Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:7]=2[CH:13]=1.C([O-])([O-])=O.[Na+].[Na+].Br[CH:21](Cl)[CH2:22][CH3:23]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][CH2:9][N:8]3[C:7]=2[C:13]=1[CH2:21][CH2:22][CH2:23]3
Reactant: CCC(Cl)Br
Reactant: COc1ccc2c(c1)NCCCC2
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ccc2c3c1CCCN3CCCC2
Reaction time: 18 h

Procedure:
To a solution of 8-methoxy-2,3,4,5-tetrahydro-1H-benzo[b]azepine (0.25 g) in bromochloropropane (2 mL), Na2CO3 (0.6 g) was added, and the reaction heated to reflux. After stirring for 18 hours, the heat was removed, the reaction partitioned between water (30 mL) and ether (25 mL), the layers separated, and the organic layer washed with brine, dried (Na2SO4) and concentrated. The crude product was purified by silica gel chromatography (gradient of EtOAc in heptane) to provide the title compound (0.27 g) as a clear oil: 1H NMR (DMSO-d6) δ 6.82 (d, 1H); 6.36 (d, 1H), 3.68 (s, 3H), 3.04-3.00 (m, 2H), 2.89-2.85 (m, 2H), 2.60-2.57 (m, 2H), 2.53-2.49 (m, 2H), 1.70-1.61 (m, 4H), 1.48-1.40 (m, 2H); MS expected 218 (C14H20NO, M+1), found 218.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][C:6]1[CH:32]=[CH:31][C:9]([O:10][CH2:11][C@@H:12]([NH:14][CH2:15][C@@H:16]([O:23][Si](C(C)(C)C)(C)C)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:13])=[CH:8][CH:7]=1)=[O:4].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:1][O:2][C:3]([CH2:5][C:6]1[CH:32]=[CH:31][C:9]([O:10][CH2:11][C@@H:12]([NH:14][CH2:15][C@H:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[OH:23])[CH3:13])=[CH:8][CH:7]=1)=[O:4]
Reactant: COC(=O)Cc1ccc(OC[C@H](C)NC[C@@H](O[Si](C)(C)C(C)(C)C)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(OC[C@H](C)NC[C@@H](O)c2ccccc2)cc1
Yield: 79.7 %

Procedure:
Following a procedure similar to that described in Example 27, but using 970 mg of N-[2-(4-methoxycarbonylmethylphenoxy)-1(S)-methylethyl]-2(S)-t-butyldimethylsilyloxy-2-phenylethanamine (prepared as described in Preparation 30), 20 ml of tetrahydrofuran and 1.7 g of tetrabutylammonium fluoride, 0.58 g of the title compound was obtained as crystals, melting at 70°-71° C.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([N:5]1[CH2:15][CH:14]2[CH2:16][CH:7]([C:8]3[CH:9]=[C:10]([N+:18]([O-])=O)[C:11]([OH:17])=[CH:12][C:13]=32)[CH2:6]1)=[O:4]>CO.[Pd]>[F:22][C:2]([F:1])([F:21])[C:3]([N:5]1[CH2:15][CH:14]2[CH2:16][CH:7]([C:8]3[CH:9]=[C:10]([NH2:18])[C:11]([OH:17])=[CH:12][C:13]=32)[CH2:6]1)=[O:4]
Reactant: O=C(N1CC2CC(C1)c1cc([N+](=O)[O-])c(O)cc12)C(F)(F)F
Agent: [Pd]
Solvent: CO
Product: Nc1cc2c(cc1O)C1CC2CN(C(=O)C(F)(F)F)C1

Procedure:
2,2,2-Trifluoro-1-(4-hydroxy-5-nitro-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-10-yl)-ethanone (575 mg, 1.82 mmol) was hydrogenated in methanol under a H2 atmosphere at (45 psi, or approximately 3 atmospheres) over 10% Pd/C (80 mg) for 1.5 hours then filtered through a Celite pad and concentrated to white solids (450 mg, 86%). (TLC 5% methanol/CH2Cl2 (NH3) Rf 0.6). 1H NMR (400 MHz, CD3O)6.67–6.59 (m, 2H), 4.12 (m, 1H), 3.73 (m, 1H), 3.73 (m, 1H), 3.51 (m, 1H), 3.07 (m, 2H), 2.24 (m, 1H), 1.94 (d, J=10.5 Hz, 1H). GCMS m/e 286 (M+).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:17]=[CH:16][C:10]2[C:11](=[O:15])[CH:12]=[CH:13][O:14][C:9]=2[CH:8]=1.[C:18]1([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O>[C:18]1([N:24]2[CH2:29][CH2:28][N:27]([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]3[CH:17]=[CH:16][C:10]4[C:11](=[O:15])[CH:12]=[CH:13][O:14][C:9]=4[CH:8]=3)[CH2:26][CH2:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=c1ccoc2cc(OCCCCCl)ccc12
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: O
Product: O=c1ccoc2cc(OCCCCN3CCN(c4ccccc4)CC3)ccc12

Procedure:
The title compound was prepared by the method described above in Examples 1-3. Thus, 7-(4-chlorobutoxy)-4H-1-benzopyran-4-one, as prepared above in Preparation 2, (3.79 g, 15 mmol) was treated with 1-phenylpiperazine (2.59 g; 16 mmol) in the usual way, yielding 3.76 g of 7-[4-(4-phenyl-1-piperazinyl)butoxy-]4H-1-benzopan-4-one.1.5 HCL (H2O), mp 204°-206° C.
Reaction SMILES: [CH3:1][C:2]([CH3:16])=[CH:3][CH2:4][CH2:5]/[C:6](/[CH3:15])=[CH:7]\[CH2:8][CH2:9][C:10]([OH:14])([CH:12]=[CH2:13])[CH3:11]>C(Cl)(Cl)(Cl)Cl>[CH3:1][C:2]([CH3:16])=[CH:3][CH2:4][CH2:5]/[C:6](/[CH3:15])=[CH:7]/[CH2:8][CH2:9][C:10]([OH:14])([CH:12]=[CH2:13])[CH3:11]
Reactant: C=CC(C)(O)CC/C=C(/C)CCC=C(C)C
Solvent: ClC(Cl)(Cl)Cl
Product: C=CC(C)(O)CC/C=C(\C)CCC=C(C)C

Procedure:
Next, 1,000 g. of a mixture of cis- and trans-nerolidol in a ratio of 40:60 were rectified using a rectifying column having about 40 theoretical plates at 135° - 140° C. of the column bottom temperature at 0.3 - 0.5 mmHg of reduced pressure under reflux ratio of 10 to obtain 183 g. of cis-nerolidol (0.3 mmHg). This yield was 46 percent of distillation yield for cis-isomer charged. Its refractive index was nD30 = 1.4753 and its NMR spectrum in carbon tetrachloride is shown in FIG. 4. 324 g. of trans-nerolidol were obtained from the distillate having b.p. 107° - 110° C. (0.5 mmHg). This was 54 percent of distillation yield for trans-isomer charged. Its refractive index was nD30 = 1.4754 and its NMR spectrum is shown in FIG. 6. 477 g. of intermediate distillate in a ratio of 46:54 of cis- : trans-isomer were also obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([C:17]4[C:18](O)=[N:19][CH:20]=[N:21][CH:22]=4)=[C:11]3[O:10][N:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:18]1[C:17]([C:16]2[CH:15]=[CH:14][N:13]=[C:12]3[C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)=[N:9][O:10][C:11]=23)=[CH:22][N:21]=[CH:20][N:19]=1
Reactant: Oc1ncncc1-c1ccnc2c(-c3ccc(F)cc3)noc12
Reactant: O=P(Cl)(Cl)Cl
Product: Fc1ccc(-c2noc3c(-c4cncnc4Cl)ccnc23)cc1
Temperature: 90 °C
Yield: 100.6 %

Procedure:
A suspension of 5-(3-(4-fluorophenyl)isoxazolo[4,5-b]pyridin-7-yl) pyrimidin-4-ol (45 mg, 0.146 mmol) in phosphorus oxychloride (503 μl, 5.40 mmol) was heated at 90° C. for 1 h, then allowed to cool to room temperature. The solvent was evaporated to afford the title compound (48 mg, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([CH2:8][C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=[O:11])=[O:7])=[CH:4][CH:3]=1.Cl.[CH2:18](O)[CH3:19]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH2:8][C:9]([CH3:13])([CH3:14])[C:10]([O:12][CH2:18][CH3:19])=[O:11])=[O:7])=[CH:15][CH:16]=1
Reactant: CCO
Reactant: CC(C)(CC(=O)c1ccc(Cl)cc1)C(=O)O
Agent: Cl
Product: CCOC(=O)C(C)(C)CC(=O)c1ccc(Cl)cc1

Procedure:
3-(4-Chlorobenzoyl)-2,2-dimethylpropionic acid (13.7 g) was dissolved in ethanol (100 ml) which had been saturated with gaseous hydrogen chloride. The solution as refluxed for eight hours. The solvent was distilled off and replaced by ether. The ethereal solution was washed with saturated sodium bicarbonate solution, then with brine, dried over magnesium sulphate and concentrated in vacuo to yield 14.5 g of ethyl 3-(4-chlorobenzoyl)-2,2-dimethylpropionate as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:30][CH3:31])=[CH:4][C:5]([O:28][CH3:29])=[C:6]([NH:8][C:9]([CH2:11][N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]([CH2:23][C:24]([OH:26])=O)[C:13]2=[O:27])=[O:10])[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:56]([O:60][C:61](=[O:68])[NH:62][C@@H:63]1[CH2:67][CH2:66][NH:65][CH2:64]1)([CH3:59])([CH3:58])[CH3:57].CCN(C(C)C)C(C)C>O.CN(C=O)C>[C:56]([O:60][C:61](=[O:68])[NH:62][C@H:63]1[CH2:67][CH2:66][N:65]([C:24](=[O:26])[CH2:23][N:14]2[C:15](=[O:22])[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:12]([CH2:11][C:9](=[O:10])[NH:8][C:6]3[CH:7]=[C:2]([Cl:1])[C:3]([O:30][CH3:31])=[CH:4][C:5]=3[O:28][CH3:29])[C:13]2=[O:27])[CH2:64]1)([CH3:59])([CH3:57])[CH3:58]
Reactant: COc1cc(OC)c(NC(=O)Cn2c(=O)n(CC(=O)O)c(=O)c3ccccc32)cc1Cl
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(OC)c(NC(=O)Cn2c(=O)n(CC(=O)N3CC[C@H](NC(=O)OC(C)(C)C)C3)c(=O)c3ccccc32)cc1Cl
Temperature: 25 °C

Procedure:
To a vial charged with {1-[(5-chloro-2,4-dimethoxy-phenylcarbamoyl)-methyl]-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}-acetic acid (50.1 mg, 0.11 mmol), HATU (50.1 mg, 0.12 mmol), and (R)-pyrrolidin-3-yl-carbamic acid tert butyl ester (22.8 mg, 0.12 mmol), DMF (3 ml) was added. The stirring mixture is treated with DIPEA (33 μL, 0.275 mmol) and stirred at RT. Water is added to the mixture with stirring giving rise to a solid. This is filtered off and washed with water to afford the title compound; [M+H]+ 616
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[CH3:10][O:11][C:12](=[O:33])[CH:13]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)Cl>[CH3:10][O:11][C:12](=[O:33])[CH:13]=[CH:7][C:4]1[CH:5]=[CH:6][C:1]([CH3:9])=[CH:2][CH:3]=1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(C=O)cc1
Solvent: ClCCl
Product: COC(=O)C=Cc1ccc(C)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 94.8 %

Procedure:
1 g of p-tolualdehyde (8.3 mM) and 4.16 g of triphenyl phosphanyliden-acetic acid methyl ester (12.45 mM) were dissolved in methylene chloride, the reaction solution was stirred at 90° C. for overnight. After the resluting mixture was concentrated under reduced pressure, a solvent mixture mixed with EtOAc and hexane (1:7) was added thereto with stirring for 1 hr. And then white solid was removed on filter, the residue was filtered and concentrated in vacuo to give 1.39 g of 3-p-tolyl-acrylic acid methyl ester (40aa) (yield: 95%).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:8])=[CH:5][CH:4]=1.[CH3:17][C:18]([N+:22]([O-:24])=[O:23])([CH3:21])[CH2:19]O.[OH-].[Na+].Cl>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O>[CH3:17][C:18]([N+:22]([O-:24])=[O:23])([CH3:21])[CH2:19][NH:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:8])=[CH:15][CH:16]=1
Reactant: CC(C)(CO)[N+](=O)[O-]
Reactant: Nc1ccc(C(=O)CCCC(=O)O)cc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: O
Product: CC(C)(CNc1ccc(C(=O)CCCC(=O)O)cc1)[N+](=O)[O-]
Yield: 82.4 %

Procedure:
A mixture of γ-(p-aminobenzoyl)butyric acid hydrochloride (349.5 g), 2-methyl-2-nitro-1-propanol (222 g), sodium hydroxide (114.8 g), benzyltriethyl ammonium chloride (6.35 g) and water (1.5 liters) was refluxed for 40 hours. Concentrated hydrochloric acid (170 ml) was added to the reaction mixture to acidify it. The precipitated crystals were collected by filtration to give γ-[4-(2-methyl-2-nitropropylamino)benzoyl]butyric acid (364.46 g).
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH3:6])([OH:5])[CH3:4].[Si:7](Cl)([CH2:12][CH3:13])([CH2:10][CH3:11])[CH2:8][CH3:9].CN1CCOCC1>C(Cl)Cl.O>[Cl:1][CH2:2][C:3]([O:5][Si:7]([CH2:12][CH3:13])([CH2:10][CH3:11])[CH2:8][CH3:9])([CH3:6])[CH3:4]
Reactant: CC(C)(O)CCl
Reactant: CC[Si](Cl)(CC)CC
Solvent: CN1CCOCC1
Solvent: O
Solvent: ClCCl
Product: CC[Si](CC)(CC)OC(C)(C)CCl
Reaction time: 0.25 h
Yield: 100 %

Procedure:
A 250 mL round bottom flask was charged with 1-chloro-2-methylpropan-2-ol (2.0 g, 18 mmol). DCM (60 mL) was added, followed by Et3SiCl (3.4 mL, 20 mmol) and then NMM (3 mL, 27 mmol) and the reaction was stirred at rt for 36 hrs. Water (50 mL) and DCM (50 mL) were added and the aqueous layer extracted with DCM (two×30 mL). The combined organic extracts were washed with water and dried over MgSO4. After filtering, the solvents were removed in vacuo, keeping the bath temperature at 22° C. The intermediate was placed under a 10 mm Hg vacuum for 15 min to provide (ca. 18 mmol, 100% yield) of ((1-chloro-2-methylpropan-2-yl)oxy)triethylsilane as a pale yellow oil. This material was used as is in the next step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C:14]2([CH:17]=[CH2:18])[CH2:16][CH2:15]2)[CH2:11][O:10][C:9]1([CH3:20])[CH3:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH2:21].[OH-].[Na+].OO>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C:14]2([CH2:17][CH2:18][OH:21])[CH2:15][CH2:16]2)[CH2:11][O:10][C:9]1([CH3:20])[CH3:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O
Reactant: C=CC1(C[C@H]2COC(C)(C)N2C(=O)OC(C)(C)C)CC1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@@H](CC2(CCO)CC2)COC1(C)C
Reaction time: 3 h

Procedure:
2.5 ml of diborane-dimethylsulfide complex are added to 18.0 g of 3-tert-butoxycarbonyl-2,2-dimethyl-4(S)-[(1-vinylcyclopropyl)methyl]-1,3-oxazolidine, dissolved in 300 ml of tetrahydrofuran at 0° C. in the course of 3 minutes and the mixture is then stirred for 3 h, while cooling with ice. 5 ml of water, 16 ml of 2N sodium hydroxide solution and 8.5 ml of a 30% hydrogen peroxide solution are added in succession and the mixture is subsequently stirred at room temperature for 1 h. It is then diluted with ice-cold potassium carbonate solution and the aqueous phase is extracted with ethyl acetate. Purification of the crude product is carried out over 900 g of silica gel (mobile phase B): Rf (B)=0.25; anal. calc. for C16H35NO4 : C 64.18%, H 9.76%, N 4.68%; found C 64.05%, H 9.76%, N 4.73%.
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[CH:12]=[N:11][CH:10]=[C:9]([OH:17])[C:8]=3[C:7](=[O:18])[C:6]=2[C:5]([F:19])=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:38]=[CH:37][C:25]([CH2:26]OC(=NC(C)C)NC(C)C)=[CH:24][CH:23]=1>ClCCl>[Cl:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[CH:12]=[N:11][CH:10]=[C:9]([O:17][CH2:26][C:25]4[CH:37]=[CH:38][C:22]([O:21][CH3:20])=[CH:23][CH:24]=4)[C:8]=3[C:7](=[O:18])[C:6]=2[C:5]([F:19])=[CH:4][CH:3]=1
Reactant: COc1ccc(COC(=NC(C)C)NC(C)C)cc1
Reactant: O=C1c2c(O)cncc2C(=O)c2c(Cl)ccc(F)c21
Solvent: ClCCl
Product: COc1ccc(COc2cncc3c2C(=O)c2c(F)ccc(Cl)c2C3=O)cc1

Procedure:
A solution of 9-chloro-6-fluoro-4-hydroxybenzo[g]isoquinoline-5,10-dione of Preparative Example 28 (0.050 g) and O-p-methoxybenzyl-N,N'-diisopropylisourea prepared in Step a (0.095 gs) in dichloromethane (1 mL) is stirred at room temperature for 3.5 h under a nitrogen blanket. The dark reddish-brown mixture is purified by flash chromatography over silica gel using gradient elution commencing with 100:2 (300 mL) followed by 100:4 (300 mL) mixtures of chloroform: tert-butyl methyl ether. Removal of the eluent yields 9-chloro-6-fluoro-4-(p-methoxy benzyloxy)benzo[g]isoquinoline-5,10-dione as a yellow-brown solid (0.032 g.)
Reaction SMILES: [NH:1]([C:8]1[CH:9]=[C:10]([C:24]([OH:26])=[O:25])[C:11](=[CH:15][C:16]=1[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CC(OC(C)=O)=O>[NH:17]([C:16]1[CH:15]=[C:11]2[C:12](=[O:14])[O:26][C:24](=[O:25])[C:10]2=[CH:9][C:8]=1[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)c1cc(Nc2ccccc2)c(Nc2ccccc2)cc1C(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=O)c2cc(Nc3ccccc3)c(Nc3ccccc3)cc21

Procedure:
A solution of 2 g of 4,5-dianilino-phthalic acid (Example 1'b)) in acetanhydride is heated to 60° C. for 30 min, resulting in a strongyellow colouring of the reaction mixture. After evaporation, yellow crystals of the crude title compound remain which are recrystallized from acetone/diethyl ether; the title compound has a m.p. of 196°-197° C. C20H14N2O3 : molecular weight calculated 330, found 330 (FD-MS).
Reaction SMILES: [CH2:1]([NH:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[O:15][CH3:16])[CH2:6]1)[CH2:2][CH3:3].[O:17]([CH2:24][C:25](O)=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[B-][N+](C)(C)C>CCOCC>[CH2:1]([N:4]([CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[O:15][CH3:16])[CH2:6]1)[CH2:25][CH2:24][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:2][CH3:3]
Reactant: O=C(O)COc1ccccc1
Reactant: CCCNC1CCc2c(cccc2OC)C1
Agent: [B-][N+](C)(C)C
Solvent: CCOCC
Product: CCCN(CCOc1ccccc1)C1CCc2c(cccc2OC)C1

Procedure:
A mixture of 2-(N-n-propylamino)-5-methoxytetralin (7.0 g, 0.0319 mol; prepared according to J. Chem. Soc., 1965, pp. 26-36), phenoxyacetic acid (4.86 g, 0.0319 mol), and borane trimethylamine complex (2.33 g, 0.0319 mol) was refluxed in xylenes overnight. The cooled reaction mixture was extracted with NaHCO3 and the organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The resulting oil was subjected to flash chromatography (silica; 9:1 pet ether/EtOAc) and product was isolated: NMR of the free base (300 MHz, CDCl3): δ7.3-6.6(m, 8H), 4.0(t, 2H), 3.7(s, 3H), 3.1-2.5(m, 9H), 2.1(m, 1H), 1.7-1.4(m, 3H), 0.9(t, 3H). The free base thus isolated was converted to a hydrochloride salt by the addition of dry ether-HCL.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([C:12]([NH2:14])=O)[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=S>>[CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([C:12]#[N:14])[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1
Reactant: Cc1cnc2c(c1)CCCC2C(N)=O
Agent: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Product: Cc1cnc2c(c1)CCCC2C#N

Procedure:
3-Methyl-5,6,7,8-tetrahydroquinoline-8-carboxamide was treated with P2S5 to give 3-methyl-8-cyano-5,6,7,8 -tetrahydroquinoline which was treated with H2S as described in Example 8 giving the title compound as colourless needles from benzene m.p. 151° (50% yield) (Found: C, 63.71; H, 6.85; N, 13.38% C11H14N2S requires: C, 64.04; H, 6.84; N, 13.58%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C:14]2([CH2:17][CH2:18][OH:19])[CH2:16][CH2:15]2)[CH2:11][O:10][C:9]1([CH3:21])[CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[K+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C:14]2([CH2:17][CH2:18][O:19][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:16][CH2:15]2)[CH2:11][O:10][C:9]1([CH3:21])[CH3:20])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1[C@@H](CC2(CCO)CC2)COC1(C)C
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@@H](CC2(CCOCc3ccccc3)CC2)COC1(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
15.1 g of 3-tert-butoxycarbonyl-2,2-dimethyl-4(S)-[1-(2-hydroxyethyl)cyclopropylmethyl]-1,3-oxazolidine are dissolved in 50 ml of tetrahydrofuran, and 14.2 g of a potassium hydride suspension (20% in oil) are added at 0° C. The mixture is stirred at 0° C. for 1 h and 6.3 ml of benzyl bromide are then added dropwise, while stirring. After 90 min., 100 ml of water are slowly added to the reaction mixture and the aqueous phase is extracted with diethyl ether. This gives the title compound: Rf (A)=0.8; FAB-MS: (M+H)+ =390.
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[C:11]([CH:27]=[CH:28][CH:29]=1)[CH:12]([C:14]1[CH:26]=[CH:25][C:17]([C:18]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=1)O)(C(C)(C)C)(C)C.S(Cl)(Cl)=O.[CH3:34][C@H:35]1[CH2:40][NH:39][C@H:38]([CH3:41])[CH2:37][NH:36]1.O.[F-].C([N+](CC)(CC)CC)C>>[CH2:23]([N:20]([CH2:21][CH3:22])[C:18](=[O:19])[C:17]1[CH:16]=[CH:15][C:14]([C@@H:12]([N:36]2[CH2:37][C@H:38]([CH3:41])[NH:39][CH2:40][C@H:35]2[CH3:34])[C:11]2[CH:27]=[CH:28][CH:29]=[C:9]([OH:8])[CH:10]=2)=[CH:26][CH:25]=1)[CH3:24]
Reactant: CCN(CC)C(=O)c1ccc(C(O)c2cccc(O[Si](C)(C)C(C)(C)C)c2)cc1
Reactant: C[C@@H]1CN[C@@H](C)CN1
Agent: CC[N+](CC)(CC)CC
Agent: [F-]
Solvent: O
Solvent: O=S(Cl)Cl
Product: CCN(CC)C(=O)c1ccc([C@H](c2cccc(O)c2)N2C[C@H](C)NC[C@H]2C)cc1

Procedure:
4-(3-(tert-Butyldimethylsilyloxy)-α-hydroxybenzyl)-N,N-diethylbenzamide (Example 1, infra) was treated with thionyl chloride and trans-2,5-dimethylpiperazine as described in Example 5. The crude mixture of diastereomers was purified by chromatography on silica gel (Waters Prep 500) with dichloromethane:ethanol:triethylamine (100:0.25:0.1). The less mobile isomer (1.28 g, 2.5 mmol) was dissolved in acetonitrile and treated with tetraethylammonium fluoride hydrate (0.6 g, 4.0 mmol) as in Example 7 to give 0.46 g of (±)-N,N-diethyl-4-((αR*)-3-hydroxy-α-((2R*,5S*)-2,5-dimethyl-1-piperazinyl)benzyl)benzamide as a white solid, mp 175°-177° C.
Reaction SMILES: [OH-].[Na+].Cl.[CH2:4]([O:6][NH2:7])[CH3:5].[OH:8][C:9]1[CH2:14][CH:13]([C:15]2[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=2)[CH2:12][C:11](=[O:23])[C:10]=1[C:24](=O)[CH2:25][CH3:26]>O.C(O)C>[CH2:4]([O:6][N:7]=[C:24]([C:10]1[C:11](=[O:23])[CH2:12][CH:13]([C:15]2[CH:16]=[CH:17][C:18]([S:21][CH3:22])=[CH:19][CH:20]=2)[CH2:14][C:9]=1[OH:8])[CH2:25][CH3:26])[CH3:5]
Reactant: CCC(=O)C1=C(O)CC(c2ccc(SC)cc2)CC1=O
Reactant: CCON
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCON=C(CC)C1=C(O)CC(c2ccc(SC)cc2)CC1=O
Temperature: 25 °C
Yield: 82.7 %

Procedure:
A solution of sodium hydroxide (0.15 g) in water (5 ml) and then ethoxyamine hydrochloride (0.37 g) were added to a solution of 3-hydroxy-5-(4-methylthiophenyl)-2-propionylcyclohex-2-en-1-one (1.0 g) in ethanol (40 ml). The mixture was stirred at room temperature and the progress of the reaction was monitored by thin layer chromatography on silica gel (eluant dichloromethane). On completion of the reaction the solvent was removed by distillation under reduced pressure. The residue was treated with dichloromethane and the organic phase was washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated to give 2-[1-(ethoxyimino)propyl]-3-hydroxy-5-(4-methylthiophenyl)cyclohex-2-en-1-one (0.95 g) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=2[CH:13]=1.Cl[C:15]1[N:20]=[C:19]([NH:21][C:22]2[C:31]([F:32])=[CH:30][C:29]([F:33])=[CH:28][C:23]=2[C:24]([NH:26][CH3:27])=[O:25])[C:18]([Cl:34])=[CH:17][N:16]=1>>[Cl:34][C:18]1[C:19]([NH:21][C:22]2[C:31]([F:32])=[CH:30][C:29]([F:33])=[CH:28][C:23]=2[C:24]([NH:26][CH3:27])=[O:25])=[N:20][C:15]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=3[CH:13]=2)=[N:16][CH:17]=1
Reactant: CNC(=O)c1cc(F)cc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)NC(=O)CCC2
Product: CNC(=O)c1cc(F)cc(F)c1Nc1nc(Nc2ccc3c(c2)NC(=O)CCC3)ncc1Cl

Procedure:
Title compound was prepared from 8-Amino-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3,5-difluoro-N-methyl-benzamide in an analogous manner to Example 1221d. Title compound was isolated as a beige solid (136 mg, 82%). MP=250-252 (dec), HPLC purity=93%, LCMS=473.14 (M+H), HNMR (DMSO), 9.54 (bs, 1H), 9.38 (s, 1H), 9.28 (s, 1H), 8.52 (d, J=4.4 Hz, 1H), 8.21 (s, 1H), 7.53 (dd, J=7.9 Hz, 1H), 7.36 (d, J=8.6 Hz, 1H), 7.17 (d, J=7.9 Hz, 1H), 7.04 (s, 1H), 6.97 (d, J=8.1 Hz, 1H), 2.72 (d, J=4.0 Hz, 3H), 2.59-2.56 (m, 2H), 2.09-2.03 (m, 4H).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH:3]1C=CCC[C:4]1([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10].C(O)(=O)C.O.[OH-].[Na+]>C1CCCCC1>[CH3:20][N:2]([CH3:1])[CH2:3][CH:4]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)C1(c2ccccc2)CCC=CC1N(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCCCC1
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(CN(C)C)c1ccccc1

Procedure:
13.7 g (0.05 mol) of ethyl 2-dimethylamino-1-phenyl-3-cyclohexene-1-carboxylate (mixture of cis and trans isomers) [ethyl 3-dimethylamino-2-phenylpropionate content (HPLC): 1%], dissolved in 40 ml of cyclohexane, was refluxed with 3.0 g (0.05 mol) of acetic acid for 2 hours. After cooling, 30 ml of water were added. The two-phase mixture was made alkaline with sodium hydroxide solution. The aqueous phase was then separated off. The organic phase was washed with 30 ml of water and concentrated. 13.4 g (98%) of ethyl 2-dimethylamino-1-phenyl-3-cyclohexene-1-carboxylate isomer mixture of unchanged composition in respect of the cis/trans ratio were obtained with an ethyl 3-dimethylamino-2-phenyl-propionate content of 0.05% (HPLC).