Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:13][C:14]4[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:15]=4[N:16]=3)=[CH:8][C:7]=2[F:22])[CH2:3][CH2:2]1.O[CH2:24][C@@H:25]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH3:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:13][C:14]4[CH:20]=[C:19]([O:21][CH2:26][C@@H:25]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:33])[CH3:32])[CH3:24])[CH:18]=[CH:17][C:15]=4[N:16]=3)=[CH:8][C:7]=2[F:22])[CH2:2][CH2:3]1
Reactant: Oc1ccc2nc(-c3ccc(OCC4CC4)c(F)c3)oc2c1
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C[C@@H](COc1ccc2nc(-c3ccc(OCC4CC4)c(F)c3)oc2c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.8 %

Procedure:
To a solution of 2-(4-(cyclopropylmethoxy)-3-fluorophenyl)-1,3-benzoxazol-6-ol (1.00 g), tert-butyl ((2S)-1-hydroxypropan-2-yl)carbamate (0.878 g) and triphenylphosphine (1.32 g) in THF (10 mL) was added dropwise diisopropyl azodicarboxylate toluene solution (1.9 M, 2.64 mL), and the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate) to give the title compound (0.744 g). 1H NMR (300 MHz, CDCl3) δ 0.35-0.45 (2H, m), 0.63-0.76 (2H, m), 1.29-1.39 (4H, m), 1.46 (9H, s), 3.91-4.02 (4H, m), 4.04-4.18 (1H, m), 4.70-4.85 (1H, m), 6.95 (1H, dd, J=8.7, 2.3 Hz), 7.04 (1H, t, J=8.3 Hz), 7.10 (1H, d, J=2.3 Hz), 7.60 (1H, d, J=8.7 Hz), 7.84-8.01 (2H, m).
Reaction SMILES: [CH2:1]([C:9]1[C:10](Cl)=[N:11][C:12]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C@@H:28]([CH3:31])[CH2:29][CH3:30])=[CH:18][CH:17]=2)=[N:13][C:14]=1Cl)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[O-2].[Mg+2].C(O)C>[C].[Pd].O>[CH2:1]([C:9]1[CH:14]=[N:13][C:12]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C@@H:28]([CH3:31])[CH2:29][CH3:30])=[CH:18][CH:17]=2)=[N:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCc1c(Cl)nc(-c2ccc(OCCCCC[C@@H](C)CC)cc2)nc1Cl
Agent: [Pd]
Agent: [Mg+2]
Agent: [O-2]
Solvent: CCO
Solvent: O
Product: CCCCCCCCc1cnc(-c2ccc(OCCCCC[C@@H](C)CC)cc2)nc1

Procedure:
Pour 1.88 g of optically active (s)-5-n-octyl-2-[4-(6-methyloctyloxy)phenyl]-4,6-dichloro-pyrimidine, 0.4 g of 10% palladium-carbon, 0.55 g of magnesium oxide, 60 ml of ethanol, and 45 ml of water, into a 200 ml flask, then add hydrogen under oil bath conditions at 50° C., until the logical amount of hydrogen has been absorbed. The catalyst is filtered and separated, then ether is extracted. After the ether layer is washed with water and with saturated salt water, and dried, the ether is evaporated. The resultant impure product is repeatedly refined, and 0.9 g of optically active (s)-5-n-octyl-2-[4-(6-methyloctyloxy)phenyl]-pyrimidine is obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:46])[NH:7][CH2:8][CH:9]([C:30]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][C:31]=1[CH3:45])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][O:20][C:21]2[C:26]([Cl:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=2[Cl:29])=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[CH2:54][CH2:55][C:56]([O:58][CH3:59])=[O:57]>>[C:1]([O:5][C:6]([NH:7][CH2:8][CH:9]([C:30]1[CH:35]=[CH:34][C:33]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=2[CH2:54][CH2:55][C:56]([O:58][CH3:59])=[O:57])=[CH:32][C:31]=1[CH3:45])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][O:20][C:21]2[C:22]([Cl:29])=[CH:23][C:24]([CH3:28])=[CH:25][C:26]=2[Cl:27])=[CH:15][CH:16]=1)=[O:46])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)CCc1ccccc1Br
Reactant: Cc1cc(Cl)c(OCCOc2ccc(CC(CNC(=O)OC(C)(C)C)c3ccc(B4OC(C)(C)C(C)(C)O4)cc3C)cc2)c(Cl)c1
Product: COC(=O)CCc1ccccc1-c1ccc(C(CNC(=O)OC(C)(C)C)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)c(C)c1

Procedure:
Prepared according to the procedure described in EXAMPLE 1, step 1 using tert-butyl {3-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}-2-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propyl}carbamate from step 1 and commercially available methyl 3-(2-bromophenyl)propanoate as starting materials. Purification by column chromatography on silica gel (Combi-Flash by ISCO), eluting with Hex/EtOAc (10 to 50% in 30 min) afforded the desired compound as a foam.
Reaction SMILES: [OH:1][CH:2]1[C:8]2=[N:9][C:10]([CH3:18])=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:12]=[C:7]2[CH2:6][CH2:5][CH2:4][CH2:3]1.[H-].[Na+].[CH3:21]I.O>C1COCC1>[CH3:21][O:1][CH:2]1[C:8]2=[N:9][C:10]([CH3:18])=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:12]=[C:7]2[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CCOC(=O)c1cc2c(nc1C)C(O)CCCC2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2c(nc1C)C(OC)CCCC2
Reaction time: 1 h
Yield: 58.4 %

Procedure:
In an atmosphere of argon, ethyl 9-hydroxy-2-methyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-3-carboxylate (1.04 g, 4.16 mmol) was dissolved in anhydrous THF (8.0 ml), and the solution was mixed with sodium hydride (182.3 mg, 4.56 mmol) at 0° C. This was stirred at the same temperature for 1 hour, mixed with methyl iodide (0.33 ml, 4.76 mmol) by its dropwise addition and then stirred at room temperature for 1.5 hours. The reaction solution was mixed with water and extracted with ethyl acetate, and the thus obtained organic layer was washed with water and saturated brine in that order and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (ether:hexane=1:1) to obtain the title compound (639.8 mg, 58.4%) as yellow oil.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.[CH3:29][N:30]1[C:38](=[O:39])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[NH:31]1>>[OH:22][C:19]([CH:16]1[CH2:17][CH2:18][N:13]([CH2:12][C:7]2[N:8]([CH3:11])[C:9]3[C:5]([N:6]=2)=[C:4]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[N:3]=[C:2]([N:31]2[C:32]4[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:38](=[O:39])[N:30]2[CH3:29])[N:10]=3)[CH2:14][CH2:15]1)([CH3:20])[CH3:21]
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: Cn1[nH]c2ccccc2c1=O
Product: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-n3c4ccccc4c(=O)n3C)nc21

Procedure:
Following General Procedure I for Buchwald coupling, 2-(1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol and 2-methyl-1,2-dihydroindazol-3-one were reacted to give 220. LCMS m/z: 521.3 (MH+)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([Br:26])[C:5]([C@@H:8]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)=[N:6][CH:7]=1.[Br:27]N1C(=O)CCC1=O>C(#N)C>[NH2:1][C:2]1[CH:3]=[C:4]([Br:26])[C:5]([C@@H:8]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])[CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)=[N:6][C:7]=1[Br:27]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)c1ncc(N)cc1Br
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)c1nc(Br)c(N)cc1Br
Reaction time: 0.08 h

Procedure:
A solution of (S)-tert-butyl (1-(5-amino-3-bromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate (46A, 960 mg, 2.24 mmol) in 20 mL of acetonitrile was cooled to 0° C. and treated with N-bromosuccinimide (399 mg, 2.24 mmol) as a solution in 20 mL of acetonitrile. After 5 min, the reaction mixture was partitioned with EtOAc and saturated aqueous NaHCO3. The organic layer was separated and washed with brine, then dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with EtOAc/hexanes to afford the title product. MS (m/z): 507.52 [M+H]+.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.[NH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33]>C(Cl)Cl>[C:1]([NH:8][C@@H:9]([C:11]([NH:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])=[O:13])[CH3:10])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)CN
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)CNC(=O)[C@@H](C)NC(=O)OC(C)(C)C
Temperature: -70 °C

Procedure:
18.9 Grams of Boc-D-alanine are dissolved in 100 ml of methylene chloride, and 22.0 ml of N-methylmorpholine is added. The solution is cooled to -70° C. and 13.0 ml of isobutylchloroformate is added. The reaction mixture is warmed to -15° C. and again cooled to -70° C. and 12.6 g of methyl glycinate hydrochloride is added. The reaction mixture is stirred for sixteen hours at room temperature then extracted three times with a 1.0 M solution of potassium bisulfate, saturated potassium bicarbonate solution, and a saturated sodium chloride solution. The methylene chloride solution is dried over anhydrous sodium sulfate, filtered and stripped of solvent. The product is purified by chromatography on silica gel using methanol-chloroform eluant. Removal of the solvent provides methyl Boc-D-alanylglycinate.
Reaction SMILES: [SnH](CCCC)(CCCC)[CH2:2][CH2:3][CH2:4]C.CC(N=NC(C#N)(C)C)(C#N)C.[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27]1>C1C=CC=CC=1>[CH:3]([N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27]1)([CH3:4])[CH3:2]
Reactant: c1ccc2c(c1)CCN2
Reactant: CCCC[SnH](CCCC)CCCC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Product: CC(C)N1CCc2ccccc21

Procedure:
A three-hour addition of nBu3SnH (154 μL, 573 μmol) and AIBN (34 mg, 208 μmol) solution in benzene (1 mL) to a refluxing solution of the unpurified ketimine (125 mg, 521 μmol) in benzene (50 mL) delivered, after flash chromatography (30% CH2Cl2 Hexanes) 0.024 g (30%) of the desired indoline as a colorless oil. Rf=0.1 (30% CH2Cl2 Hexanes); IR (film) 3047, 1607 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.04 (t, J=6.7 Hz, 2H), 6.59 (t, J=7.4 Hz, 1H), 6.42 (d, J=8.1 Hz, IH), 3.83 (sep, J=6.6 Hz, 1H), 3.33 (t, J=8.5 Hz, 2H), 2.93 (t, J=8.3 Hz, 2H), 1.15 (d, J=6.7 Hz, 6H); 13C NMR (100 MHz, CDCl3) ppm 151.5, 130.5, 127.5, 124.6, 117.1, 107.3, 46.0, 45.7, 28.4, 18.4; HRMS (EI) Exact mass calcd for C11H15N [M]+, 161.1204. Found 161.1201.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]1)[N:6]=[CH:5]2.[C:23]([C@@H:27]1[CH2:32][CH2:31][C@H:30](O)[CH2:29][CH2:28]1)([CH3:26])([CH3:25])[CH3:24].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O.C1COCC1>[C:23]([C@H:27]1[CH2:32][CH2:31][C@H:30]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([CH2:12][N:13]2[CH2:14][CH2:15][CH:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:17][CH2:18]2)[N:6]=[CH:5]3)[CH2:29][CH2:28]1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[C@H]1CC[C@@H](O)CC1
Reactant: COC(=O)C1CCN(Cc2ncc3cc(O)ccc3n2)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C1CCN(Cc2ncc3cc(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Into a 25 mL round bottom flask was added methyl 1-((6-hydroxyquinazolin-2-yl)methyl)piperidine-4-carboxylate (0.5 g, 1.6 mmol), cis-4-tert-butylcyclohexanol (0.38 g, 0.24 mmol, 1.5 eq), PPh3 (0.87 g, 3.3 mmol, 2 eq) and dry THF (0.5 mL) under N2 atmosphere. Then DIAD (0.53 g, 0.33 mmol, 2 eq) was quickly added in one portion at room temperature. The reaction mixture was stirred at rt for 0.5 h, diluted with water (20 mL) and extracted with DCM (20 ml*3). The combined organic lays were dried over MgSO4 and concentrated. The residue was purified by prep-TLC (DCM/MeOH=15/1) to give methyl 1-((6-(trans-4-tert-butylcyclohexyloxy)quinazolin-2-yl)methyl)piperidine-4-carboxylate (300 mg, yield: 20%) as brown oil. 1HNMR (400 MHz, CDCl3) δ: 9.27 (s, 1H), 7.87 (d, J=8.8 Hz, 1H), 7.45 (dd, J=8.8, 2.8 Hz, 1H), 7.07 (d, J=2.8 Hz, 1H), 4.30˜4.20 (m, 1H), 3.94 (s, 2H), 3.59 (s, 3H), 3.00˜2.98 (m, 2H), 2.28˜2.18 (m, 4H), 1.85-1.82 (m, 6H), 1.40˜1.34 (m, 2H), 1.18˜1.03 (m, 4H), 0.86 (s, 9H); ESI-MS: m/z 440.1 (M+1)+.
Reaction SMILES: S(=O)(=O)(O)[OH:2].N[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][S:14]([NH:17][CH3:18])(=[O:16])=[O:15])=[CH:9][CH:8]=1.N([O-])=O.[Na+]>O>[OH:2][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][S:14]([NH:17][CH3:18])(=[O:16])=[O:15])=[CH:9][CH:8]=1
Reactant: O=S(=O)(O)O
Reactant: CNS(=O)(=O)Cc1ccc(N)cc1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CNS(=O)(=O)Cc1ccc(O)cc1
Temperature: 0 °C
Yield: 82.2 %

Procedure:
Add sulfuric acid (2.5 mL, 44.9 mmol) to a suspension of 1-(4-aminophenyl)-N-methyl-methanesulfonamide (7.5 g, 37.5 mmol) in water (56.2 mL) and chill the reaction mixture to 0° C. Slowly, drop wise add a solution of sodium nitrite (2.8 g; 41.2 mmol) in water (37.5 mL) to this slurry. Stir the resulting mixture at 0° C. for 20 m, then remove the ice bath and heat the reaction at 100° C. Cool the mixture to room temperature. Quench the reaction with an excess of water and extract with EtOAc. Combine the EtOAc extracts, wash the extracts with brine; dry over MgSO4; filter; and concentrate the filtrate under reduced pressure to yield the title compound as an orange solid (6.2 g, 66%). MS (m/z): 219 (M+H2O).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[F:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:15]=1[Sn](CCCC)(CCCC)CCCC>CN(C=O)C.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.[Cu]I>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:15]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[F:9])=[N:3][CH:4]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1F
Reactant: Brc1ccc(Br)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Product: Fc1cnccc1-c1ccc(Br)cn1
Temperature: 130 °C
Yield: 61.8 %

Procedure:
In a schlenck tube, a mixture of 2,5-dibromopyridine (2.11 mmol, 0.500 g), 3-fluoro-4-(tributylstannyl)pyridine (2.32 mmol, 0.896 g), PdCl2(PPh3)2 (0.21 mmol, 0.148 g), CuI (0.43 mmol, 0.080 g) in DMF (5 ml) was heated at 130° C. for 12 hours, under argon atmosphere. The solvent was evaporated and the crude mixture was extracted between water and ethyl acetate. The solid residue was purified by chromatography over SiO2 eluting with DCM/methanol mixtures affording 0.330 g (yield 62%) of the expected product.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][NH:17][C:18](=[O:20])[CH3:19])[CH:14]=3)[CH2:9][CH2:8]2)[CH2:3][CH2:2]1.[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([CH2:26][CH2:27]Br)=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([CH2:26][CH2:27][N:1]2[CH2:2][CH2:3][CH:4]([N:7]3[C:15]4[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][NH:17][C:18](=[O:20])[CH3:19])[CH:14]=4)[CH2:9][CH2:8]3)[CH2:5][CH2:6]2)=[CH:24][CH:23]=1
Reactant: Clc1ccc(CCBr)cc1
Reactant: CC(=O)NCc1ccc2c(c1)N(C1CCNCC1)CC2
Product: CC(=O)NCc1ccc2c(c1)N(C1CCN(CCc3ccc(Cl)cc3)CC1)CC2
Yield: 63.7 %

Procedure:
1-(Piperidin-4-yl)-6-acetamidomethylindoline (250 mg) and 4-chlorophenethyl bromide (240 mg) were treated as in Example 2 to give the title compound (240 mg) as white scaly crystals (yield: 63%).
Reaction SMILES: [OH-:1].[K+].[O:3]1[CH2:7][CH2:6][CH2:5][CH2:4]1.O>O>[CH:6]12[CH2:7][CH:4]([CH:4]=[CH:5]1)[CH2:5][CH:6]2[C:7]([OH:3])=[O:1]
Reactant: [OH-]
Reactant: C1CCOC1
Agent: [K+]
Solvent: O
Product: O=C(O)C1CC2C=CC1C2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
67.0 g (269 mmol) of the Diels-Alder adduct was dissolved in 1040 ml of a mixture solvent of tetrahydrofuran-water (5:2), 70.5 g (1.08 mol) of potassium hydroxide (85%) in 300 ml of water was added on ice cooling, and the mixture was stirred at room temperature for 24 hours. After distilling out tetrahydrofuran, the product was neutralized with 94 ml of concentrated hydrochloric acid and extracted with a mixture solvent of hexane-methylene chloride (98:2) (200 ml×4). The extract was dried on anhydrous magnesium sulfate, the solution was filtered, and the solvent was distilled off to obtain 38.8 g of crude 5-norbornene-2-carboxylic acid. Crude yield: 100%.
Reaction SMILES: Cl[C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][N:7]=1.Cl.[CH3:11][O:12][C:13](=[O:16])[CH2:14][NH2:15].C(N(CC)CC)C>CCOCC>[C:8]([C:3]1[C:2]([NH:15][CH2:14][C:13]([O:12][CH3:11])=[O:16])=[N:7][CH:6]=[CH:5][N:4]=1)#[N:9]
Reactant: COC(=O)CN
Reactant: N#Cc1nccnc1Cl
Agent: Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COC(=O)CNc1nccnc1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.5 %

Procedure:
In 8 ml of ether there was dissolved chlorocyanopyrazine (0.42 g; 0.003 M) prepared in Step B above, after which there was added glycine methyl ester hydrochloride (378 mg; 0.003 M), followed by triethylamine (607 mg, 0.84 ml; 0.006 M). The reaction mixture was stirred at room temperature overnight. The resulting precipitate was filtered, washed twice with ether, and the filtrate concentrated under vacuum, then passed through a silica gel column and eluted with dichloromethane to give the title compound (130 mg).
Reaction SMILES: [Cl-].[C:2]1([P:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:10])[O-])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>CN(C=O)C>[C:11]1([P:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[O:10])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C1CNCCN1
Reactant: O=P([O-])(c1ccccc1)c1ccccc1
Agent: [Cl-]
Solvent: CN(C)C=O
Product: O=P(c1ccccc1)(c1ccccc1)N1CCNCC1
Reaction time: 4 h

Procedure:
20 g (84.5 mmol) diphenylphosphinate chloride dissolved in 30 ml DMF are added dropwise to a solution of 21.8 g (253 mmol) piperazine in DMF. After four hours, the solution is concentrated under vacuum, taken up in chloroform and extracted by shaking with 10% hydroxide solution. The organic phase is dried over sodium sulfate and solvent is removed under vacuum. The residue is chromatographically purified over silica gel with CHCl3/CH3OH/TEA (90/10/0 to 90/10/6): yield 12 g (49%).
Reaction SMILES: [CH3:1][N:2]1[CH2:9][CH2:8][CH2:7][C@H:3]1[C:4]([OH:6])=O.[NH2:10][C@H:11]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C.C(OCC)(=O)C>[C:19]([O:18][C:16]([N:13]1[CH2:14][CH2:15][C@H:11]([NH:10][C:4](=[O:6])[C@@H:3]2[CH2:7][CH2:8][CH2:9][N:2]2[CH3:1])[CH2:12]1)=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Reactant: CN1CCC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1CCC[C@H]1C(=O)N[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
To a suspension of 1-methyl-L-proline (600 mg) and (3S)-3-amino-1-(tert-butoxycarbonyl)pyrrolidine (758 mg) in anhydrous DMF (10 ml), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (856 mg) and 1-hydroxybenzotriazole (550 mg) were added. The mixture was stirred overnight at room temperature. To the reaction mixture, ethyl acetate was added. The resulting mixture was washed with an aqueous solution of sodium carbonate, 15% saline and saturated saline, dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure. The residue was purified by chromatography through a silica gel column (ethyl acetate, 5% methanol/ethyl acetate, 10% methanol/ethyl acetate), whereby 1.11 g of (3S)-1-(tert-butoxycarbonyl)-3-(1-methyl-L-prolylamino)pyrrolidine were obtained.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:11][C@@H:12]([CH3:33])[C:13]([NH:15][CH:16]1[C:22](=[O:23])[N:21]([CH3:24])[C:20]2[CH:25]=[CH:26][CH:27]=[CH:28][C:19]=2[C:18]2[CH:29]=[CH:30][CH:31]=[CH:32][C:17]1=2)=[O:14]>C1(C)C=CC=CC=1>[CH3:24][N:21]1[C:22](=[O:23])[CH:16]([NH:15][C:13]([C@@H:12]([O:11][C:9](=[O:10])[NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH3:33])=[O:14])[C:17]2[CH:32]=[CH:31][CH:30]=[CH:29][C:18]=2[C:19]2[CH:28]=[CH:27][CH:26]=[CH:25][C:20]1=2
Reactant: O=C=NCc1ccccc1
Reactant: C[C@H](O)C(=O)NC1C(=O)N(C)c2ccccc2-c2ccccc21
Solvent: Cc1ccccc1
Product: C[C@H](OC(=O)NCc1ccccc1)C(=O)NC1C(=O)N(C)c2ccccc2-c2ccccc21
Temperature: 100 °C

Procedure:
Benzylisocyanate (13.3 mg, 0.1 mmol) was added to a solution of (S)-2-hydroxy-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-propionamide (30 mg, 0.1 mmol) in Toluol (1 ml) and heated to 100° C. for 1 week. The solvent was evaporated and the residue was dissolved in DMF (0.5 ml). The title compound, MS: m/e=444.4 (M+H+) (29 mg, 67%), was isolated from this mixture by automated, preparative HPLC (YMC CombiPrep C18 column 50×20 mm, solvent gradient 5–95% CH3CN in 0.1% TFA(aq) over 6.0 min, λ=230 nm, flow rate 30 ml/min).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Br.[P:13]([O:20]CC)([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16]>>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][P:13](=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16]
Reactant: CCOP(OCC)OCC
Reactant: FC(F)(F)c1cccc(CBr)c1
Product: CCOP(=O)(Cc1cccc(C(F)(F)F)c1)OCC

Procedure:
A mixture of 3-trifluoromethylbenzyl bromide (5.74 g, 24.0 mmol) and triethyl phosphite (4.98 g, 30 mmol) was heated at reflux under nitrogen for 3 hours. The excess triethyl phosphite was removed by distillation and the crude product obtained was distilled at 140°-145° C. at 4 mm to yield 6.44 g (90.7%) of analytically pure product as a clear liquid, D.C.I.M.S.[MH+, 297].
Reaction SMILES: [O:1]=[C:2]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[CH2:3][CH2:4][C:5]([O:7]C)=[O:6]>Cl>[O:1]=[C:2]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6]
Reactant: COC(=O)CCC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: Cl
Product: O=C(O)CCC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Yield: 99 %

Procedure:
In a manner similar to Example 4, Step (b), 4-oxo-4-(4′-trifluoromethyl-biphenyl-4-yl)-butyric acid, methyl ester (1.34 g, 0.00398 mol) was refluxed in 6 M aqueous hydrochloric acid (24 mL) to give 1.27 g of 4-oxo-4-(4′-trifluoromethyl-biphenyl-4-yl)-butyric acid as an 80% pure solid. A portion (0.059 g) of the material was purified by chromatography on silica gel (7 g, 230-400 mesh), eluting with dichloromethane (15×10 mL); dichloromethanemethanol (15:1; 16×10 mL) to give 0.0476 g of pure 4-oxo-4-(4′-trifluoromethyl-biphenyl-4-yl)-butyric acid as an off-white solid; mp 172-174° C.