Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.O.N.[CH2:29](O)[CH3:30]>>[C:1]1([C:7]2[N:8]=[C:9]([CH2:17][CH2:18][C:19]([O:21][CH2:29][CH3:30])=[O:20])[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CCc1nc(-c2ccccc2)cc2ccccc12
Reactant: CCO
Agent: N
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)CCc1nc(-c2ccccc2)cc2ccccc12

Procedure:
3-Phenyl-1-isoquinolinepropanoic acid (6.7 g) and concentrated sulphuric acid (7 cc) in ethanol (0 cc) are stirred for 20 hours at 20° C. The solution is poured into water (400 cc) and the aqueous phase alkalinised with concentrated ammonia solution. The mixture is extracted with methylene chloride (3×100 cc), and the organic phase dried and evaporated to dryness under reduced pressure. Ethyl 3-phenyl-1-isoquinolinepropionate (6.3 g), m.p. 60° C., is obtained.
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:48])[CH:6]([O:18][P:19]([CH:22]([NH:26][C:27](=[O:47])[CH:28]([NH:36][C:37]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH:23]([CH3:25])[CH3:24])([OH:21])=[O:20])[CH2:7][CH2:8][CH2:9][NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C(OCC)(=O)C>C(#N)C>[CH2:40]([O:39][C:37]([NH:36][CH:28]([CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:27]([NH:26][CH:22]([P:19]([OH:21])([O:18][CH:6]([CH2:7][CH2:8][CH2:9][NH:10][C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])[C:5]([OH:48])=[O:4])=[O:20])[CH:23]([CH3:25])[CH3:24])=[O:47])=[O:38])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: COC(=O)C(CCCNC(=O)OC(C)(C)C)OP(=O)(O)C(NC(=O)C(Cc1ccccc1)NC(=O)OCc1ccccc1)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)C(NC(=O)C(Cc1ccccc1)NC(=O)OCc1ccccc1)P(=O)(O)OC(CCCNC(=O)OC(C)(C)C)C(=O)O
Reaction time: 3 h
Yield: 100.1 %

Procedure:
1 M LiOH (3.5 mL) was added to a solution of 2-{[1-(2-benzyloxycarbonylamino-3-phenyl-propionylamino)-2-methyl-propyl]-hydroxy-phosphinoyloxy}-5-tert-butoxycarbonylamino-pentanoic acid methyl ester (211 mg, 0.32 mmol) in acetonitrile (3.5 mL) and the mixture was stirred for 3 h. Ethyl acetate was added and the mixture was washed with 1 M HCl, dried and concentrated to give crude 2-{[1-(2-benzyloxycarbonylamino-3-phenyl-propionylamino)-2-methyl-propyl]-hydroxy-phosphinoyloxy}-5-tert-butoxycarbonylamino-pentanoic acid (208 mg, 100%).
Reaction SMILES: Cl.[NH:2]=[C:3]1[CH2:8][CH2:7][CH2:6][CH2:5][NH:4]1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O.C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C>[C:13]1([C:11]2[N:2]=[C:3]3[CH2:8][CH2:7][CH2:6][CH2:5][N:4]3[CH:10]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N=C1CCCCN1
Reactant: O=C(CBr)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(-c2cn3c(n2)CCCC3)cc1
Temperature: 25 °C
Yield: 71 %

Procedure:
Combine 2-iminopiperidine hydrochloride (4.9 g, 36.4 mmol, 3 equiv) and 2-bromoacetophenone (2.4 g, 12.1 mmol) with Na2CO3 (5.1 g, 48.4 mmol) in dry DMF (15 mL) and heat the mixture at 80° C. for 16 hours. Then, cool the mixture to room temperature, add water (200 mL), and extract with ether (3×100 mL). Wash the combined organic layers with water (2×50 mL), and re-extract the aqueous layer with ether (2×50 mL). Wash the combined organic layers with saturated aqueous sodium chloride (100 mL), dry (MgSO4), and concentrate in vacuo. Purify the residue by flash chromatography (SiO2; eluent: CH2Cl2 to CH2Cl2:MeOH 50:1) to obtain a brown solid, 1.7 g, 71% yield. MS(ES+): m/z=199.1 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[BH4-].[Na+]>CO.C(O)(=O)C>[O:11]=[C:6]1[C:7]2[C:3](=[C:2]([NH:1][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:10]=[CH:9][CH:8]=2)[CH2:4][N:5]1[CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19]
Reactant: Nc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=C1CCC(N2Cc3c(NCc4ccccc4)cccc3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.1 %

Procedure:
A stirred mixture of 3-(4-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione (518 mg, 2.0 mmol) and benzaldehyde (0.21 ml, 2.0 mmol) in methanol (20 ml) was heated to reflux for 5 h. The solvent was removed in vacuo to give a solid. The solid was re-dissolved in acetic acid (20 ml). The stirred solution was heated to reflux for 1 h, and was then allowed to cool to room temperature. To the stirred solution was added sodium borohydride (90 mg, 2.3 mmol) and stirring continued at room temperature for 18 h. The resulting suspension was filtered and washed with acetic acid (10 ml) and ether (20 ml) to give 3-{1-oxo-4-[benzylamino]isoindolin-2-yl}piperidine-2,6-dione as an off-white solid (420 mg, 60% yield): mp, 257–259° C.; 1H NMR (DMSO-d6) δ 2.01–2.07 (m, 1H, CHH), 2.23–2.30 (m, 1H, CHH), 2.49–2.65 (m, 1H, CHH), 2.85–3.00 (m, 1H, CHH), 4.19 (d, J=17 Hz, 1H, CHH), 4.31 (d, J=17 Hz, 1H, CHH), 4.39 (d, J=5.7 Hz, 2H, CH2), 5.12 (dd, J=5.1, 13 Hz, 1H, NCH), 6.37 (t, J=5.9 Hz, 1H, NH), 6.62 (d, J=8.0 Hz, 1H, Ar), 6.91 (d, J=7.3 Hz, 1H, Ar), 7.19–7.40 (m, 6H, Ar), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.79, 31.25, 45.79, 46.09, 51.56, 110.32, 112.34, 126.72, 127.05, 128.32, 129.07, 132.08, 139.72, 143.33, 168.82, 171.22, 172.90; Anal Calcd for C20H19N3O3: C, 68.75; H, 5.48; N, 12.03. Found C, 68.73; H, 5.41; N, 12.04.
Reaction SMILES: C(OC(=O)O[C@H:6]1[CH2:10][C@@H:9]([N:11]2[CH:19]=[N:18][C:17]3[C:12]2=[N:13][C:14]([Cl:21])=[N:15][C:16]=3[Cl:20])[CH:8]=[CH:7]1)C.[NH:23]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:31]([N:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:6]1[CH2:10][C@@H:9]([N:11]2[CH:19]=[N:18][C:17]3[C:12]2=[N:13][C:14]([Cl:21])=[N:15][C:16]=3[Cl:20])[CH:8]=[CH:7]1)([O:33][C:34]([CH3:36])([CH3:37])[CH3:35])=[O:32]
Reactant: CCOC(=O)O[C@@H]1C=C[C@H](n2cnc3c(Cl)nc(Cl)nc32)C1
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@@H]1C=C[C@H](n2cnc3c(Cl)nc(Cl)nc32)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Carbonic acid (1S,4R)-4-(2,6-dichloro-purin-9-yl)-cyclopent-2-enyl ester ethyl ester (2.5 g, 7.29 mmol), di-t-butyl iminodicarboxylate (1.74 g, 8.02 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.33 g, 0.36 mmol) and triphenylphosphine (0.29 g, 1.09 mmol) are placed in an oven-dried flask under an atmosphere of argon. Dry deoxygenated THF (30 ml) is added and the reaction mixture is stirred at room temperature. The reaction is shown to be complete by LCMS after 3 hours. The solvent is removed in vacuo and the title compound is obtained after purification by flash column chromatography (silica, ethyl acetate/isohexane 4:1) 1H nmr (CDCl3, 400 MHz); 8.70 (s, 1H), 6.20 (m, 1H), 5.85 (m, 1H), 5.80 (m, 1H), 5.40 (m, 1H), 3.20 (m, 1H), 2.15 (m, 1H), 1.55 (s, 18H), MS (ES+) m/e 470 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([CH2:9][CH2:10][CH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:6](O)=O)[CH3:2].C=O.N1CCCCC1>N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:19])[C:5](=[CH2:6])[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)[CH3:2]
Reactant: CCOC(=O)C(CCCCC1CCCCC1)C(=O)O
Agent: C=O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: C=C(CCCCC1CCCCC1)C(=O)OCC

Procedure:
16.6 g of 6-cyclohexyl-2-methylenehexanoic acid ethyl ester, in the form of a nearly colourless oil, which is purified by chromatography on silica gel (migrating agent: 80:20 petroleum ether/ethyl acetate), are obtained by the procedure described in Example (1b) from 26 g of (4-cyclohexylbutyl)-malonic acid ethyl ester, 3.1 g of paraformaldehyde, 19 ml of pyridine and 1.2 ml of piperidine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH:14]1[C:26]2[NH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]=2[CH:17]=[CH:16][CH:15]=1.CC(C)([O-])C.[Na+].C1(C)C(C)=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[CH-]1C(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=C1.[CH-]1C(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=C1.[Fe+2].C1(C)C=CC=CC=1>[C:5]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:7][C:2]([N:25]2[C:26]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:19]3[C:24]2=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:3][CH:4]=1
Reactant: Brc1ccc(-c2ccccc2)cc1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: Cc1ccccc1C
Product: c1ccc(-c2ccc(-n3c4ccccc4c4ccccc43)cc2)cc1
Temperature: 120 °C
Reaction time: 7.5 h
Yield: 87.7 %

Procedure:
12 g (50 mmol) of 4-bromobiphenyl, 8.4 g (50 mmol) of carbazole, 230 mg (1 mmol) of palladium acetate, 1.8 g (3.0 mmol) of 1,1-bis(diphenylphosphino)ferrocene, and 13 g (180 mmol) of sodium-tert-butoxide were put in a three-neck flask and the atmosphere of the flask was substituted by nitrogen, and then, 80 mL of dehydrated xylene was added thereto, and deaeration was performed. Under a nitrogen atmosphere, it was heated and stirred at 120° C. for 7.5 hours. After the termination of the reaction, about 600 mL of hot toluene was added to this suspension, and filtered twice through florisil, alumina, and Celite®. The obtained filtrate was concentrated, hexane was added thereto, and recrystallization was conducted. This was filtered, and the residue was collected and dried to obtain 14 g (yield: 87%) of 9-(4-biphenylyl)carbazole which was cream-colored powder.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7]3[N:15]=[CH:16][CH:17]=[CH:18][C:6]=3[N:5]2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.CC1(C)C(C)(C)OB([C:46]2[CH:51]=[CH:50][C:49]([N:52]3[CH2:57][CH2:56][CH2:55][CH2:54][C:53]3=[O:58])=[CH:48][CH:47]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.O.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[C:33]([O:32][C:31](=[O:37])[NH:30][C:26]1([C:23]2[CH:24]=[CH:25][C:20]([C:19]3[N:5]4[C:6]5[CH:18]=[CH:17][CH:16]=[N:15][C:7]=5[NH:8][C:9]5[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=5[C:4]4=[N:3][C:2]=3[C:46]3[CH:51]=[CH:50][C:49]([N:52]4[CH2:57][CH2:56][CH2:55][CH2:54][C:53]4=[O:58])=[CH:48][CH:47]=3)=[CH:21][CH:22]=2)[CH2:29][CH2:28][CH2:27]1)([CH3:35])([CH3:34])[CH3:36]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(Br)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Reactant: CC1(C)OB(c2ccc(N3CCCCC3=O)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccc(N5CCCCC5=O)cc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 160 °C
Yield: 54.6 %

Procedure:
A mixture of tert-butyl {1-[4-(2-bromo-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamate (50.0 mg, 0.0895 mmol), 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidin-2-one (40.5 mg, 0.134 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (6.34 mg, 0.00895 mmol) and 2 M Na2CO3 (0.0895 mL, 0.179 mmol) in DMF (1.00 mL) was heated at 160° C. under microwave irradiation for 1 hour. After cooling to room temperature, the mixture was diluted with water and extracted with CHCl3 (×3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated. The residue was purified by PTLC (CHCl3/MeOH=9:1, EtOAc/CHCl3=1:1) to afford desired product (31.9 mg, 54.6%) as a pale yellow solid. 1HNMR (CDCl3) 500 MHz δ: 8.16 (dd, J=7.7, 1.4 Hz, 1H), 8.03-7.97 (m, 1H), 7.61 (d, J=8.0 Hz, 2H), 7.35 (d, J=8.0 Hz, 2H), 7.31-7.25 (m, 1H), 7.21-7.10 (m, 5H), 6.95 (d, J=7.4 Hz, 1H), 6.84-6.69 (m, 1H), 6.59 (dd, J=8.0, 4.6 Hz, 1H), 6.51-6.45 (m, 1H), 5.21 (br s, 1H), 3.64-3.57 (m, 2H), 2.61-2.26 (m, 6H), 2.18-2.07 (m, 1H), 1.97-1.80 (m, 5H), 1.40 (br s, 9H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[S:9][CH3:10].C([Li])CCC.[B:16](OC)([O:19]C)[O:17]C.[OH-].[Na+]>C1COCC1>[CH3:10][S:9][C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[B:16]([OH:19])[OH:17]
Reactant: CSc1cc(F)ccc1Br
Reactant: COB(OC)OC
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CSc1cc(F)ccc1B(O)O
Temperature: -78 °C
Yield: 83.1 %

Procedure:
Dissolve 1-bromo-4-fluoro-2-methylsulfanyl-benzene (22 g, 99.6 mmol) in dry THF (500 mL) and cool to −78° C. under nitrogen. Add butyl lithium (2.5M in hexanes, 48 mL, 120 mmol) slowly and stir for 10 minutes after complete addition. Add trimethyl borate (22 mL, 200 mmol) and warm to room temperature. Pour into 0.1 M NaOH and extract with ether. Acidify the aqueous layer to pH 2 with concentrated HCl. Extract with ether, rry the organic layer with sodium sulfate, filter and concentrate in vacuo to yield 15.4 g (83%) of the title compound.
Reaction SMILES: [CH2:1]1[C:10]2[C:5]3=[C:6]([CH2:11][CH2:12][C:13](=[O:14])[N:4]3[CH2:3][CH2:2]1)[CH:7]=[CH:8][CH:9]=2.[Cl:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20](Cl)=[O:21]>>[Cl:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([C:8]1[CH:9]=[C:10]2[C:5]3=[C:6]([CH2:11][CH2:12][C:13](=[O:14])[N:4]3[CH2:3][CH2:2][CH2:1]2)[CH:7]=1)=[O:21]
Reactant: O=C(Cl)CCCCCl
Reactant: O=C1CCc2cccc3c2N1CCC3
Product: O=C(CCCCCl)c1cc2c3c(c1)CCC(=O)N3CCC2

Procedure:
Using 2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-one and 5-chlorovaleryl chloride according to the same method as that of Reference Example 1, the title compound (3.53 g) was obtained as colorless crystals having a melting point of 83–84° C.
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([C:7]1([C:20]([O:22][CH3:23])=[O:21])[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)[CH:5]=C.ClCCl.CSC>CO>[O:1]=[CH:5][CH2:4][C:7]1([C:20]([O:22][CH3:23])=[O:21])[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1
Reactant: O=[O+][O-]
Reactant: C=CCC1(C(=O)OC)CCN(C(=O)OC(C)(C)C)CC1
Solvent: CO
Solvent: ClCCl
Solvent: CSC
Product: COC(=O)C1(CC=O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Ozone was bubbled through a −78° C. solution of 1-tert-butyl 4-methyl 4-allylpiperidine-1,4-dicarboxylate (4.0 g, 14.1 mmol) in 3:1 dichloromethane:methanol over 30 min to produce a blue solution. Nitrogen was bubbled through the reaction mixture for 30 min, then dimethylsulfide (5.2 mL, 70.6 mmol) was added and the reaction warmed to room temperature. After 3 h, the reaction mixture was concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of 5 to 50% ethyl acetate:hexane to give the title compound (1.72 g). MS: m/z 230.1 (M−tBu).
Reaction SMILES: CO[C:3]([C:5]1[NH:6][N:7]=[C:8]([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])[CH:9]=1)=[O:4].[F:22][C:23]([F:27])([F:26])[CH2:24][NH2:25]>>[F:22][C:23]([F:27])([F:26])[CH2:24][NH:25][C:3]([C:5]1[NH:6][N:7]=[C:8]([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])[CH:9]=1)=[O:4]
Reactant: CCCCc1noc(C)c1COc1cc(C(=O)OC)[nH]n1
Reactant: NCC(F)(F)F
Product: CCCCc1noc(C)c1COc1cc(C(=O)NCC(F)(F)F)[nH]n1
Yield: 98 %

Procedure:
As described for example 26d, 5-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.34 mmol) was converted, using 2,2,2-trifluoroethylamine instead of 4-aminotetrahydropyran, to the title compound (120 mg, 98%) which was obtained as a colorless oil. MS: m/e=361.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][C:4](=[O:7])[C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:10][CH:9]=1.CC1(C)C(C)(C)OB([C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:28][CH:27]=2)O1.ClCCl.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:14]([C:11]1[CH:12]=[CH:13][C:8]([C:3]2[C:4](=[O:7])[CH2:5][CH2:6][C:2]=2[C:26]2[CH:27]=[CH:28][C:29]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[CH:30][CH:31]=2)=[CH:9][CH:10]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)c1ccc(C2=C(Br)CCC2=O)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1ccc(C2=C(c3ccc(C(C)(C)C)cc3)C(=O)CC2)cc1
Yield: 49.3 %

Procedure:
A mixture of Example 7D (88 mg, 0.300 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (105 mg, 0.330 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (24.51 mg, 0.030 mmol) and K2CO3 (83 mg, 0.600 mmol) in 1,4-dioxane (2 mL) and water (0.5 mL) was stirred at 100° C. for 16 hours. The mixture was diluted with ethyl acetate (30 mL) and washed with brine (10 mL×4). The organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative thin layer chromatography (eluted with petroleum ether/ethyl acetate=2:1, v/v) to afford the title compound (60 mg, 0.148 mmol, 49.3% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.28-7.36 (m, 6H), 7.14 (d, J=8.0 Hz, 2H), 6.52 (s, 1H), 3.00-3.03 (m, 2H), 2.66-2.69 (m, 2H), 1.51 (s, 9H), 1.32 (s, 9H); LC/MS (ESI) m/z 406 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14](OCC)=[O:15])=[C:12]([CH3:19])[NH:11][C:10]([CH3:20])=[C:9]1[C:21]([O:23][CH2:24][CH3:25])=[O:22]>CN(C=O)C>[CH2:24]([O:23][C:21]([C:9]1[CH:8]2[C:13](=[C:12]([CH3:19])[NH:11][C:10]=1[CH3:20])[C:14](=[O:15])[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]2=1)=[O:22])[CH3:25]
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1ccccc1N
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(C)NC(C)=C2C(=O)Nc3ccccc3C21

Procedure:
Diethyl 1,4-dihydro-4-(2-aminophenyl)-2,6-dimethyl-3,5-pyridine dicarboxylate (90.0 gms., 0.26 mole) was dissolved in 250 ml dry DMF and the solution refluxed for a period of 72 hours. The solvent was removed under vacuum and the residue recrystallized twice from ethyl acetate to afford 5.4 gms (7%), m.p. 236°-238° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[Cl:32][C:33]1[CH:34]=[C:35]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH:36]=[CH:37][C:38]=1[Cl:39]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:30])([F:31])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([N:43]4[CH2:42][CH2:41][N:40]([C:35]5[CH:36]=[CH:37][C:38]([Cl:39])=[C:33]([Cl:32])[CH:34]=5)[CH2:45][CH2:44]4)=[O:24])=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1)N1CCN(c2ccc(Cl)c(Cl)c2)CC1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-(3,4-dichlorophenyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z=659.92 (M+H+); retention time=1.12 minutes.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]([CH:24]=[O:25])=[C:11]([C:26]3[CH2:27][CH2:28][O:29][CH2:30][CH:31]=3)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:33]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][C:34]=1[F:43]>>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:19])([CH3:20])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:22])[CH3:23])[C:12]([C@H:24]([C:33]3[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][C:34]=3[F:43])[OH:25])=[C:11]([C:26]3[CH2:27][CH2:28][O:29][CH2:30][CH:31]=3)[C:10]1=2)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: Fc1cc(C(F)(F)F)ccc1Br
Reactant: CC(C)c1nc2c(c(C3=CCOCC3)c1C=O)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Product: CC(C)c1nc2c(c(C3=CCOCC3)c1[C@@H](O)c1ccc(C(F)(F)F)cc1F)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2

Procedure:
Obtained by starting from (S)-5-(tert-butyldimethylsilyloxy)-4-(3,6-dihydro-2H-pyran-4-yl)-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-3-carbaldehyde and 1-bromo-2-fluoro-4-(trifluoromethyl)benzene.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:12])[CH:3]=1.IC.[C:15](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:15][O:7][C:6](=[O:8])[C:5]1[C:9]([CH3:11])=[CH:10][C:2]([Br:1])=[CH:3][C:4]=1[CH3:12]
Reactant: Cc1cc(Br)cc(C)c1C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1c(C)cc(Br)cc1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 102.3 %

Procedure:
To a stirred solution of 4-bromo-2,6-dimethylbenzoic acid (2.81 g, 12.3 mmol) in DMF (30 mL) was added iodomethane (2.30 mL, 36.9 mmol) and potassium carbonate (5.09 g, 36.9 mmol) and reaction was stirred at room temperature for 1.5 hours. The reaction mixture was partitioned between water and ethyl acetate and the organic layer was washed with brine. The solvent was removed under reduced pressure to yield an amber oil (3.06 g). 1H NMR (300 MHz, CDCl3): δ 7.22 (S, 2H), 3.92 (s, 3H), 2.30 (s, 6H).
Reaction SMILES: [CH2:1]([N:4]([CH2:16][CH2:17][CH3:18])[CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[NH2:15])[O:7][CH2:6]1)[CH2:2][CH3:3].[N-:19]=[N+:20]=[N-].[Na+]>O>[CH2:16]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[N:15]=[N+:19]=[N-:20])[O:7][CH2:6]1)[CH2:17][CH3:18]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCN(CCC)C1COc2cccc(N)c2C1
Agent: [Na+]
Solvent: O
Product: CCCN(CCC)C1COc2cccc(N=[N+]=[N-])c2C1
Reaction time: 0.25 h

Procedure:
3-Dipropylamino-5-aminochroman (Example 14; 0.050 g, 0.20 mmol) was diazotized according to the procedure of Example 15. After stirring for 15 minutes, sodium azide (0.026 g, 0.4 mmol) in water (1.0 ml) was added. After stirring at 5° C. overninght the solution was worked-up and purified according to the procedure of Example 15 to give the title compound. Mp 167°-168° C. (oxalate).
Reaction SMILES: Cl.C(O[C:7]([N:9]1[CH2:30][CH2:29][CH2:28][C@H:10]1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][C@H:14]1[CH:18]([OH:27])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:12])=[O:8])(C)(C)C.Cl.[C:32]1([CH2:38][C@H:39]([N:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)C(O)=O)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[OH:27][CH:18]([C@@H:14]1[CH2:15][CH2:16][CH2:17][N:13]1[C:11](=[O:12])[C@@H:10]1[CH2:28][CH2:29][CH2:30][N:9]1[C:7](=[O:8])[C@@H:39]([N:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1)[CH2:38][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(O)COc1ccccc1
Reactant: O=C(O)[C@H](Cc1ccccc1)N1CCCCC1
Agent: Cl
Product: O=C([C@H](Cc1ccccc1)N1CCCCC1)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(O)COc1ccccc1
Yield: 84.9 %

Procedure:
The residue obtained by treating, with 4N hydrochloric acid, (2S)-1-[N-(tert-butoxycarbonyl)-L-prolyl]-2-(1-hydroxy-2-phenoxyethyl)pyrrolidine (751 mg) prepared in Example 46-C) was subjected to condensation with (2S)-3-phenyl-2-(1-piperidinyl)propionic acid hydrochloride (500 mg) in the same manner as in Example 48-B) to give 818 mg of the title compound.