON)O1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1ccc(Nc2c(C(=O)NOC[C@H]3COC(C)(C)O3)ccc(F)c2F)c(F)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirring solution of the product of Example 1, Step D, 2-[(4-ethyl-2-fluorophenyl)amino]-3,4-difluorobenzoic acid (0.480 g, 1.626 mmol) in dichloromethane (25 mL) is added to the product of Example 31, Step D, (R)-O-(2,2-dimethyl-[1,3]dioxan-4-ylmethyl)-hydroxylamine (0.38 g, 2.57 mmol), triethylamine (0.54 mL, 3.85 mmol), and benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (1.34 g, 2.57 mmol) and allowed to stir at ambient temperature for 90 minutes. The reaction mixture was concentrated in vacuo and the affording residue was partitioned between ethyl acetate and water. The organic layers were washed twice with saturated sodium carbonate solution and twice with brine. The organic layer was collected, dried over sodium sulfate, filtered and concentrated in vacuo. N-((R)-2,2-Dimethyl-[1,3]dioxolan-4-ylmethoxy)-2-(4-ethyl-2-fluoro-phenylamino)-3,4-difluoro-benzamide was isolated via silica column chromatography in 4:1 hexanes/ethyl acetate, then 3:1 hexanes/ethyl acetate affording a white foam (0.515 g, 56.7%).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:9][CH:8]=[C:7]([C:10](OC)=[O:11])[CH:6]=1)[CH3:3].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C(OCC)C>[CH3:3][N:2]([CH2:4][C:5]1[S:9][CH:8]=[C:7]([CH2:10][OH:11])[CH:6]=1)[CH3:1]
Reactant: COC(=O)c1csc(CN(C)C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CN(C)Cc1cc(CO)cs1
Yield: 93.1 %

Procedure:
A solution of methyl 5-(dimethylaminomethyl)-3-thiophenecarboxylate (1.5 g) in diethylether (50 ml) was treated with lithium aluminium hydride (0.21 g). After 1 hour water (2 ml) was added and the solution was filtered through diatomaceous earth. Evaporation of the filtrate gave an oily residue which distilled to give the title compound as an oil (1.2 g) b.p. (120°/0.1 mm).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](CS([O-])(=O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:19]=[N+:20]=[N-:21].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:19]=[N+:20]=[N-:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC(CS(=O)(=O)[O-])CC1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(N=[N+]=[N-])CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
N-tert-butyloxycarbonyl-4-piperidinemethanesulfonate (10.0 g, 36 mmol) was dissolved in DMF (100 mL), sodium azide (NaN3, 7.0 g, 108 mmol) was added, the reaction mixture was warmed to 100° C., and the reaction was performed overnight. The solvent in the resultant mixture was evaporated under reduced pressure, water (100 mL) and ethyl acetate (100 mL) were added, the organic phase was separated, washed with water (100 mL×2) and saturated brine successively, dried over anhydrous sodium sulfate, and then evaporated under reduced pressure to remove ethyl acetate so as to yield the target product as light yellow liquid (8.2 g, 36 mmol; yield=100%). The crude produce was directly used for the reaction in the next step.
Reaction SMILES: CO.[CH2:3]([O:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:18]1[O:20][C@@H:19]1[CH2:21][OH:22]>C(O)C>[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]([NH:15][CH2:18][CH:19]([OH:20])[CH2:21][OH:22])=[CH:16][CH:17]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Reactant: OC[C@@H]1CO1
Solvent: CO
Solvent: CCO
Product: OCC(O)CNc1ccc(OCc2ccccc2)cc1

Procedure:
The product is obtained with a 90% yield; m.p.: 102° C.; [α]D20 =+12,7° (c=1, CH3OH). This same product can be obtained by heating 4-benzyloxyaniline in ethanol in the presence of (R)-glycidol.
Reaction SMILES: O.C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[C:29](=[O:30])[C:28]([C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)=[CH:27][N:26]([CH2:38][CH2:39][F:40])[CH:25]=3)=[O:23])=[CH:17][CH:16]=2)=[CH:13][C:12](Br)=[CH:11][N:10]=1.CC1(C)C(C)(C)OB([C:50]2[CH:51]=[N:52][N:53]([CH:55]3[CH2:60][CH2:59][N:58]([C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[CH2:57][CH2:56]3)[CH:54]=2)O1>C(COC)OC.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>[NH2:8][C:9]1[N:10]=[CH:11][C:12]([C:50]2[CH:51]=[N:52][N:53]([CH:55]3[CH2:56][CH2:57][N:58]([C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[CH2:59][CH2:60]3)[CH:54]=2)=[CH:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]2[C:29](=[O:30])[C:28]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)=[CH:27][N:26]([CH2:38][CH2:39][F:40])[CH:25]=2)=[O:23])=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: Nc1ncc(Br)cc1-c1ccc(NC(=O)c2cn(CCF)cc(-c3ccc(F)cc3)c2=O)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: [Cs+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(-c4ccc(NC(=O)c5cn(CCF)cc(-c6ccc(F)cc6)c5=O)cc4)c3)cn2)CC1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 120.8 %

Procedure:
Water (0.5 ml), cesium carbonate (60 mg) and tetrakis(triphenylphosphine)palladium (16 mg) were added to a solution of the compound obtained in Step 1 of Example 43 (75 mg) and tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate (59 mg) in dimethoxyethane (4 ml). The mixture was stirred under microwave irradiation at 100° C. for 10 minutes. After leaving to cool, the reaction product was purified by silica gel column chromatography [chloroform:methanol=99:1->9:1 (v/v)]. Further, the resulting crude purified product was crystallized from ethyl acetate to give 120 mg of the title compound as a solid.
Reaction SMILES: [F:1][C:2]1([F:15])[C:6]([F:8])([F:7])[C:5]2[CH:9]=[CH:10][CH:11]=[C:12]([CH2:13]O)[C:4]=2[O:3]1.[Br-:16].[Li+].C[Si](Cl)(C)C>C(#N)C>[F:1][C:2]1([F:15])[C:6]([F:8])([F:7])[C:5]2[CH:9]=[CH:10][CH:11]=[C:12]([CH2:13][Br:16])[C:4]=2[O:3]1
Reactant: [Br-]
Reactant: OCc1cccc2c1OC(F)(F)C2(F)F
Agent: C[Si](C)(C)Cl
Agent: [Li+]
Solvent: CC#N
Product: FC1(F)Oc2c(CBr)cccc2C1(F)F

Procedure:
This compound is prepared in a manner analogous to that of Step A of Example 5, using 11.1 grams (0.05 mole) of 2,2,3,3-tetrafluoro-2,3-dihydrobenzofuran-7-ylmethanol, 8.7 grams (0.1 mole) of lithium bromide, and 13.5 grams (0.125 mole) of trimethylsilyl chloride in 100 mL of acetonitrile, yielding 2,2,3,3-tetrafluoro-2,3-dihydrobenzofuran-7-ylmethyl bromide.