Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:10][C:11](=[O:24])[C@@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1C(OC(C)(C)C)=O)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].Cl>CCOC(C)=O>[CH2:1]([O:10][C:11](=[O:24])[C@@H:12]1[CH2:16][CH2:15][CH2:14][NH:13]1)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)OCC(=O)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(COC(=O)[C@@H]1CCCN1)c1ccccc1
Yield: 93.6 %

Procedure:
Boc-L-proline phenacyl ester (0.29 g, 0.87 mmol) was dissolved in EtOAc (25 mL) and a steady current of HCl was passed through the solution for approximately 40 min, when TLC analysis showed the deprotection to be complete. The solvent was evaporated to provide a white crystalline material. Recrystallization from petroleum ether gave clear crystals (0.19 g, 94%); FABMS 234.2 (M+H), 467.2 (2M+H); HRFABMS calcd for C13H16NO3 (M+H) 234.1130, found 234.1129.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN(C)C=O.O>[CH2:22]([O:21][C:19](=[O:20])[CH2:18][O:10][C:7]1[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=1)[CH3:23]
Reactant: CCOC(=O)CBr
Reactant: CC(C)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(C(C)C)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 98 %

Procedure:
To a solution of 4-isopropylphenol (1.007 g, 7.39 mmol) in 15 mL dimethylformamide was added potassium carbonate (2.04 g, 14.79 mmol) and ethyl bromoacetate (1.23 mL, 11.09 mmol). The reaction was stirred for 48 h at ambient temperature. The mixture was diluted with 500 mL water and extracted with diethyl ether (2×200 mL). The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resultant oil was flash chromatographed with 10% ethyl acetate/hexanes to yield 1.61 g (98%) of ethyl-(4-isopropylphenoxy)acetate as a clear oil.
Reaction SMILES: [N:1]1([C:5]2[N:14]=[C:13]3[C:8]([C:9](=[O:24])[C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:11][N:12]3[CH2:15][CH2:16][C:17]#[N:18])=[CH:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[Cl:25]N1C(C)(C)C(=O)N(Cl)C1=O>C(Cl)(Cl)Cl>[N:1]1([C:5]2[N:14]=[C:13]3[C:8]([C:9](=[O:24])[C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:11][N:12]3[CH2:15][CH2:16][C:17]#[N:18])=[CH:7][C:6]=2[Cl:25])[CH2:2][CH2:3][CH2:4]1
Reactant: CC1(C)C(=O)N(Cl)C(=O)N1Cl
Reactant: CCOC(=O)c1cn(CCC#N)c2nc(N3CCC3)ccc2c1=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(CCC#N)c2nc(N3CCC3)c(Cl)cc2c1=O

Procedure:
A solution of EXAMPLE 81C (0.50 g) and 1,3-dichloro-5,5-dimethylhydantoin (0.30 g) in chloroform (100 mL) was refluxed for 2 hours then cooled, diluted with chloroform, washed with 10% sodium bisulfate and brine, and dried (MgSO4), filtered, and concentrated; and the concentrate was crystallized from dichloromethane/ethyl acetate/hexanes.
Reaction SMILES: Cl.CC(C)CCN[C:7]1[C:8]([C:23]([NH2:25])=[O:24])=[C:9]([CH3:22])[C:10]2[CH2:16][CH2:15][C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[O:12][C:11]=2[CH:21]=1.[CH3:27][S:28]([OH:31])(=[O:30])=[O:29]>C1COCC1>[CH3:27][S:28]([OH:31])(=[O:30])=[O:29].[CH3:10][CH:9]([CH3:22])[CH2:8][CH2:23][NH:25][CH2:10][C:16]1[CH:19]=[CH:20][C:13]2[O:12][C:11]3[CH:22]=[CH:9][C:8]([C:23]([NH2:25])=[O:24])=[CH:7][C:21]=3[CH2:18][CH2:17][C:14]=2[CH:15]=1
Reactant: Cc1c2c(cc(NCCC(C)C)c1C(N)=O)Oc1ccccc1CC2
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)CCNCc1ccc2c(c1)CCc1cc(C(N)=O)ccc1O2

Procedure:
Dissolve amine of example 1 in THF (0.1M solution). Add metanesulfonic acid (1 equiv). Isolate the white precipitate by vacuum filtration to obtain the title compound. 1H-NMR (CD3OD, 300 MHz): 7.90-7.87 (m, 2H), 7.51-7.37 (m, 4H), 4.31 (s, 2H), 3.36 (s, 4H), 3.22-3.19 (m, 2H), 2.87 (s, 3H), 1.86-1.73 (m, 3H), 1.14 (d, 6H, J=6.5 Hz). Electrospray MS M+1 ion=339.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH2:13][NH:12][CH:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:20]([O:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1)[C:21]#[C:22][CH3:23].O>N1C=CC=CC=1>[CH2:18]([O:17][C:15]([CH:11]1[CH2:10][N:9]([C:7]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:8])[CH2:14][CH2:13][N:12]1[S:31]([C:28]1[CH:27]=[CH:26][C:25]([O:24][CH2:20][C:21]#[C:22][CH3:23])=[CH:30][CH:29]=1)(=[O:33])=[O:32])=[O:16])[CH3:19]
Reactant: CCOC(=O)C1CN(C(=O)N2CCOCC2)CCN1
Reactant: CC#CCOc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: CC#CCOc1ccc(S(=O)(=O)N2CCN(C(=O)N3CCOCC3)CC2C(=O)OCC)cc1
Reaction time: 8 h
Yield: 80.7 %

Procedure:
The ethyl 4-(4-morpholinylcarbonyl)-2-piperazinecarboxylate (0.41 g, 1.55 mmol) was dissolved in pyridine (1.44 mL). To this solution was added a solution of 4-but-2-ynyloxy-benzenesulfonyl chloride (0.38 g, 1.55 mmol) in pyridine (1 mL). The reaction was stirred overnight and then poured into water. The mixture was extracted three times with chloroform. The organics were combined, washed with 10% HCl, twice with water, then brine and dried over Na2SO4. The solution was filtered and concentrated in vacuo to provide 0.6 g (81%) of 1-(4-but-2-ynyloxy-benzenesulfonyl)-4-(morpholine-4-carbonyl)-piperazine-2-carboxylic acid ethyl ester as a gold oil. Electrospray Mass Spec 480.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:24]C)[N:6]2[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>Cl>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:24])[N:6]2[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COc1nc2c(N)nc(OCCCCO)nc2n1Cc1ccccc1
Agent: Cl
Product: Nc1nc(OCCCCO)nc2c1nc(O)n2Cc1ccccc1
Yield: 73.2 %

Procedure:
6-Amino-9-benzyl-2-(4-hydroxybutoxy)-8-methoxypurine (114 mg, 0.332 mmol) in concentrated hydrochloric acid (20 ml) was stirred at room temperature for 12 hours. The reaction mixture was evaporated in vacuo to dryness and to the residue was added aqueous ammonia. The resulting crystals were filtered to give the subject compound (80 mg, yield 73%).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].Br.Br[CH2:7][C:8]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=O.N>O>[N:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:8]2[N:1]=[C:2]([NH2:4])[S:3][CH:7]=2)[CH:11]=1
Reactant: O=C(CBr)c1cccnc1
Reactant: NC(N)=S
Agent: Br
Agent: N
Solvent: O
Product: Nc1nc(-c2cccnc2)cs1
Reaction time: 1 h
Yield: 97.7 %

Procedure:
A solution of thiourea (70,4 g) in water (265 ml) was added dropwise to a stirred solution of 3-bromoacetylpyridine hydrobromide (251,6 g) in water (1 1) over 15 minutes. The solution, which turned yellow and became quite hot, was allowed to stand for one hour, and was then basified by addition of aqueous ammonia. The resulting solid was filtered off, washed with water, and dried in vacuo at 65° C. to give 4-(pyridin-3-yl)-thiazol-2-amine, (155 g) Mp 200° C.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10]N)=[CH:6][CH:5]=1)#[N:3].[C:12]([O:20][CH:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)(=O)C>[C:12]([O:20][CH:21]1[CH2:22][C:23]2[C:8]3[C:7](=[CH:6][CH:5]=[C:4]([C:2]#[N:3])[CH:9]=3)[NH:10][C:24]=2[CH2:25][CH2:26]1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#Cc1ccc(NN)cc1
Reactant: O=C1CCC(OC(=O)c2ccccc2)CC1
Agent: Cl
Solvent: CC(=O)O
Product: N#Cc1ccc2[nH]c3c(c2c1)CC(OC(=O)c1ccccc1)CC3
Yield: 47.9 %

Procedure:
4-Cyanophenyl hydrazine hydrochloride (20.2 g) and 4-benzoyloxycyclohexanone (25.9 g) were dissolved in glacial acetic acid (400 ml) and the mixture was heated under reflux for 1.5 hr. After allowing to cool, the mixture was filtered, and the filtrate was evaporated to dryness, and neutralized with aqueous sodium bicarbonate solution to give a solid precipitate, which was purified by chromatography (SiO2 ; hexane/ethyl acetate) to give 3-benzoyloxy-6-cyano-1,2,3,4-tetrahydrocarbazole (18 g). This product (11.6 g) was suspended in ethanol (230 ml) and treatei with 2.5% aqueous potassium hydroxide solution (120 ml), and heated under reflux for 1 hr. The cooled mixture was neutralized with glacial acetic acid and evaporated to a solid residue, which was washed with water, and dried to give 3-hydroxy-6-cyano-1,2,3,4-tetrahydrocarbazole (6.6 g).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:12]([O:8][C:6]1[CH:7]=[C:2]([I:1])[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(I)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(I)cc1OCc1ccccc1
Temperature: 65 °C

Procedure:
To a solution of 5-iodo-2-nitrophenol (2.65 g, 10 mmol) (J. Org. Chem. 1998, 63, 4199-4208) in DMF (10 mL) is added benzyl bromide (1.71 g, 10 mmol) and K2CO3 (2.07 g, 15 mmol) and the mixture is heated at 65° C. for 30 min. Then water is added (400 mL) and it is extracted by EtOAc (2×200 mL). The water layer is then acidified and extracted with EtOAc (100 mL). The combined EtOAc layer is then washed with 1N HCl and brine, dried with NaSO4 and concentrated to give the title compound as a yellow solid.
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.O.[OH-].[Li+].Cl>C1COCC1.O>[CH2:18]([C:13]1[C:12]([CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:22])=[O:2])=[CH:5][N:6]=2)=[C:16]([CH3:17])[O:15][N:14]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCc1noc(C)c1COc1ccc(C(=O)OC)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCc1noc(C)c1COc1ccc(C(=O)O)cn1
Reaction time: 5 h
Yield: 68.3 %

Procedure:
To a suspension of 6-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (1.0 g, 3.3 mmol) in THF (6 mL) was added a solution of lithium hydroxide monohydrate (248 mg, 9.8 mmol) in water (6 mL) added and the resulting mixture stirred at room temperture for 5 h. The mixture was acidified to pH 4 with HCl (1 N, 4.5 mL) and the resulting mixture extracted with ethyl acetate. The combined organic layers were then washed with water and brine, dried over sodium sulfate and evaporated. Purification by chromatography (silica, heptane:ethyl acetate=1:0 to 0:1) afforded the title compound (654 mg, 76%) which was obtained as a white solid. MS: m/e=291.2 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:7]=[C:6]([CH2:17][O:18][CH3:19])[C:3]=1[CH:4]=[O:5].[O:20](S(C(F)(F)F)(=O)=O)[S:21]([C:24]([F:27])([F:26])[F:25])(=O)=[O:22]>ClCCl.O>[CH:4]([C:3]1[C:6]([CH2:17][O:18][CH3:19])=[CH:7][C:8]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[CH:9][C:2]=1[O:1][S:21]([C:24]([F:27])([F:26])[F:25])(=[O:22])=[O:20])=[O:5]
Reactant: COCc1cc(OC2CCCCO2)cc(O)c1C=O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: COCc1cc(OC2CCCCO2)cc(OS(=O)(=O)C(F)(F)F)c1C=O
Yield: 67.3 %

Procedure:
A solution of 2-hydroxy-6-methoxymethyl-4-(tetrahydro-pyran-2-yloxy)-benzaldehyde (5.18 g, 19.5 mmol) and TEA (10.9 mL, 78.0 mmol) in dichloromethane (100 mL) was treated with Tf2O (7.20 mL, 42.8 mmol) at −78° C. for 1 h. The mixture was diluted with water (150 mL) and extracted with dichloromethane. The organic phases were separated, dried (Na2SO4), and concentrated to dryness. The residue was purified by the flash column chromatography (silica, hexanes/ethyl acetate=4:1), affording the title compound (5.23 g, 67%). 1H NMR (300 MHz, CDCl3) δ 10.29 (s, 1H), 7.44 (s, 1H), 6.99 (s, 1H), 5.60-5.58 (m, 1H), 4.84 (s, 2H), 3.78-3.74 (m, 1H), 3.68-3.62 (m, 1H), 3.51 (s, 3H), 1.91-1.88 (m, 2H), 1.74-1.68 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[C:12]([C:21]3[CH:26]=[CH:25][C:24]([S:27](C)(=[O:29])=[O:28])=[CH:23][CH:22]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[NH3:31]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[C:12]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([NH2:31])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: N
Reactant: CC(C)CCc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)c(Cl)c2)c1=O
Product: CC(C)CCc1c(-c2ccc(S(N)(=O)=O)cc2)cnn(-c2ccc(F)c(Cl)c2)c1=O

Procedure:
The title compound was prepared according to the method of Example 384 , substituting 2-(3-chloro-4-fluorophenyl)-4-(3-methylbutyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 102 mg, 61.8%). mp 154-156° C. 1H NMR (300 MHz, DMSO-d6) δ 0.75 (d, 6H), 1.4, (m, 3H), 2.48 (m, 2H), 7.54 (s, 2H), 7.6 (m, 1H), 7.69 (m, 2H), 7.93 (dd, 1H), 8.05 (m, 2H). MS (DCI/NH3) m/z 450 (M+H)+, 468 (M+NH4)+. Anal. calc. for C22H22FN2O3SCl.0.25H2O: C, 58.86; H, 4.94; N, 6.24. Found: C, 59.23; H, 5.12; N, 6.00.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12](=[O:19])[O:11][C:10]2=[O:20])[CH:5]=[CH:4][N:3]=1.[CH2:21]([O:23][C:24](=[O:29])[CH2:25][N:26]=[C:27]=[O:28])[CH3:22]>N1C=CC=CC=1>[CH2:21]([O:23][C:24](=[O:29])[CH2:25][NH:26][C:27]([NH:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12](=[O:19])[O:11][C:10]2=[O:20])[CH:5]=[CH:4][N:3]=1)=[O:28])[CH3:22]
Reactant: Nc1cc(Cn2c(=O)oc(=O)c3ccccc32)ccn1
Reactant: CCOC(=O)CN=C=O
Solvent: c1ccncc1
Product: CCOC(=O)CNC(=O)Nc1cc(Cn2c(=O)oc(=O)c3ccccc32)ccn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 1-(2-amino-pyridin-4-ylmethyl)-1H-benzo[d][1,3]oxazine-2,4-dione (600 mg, see preparation 7b) in pyridine (7 ml) was added isocyanato-acetic acid ethyl ester (0.4 ml). The reaction mixture was stirred at room temperature for 3 hours, and the solvent was evaporated under reduced pressure. The residue was dissolved in EtOAc and washed with water and brine. The organic layer was dried (MgSO4) and evaporated under reduced pressure. The resulting oil was treated with EtOAc (3 ml) and gave a precipitate that was isolated by filtration and dried in vacuo, affording {3-[4-(2,4-Dioxo-4H-benzo[d][1,3]oxazin-1-ylmethyl)-pyridin-2-yl]-ureido}-acetic acid ethyl ester (0.53 g). Step 2: This anhydride intermediate was converted into the title compound by reaction with O-(4-cyanobenzyl)hydroxylamine hydrochloride (see preparation 10), using general procedure 1A. 13C-NMR (DMSO-d6) δ 170.3, 167.4, 154.8, 153.5, 151.4, 148.5, 146.7, 141.8, 132.7, 132.2, 129.1, 128.0, 118.6, 115.4, 114.8, 112.9, 111.5, 110.7, 109.3, 76.0, 60.3, 45.2, 41.2, 14.0.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:3].[Al+3].[Cl-].[Cl-].[Cl-].Cl[CH2:15]Cl>>[CH2:15]1[C:5]2[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:2][CH2:3]1.[CH3:3][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:1]
Reactant: ClCCl
Agent: C=C(C)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: c1ccc2c(c1)CCC2

Procedure:
Alpha-methylstyrene (AMS) (2.0 L, 15.4 mole) was added slowly with stirring over 2 to 3 hrs to a mixture of AlCl3 (0.7 g, 5.2 mole) and dichloromethane (1.0L, dried over 3Å molecular sieves) in 4L beaker, in a drybox at room temperature. After the addition of 1L AMS, about 0.2L dichloromethane was added to make up for the solvent evaporated due to the reaction exotherm. After the addition of all AMS, the reaction mixture was deactivated with 0.3L methanol, washed three times with water, dried over calcium chloride, filtered and volatiles stripped first using a rotary evaporator and then high vacuum. Yield was 1,685 g (93%) of colorless, transparent oil. The material was analyzed to contain 60.5% dimer; 1,1,3-trimethyl-3-phenylindan (Registry No. 3910-35-8; GC/MS: Calc. 236.726, Found 236,157); and 39.5% trimer isomers; 1,3-dimethyl-1-(2-methyl-2-phenylpropyl)-3-phenylindan (Registry No. 41906-7-2; GC/MS: Calc. 354.905, Found 354.234). 1H NMR (CDCl3): ppm 0.8-2.7 (m, br, aliph.13H), 7.0-7.3 (m, br, arom.11 H) The viscosity of the mixture of compounds at 26° C. was 782 cp and was adjusted to 880 cp by distilling off 57 g dimer on a Kugelrohr. When the mixture was distilled, the composition of the distillate was 56.4% dimer and 41.8% trimer.
Reaction SMILES: C([N:8]1[CH2:17][CH2:16][C:15]2[N:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)(=O)C.[Pd]>[N:14]1[C:15]2[CH2:16][CH2:17][NH:8][CH2:9][C:10]=2[CH:11]=[CH:12][CH:13]=1
Reactant: c1ccc(CN2CCc3ncccc3C2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: c1cnc2c(c1)CNCC2
Yield: 94.2 %

Procedure:
6-Benzyl-5,6,7,8-tetrahydro-1,6-naphthyridine (5.0 g, 22.3 mmol) was dissolved in acetic acid (150 ml) and treated with 10% palladium on carbon (2.5 g). The reaction mixture was subjected to 40 psig hydrogen at 55° on a Parr hydrogenation apparatus for 18 hours; the mixture was then filtered through Super-Cel. The filtrate was evaporated to an amber oil, which was dissolved in 6N sodium hydroxide solution and extracted with toluene (2×50 ml) and methylene chloride (2×50 ml). The combined organic extracts were dried over magnesium sulfate, and concentrated in vacuo to provide the title product as a light amber oil (2.8 g, 21 mmol, 94% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:5]2=[CH:6][N:7]=1.[CH2:14]([NH:21][CH2:22][CH2:23][NH2:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([NH:21][CH2:22][CH2:23][NH:24][C:11]([C:9]1[NH:8][C:5]2=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]2[CH:10]=1)=[O:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Reactant: NCCNCc1ccccc1
Product: O=C(NCCNCc1ccccc1)c1cc2cc(Cl)ncc2[nH]1

Procedure:
The title compound was prepared as outlined in EXAMPLE 1 from 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 18) and 2-benzylaminoethylamine. The product was purified by mass directed purification to give the title compound as an off-white solid. m/z (ES)=329 [M+H]+; RT=2.75 min.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[C:13](Br)[N:14]=1)[N:11]([CH2:16][CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:8]2)=[O:4].C([Sn](CCCC)(CCCC)[C:35]1[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=1)CCC.CCOC(C)=O.Cl>CN(C=O)C.[Cl-].[Na+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[C:13]([C:35]3[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=3)[N:14]=1)[N:11]([CH2:16][CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:8]2)=[O:4]
Reactant: CCC(CC)Cn1c(=O)c(-c2ccccc2)cc2c(O)c(C(=O)OC)nc(Br)c21
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCC(CC)Cn1c(=O)c(-c2ccccc2)cc2c(O)c(C(=O)OC)nc(-c3cccnc3)c21
Temperature: 120 °C
Yield: 47.2 %

Procedure:
A mixture of 8-bromo-1-(2-ethyl-butyl)-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (64 mg, 0.139 mmol), 3-tributylstannanyl-pyridine (0.070 mL, 0.209 mmol) and PdCl2(PPh3)2 (20 mg, 0.028 mmol) in 3 mL of DMF was heated at 120° C. for 2.5 h under nitrogen atmosphere. After the mixture was cooled to r.t., EtOAc and brine were added. 1 M HCl was added until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the combined organic layer was washed with water and dried over MgSO4. After evaporating the solvent in vacuo, the crude product was purified by silica gel chromatography (5-90% EtOAc/hexanes+1% AcOH) to give 30 mg of the title compound. MS: (+) m/z 458.49 (M+1).
Reaction SMILES: [C:1]([O:9][C@H:10]1[CH2:15][C@@H:14]([O:16][Si](C(C)(C)C)(C)C)[CH2:13][N:12]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(O)(C)C>CO>[C:1]([O:9][C@H:10]1[CH2:15][C@@H:14]([OH:16])[CH2:13][N:12]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH2:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@H](OC(=O)c2ccccc2)CN(C(=O)OCc2ccccc2)C1
Agent: Cl
Solvent: CC(C)O
Solvent: CO
Product: O=C(O[C@H]1C[C@@H](O)CN(C(=O)OCc2ccccc2)C1)c1ccccc1
Reaction time: 3 h
Yield: 95 %

Procedure:
To a solution of (3S,5R)-benzyl 3-(benzoyloxy)-5-(tert-butyl-dimethylsilyloxy)-piperidine-1-carboxylate (1 eq) in 30 mL of methanol was added 3.8M HCl in isopropanol (4 eq). The reaction mixture was allowed to stand at room temperature for 3 hours at which point it was concentrated under reduced pressure. The resulting residue was diluted with 120 mL of EtOAc, washed with sat. aq. sodium bicarbonate, brine, then dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (EtOAc:hexanes=1:1) to yield (3S,5R)-benzyl 3-(benzoyloxy)-5-hydroxypiperidine-1-carboxylate (95%). LC/MS (m/z): 355.9 (MH+). HPLC: Rt:3.62 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](=O)[C:8](=O)[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)=[CH:3][CH:2]=1.CCO.[CH2:24]([NH2:27])[CH2:25][NH2:26].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1(C)C=CC=CC=1>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)=[N:27][CH:24]=[CH:25][N:26]=2)=[CH:3][CH:2]=1
Reactant: NCCN
Reactant: O=C(C(=O)c1cccc(C(F)(F)F)c1)c1ccncc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: FC(F)(F)c1cccc(-c2nccnc2-c2ccncc2)c1
Temperature: 50 °C
Reaction time: 18 h
Yield: 4 %

Procedure:
Under Ar, a solution of 46 (2.3 g, 8.2 mmol) in abs. EtOH (100 mL) was treated with ethylene diamine (0.58 g, 9.6 mmol) and heated at 50° C. After 18 h, the solution was concentrated to dryness. The residue was partitioned between H2O and EtOAc (3×) and the organic extracts were dried, filtered and concentrated to dryness. The residue was treated with toluene (125 mL) and DDQ (3.8 g, 16.7 mmol) and then heated to 80° C. After 18 h, the reaction was concentrated to dryness. The residue was dry packed with silica gel (100 mL) and chromatographed on a Still column (80 mm). The product was eluted with EtOAc and the common fraction concentrated to dryness. The residue was treated with Et2O and ethanolic-HCl and concentrated to dryness. The residue was triturated from EtOAc and filtered to yield 100 mg of 47.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[C:11]([OH:13])=O.S(Cl)([Cl:16])=O>>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[C:11]([Cl:16])=[O:13]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C1CCc2ccccc2O1
Product: O=C(Cl)C1CCc2ccccc2O1
Yield: 97.6 %

Procedure:
89.0 g (0.5 mol) chroman-2-carboxylic acid and 71.4 g (0.6 mol) thionyl chloride were heated to 80° for 4-5 hours (end of gas evolution). Destillation (77°-80°/0.1 torr) yielded 96.0 g (98%) chroman-2-carboxylic acid chloride
Reaction SMILES: [CH:1]1([CH2:4][CH:5]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[C:6]([OH:8])=O)[CH2:3][CH2:2]1.[CH3:16][NH:17][C@H:18]1[CH2:37][N:22]2[C:23]3[C:28]([C:29]([CH2:30][C:31]([O:33]CCC)=[O:32])=[C:21]2[CH2:20][CH2:19]1)=[CH:27][CH:26]=[CH:25][CH:24]=3>>[CH:1]1([CH2:4][CH:5]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[C:6]([N:17]([CH3:16])[C@H:18]2[CH2:37][N:22]3[C:23]4[C:28]([C:29]([CH2:30][C:31]([OH:33])=[O:32])=[C:21]3[CH2:20][CH2:19]2)=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:8])[CH2:2][CH2:3]1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Reactant: O=C(O)C(CC1CC1)c1ccc(F)cc1
Product: CN(C(=O)C(CC1CC1)c1ccc(F)cc1)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 1 (Method A) from 3-cyclopropyl-2-(4-fluorophenyl)propanoic acid and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 449.