Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[S:8][CH:9]=[C:10]([C:12](OCC)=[O:13])[N:11]=2)[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[N:1]1([C:7]2[S:8][CH:9]=[C:10]([CH2:12][OH:13])[N:11]=2)[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1csc(N2CCSCC2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1csc(N2CCSCC2)n1

Procedure:
The reaction described in Preparation 15 was repeated, but using 1.5 g of ethyl 2-(thiomorpholin-4-yl)thiazole -4-carboxylate, 0.26 g of lithium aluminum hydride and 15 ml of tetrahydrofuran, giving the title compound as a colorless powder.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]2[CH2:14][CH:9]1[CH2:10][N:11]2[CH2:15][C:16]#[N:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Ni].N>[CH2:1]([N:8]1[CH2:13][CH:12]2[CH2:14][CH:9]1[CH2:10][N:11]2[CH2:15][CH2:16][NH2:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CCN1CC2CC1CN2Cc1ccccc1
Agent: [Ni]
Agent: N
Product: NCCN1CC2CC1CN2Cc1ccccc1
Yield: 85.8 %

Procedure:
A solution of 5.74 g (25.3 mmoles) of 140 and 50 mL of NH3 were hydrogenated with 2 g of Raney nickel in a steel autoclave at 100 bar H2 and 100° C. for 2 hours. The catalyst was filtered off with suction and the solution was evaporated and distilled using a bulb tube (boiling point: 135°–145° C. at 0.01 mbar): 5.02 g of 141 as a colorless oil (87% of the theoretical yield).
Reaction SMILES: Cl[C:2](Cl)([C:12]([CH3:14])=[O:13])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[H][H]>O.C1(C)C=CC=CC=1.[H][H]>[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:4])[CH2:2][C:12]([CH3:14])=[O:13]
Reactant: [H][H]
Reactant: CC(=O)C(Cl)(Cl)C(=O)Nc1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)CC(=O)Nc1ccccc1

Procedure:
2.46 g (0.01 mole) of α,α-dichloroacetoacetanilide was dissolved in 20 ml of water and 30 ml of toluene, and dehalogenated with hydrogen using 5% Pd/C as catalyst. Hydrogen was allowed to react until no more would be absorbed. The first equivalent (251 ml at 739 mm pressure and 25° C.) was absorbed in 50 minutes (a rate of about 5 ml/min) whereas the 274 ml (second equivalent) was absorbed at the much slower rate of about 0.9 ml/min. On the basis of the hydrogen absorbed, it was concluded that the dehalogenation had proceeded to remove both chlorines and hence to give acetoacetanilide. This was confirmed by filtering off the catalyst, separating off the water phase and finally isolating the product from the toluene. Obtained were 1.57 g or 89% of acetoacetanilide, mp 79°-84° C.
Reaction SMILES: [Cl:1][C:2]1[S:14][C:5]2=[N:6][C:7]([Cl:13])=[C:8]([C:10](=[O:12])[CH3:11])[CH:9]=[C:4]2[CH:3]=1>C1COCC1>[Cl:1][C:2]1[S:14][C:5]2=[N:6][C:7]([Cl:13])=[C:8]([C@H:10]([OH:12])[CH3:11])[CH:9]=[C:4]2[CH:3]=1
Reactant: CC(=O)c1cc2cc(Cl)sc2nc1Cl
Solvent: C1CCOC1
Product: C[C@@H](O)c1cc2cc(Cl)sc2nc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-(2,6-Dichlorothieno[2,3-b]pyridin-5-yl)ethanone (3.6 g, 14.63 mmol) was dissolved in THF (100 mL) and ccoled to −55° C. in a dry ice/MeCN bath. To this solution was added a solution of (+)-dip-chloride(tm) (10.32 g, 32.2 mmol) in THF dropwise. The reaction was allowed to warm slowly to rt overnight and quenched by addition of 10 mL of acetone and 50 mL of 50% sat. Na2CO3. The reaction was stirred for 1 h and diluted with 400 mL of ethyl acetate. The organic layer was washed with 2×100 mL of 50% sat Na2CO3, 2×100 mL of water, and 2×100 mL of brine. The reaction was dried over MgSO4, filtered and concentrated. The residue was slurried in 100 mL water/200 mL hexanes for 3 h to form white ppt that was filtered and dried to afford (R)-1-(2,6-dichlorothieno[2,3-b]pyridin-5-yl)ethanol. Enantiomeric excess as determined by chiral HPLC was found to be =99%. 1H NMR (400 MHz, CDCl3) δ 8.19 (d, J=0.8 Hz, 1H), 7.14 (s, 1H), 5.32 (qdd, J=6.3, 3.5, 0.8 Hz, 1H), 2.07 (J=3.5 Hz, 1H), 1.56 (d, J=6.6 Hz, 3H) ppm.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:29](O)=[O:30])[CH2:19][C:20]3[CH:25]=[C:24]([CH3:26])[C:23]([OH:27])=[C:22]([CH3:28])[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:32]=[CH:33][CH:34]=[CH:35][C:4]=2[NH:3]1.[CH3:36][N:37]1[CH2:42][CH2:41][CH:40]([CH:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH2:39][CH2:38]1>>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:19][C:20]3[CH:25]=[C:24]([CH3:26])[C:23]([OH:27])=[C:22]([CH3:28])[CH:21]=3)[C:29]([N:46]3[CH2:47][CH2:48][CH:43]([CH:40]4[CH2:39][CH2:38][N:37]([CH3:36])[CH2:42][CH2:41]4)[CH2:44][CH2:45]3)=[O:30])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:32]=[CH:33][CH:34]=[CH:35][C:4]=2[NH:3]1
Reactant: CN1CCC(C2CCNCC2)CC1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(C)c1O
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(C3CCN(C)CC3)CC2)cc(C)c1O

Procedure:
Prepared analogously to Example 1i from 150 mg (0.31 mmol) (R)-2-(4-hydroxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 62 mg (0.34 mmol) 1-methyl-[4,4′]bipiperidinyl.
Reaction SMILES: [C:1](=[O:12])([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])OC(C)(C)C.[CH2:13]([O:15][CH:16]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][NH:35][CH3:36])[CH:29]=2)=[CH:24][CH:23]=1)[C:17]([O:19][CH3:20])=[O:18])[CH3:14].C(N(CC)CC)C>ClCCl>[C:8]([O:7][C:1]([CH2:36][NH:35][CH2:34][C:30]1[CH:29]=[C:28]([C:25]2[CH:26]=[CH:27][C:22]([CH2:21][CH:16]([O:15][CH2:13][CH3:14])[C:17]([O:19][CH3:20])=[O:18])=[CH:23][CH:24]=2)[CH:33]=[CH:32][CH:31]=1)=[O:12])([CH3:9])([CH3:10])[CH3:11]
Reactant: CCOC(Cc1ccc(-c2cccc(CNC)c2)cc1)C(=O)OC
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(Cc1ccc(-c2cccc(CNCC(=O)OC(C)(C)C)c2)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 96 %

Procedure:
A solution of 0.4 g (1.9 mmol) of di-tert-butyl carbonate in 5 ml of dichloromethane is added dropwise to a solution of 0.6 g (1.9 mmol) of methyl 2-ethoxy-3-(3′-methylaminomethylbiphenyl-4-yl)propionate and 0.25 ml (1.9 mmol) of triethylamine in 10 ml of dichloromethane. After stirring at room temperature for 48 hours, the medium is washed with water, extracted with dichloromethane, dried over magnesium sulfate, filtered and evaporated to dryness. The residue obtained is purified by chromatography on a column of silica eluted with a 9/1 heptane/ethyl acetate mixture. 0.78 g of methyl 3-{3′-[(tert-butoxycarbonylmethylamino)-methyl]biphenyl-4-yl}-2-ethoxypropionate is obtained in a yield of 85%.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:36]=[CH:35][C:22]([C:23]([N:25]2[CH:29]([C:30]([O:32]CC)=[O:31])[CH2:28][S:27][CH2:26]2)=[O:24])=[CH:21][CH:20]=1>C(=O)(O)[O-].[Na+].CC(C)=O>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([N:25]2[CH:29]([C:30]([OH:32])=[O:31])[CH2:28][S:27][CH2:26]2)=[O:24])=[CH:35][CH:36]=1
Reactant: CCOC(=O)C1CSCN1C(=O)c1ccc(NCCCCCCCCCCCCCCCCBr)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(O)C1CSCN1C(=O)c1ccc(NCCCCCCCCCCCCCCCCBr)cc1

Procedure:
One-tenth mole of 4-(16-bromohexadecylamino)benzoyl chloride hydrochloride in methylene chloride is added to a solution of 0.1 mole of ethyl thiazolidine-4-carboxylate in chloroform containing two equivalents of triethylamine. After 5 hours at 20° C. the solution is filtered and evaporated to a white solid which is recrystallized from acetonitrile to yield 3-[4-(16-bromohexadecylamino)benzoyl]-4-carbethoxythiazolidine. By means of the alkaline hydrolysis method of Example 10, the ethyl ester is converted to the subject carboxylic acid. This acid is also prepared using the procedure of this Example except that the acylation of the thiazolidine-4-carboxylic acid is carried out in aqueous acetone sodium bicarbonate solution.
Reaction SMILES: [OH:1][C:2]1[CH:36]=[CH:35][C:5]([C:6]([CH2:8][NH:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=2[CH:18]2[CH2:27][CH2:26][C:25]3[CH:24]=[C:23]([O:28]C(=O)C(C)(C)C)[CH:22]=[CH:21][C:20]=3[CH2:19]2)=O)=[CH:4][CH:3]=1.Cl[CH2:38][C:39]([N:41]([CH3:43])[CH3:42])=O>>[CH3:42][N:41]([CH3:43])[CH2:39][CH2:38][O:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][CH2:8][NH:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=2[CH:18]2[CH2:27][CH2:26][C:25]3[CH:24]=[C:23]([OH:28])[CH:22]=[CH:21][C:20]=3[CH2:19]2)=[CH:4][CH:3]=1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCC(=O)c2ccc(O)cc2)c1
Reactant: CN(C)C(=O)CCl
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCc2ccc(OCCN(C)C)cc2)c1
Yield: 22.9 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)methylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 2-chloro-N,N-dimethylacetamide (13 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (5.4 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:16])=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([O:12][CH2:13][CH3:14])[C:6]=2[CH:15]=1.[C:17]1([CH3:24])[C:18]([CH3:23])=[CH:19][CH:20]=[CH:21][CH:22]=1>>[CH2:13]([O:12][N:7]1[C:6]2[CH:15]=[C:2]([N:1]3[CH:23]=[C:18]4[C:17]([CH2:22][CH2:21][CH2:20][CH2:19]4)=[CH:24]3)[C:3]([F:16])=[CH:4][C:5]=2[O:10][CH2:9][C:8]1=[O:11])[CH3:14]
Reactant: CCON1C(=O)COc2cc(F)c(N)cc21
Reactant: Cc1ccccc1C
Product: CCON1C(=O)COc2cc(F)c(-n3cc4c(c3)CCCC4)cc21
Reaction time: 0.25 h

Procedure:
A mixture consisting of 6-amino-4-ethoxy-7-fluoro-1,4-benzoxazin-3(4H)-one (1.06 g), 1,2-cyclohexanedicarboxyaldehyde (0.7 g) and xylene (50 ml) was stirred for 15 minutes under heat-refluxing. After the solvent had been distilled off under reduced pressure, the residue was purified through silica-gel chromatography (eluent: hexane/ethyl acetate=19/1) to obtain the aimed 4-ethoxy-7-fluoro-6-(4,5,6,7-tetrahydroisoindole-2-yl)-1,4-benzoxazin-3(4H)-one (1.37 g). nD20 1.5797
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[CH:10]=[C:11]([C@H:17]2[CH2:21][CH2:20][CH2:19][N:18]2C(OC(C)(C)C)=O)[C:12]([O:15][CH3:16])=[N:13][CH:14]=1>C(Cl)Cl>[F:8][C:9]1[CH:10]=[C:11]([C@H:17]2[CH2:21][CH2:20][CH2:19][NH:18]2)[C:12]([O:15][CH3:16])=[N:13][CH:14]=1
Reactant: COc1ncc(F)cc1[C@H]1CCCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ncc(F)cc1[C@H]1CCCN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.9 %

Procedure:
A DCM (12 mL) solution of TFA (11.3 mL, 146 mmol) was added to (R)-tert-butyl 2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidine-1-carboxylate (4.33 g, 14.6 mmol) and stirred at ambient temperature for 1 hour. The reaction was then concentrated, taken up in EtOAc, then washed with NaHCO3 and brine. The organic phase was dried (MgSO4), filtered, and concentrated, and the crude material was purified by silica column chromatography eluting with a 1-2% 7 N NH3-MeOH/DCM to afford (R)-5-fluoro-2-methoxy-3-(pyrrolidin-2-yl)pyridine as a liquid (1.40 g, 49% yield).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].N1C=CC=CC=1.O[CH2:23][C:24]([CH3:46])([CH3:45])[O:25][C:26]1[C:27]([CH2:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[C:28]2[C:33](=[CH:34][CH:35]=1)[C:32](=[O:36])[CH2:31][CH2:30][CH2:29]2>ClCCl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][CH2:45][C:24]([CH3:46])([O:25][C:26]1[CH:35]=[CH:34][C:33]2[C:32](=[O:36])[CH2:31][CH2:30][CH2:29][C:28]=2[C:27]=1[CH2:37][CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[CH3:23])(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CC(C)(CO)Oc1ccc2c(c1CCc1ccccc1)CCCC2=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(COS(=O)(=O)C(F)(F)F)Oc1ccc2c(c1CCc1ccccc1)CCCC2=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 90 %

Procedure:
Trifluoromethanesulfonic anhydride (0.12 mL, 0.74 mmol) was added to a solution of pyridine (0.14 mL, 1.77 mmol) in dichloromethane (0.5 mL). The resulting mixture was added over 15 min to an ice-cooled solution of 6-(2-hydroxy-1,1-dimethylethoxy)-5-(2-phenylethyl)-3,4-dihydro-1(2H)-naphthalenone (100 mg, 0.30 mmol) in dichloromethane (0.5 mL). The resulting mixture was stirred for 15 min and was then quenched by the addition of water (2 mL). The mixture was diluted with 1 M aqueous hydrochloric acid (10 mL) and extracted with ethyl acetate (3×5 mL). The combined extracts were washed with 1 M aqueous hydrochloric acid (10 mL), saturated aqueous copper sulfate (3×5 mL), and was then dried (brine, Na2SO4) and concentrated. The residue was purified by dry-flash column chromatography (SiO2, 5-40% ethyl acetate-hexane) to give 2-methyl-2-{[5-oxo-1-(2-phenylethyl)-5,6,7,8-tetrahydro-2-naphthalenyl]oxy}propyl trifluoromethanesulfonate as a colorless oil, 125 mg, 90% yield. NMR spectrum was consistent with structure. MS EI: M+• 470.1376 (M+• 470.1375).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]2[NH:6][C:7](=O)[O:8][C:9]([CH3:11])([CH3:10])[C:4]=2[CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:24])=CC=1>>[Br:1][C:2]1[CH:14]=[CH:13][C:5]2[NH:6][C:7](=[S:24])[O:8][C:9]([CH3:11])([CH3:10])[C:4]=2[CH:3]=1
Reactant: CC1(C)OC(=O)Nc2ccc(Br)cc21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: CC1(C)OC(=S)Nc2ccc(Br)cc21

Procedure:
The product was prepared, from 6-bromo-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one and Lawesson's reagent using the procedure of Example 9, as a white solid: mp 221-222.5° C.; 1H-NMR (CDCl3) δ 9.38 (s, 1H, D2O exchangeable), 7.42 (dd, 1H, J=8.5, 2.1 Hz), 7.29 (d, 1H, J=2.0 Hz), 6.76 (d, 1H, J=8.4 Hz), 1.76 (s, 6H); MS (EI) m/z 272 ([M+H]+, 94%), 274 ([M+H]+, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][CH:11]([CH2:13]S([O-])(=O)=O)[O:10][N:9]=2)=[CH:4][C:3]=1[F:18].[N-:19]=[N+:20]=[N-:21].[Na+]>CN(C=O)C>[N:19]([CH2:13][CH:11]1[O:10][N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([F:18])[CH:4]=2)[CH2:12]1)=[N+:20]=[N-:21]
Reactant: O=S(=O)([O-])CC1CC(c2ccc(Br)c(F)c2)=NO1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC1CC(c2ccc(Br)c(F)c2)=NO1
Temperature: 80 °C
Reaction time: 5 h
Yield: 96.1 %

Procedure:
[3-(4-Bromo-3-fluorophenyl)-4,5-dihydroisoxazol-5-yl]methane sulfonate (9.85 g, 28 mmol) was dissolved in dry DMF (100 ml). Sodium azide (2.73 g, 42 mmol) was added and the reaction mixture stirred at 80° C. for 5 hours. The reaction mixture was concentrated in vacuo then azeotroped with xylene (20 ml). The crude product was dissolved in ethyl acetate (100 ml) and washed with water (100 ml). The organic layer was separated, dried over magnesium sulfate, filtered then concentrated in vacuo to yield 8.046 g of the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15](Cl)=[O:16])=[CH:10][C:9]=2[CH3:18])=[O:7])=[CH:4][CH:3]=1.[O-2].[Mg+2].[NH2:23][C@H:24]([C:30]([OH:32])=[O:31])[CH2:25][CH2:26][C:27](=[O:29])[NH2:28].Cl>O1CCOCC1.O>[OH2:7].[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]([NH:23][C@H:24]([C:30]([OH:32])=[O:31])[CH2:25][CH2:26][C:27](=[O:29])[NH2:28])=[O:16])=[CH:10][C:9]=2[CH3:18])=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1cc(CC(=O)Cl)n(C)c1C(=O)c1ccc(Cl)cc1
Reactant: NC(=O)CC[C@H](N)C(=O)O
Agent: Cl
Agent: [Mg+2]
Agent: [O-2]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(CC(=O)N[C@@H](CCC(N)=O)C(=O)O)n(C)c1C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 64 h
Yield: 20.6 %

Procedure:
A solution of 30.5 g (0.1 mole) of [5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrol-2-yl]-acetyl chloride in 150 ml of dioxane was added slowly at 0°-5° C. to a suspension of 5.88 g (0.15 mole) of magnesium oxide and 14.3 g (0.1 mole) of L-glutamine in 300 ml of water. The resulting yellow suspension was stirred at room temperature for 64 hours. The mixture was acidified with 1N hydrochloric acid and cooled. The precipitate was collected, washed with water and air dried. It was recrystallized three times from 2-propanol to give 10.8 g of light tan solid which was subjected to chromatography on silica gel. The column was eluted with chloroform:acetic acid:methanol (95:05:4.5). The major compound bearing fraction was concentrated to dryness and the residue recrystallized from acetone, water (2:1) to give 4.5 g (10% yield) of pale yellow crystalline N-{[5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrol-2-yl]-acetyl}-glutamine, hydrate (1:1), m.p. 186°-188° C.
Reaction SMILES: [C:1]([C:3]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[NH:5][C:4]=1[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)#[N:2].C([O-])(O)=[O:22].[Na+]>S(=O)(=O)(O)O>[NH2:2][C:1]([C:3]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)[NH:5][C:4]=1[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)=[O:22]
Reactant: O=C([O-])O
Reactant: Cc1c(-c2ccncc2)[nH]c(-c2ccncc2)c1C#N
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1c(-c2ccncc2)[nH]c(-c2ccncc2)c1C(N)=O
Temperature: 85 °C
Reaction time: 15 h
Yield: 51 %

Procedure:
3-Cyano-4-methyl-2,5-di(4-pyridyl)-1H-pyrrole (200 mg, 0.77 mmol) was dissolved in sulfuric acid (3 mL) and the mixture was stirred for 15 hours at 85° C. After cooling, fuing sulfuric acid (1 drop) was added to the reaction mixture and stirred for 1 hour at room temperature. The reaction mixture was neutralized by saturated aqueous NaHCO3 solution, and the resulting precipitates were collected by filtration. Recrystallization from EtOH gave the title compound (110 mg, 51% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:15][NH2:16])=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.[CH:22](O)=O>>[CH2:1]([O:8][C:9]1[C:10]2[N:11]([CH:22]=[N:16][CH:15]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CO
Reactant: NCc1ncccc1OCc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: c1ccc(COc2cccn3cncc23)cc1

Procedure:
This compound is prepared according to the same procedure as in preparation II (stage C) from 2.8 g (13.25 mmol) of 1-[3-(benzyloxy)pyridin-2-yl]methanamine [described in Inorg. Chem., (2003), 42(14), 4401] by formylation with formic acid and then cyclization by reaction with phosphoryl chloride. 1.74 g of a brown oil are obtained.
Reaction SMILES: C([O:8][CH2:9][CH:10]1[CH2:17][CH2:16][CH2:15][CH2:14][C:11]21[CH2:13][CH2:12]2)C1C=CC=CC=1.[H][H]>CO.CCOC(C)=O>[CH2:12]1[C:11]2([CH2:14][CH2:15][CH2:16][CH2:17][CH:10]2[CH2:9][OH:8])[CH2:13]1
Reactant: [H][H]
Reactant: c1ccc(COCC2CCCCC23CC3)cc1
Solvent: CCOC(C)=O
Solvent: CO
Product: OCC1CCCCC12CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-((benzyloxy)methyl)spiro[2,5]-octane (0.42 g, 1.8 mmol) in a 5:1 MeOH-EtOAc (12 mL) Pd/C (0.05 g, 5 wt %, 50% wet Degussa type) was added. The flask was fitted with a balloon of hydrogen, and the heterogeneous reaction mixture was stirred for 2 hours under a hydrogen atmosphere at rt. The catalyst solids were filtered off and the filtrate was concentrated under vacuum to give the desired product spyri[2.5]octan-4-ylmethanol as clear oil. 1H NMR (400 MHz, CDCl3) δ 3.74-3.62 (m, 2H), 3.48 (d, J=5.2 Hz, 2H), 1.65-1.59 (m, 2H), 1.51-1.43 (m, 3H), 1.27-1.24 (m, 1H), 1.12-1.11 (m, 1H), 0.96-0.95 (m, 1H), 0.41-0.37 (m, 1H), 0.29-0.17 (m, 3H). MS m/z 123.1 (M−17+1).
Reaction SMILES: C(ON[C:10]([C@H:12]1[C@@H:17]([OH:18])[C@H:16]([OH:19])[C@@H:15]([OH:20])[CH2:14][N:13]1[S:21]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][O:33][CH2:34][CH3:35])=[CH:26][CH:25]=1)(=[O:23])=[O:22])=[O:11])C1C=CC=CC=1.C[OH:37]>[Pd]>[CH2:34]([O:33][CH2:32][CH2:31][O:30][C:27]1[CH:26]=[CH:25][C:24]([S:21]([N:13]2[CH2:14][C@H:15]([OH:20])[C@@H:16]([OH:19])[C@H:17]([OH:18])[C@@H:12]2[C:10]([OH:37])=[O:11])(=[O:22])=[O:23])=[CH:29][CH:28]=1)[CH3:35]
Reactant: CCOCCOc1ccc(S(=O)(=O)N2C[C@H](O)[C@@H](O)[C@H](O)[C@@H]2C(=O)NOCc2ccccc2)cc1
Reactant: CO
Agent: [Pd]
Product: CCOCCOc1ccc(S(=O)(=O)N2C[C@H](O)[C@@H](O)[C@H](O)[C@@H]2C(=O)O)cc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
The above compound (6) (1.66 g) was dissolved in methanol (70 mL) and 10% Pd—C (350 mg) was added, and then the mixture was stirred under a hydrogen atmosphere at 40° C. for one hour. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel medium pressure column chromatography (chloroform:methanol=10:1→5:1) to obtain the titled compound (815 mg) as a colorless powder.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](Cl)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:20]2([OH:26])[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]2)[CH:17]=[CH:18][CH:19]=1>>[OH:26][C:20]1([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([O:13][CH3:12])[CH:15]=2)[CH2:25][CH2:24][CH2:23][N:22]([C:9](=[O:10])[CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:21]1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: COc1cccc(C2(O)CCCNC2)c1
Product: COc1cccc(C2(O)CCCN(C(=O)CCc3ccccc3)C2)c1

Procedure:
The compound of Example 53 was prepared according to the general preparation protocol A from 3-phenyl-propionyl chloride and 3-(3-methoxy-phenyl)-piperidine-3-ol.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:13]([CH3:14])=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][C:6]=1[CH3:15])[CH:2]=[CH2:3].S(Cl)([Cl:18])=O>C(Cl)(Cl)Cl>[CH2:1]([O:4][C:5]1[C:13]([CH3:14])=[CH:12][C:8]([C:9]([Cl:18])=[O:10])=[CH:7][C:6]=1[CH3:15])[CH:2]=[CH2:3]
Reactant: O=S(Cl)Cl
Reactant: C=CCOc1c(C)cc(C(=O)O)cc1C
Solvent: ClC(Cl)Cl
Product: C=CCOc1c(C)cc(C(=O)Cl)cc1C

Procedure:
To a solution of 4-allyloxy-3,5-dimethyl-benzoic acid (5.26 g, 25.5 mmol) in CHCl3 (75 mL), thionylchloride (7.5 mL, 103 mmol) is added at rt. The mixture is refluxed for 2 h before the solvent is evaporated to give crude 4-allyloxy-3,5-dimethyl-benzoic acid chloride as a brownish oil. To a solution of the acid chloride in DCM (50 mL) hydrazine (75 mL of a 1 M solution in THF) in DCM (250 mL) is added at 0° C. The mixture is stirred at rt for 15 h before it is diluted with diethyl ether and extracted with 1 N aq. HCl (75 mL, then 5×50 mL). The combined aq. extracts are basified by adding 33% aq. KOH solution and extracted with DCM (5×50 mL). The combined DCM extracts are dried over Na2SO4, filtered and evaporated to give 4-allyloxy-3,5-dimethyl-benzoic acid hydrazide (5.39 g) as a white solid; LC-MS: tR=0.71 min, [M+1]+=221.20, 1H NMR (D6-DMSO): δ 2.22 (s, 6H), 4.28-4.37 (m, 2H), 4.39 (s, 2H), 5.19-5.28 (m, 1H), 5.36-5.47 (m, 1H), 6.00-6.15 (m, 1H), 7.49 (s, 2H), 9.55 (s, 1H).
Reaction SMILES: C([O:3][C:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][C:7]2[CH:15]=[C:16]([CH2:19][C:20]([O:22]CC)=[O:21])[CH:17]=[CH:18][C:6]=2[CH:5]=1)C.Br>C1(C)C(C)=CC=CC=1>[O:3]=[C:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][C:7]2[CH:15]=[C:16]([CH2:19][C:20]([OH:22])=[O:21])[CH:17]=[CH:18][C:6]=2[CH2:5]1
Reactant: CCOC(=O)Cc1ccc2c(c1)Cc1ccccc1C(OCC)=C2
Agent: Br
Solvent: Cc1ccccc1C
Product: O=C(O)Cc1ccc2c(c1)Cc1ccccc1C(=O)C2
Yield: 84.7 %

Procedure:
In 1 ml of xylene was dissolved 0.1 g of ethyl 10-ethoxy-5H-dibenzo[a,d]cycloheptene-3-acetate obtained in Example 13, and 5 ml of 47% hydrobromic acid was added. The mixture was heated under reflux for 2 hours with vigorous stirring. After the reaction, the reaction mixture was cooled, and then worked up in the same way as in Example 19 to afford 0.07 g of 10,11-dihydro-10-oxo-5H-dibenzo[a,d]cycloheptene-3-acetic acid as a colorless crystalline powder (recrystallized from a mixture of methanol and n-hexane) having a melting point of 186° to 187.5° C.
Reaction SMILES: [F:1][CH:2]([F:15])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:14])=[C:9]([C:11](=O)[CH3:12])[CH:10]=1.[CH3:16][C:17]([S@:20]([NH2:22])=[O:21])([CH3:19])[CH3:18]>>[F:1][CH:2]([F:15])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:14])=[C:9]([CH:11]([NH:22][S@@:20]([C:17]([CH3:19])([CH3:18])[CH3:16])=[O:21])[CH3:12])[CH:10]=1
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1cc(OCC(F)F)ccc1C
Product: Cc1ccc(OCC(F)F)cc1C(C)N[S@](=O)C(C)(C)C
Yield: 61 %

Procedure:
The title compound is prepared in 61% yield (400 mg, clear colorless oil) from 1-(5-(2,2-difluoroethoxy)-2-methylphenyl)ethanone (440 mg, 2.1 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.