Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=1)[CH2:11][NH:12][C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]2[CH2:21][C@H:20]2[C:22](O)=[O:23])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:52][CH2:53][C:54]1[CH:59]=[CH:58][N:57]=[CH:56][CH:55]=1>ClCCl.CN(C=O)C>[C:2]1([O:1][C:8]2[CH:9]=[C:10]([CH2:11][NH:12][C:13]3[CH:18]=[CH:17][C:16]([C@@H:19]4[CH2:21][C@H:20]4[C:22]([NH:52][CH2:53][C:54]4[CH:59]=[CH:58][N:57]=[CH:56][CH:55]=4)=[O:23])=[CH:15][CH:14]=3)[CH:25]=[CH:26][CH:27]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccc(NCc2cccc(Oc3ccccc3)c2)cc1
Reactant: NCc1ccncc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(NCc1ccncc1)[C@@H]1C[C@H]1c1ccc(NCc2cccc(Oc3ccccc3)c2)cc1
Reaction time: 0.25 h
Yield: 77 %

Procedure:
To a mixture of racemic-(trans)-2-{4-[(3-phenoxybenzyl)amino]phenyl}cyclopropanecarboxylic acid (I-2a) (0.10 g, 0.231 mmol) in dichloromethane (2 mL) and DMF (3 mL) was added HATU (0.27 g, 0.71 mmol). The mixture was stirred for 15 min followed by addition of 4-(aminomethyl)pyridine (0.10 g, 0.94 mmol). The solution stirred for 6 h after which the dichloromethane was removed via rotavap. Sat. NaHCO3 and ethyl acetate were added and the organic layer separated and washed with H2O, dried over MgSO4, filtered and concentrated. The resulting oil was triterated with Et2O and formed a cream ppt which was filtered and dried under high vacuum to give the title compound as a cream powder (0.08 g, 40%). 1H NMR (400 MHz, CDCl3) δ 8.56 (d, J=5.4 Hz, 2H), 7.34-7.28 (m, 3H), 7.26 (d, J=5.5 Hz, 2H), 7.11-7.07 (m, 2H), 7.01-6.99 (m, 3H), 6.92-6.90 (m, 3H), 6.55 (d, J=8.4 Hz, 2H), 6.01-5.98 (m, 1H), 4.50-4.47 (m, 2H), 4.29 (s, 2H), 4.03 (s, 1H), 2.48-2.43 (m, 1H), 1.58-1.51 (m, 1H), 1.24-1.19 (m, 2H). ES-MS m/z 450 (MH+).
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)[CH2:3][C:4](O)=[O:5].CO>C1COCC1>[NH2:1][CH:2]([C:7]1[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=1)[CH2:3][CH2:4][OH:5]
Reactant: NC(CC(=O)O)c1ccc(Cl)cc1
Solvent: CO
Solvent: C1CCOC1
Product: NC(CCO)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56.8 %

Procedure:
Borane-tetrahydrofuran complex (94.0 mL, 93.92 mmol) was added dropwise to a stirred suspension of 3-amino-3-(4-chlorophenyl)propionic acid (2.50 g, 12.52 mmol) in THF (75 mL) at 0° C. over a period of 20 minutes under nitrogen. The resulting suspension was stirred at 0° C. for 30 minutes then at 22° C. for 5 hours. The reaction mixture was added portionwise to methanol (500 mL). The mixture was concentrated, redissolved in methanol (250 mL) and reconcentrated (this process was repeated three times). The residue was dissolved in DCM (200 mL) and washed with 1N NaOH (150 mL). The aqueous layer was extracted with DCM (5×100 mL) and the extracts combined with the organic layer. The combined organics were washed with saturated brine (2×150 mL), dried over MgSO4 and concentrated to afford a white semi-solid. The crude product was purified by flash silica chromatography, elution gradient 5 to 7% (10:1 MeOH/conc. NH3 (aq)) in DCM. Pure fractions were evaporated to dryness to afford 3-amino-3-(4-chlorophenyl)propan-1-ol (1.320 g, 56.8%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:14]2[CH:15]=[CH:16][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Fc1ccc(Br)cc1
Product: COc1ccc(-c2ccc(F)cc2)cc1
Yield: 89 %

Procedure:
From 4-fluoro-bromobenzene and 4-methoxyphenyl boronic acid, yield 89%; mp 92-94° C. (lit.,2 94-96° C.); IR: 1504, 1276 and 1041; 1H NMR (400 MHz; CDCl3): 7.53-7.46 (4H, m), 7.11 (2H, t, J 8.7), 6.98 (2H, d, J 8.8) and 3.85 (3H, s); m/z (EI) 202 (95%, M+), 159 (100), 133 (90) and 69 (40)(Found: M+, 202.079. C13H11FO requires M, 202.079).
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[NH:15][C:16]([NH2:25])=[C:17]3[C:21]([N:22]=2)=[N:20][C:19]([O:23][CH3:24])=[N:18]3)[CH2:10][CH2:9]1.Br[CH2:27][CH2:28][CH:29]1[CH2:34][CH2:33][O:32][C:31]([CH3:36])([CH3:35])[CH2:30]1>>[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]3[CH2:27][CH2:28][CH:29]3[CH2:34][CH2:33][O:32][C:31]([CH3:36])([CH3:35])[CH2:30]3)=[C:16]([NH2:25])[N:15]=2)[CH2:10][CH2:9]1
Reactant: CC1(C)CC(CCBr)CCO1
Reactant: COc1nc2nc(OCCC3CC3)[nH]c(N)c-2n1
Solvent: O=C(O)C(F)(F)F
Product: COc1nc2c(N)nc(OCCC3CC3)nc2n1CCC1CCOC(C)(C)C1

Procedure:
Prepared similarly to Intermediate 216 from 2-[(2-cyclopropylethyl)oxy]-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 4-(2-bromoethyl)-2,2-dimethyltetrahydro-2H-pyran.
Reaction SMILES: CS[C:3]1[N:4]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:17][CH:16]=2)[C:5](=[O:14])[C:6]2[CH:12]=[CH:11][C:10](=[O:13])[NH:9][C:7]=2[N:8]=1.[O-:27][CH2:28][CH3:29].[Na+].Cl>C(O)C>[CH2:28]([O:27][C:3]1[N:4]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:17][CH:16]=2)[C:5](=[O:14])[C:6]2[CH:12]=[CH:11][C:10](=[O:13])[NH:9][C:7]=2[N:8]=1)[CH3:29]
Reactant: CC[O-]
Reactant: CSc1nc2[nH]c(=O)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOc1nc2[nH]c(=O)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Temperature: 25 °C
Yield: 84.1 %

Procedure:
2-(Methylsulfanyl)-3-[4-(2,2,2-trifluoroethoxy)phenyl]pyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (300 mg) was suspended in ethanol (9 ml), sodium ethoxide (20% ethanol solution, 1.33 g) was added thereto at room temperature, and the mixture was heated under reflux for 3 hr, and allowed to be cooled. The reaction mixture was poured into 0.5M hydrochloric acid (9 ml) under ice-cooling, and the brown precipitate was collected by filtration, washed with water, and dissolved in tetrahydrofuran (100 ml). The solution was diluted with ethyl acetate (150 ml), and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained brown residue was purified by silica gel column chromatography (ethyl acetate/hexane) and then silica gel column chromatography (NH, methanol/ethyl acetate) to give the title compound (251 mg) as a white solid.
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:11](=[O:14])[CH2:12][CH3:13].[CH2:15]1N2CN3CN(C2)CN1C3.C(OC(=O)C)(=O)C.[OH-].[Na+].S(=O)(=O)(O)O.C1CC(=O)C=C2C=1C=CC=C2>O.C(OCC)(=O)C>[CH3:13][CH:12]1[C:11](=[O:14])[C:2]2=[CH:1][C:10]3[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=3[CH:4]=[C:3]2[CH2:15]1
Reactant: CCC(=O)c1ccc2c(c1)CCCC2
Reactant: C1N2CN3CN1CN(C2)C3
Agent: O=C1C=c2ccccc2=CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Product: CC1Cc2cc3c(cc2C1=O)CCCC3
Temperature: 80 °C
Reaction time: 23 h

Procedure:
According to the procedure of Bhattacharya et. al (Synth. Commun 1996., 26, 1775-1784.) a mixture of 1-(5,6,7,8-tetrahydro-naphthalen-2-yl)-propan-1-one (37.6 g), hexamethylenetetramine (44.9 g) and acetic anhydride (38.8 mL) is heated with stirring at 80° C. for 23 hours. The mixture is allowed to cool, and added slowly to a stirred mixture of ethyl acetate (200 mL) and aqueous sodium hydroxide (200 mL, 2M). The organic layer is separated, washed with aqueous HCl, brine, and dried (Na2SO4). The solvent is removed to give a brown oil. This is added cautiously to concentrated sulfuric acid (120 mL) and the resulting mixture is heated at 55° C. for 5 hours followed by room temperature for 18 hours. The reaction is diluted with water and extracted with dichloromethane. After drying (Na2SO4) the solvent is removed to give an oil. The product is purified by chromatography (silica, ethyl acetate/hexane) to give a geometrical mixture of isomers containing 2-Methyl-1,2,6,7,8,9-hexahydro-cyclopenta[.a.]naphthalen-3-one and the title compound.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([C:8]([F:11])([F:10])[F:9])[CH2:5][N:4]([C:12]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:13]=2[CH:14]=O)[CH2:3]1.[NH:23]1[C:30](=[O:31])[CH2:29][C:27](=[O:28])[NH:26][C:24]1=[O:25]>CO>[CH3:1][C@@H:2]1[C@H:3]2[C:29]3([CH2:14][C:13]4[C:12]([N:4]2[CH2:5][C@H:6]([C:8]([F:10])([F:9])[F:11])[O:7]1)=[CH:19][CH:18]=[C:17]([N+:20]([O-:22])=[O:21])[CH:16]=4)[C:27](=[O:28])[NH:26][C:24](=[O:25])[NH:23][C:30]3=[O:31]
Reactant: O=C1CC(=O)NC(=O)N1
Reactant: C[C@@H]1CN(c2ccc([N+](=O)[O-])cc2C=O)C[C@H](C(F)(F)F)O1
Solvent: CO
Product: C[C@H]1O[C@@H](C(F)(F)F)CN2c3ccc([N+](=O)[O-])cc3CC3(C(=O)NC(=O)NC3=O)[C@H]12
Temperature: 80 °C
Reaction time: 0.43 h

Procedure:
2-[cis-2-methyl-6-(trifluoromethyl)morpholin-4-yl]-5-nitrobenzaldehyde (212 mg, 0.67 mol) is combined with barbituric acid (95 mg, 0.67 mmol, Aldrich) in a vial with MeOH (3 mL). The sealed reaction is heated to 80° C. on a shaker block for 21 hours and then the solvent is removed by rotary evaporation. The product is purified on a Biotage Flash 25M+ using a 26 minute linear gradient of 2.5%–10% MTBE in CH2Cl2 eluent. The product is dried under vacuum yielding a yellow-orange solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.01, 2.93, 3.46, 3.66, 3.73, 4.04, 4.40, 4.48, 7.10, 7.88, 8.01, 11.63, 11.94.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[N:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2([C:47]([NH2:49])=[O:48])[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH:36]=1.C(OCC)(=O)C>CO.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][N:44]3[CH2:45][CH2:46][C:41]([C:37]4[CH:36]=[N:35][CH:40]=[CH:39][CH:38]=4)([C:47]([NH2:49])=[O:48])[CH2:42][CH2:43]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NC(=O)C1(c2cccnc2)CCNCC1
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Solvent: ClCCl
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4cccnc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 88.6 using 2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (3.2 g, 6 mmol) and 4-(pyridin-3-yl)-piperidine-4-carboxylic acid amide (1.03 g, 5 mmol). Chromatograph on silica gel eluting sequentially with ethyl acetate, 4% methanol/dichloromethane, 6% methanol/dichloromethane, 8% methanol/dichloromethane, and then 10% methanol/dichloromethane to give the title compound: Rf =0.32 (silica gel, 10% methanol/dichloromethane).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:26]=[CH:25][CH:24]=[CH:23][C:8]=3[CH2:9][CH2:10][CH:11]([NH:12]C(=O)OCC3C=CC=CC=3)[C:5]2=[N:4][CH:3]=1.[H][H]>C(O)C.[Pd]>[CH3:1][C:2]1[N:6]2[C:7]3[CH:26]=[CH:25][CH:24]=[CH:23][C:8]=3[CH2:9][CH2:10][CH:11]([NH2:12])[C:5]2=[N:4][CH:3]=1
Reactant: [H][H]
Reactant: Cc1cnc2n1-c1ccccc1CCC2NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: Cc1cnc2n1-c1ccccc1CCC2N
Reaction time: 7 h
Yield: 87.2 %

Procedure:
Combine benzyl N-(1-methyl-5,6-dihydro-4H-imidazo[1,2-a][1]benzazepin-4-yl)carbamate (0.99 g, 2.85 mmol) and 10% Pd/C (200 mg, 1.88 mmol) in absolute ethanol (50 mL). Place the mixture on a Parr shaker for 7 hours (hydrogen (H2) 60 psi, ambient temperature). Remove the catalyst by filtration, add 10% Pd/C (200 mg, 1.88 mmol) to the filtrate, and place the mixture on a Parr shaker for 7 additional hours (60 psi, ambient temperature). After 7 hours, add more 10% Pd/C (189 mg, 1.78 mmol) and shake for 7 additional hours. Remove the catalyst by filtration and concentrate the filtrate under reduced pressure to give the title compound (0.53 g, 87%): MS (m/z): 214 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:9]2C(=O)[O:12][N:11]=[C:10]2[C:15]2[C:16]([NH:20][C:21]([C:23]3[NH:27][N:26]=[N:25][N:24]=3)=O)=[N:17][O:18][N:19]=2)[CH:5]=[CH:6][C:7]=1[F:8].P(Cl)(Cl)(Cl)(Cl)Cl.C([BH3-])#N.[Na+]>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:15]2[C:16]([NH:20][CH2:21][C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[N:17][O:18][N:19]=2)=[N:11][OH:12])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(Nc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1)c1nnn[nH]1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: c1ccncc1
Product: ON=C(Nc1ccc(F)c(Br)c1)c1nonc1NCc1nnn[nH]1
Temperature: 0 °C
Reaction time: 2 h
Yield: 18.6 %

Procedure:
A solution of N-{4-[4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}-1H-tetrazole-5-carboxamide (12 mg, 27 μmol) in pyridine (0.3 mL) was treated with phosphorus pentachloride (13 mg, 60 μmol) at 25° C. The reaction mixture was stirred at 0° C. for 2 h, concentrated, rediluted with toluene and concentrated to a residue. This material was diluted with ethanol (1 mL), treated with sodium cyanoborohydride (5 mg, 82 μmol), and stirred for 2 h. The reaction mixture was concentrated, diluted with ethanol (1 mL), treated with 2.0 M sodium hydroxide in water (0.2 mL), and stirred for 45 min. Purification of the crude reaction mixture by preparative LCMS gave the desired product (2 mg, 19%). LCMS for C11H10BrFN9O2 (M+H)+: m/z=398.0, 400.0.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][C:20]=1[N+:21]([O-])=O)[NH:7][C:8](=[O:17])[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)([O-])=O.[CH3:24][N:25]([CH3:34])[C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=1>>[CH3:24][N:25]([CH3:34])[C:26]1[CH:33]=[CH:32][C:29]([C:30]2[NH:21][C:20]3[CH:19]=[CH:18][C:6]([NH:7][C:8](=[O:17])[C:9]4[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=4)=[CH:5][C:4]=3[N:1]=2)=[CH:28][CH:27]=1
Reactant: COc1ccc(C(=O)Nc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)cc1
Reactant: CN(C)c1ccc(C=O)cc1
Product: COc1ccc(C(=O)Nc2ccc3[nH]c(-c4ccc(N(C)C)cc4)nc3c2)cc1

Procedure:
Compound 208 was prepared according to the procedure similar to that described in Scheme III from 3,4-dinitro-N-(4-methoxybenzoyl)aniline and 4-dimethylaminobenzaldehyde. 1H NMR (500 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.39 (d, J=1.5 Hz, 1H), 8.08 (d, J=9.5 Hz, 2H), 8.01 (d, J=7 Hz, 2H), 7.79 (dd, J=2, 9 Hz, 1H), 7.67 (d, J=9 Hz, 1H), 7.09 (d, J=9 Hz, 2H), 6.96 (d, J=9 Hz, 2H), 3.82 (s, 3H), 3.08 (s, 6H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1([CH3:27])[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:24](=O)[CH3:25])[CH:22]=2)[O:17][CH2:16][CH2:15]1.P(Cl)(OCC)(OCC)=O>O1CCCC1.CCCCCC>[CH3:13][C:14]1([CH3:27])[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:24]#[CH:25])[CH:22]=2)[O:17][CH2:16][CH2:15]1
Reactant: CC(=O)c1ccc2c(c1)C(C)(C)CCO2
Agent: CCOP(=O)(Cl)OCC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C#Cc1ccc2c(c1)C(C)(C)CCO2
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 2.47 g (24.41 mmol) of diisopropylamine in 40 ml dry tetrahydrofuran under argon at -78° C. was added dropwise 15.2 ml of 1.6M (24.32 mmol) n-butyl lithium in hexane. Mixture was stirred at -78° C. for 1 hour and then treated dropwise with a solution of 4.98 g (24.38 mmol) of 4,4-dimethyl-6-acetylchroman in 4 ml of dry tetrahydrofuran. After stirring at -78° C. for 1 hour, the solution was treated with 4.2 g (24.36 mmol) of diethyl chlorophosphate. The cooling bath was then removed and mixture stirred at room as temperature for 2.75 hours. This solution was then transferred using a double ended needle to a solution of lithium diisopropyl amide (prepared as per Example 4) using 4.95 g (48.92 mmol) of diisopropylamine and 30.5 ml of 1.6M (48.8 mmol) n-butyl lithium in hexane in 80 ml dry tetrahydrofuran at -78° C. The cooling bath was removed and mixture stirred at room temperature for 18 hours and then quenched with 50 ml water and 25 ml of 3N hydrogen chloride. The mixture was extracted with 2×100 ml and 3×50 ml of pentane and the combined organic fractions washed with 3N hydrogen chloride, water, saturated NaHCO3 and saturated NaCl solution and then dried (MgSO4). Solvent was then removed in vacuo and the residue purified by flash chromatography (silica; 10% ethyl acetate in hexane) followed by kugelrohr distillation (70° C.; 0.35 mm) to give the title compound as a colorless crystalline solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O>>[F:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[C:11](=[O:13])[CH2:10][CH2:9][CH2:8]2
Reactant: O=C(O)CCCc1cccc(F)c1
Agent: O=S(=O)(O)O
Product: O=C1CCCc2cc(F)ccc21
Temperature: 45 °C
Reaction time: 3 h
Yield: 73.9 %

Procedure:
Crude 4-(3-fluorophenyl)butyric acid (8.83 kg) was added to concentrated sulfuric acid (30 kg) in a chemical reactor at a rate such that the pot temperature stayed between 40° C. and 60° C. (jacket heating was not necessary). The reaction was stirred at 45° C. for 3 hours and reaction completion was confirmed by LC. The reaction mixture was cooled and quenched with water (16 L), and then extracted with 35% THF in methylene chloride (25.8 kg). The organic layer was separated and washed with water (16 L), saturated aqueous NaHCO3 (16.9 kg) and then a mixture of water (16.1-kg)/brine (4.7-kg). The organic later was concentrated under vacuum and re-stripped with the aid of hexane to remove water and afford 6-fluoro-3,4-dihydro-2H-naphthalen-1-one as an oil (5.88 kg): MS (M+1)=165; H1 NMR (300 MHz): δ ppm (CDCl3): 2.14 (2H, m, J=6.03, 5.75 Hz), 2.64 (2H, dd, J=6.03, 5.75 Hz); 2.94 (2H, t, J=6.03), 6.9-7.0 (2H, m, J=2.26, 2.64, 6.03 Hz), 8.02-8.07 (1H, dd, J=6.03).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7](O)=[O:8].[CH2:13]([N:15](CC)[CH2:16]C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CNC.O1CCCC1>C(#N)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([N:15]([CH3:16])[CH3:13])=[O:8]
Reactant: CCN(CC)CC
Reactant: COc1ncc(Br)cc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CC#N
Product: COc1ncc(Br)cc1C(=O)N(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 5-bromo-2-methoxynicotinic acid (80 mg, 0.34 mmol), triethylamine (192 μl, 1.38 mmol) and 2-(1 H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate in acetonitrile (1 mL) was added dimethylamine, 2 M in tetrahydrofuran (172 μl, 0.34 mmol). The reaction mixture was stirred at ambient temperature under an atmosphere of nitrogen for 3 h. The mixture was partitioned between water and ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated in vacuo to give a crude product which was purified by column chromatography using a gradient of ethyl acetate in heptane affording 54 mg (60%) of the title compound as a white solid: 1H NMR (400 MHz, DMSO-d6) ppm 8.36 (d, 1 H), 7.91 (d, 1 H), 3.88 (s, 3 H), 2.96 (s, 3 H), 2.78 (s, 3 H); MS (ESI) m/z 259, 261[M+H+].
Reaction SMILES: [OH-].[Na+].[CH2:3]1[C@H:8]2[C:9]3[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=3[CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:7]2[CH2:6][CH2:5][N:4]1[CH2:22][CH2:23][CH2:24][C:25]([O:27]CC)=[O:26].[ClH:30]>C(O)C>[ClH:30].[CH2:3]1[C@H:8]2[C:9]3[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=3[CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:7]2[CH2:6][CH2:5][N:4]1[CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26]
Reactant: CCOC(=O)CCCN1CCN2c3ccccc3Cc3ccccc3[C@@H]2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCCN1CCN2c3ccccc3Cc3ccccc3[C@@H]2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
20 ml of a 10% w/v aqueous solution of sodium hydroxide were added to a solution of 14.34 g of ethyl (R)-4-(1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrazino[1.2-a]azepin-2-yl)butyrate (prepared as described in Example 5) in 100 ml of ethanol, and the resulting mixture was stirred at room temperature for 1 hour. At the end of this time, the pH of the reaction mixture was adjusted to a value of 2 by the addition of 10% w/v aqueous hydrochloric acid, and the solvent was removed by distillation under reduced pressure. The crystals which precipitated were collected by filtration and dried, to give the title compound, melting at 265°-268° C. (with decomposition), in a 76% yield.
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([CH:13]=[C:14]([O:16][CH3:17])[N:15]=2)[C:9]([NH:11][OH:12])=[NH:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:18]([O:25][C:26]1[C:34]([CH3:35])=[CH:33][C:29]([C:30](O)=O)=[CH:28][C:27]=1[CH2:36][CH3:37])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl.CC(=O)OCC.O>[CH2:18]([O:25][C:26]1[C:34]([CH3:35])=[CH:33][C:29]([C:30]2[O:12][N:11]=[C:9]([C:8]3[CH:13]=[C:14]([O:16][CH3:17])[N:15]=[C:6]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[CH:7]=3)[N:10]=2)=[CH:28][C:27]=1[CH2:36][CH3:37])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1cc(C(=N)NO)cc(C2CCCC2)n1
Reactant: CCc1cc(C(=O)O)cc(C)c1OCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(-c2nc(-c3cc(OC)nc(C4CCCC4)c3)no2)cc(C)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.9 %

Procedure:
To a solution of 2-cyclopentyl-N-hydroxy-6-methoxy-isonicotinamidine (870 mg, 3.70 mmol), 4-benzyloxy-3-ethyl-5-methyl-benzoic acid (1.00 g, 3.70 mmol) and DIPEA (1.44 g, 11.1 mmol) in DCM (30 mL), TBTU (1.43 g, 4.44 mmol) is added. The mixture is stirred at rt for 1 h before diluted with EA (150 mL) and water (50 mL). The org. phase is separated, washed with sat. aq. NaHCO3 solution (50 mL) followed by brine (50 mL), dried over MgSO4, filtered and concentrated. The remaining pale brown oil is dissolved in dioxane (40 mL) and then stirred at 115° C. for 48 h. The solvent is evaporated and the crude product is purified by CC on silica gel eluting with heptane:EA 1:9 to give 4-[5-(4-benzyloxy-3-ethyl-5-methyl-phenyl)-[1,2,4]oxadiazol-3-yl]-2-cyclopentyl-6-methoxy-pyridine (1040 mg) as a pale yellow oil; LC-MS**: tR=1.11 min, [M+H]+=470.26.