Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Na+].C1(C)C=CC=CC=1.[CH:18]1([CH2:24][CH2:25][C:26]([N:28]2[C@@H:32]([CH:33]([CH3:35])[CH3:34])[CH2:31][O:30][C:29]2=[O:36])=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.[C:37]([O:41][C:42](=[O:45])[CH2:43]Br)([CH3:40])([CH3:39])[CH3:38]>C1COCC1.Cl>[CH:18]1([CH2:24][CH:25]([C:26]([N:28]2[CH:32]([CH:33]([CH3:34])[CH3:35])[CH2:31][O:30][C:29]2=[O:36])=[O:27])[CH2:43][C:42]([O:41][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:45])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)[C@H]1COC(=O)N1C(=O)CCC1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)C1COC(=O)N1C(=O)C(CC(=O)OC(C)(C)C)CC1CCCCC1
Temperature: -10 °C
Reaction time: 1 h
Yield: 60.6 %

Procedure:
A solution of sodium hexamethyldisilazide (92.4 mL of a 0.6M toluene solution, Aldrich) in THF (70 mL) was cooled to −78° C. and then treated with a solution of (S)-3-cyclohexylpropionyl-4-isopropyloxazolidin-2-one (10.5 g, 39.3 mmol) in THF (30 mL) added dropwise over 10 minutes. The mixture was stirred for 1 hour and then treated with a solution of tert-butylbromoacetate (9.75 mL, 50 mmol) in THF (20 mL) added dropwise. The mixture was stirred for 1 hour, while warming to −10° C. The mixture reaction was diluted with 1M hydrochloric acid (100 mL) and the dilution was extracted with ethyl acetate (200 mL). The extract was washed with saturated aqueous sodium bicarbonate (100 mL) and brine (100 mL), dried (MgSO4), filtered and concentrated to dryness. The residue was dissolved in hexane and product was crystallized out to provide tert-butyl 3-cyclohexylmethyl-4-(4-isopropyl-2-oxooxazolidin-3-yl)-4-oxobutyrate (9.09 g, 61%). MS (M+1): 382.
Reaction SMILES: C(O)(=O)C.[NH:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[C@H:14]1[CH2:19][C@H:18]([NH:20][C:21]([C:23]2[CH:32]=[CH:31][C:26]3[O:27][CH2:28][CH2:29][O:30][C:25]=3[CH:24]=2)=[O:22])[CH2:17][CH2:16][NH:15]1.C(O[C:36]1(O[Si](C)(C)C)[CH2:38][CH2:37]1)C.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.C(OCC)(=O)C>[NH:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[C@H:14]1[CH2:19][C@H:18]([NH:20][C:21]([C:23]2[CH:32]=[CH:31][C:26]3[O:27][CH2:28][CH2:29][O:30][C:25]=3[CH:24]=2)=[O:22])[CH2:17][CH2:16][N:15]1[CH:36]1[CH2:38][CH2:37]1
Reactant: O=C(N[C@@H]1CCN[C@@H](c2nc3ccccc3[nH]2)C1)c1ccc2c(c1)OCCO2
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(N[C@@H]1CCN(C2CC2)[C@@H](c2nc3ccccc3[nH]2)C1)c1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84.6 %

Procedure:
Acetic acid (0.075 mL, 1.3 mmol) was added to a solution of N-((2R,4R)-2-(1H-benzo[d]imidazol-2-yl)piperidin-4-yl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide (50 mg, 0.13 mmol) in methanol (2 mL) and the then (1-ethoxycyclopropoxy)trimethylsilane (138 mg, 1.79 mmol) was added to the reaction solution and reaction mixture was stirred at room temperature for 10 min, then sodium cyanoborohydride (37 mg, 0.59 mmol) was added carefully. The reaction mixture was stirred at 50° C. 24 hours. Saturated sodium bicarbonate solution (10 mL) and ethyl acetate (30 mL) were added. The organic layer was separated, dried over MgSO4, and concentrated. Product was purified by Companion (ReadySep, 12 g, silica gel packed) with CH3OH/CH2Cl2 from 1%-5% to give the named compound as a white solid 46 mg (85%). LC-MS: 419.2, 417.3 (t=1.7 min).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H][H]>C(O)(=O)C.[Pt]>[CH2:7]1[CH2:6][CH2:5][CH:4]([CH2:3][C@H:2]([NH2:1])[C:10]([OH:12])=[O:11])[CH2:9][CH2:8]1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: [H][H]
Agent: [Pt]
Solvent: CC(=O)O
Product: N[C@@H](CC1CCCCC1)C(=O)O
Yield: 106.1 %

Procedure:
2 g of L-phenylalanine was dissolved in 30 ml of a 50% of acetic acid, and hydrogenated by using 200 mg of platinum as catalyst under elevated pressure (hydrogen pressure: 50 kg/cm2) for 2 hours at a temperature from 40° to 70° C. The catalyst was filtered off and the solvent was distilled off under reduced pressured to obtain 2.2 g of L-cyclohexylalanine as a colorless needle crystal.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1)[CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:21])[CH:5]([C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1)[CH2:6][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11]1)[CH3:2]
Reactant: CCOC(=O)C(CC1CCCC1)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CC1CCCC1)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.2 %

Procedure:
A solution of 3-cyclopentyl-2-(4-nitro-phenyl)-propionic acid ethyl ester (7.37 g, 25.3 mmol) in ethyl acetate (316 mL) was treated with 10% palladium on activated carbon (500 mg). The reaction mixture was stirred under hydrogen gas at 60 psi at 25° C. for 18 h. The catalyst was then filtered off through a pad of celite (ethyl acetate). The filtrate was concentrated in vacuo to give 2-(4-amino-phenyl)-3-cyclopentyl-propionic acid ethyl ester (3.52 g, 53.3%) as a yellow oil: EI-HRMS m/e calcd for C16H23NO2 (M+) 261.1727, found 261.1727.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[OH:9])=[CH:4][CH:3]=1.O[CH2:18][CH2:19][N:20]1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[O:9][CH2:18][CH2:19][N:20]2[C:21](=[O:30])[C:22]3[C:23](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]2=[O:25])=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCO
Reactant: OC(c1ccc(Cl)cc1)c1ccc(Br)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1CCOC(c1ccc(Cl)cc1)c1ccc(Br)cc1
Yield: 56.3 %

Procedure:
A mixture of (4-Bromo-phenyl)-(4-chloro-phenyl)-methanol (2.3 g, 7.73 mmol), N-(2-hydroxyethyl)phthalimide (1.4 g, 7.36 mmol) and para-toluenesulphonic acid monohydrate (560 mg, 2.94 mmol) in toluene (50 ml) was heated to reflux under Dean-Stark conditions for 17 hours. Upon cooling, the solvent was removed and the residue was partitioned between ethyl acetate and water. The organic layer was then dried (MgSO4), filtered and concentrated. The crude product was purified by column chromatography (SiO2), eluting with ethyl acetate/petroleum ether (1:4), to yield the title compound (1.95 g). LC/MS. (PS-B3) Rt 4.07 no observable mass ion.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[NH2:11][CH2:12][C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:32])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]([F:31])([F:30])[F:29])[CH2:17][CH2:16]1)=[O:14].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[F:54][C:55]1[CH:60]=[CH:59][C:58]([F:61])=[CH:57][C:56]=1[C:62]1[CH:67]=[CH:66][C:65]([C:68](O)=[O:69])=[CH:64][CH:63]=1>CN(C=O)C.O>[O:14]=[C:13]([N:15]1[CH2:16][CH2:17][N:18]([C:21](=[O:32])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]([F:31])([F:29])[F:30])[CH2:19][CH2:20]1)[CH2:12][NH:11][C:68]([C:65]1[CH:66]=[CH:67][C:62]([C:56]2[CH:57]=[C:58]([F:61])[CH:59]=[CH:60][C:55]=2[F:54])=[CH:63][CH:64]=1)=[O:69]
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Reactant: O=C(O)c1ccc(-c2cc(F)ccc2F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc(-c2cc(F)ccc2F)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 19.9 %

Procedure:
DIPEA (211 mg, 0.28 mL, 1.6 mmol) was added to a stirred solution of 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (140.5 mg, 0.399 mmol) in DMF (3 mL). HOBT (53.9 mg, 0.39 mmol) and EDCI (139.2 mg, 0.72 mmol) were then added at room temperature. After 2 minutes, 2′,5′-difluoro-biphenyl-4-carboxylic acid (85 mg, 0.36 mmol) (prepared by the method as described above) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by column chromatography (using silica gel of 60-120 mesh and 60% EtOAc in Hexane as eluent) to afford 38 mg (19.79% yield) of 2′,5′-difluoro-biphenyl-4-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide. LCMS Purity: 95.02%. 1H NMR (DMSO-d6): δ 8.7 (s, 1H), 8.0 (d, 2H), 7.9-7.65 (m, 5H), 7.6-7.46 (m, 2H), 7.44-7.25 (m, 2H), 4.3-4.1 (d, 2H), 3.6-3.4 (m, 4H), 3.26-3.04 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20]Br.C([O-])([O-])=O.[K+].[K+]>CC#N>[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][NH:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[N+:10]([O-:12])=[O:11]
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Reactant: BrCc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(NCc2ccccc2Br)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
To a solution of 4-methoxy-2-nitrobenzenamine (16.8 g, 0.1 mol) and 1-bromo-2-(bromomethyl)benzene (30 g, 0.12 mol) in CH3CN (700 mL) was added K2CO3 (27.6 g, 0.2 mol). The mixture was heated to reflux for 60 h then cooled to RT filtered and concentrated to dryness. The resulting residue was purified by FCC to provide the title compound.
Reaction SMILES: [OH:1][C:2]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:14][CH3:15].[OH:16]OS([O-])=O.[K+]>CN(C=O)C.CCOC(C)=O>[OH:1][C:2]1[C:9]([C:10]([F:12])([F:13])[F:11])=[CH:8][C:5]([C:6]([OH:16])=[O:7])=[CH:4][C:3]=1[O:14][CH3:15]
Reactant: O=S([O-])OO
Reactant: COc1cc(C=O)cc(C(F)(F)F)c1O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)O)cc(C(F)(F)F)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
A suspension of 4-hydroxy-3-methoxy-5-(trifluoromethyl)benzaldehyde (1.03 g, 4.68 mmol) and Oxone™ (3.45 g, 5.61 mmol) in DMF (10 mL) was stirred at RT for 2 h. The reaction mixture was diluted with EtOAc (40 mL) and the solution was washed sequentially with 1M HCl (40 mL) and brine (4×40 mL). The solvent was removed in vacuo and the residue was purified by silica gel chromatography (80 g, 0-10% MeOH in DCM) to afford 4-hydroxy-3-methoxy-5-(trifluoromethyl)benzoic acid (4) (392 mg, 35%) as a white solid: m/z 235 [M−H]− (ES−); 1H NMR (400 MHz, DMSO-d6) δ: 13.01 (1H, br s), 10.74 (1H, br s), 7.68 (2H, dd), 3.92 (3H, s).
Reaction SMILES: [CH2:1]([C:5]1[C:6](=[O:22])[N:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][OH:32]>CC(C)=O>[CH2:1]([C:5]1[C:6](=[O:22])[N:7]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:8]2[C:13]([C:14]=1[O:15][CH2:30][CH2:31][OH:32])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:2][CH2:3][CH3:4]
Reactant: OCCBr
Reactant: CCCCc1c(O)c2cccnc2n(-c2ccccc2)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCc1c(OCCO)c2cccnc2n(-c2ccccc2)c1=O
Yield: 58.5 %

Procedure:
Reflux a stirred solution of 16.2 gm of 3-(n-butyl)-4-hydroxy-1-phenyl-1,8-naphthyridin-2(1H)one and 11.4 gm of anhydrous potassium carbonate powder in 600 ml of dry acetone for 30 minutes. 95% 2-bromoethanol (10.3 gm) is added dropwise to the solution. The reaction is refluxed for 26 hours, cooled and the solvent removed by stripping. The resulting solid is dissolved in 500 ml chloroform and the chloroform solution is washed with 300 ml water, twice with 100 ml of 0.5N sodium hydroxide solution and finally with 100 ml of water. The chloroform solution is dried over magnesium sulfate, filtered and the solvent is removed to give the crude product. The crude product is triturated with warm isopropyl ether to give 10.9 gm of the 3-(n-butyl)-4-(2-hydroxyethoxy)-1-phenyl-1,8-naphthyridin-2(1H)one; which after recrystallization from acetone melts at 138°-140° C.
Reaction SMILES: CC1O[CH:6]([O:8][CH:9]2[C:23]3[C:14](=[C:15]([OH:55])[C:16]4[C:21]([C:22]=3[O:24][CH3:25])=[CH:20][C:19]([CH3:26])=[C:18]3[CH:27]5[O:35][C:34]6([CH:37]([O:40][CH3:41])[O:38][CH3:39])[O:36][CH:28]5[C:29]([O:42][CH:43]5[O:48][CH:47]([CH3:49])[C:46]([OH:53])([C:50]([CH3:52])=[O:51])[CH:45]([OH:54])[CH2:44]5)([C:31]56[O:33][CH2:32]5)[O:30][C:17]=43)[C:12](=[O:13])[CH:11]([OH:56])[CH2:10]2)[CH2:5][C:4]([OH:58])([CH3:57])C1OC(C)=O.C[C@@H]1O[C@@H](OC2C3C(=C(O)C4C(C=3OC)=CC(C)=C3C5OC6(C(OC)OC)O[CH:90]5[C:91]([O:105][C@@H:106]5[O:111][C@@H:110](C)[C@](O)(C(C)=O)[C@H](O)[CH2:107]5)(C6(O)CO)[O:92]C=43)C(=O)C(O)C2)C[C@](O)(C)[C@@H]1OC(C)=O>>[CH3:49][CH:47]1[O:48][CH:43]([O:42][C:29]23[C:31]4([O:33][CH2:32]4)[C:34]4([CH:37]([O:38][CH3:39])[O:40][CH3:41])[O:36][CH:28]2[CH:27]([O:35]4)[C:18]2[C:17]([O:30]3)=[C:16]3[C:15]([OH:55])=[C:14]4[C:23](=[C:22]([O:24][CH3:25])[C:21]3=[CH:20][C:19]=2[CH3:26])[CH:9]([O:8][CH:6]2[CH2:110][O:111][C:106]([O:105][C:91]([CH3:90])=[O:92])([CH3:107])[C:4]([OH:58])([CH3:57])[CH2:5]2)[CH2:10][CH:11]([OH:56])[C:12]4=[O:13])[CH2:44][CH:45]([OH:54])[C:46]1([OH:53])[CH:50]([OH:51])[CH3:52]
Reactant: COc1c2c(c(O)c3c4c(c(C)cc13)C1OC3(C(OC)OC)OC1C(OC1CC(O)C(O)(C(C)=O)C(C)O1)(O4)C31CO1)C(=O)C(O)CC2OC1CC(C)(O)C(OC(C)=O)C(C)O1
Reactant: COc1c2c(c(O)c3c4c(c(C)cc13)C1OC3(C(OC)OC)OC1C(O[C@H]1C[C@@H](O)[C@@](O)(C(C)=O)[C@H](C)O1)(O4)C3(O)CO)C(=O)C(O)CC2O[C@H]1C[C@@](C)(O)[C@H](OC(C)=O)[C@H](C)O1
Product: COc1c2c(c(O)c3c4c(c(C)cc13)C1OC3(C(OC)OC)OC1C(OC1CC(O)C(O)(C(C)O)C(C)O1)(O4)C31CO1)C(=O)C(O)CC2OC1COC(C)(OC(C)=O)C(C)(O)C1
Yield: 61.1 %

Procedure:
Analogous treatments to those described in Example 1 were carried out except the use of a fermentation medium having the following composition so that DC-45-A (5 mg), DC-45-B1 (5 mg) and DC-45-B2 (3 mg) were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=4[O:27][CH3:28])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:30][C:31]([NH:33][CH3:34])=[O:32]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:14][CH2:15][CH:16]([C:19]4[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=4[O:27][CH3:28])[CH2:17][CH2:18]3)=[O:12])=[CH:7][N:8]2[CH2:30][C:31]([NH:33][CH3:34])=[O:32])=[CH:4][CH:3]=1
Reactant: COc1cccc(OC)c1C1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1
Reactant: CNC(=O)CCl
Product: CNC(=O)Cn1cc(C(=O)N2CCC(c3c(OC)cccc3OC)CC2)c2ccc(Cl)cc21

Procedure:
Analogous to general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2,6-dimethoxy-phenyl)-piperidin-1-yl]-methanone (prepared herein) with (commercially available) 2-chloro-N-methyl-acetamide gave the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([O:30][CH3:31])=[O:29])=[CH:24][CH:23]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:32][C:33]1[CH:40]=[CH:39][C:38]([C:41]#[N:42])=[CH:37][C:34]=1[CH2:35]Br>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:35][C:34]2[CH:37]=[C:38]([C:41]#[N:42])[CH:39]=[CH:40][C:33]=2[F:32])[C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[CH:24][C:25]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:27]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#Cc1ccc(F)c(CBr)c1
Reactant: COC(=O)c1ccc(Oc2ccc(NC3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc1
Product: COC(=O)c1ccc(Oc2ccc(N(Cc3cc(C#N)ccc3F)C3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc1
Yield: 89.3 %

Procedure:
Using general procedure H, 4-[4-(4-methoxycarbonyl-phenoxy)-phenylamino]-piperidine-1-carboxylic acid tert-butyl ester (see EXAMPLE 96) (430 mg, 1.04 mmol) and 2-fluoro-5-cyanobenzyl bromide (289 mg, 1.35 mmol) afforded 4-{(5-cyano-2-fluoro-benzyl)-[4-(4-methoxycarbonyl-phenoxy)-phenyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester as a white solid (520 mg, 89%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:16])=[N:8][C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=2[CH:15]=1)=[O:5])[CH3:2].C([O-])(=O)C.[Na+].[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[CH:27]=O>C(OC(=O)C)(=O)C.C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:16])=[N:8][C:9]2[C:10](=[CH:27][C:23]3[S:22][CH:26]=[CH:25][CH:24]=3)[CH2:11][CH2:12][CH2:13][C:14]=2[CH:15]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c(nc1C)CCCC2
Reactant: O=Cc1cccs1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2c(nc1C)C(=Cc1cccs1)CCC2

Procedure:
A solution of 5,6,7,8-tetrahydro-2-methyl-3-quinolinecarboxylic acid ethyl ester as prepared in Preparation I (3.66 g) in acetic anhydride (10 ml) is treated with sodium acetate (1.37 g) and 2-thiophenecarboxaldehyde (2.24 g). The solution is heated at reflux temperature for 56 hours. The cooled mixture is diluted with toluene, filtered and the filtrate evaporated to a solid residue. The residue is triturated with hexane and filtered to yield a residue of 5,6,7,8-tetrahydro-2-methyl-8-(2-thienylmethylene)-3-quinoline carboxylic acid ethyl ester (1.91 g) m.p. 117° C.-118° C. The filtrate residue is purified on silica gel (70 g) with 9:1 Skelly B:ethyl acetate as eluent. Fractions 7-13, 20 ml each, provide additional 5,6,7,8-tetrahydro-2-methyl-8-(2-thienylmethylene)-3-quinoline carboxylic acid ethyl ester (0.73 g). An analytical sample, m.p. 117° C.-118° C. is obtained by hexane recrystallization.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:28][CH2:27][C@H:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:25]2)=[CH:20][C:19]=1[Br:37]>>[Br:37][C:19]1[CH:20]=[C:21]([N:24]2[CH2:28][CH2:27][C@H:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])[CH2:25]2)[CH:22]=[CH:23][C:18]=1[NH:17][C:14]([C:12]1[S:13][C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:10][CH:11]=1)=[O:15]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(c2ccc(N)c(Br)c2)C1
Reactant: COc1ccc(-c2ccc(C(=O)Cl)s2)cc1
Product: COc1ccc(-c2ccc(C(=O)Nc3ccc(N4CC[C@H](NC(=O)OC(C)(C)C)C4)cc3Br)s2)cc1
Yield: 39.7 %

Procedure:
Following Step 1 from General Procedure A, 5-(4-methoxyphenyl)thiophene-2-carbonyl chloride (640 mg, 2.5 mmol) was reacted with (S)-tert-butyl 1-(4-amino-3-bromophenyl)pyrrolidin-3-ylcarbamate (800 mg, 2.2 mmol) to afford the desired product (500 mg, 39%) as a light yellow solid: ESI MS m/z 573 [C27H30BrN3O4S+H]+.
Reaction SMILES: [OH:1][C:2]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([CH3:16])[CH:11]=3)[C:6]=2[CH:5]=[C:4]([CH3:17])[CH:3]=1.C(N(CC)CC)C.[CH3:25][P:26](Cl)(=[O:36])[O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[CH3:35].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[CH3:25][P:26](=[O:36])([O:1][C:2]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([CH3:16])[CH:11]=3)[C:6]=2[CH:5]=[C:4]([CH3:17])[CH:3]=1)[O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[CH3:35]
Reactant: Cc1cc(Cl)ccc1OP(C)(=O)Cl
Reactant: Cc1ccc2c(c1)C(=O)c1c(O)cc(C)cc1-2
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1ccc2c(c1)C(=O)c1c(OP(C)(=O)Oc3ccc(Cl)cc3C)cc(C)cc1-2
Temperature: -10 °C
Reaction time: 24 h

Procedure:
1-Hydroxy-3,7-dimethylfluoren-9-one (0.01 mole), triethylamine (0.011 mole) and toluene (75 ml) are charged into a glass reaction flask equipped with a stirrer, thermometer and addition funnel. The mixture is cooled to about -10° C. and a solution of O-(2-methyl-4-chlorophenyl) methylphosphonochloridate (0.011 mole) in toluene (25 ml) is slowly added with stirring. After the addition is completed the reaction mixture is allowed to slowly warm to room temperature and stirring is continued for a period of 24 hours. After this time the reaction mixture is filtered and the filtrate is stripped of solvent leaving a residue. This residue is subjected to column chromatography using mixtures of ethyl acetate and hexane as the eluant. The fractions containing product are combined and stripped of solvent to yield the desired product O-(2-methyl-4-chlorophenyl) O-(3,7-dimethylfluoren-9-one-1-yl) methylphosphonate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([N+:18]([O-])=O)[C:14]=1[O:15][CH2:16][CH3:17])[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[H][H].ClC1C=C2C(=C(N)C=1OCC1CC1)NC1C=NC=CC2=1.C(O)=O>CO.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH2:18])[C:14]=1[O:15][CH2:16][CH3:17])[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: CCOc1c(Cl)cc2c([nH]c3cnccc32)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Agent: Nc1c(OCC2CC2)c(Cl)cc2c1[nH]c1cnccc12
Solvent: CO
Solvent: O=CO
Product: CCOc1c(Cl)cc2c([nH]c3cnccc32)c1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-chloro-7-ethoxy-8-nitro-9H-β-carboline (160 mg, 0.55 mmol) was suspended in 4 ml of methanol and 25 mg of Pd/C (10%) was added. The flask was fitted with a balloon of hydrogen and the reaction mixture was stirred overnight at RT. Upon filtration through a pad of celite and evaporation of the methanol, a dark brown solid was obtained and determined to be the desired 6-chloro-7-cyclopropylmethoxy-9H-β-carbolin-8-ylamine (80 mg, 55%). 1H-NMR (300 MHz, Methanol-d4/CDCl3): δ 1.26 (t, 3H), 3.91 (q, 2H), 7.34 (s, 1H), 7.71 (d, 1H), 8.02 (s, 1H), 8.56 (s, 1H). Retention Time (LC, method: formic acid standard): 1.16 min. MS (M+H+): 262.0.
Reaction SMILES: [CH3:1][C@@:2]12[C@@H:10]([OH:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH2:13][C:14]3[C@@:20]([CH3:21])([C@H:5]1[CH2:4][CH2:3]2)[CH2:19][CH2:18][C:16](=[O:17])[CH:15]=3.CC(=[O:34])C(Cl)CCCCCCCC.O>N1C=CC=CC=1.CC(C)=O>[CH3:1][C@@:2]12[C@@H:10]([OH:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH2:13][C:14]3[C@@:20]([CH3:21])([C@H:5]1[CH2:4][CH2:3]2)[CH2:19][CH2:18][C:16](=[O:17])[CH:15]=3.[CH3:1][CH:2]([CH2:3][CH2:4][CH2:5][CH2:20][CH2:19][CH2:18][CH2:16][CH3:15])[C:10](=[O:34])[O-:11]
Reactant: CCCCCCCCC(Cl)C(C)=O
Agent: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Solvent: c1ccncc1
Solvent: CC(C)=O
Solvent: O
Product: CCCCCCCCC(C)C(=O)[O-]
Temperature: -10 °C
Reaction time: 2 h

Procedure:
To a solution of 2 g testosterone in a mixture of 8 ml pyridine and 8 ml acetone, cooled to -10° C., was added dropwise in a nitrogen atmosphere a solution of 4 ml α-methyl-decanoyl-chloride in 12 ml acetone. The mixture was stirred for 16 hours at 0° C., whereafter 4 ml pyridine and 8 ml water were added to the mixture. The mixture was stirred for 1 hour at 0° C. and 2 hours at 45° C. and then poured out in 200 ml ice-water. Extraction with diethylether neutralisation of the extracts, evaporation of the diethylether and chromatography of the residue on silicagel with toluene/ethylacetate 8/2 gave 3.0 g testosterone α-methyl-caprate in the form of an oil with [α]D20 =+77.0° (in methylenechloride) and εmol 16.800 (λmax 240 mμ).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=[O:9])[CH3:8].[BrH:11].Br.[NH+]1C=CC=CC=1.[Br-]>C(O)(=O)C>[Br:11][CH2:8][C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH3:10])=[O:9]
Reactant: Br
Reactant: CC(=O)c1ccccc1C
Agent: [Br-]
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Product: Cc1ccccc1C(=O)CBr
Temperature: 0 °C
Reaction time: 3 h
Yield: 52.5 %

Procedure:
To a 250 mL RB flask fitted with magnetic stirrer was charged 60 mL of Acetic acid. To the stirred solvent was added 1-o-tolyl-ethanone (3.0 g, 22.35 mmol) RM cooled to 0° C. was added 47% hydrobromic acid (9.7 mL, 178.63 mmol), pyridinium hydro bromide per bromide (8.6 g, 26.89 mmol) slowly. The resulting mixture was stirred at RT for 3 h. The RM was then quenched with 10% sodium bicarbonate solution in water (150 mL) at 0° C. and extracted with ethyl acetate (75 mL×2). The organic layer was washed with saturated brine solution (50 mL) and dried over anhydrous Na2SO4 and evaporated to dryness. The crude compound thus obtained was purified by column chromatography on silica gel (100/200 mesh), using petroleum ether (60-80) and ethyl acetate (ratio) as eluent to give the product (2.50 g, yield: 52.5%)