Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]2[C:4]=1[C:5](=[O:15])[C:6](=[O:14])[NH:7]2.O1C2=CC3C(=O)C(=O)NC=3C=C2OCC1.Br[CH:32]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.BrCC1OC(C(F)(F)F)=CC=1>>[C:33]1([CH:32]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[N:7]2[C:8]3[C:4](=[C:3]([O:2][CH3:1])[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=3)[C:5](=[O:15])[C:6]2=[O:14])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: COc1cc2c(c(OC)c1)C(=O)C(=O)N2
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: FC(F)(F)c1ccc(CBr)o1
Agent: O=C1Nc2cc3c(cc2C1=O)OCCO3
Product: COc1cc(OC)c2c(c1)N(C(c1ccccc1)c1ccccc1)C(=O)C2=O

Procedure:
Following the procedure as described in PREPARATION 26A and making non-critical variations using 4,6-dimethoxy-1H-indole-2,3-dione to replace 2,3-dihydro-6H-[1,4]dioxino[2,3-f]indole-7,8-dione, and bromodiphenylmethane to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, 1-(diphenylmethyl)-4,6-dimethoxy-1H-indole-2,3-dione was obtained (90%): 1H NMR (300 MHz, DMSO-d6) δ7.49-7.19 (m, 10H), 6.72 (s, 1H), 6.21 (d, J=1.5 Hz, 1H), 5.87 (d, J=1.5 Hz, 1H), 3.86 (s, 3H), 3.70 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C:7]2[CH:8]=[C:9]([NH:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:27])([F:26])[CH:23]([F:25])[F:24])[CH:16]=3)[CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1.[F:30][C:31]([F:36])([F:35])[CH:32]1[O:34][CH2:33]1>C(#N)C.FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[C:9]([N:13]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:26])([F:27])[CH:23]([F:24])[F:25])[CH:16]=3)[CH2:33][CH:32]([OH:34])[C:31]([F:36])([F:35])[F:30])[CH:10]=[CH:11][CH:12]=2)=[CH:28][CH:29]=1
Reactant: FC(F)(F)C1CO1
Reactant: Fc1ccc(Oc2cccc(NCc3cccc(OC(F)(F)C(F)F)c3)c2)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Product: OC(CN(Cc1cccc(OC(F)(F)C(F)F)c1)c1cccc(Oc2ccc(F)cc2)c1)C(F)(F)F
Temperature: 40 °C
Yield: 80.9 %

Procedure:
The N-[3-(4-fluorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amine (612 mg, 1.5 mmol) product from EX-634C and 1,1,1-trifluoro-2,3-epoxypropane (268 mg, 2.4 mmol) were dissolved in 1.0 mL of acetonitrile. Ytterbium (III) trifluoromethanesulfonate (43 mg, 0.07 mmol) was added, and the stirred solution was warmed to 40° C. for 2.5 h under an atmosphere of nitrogen, at which time HPLC analysis indicated that no secondary amine starting material remained. The reaction was quenched with water and extracted with ether. The ether layer was washed with brine and water, then dried over anhydrous MgSO4. The ether was removed in vacuo, and the crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate in hexane (1:11) to give 633 mg (81%) of the desired 3-[[3-(4-fluorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a yellow oil, 99% pure by HPLC analysis. 1H NMR (CDCl3) δ7.35 (t, 1H), 7.15 (m, 3H), 6.98 (m, 5H), 6.49 (dd, 1H), 6.38 (dd, 1H), 6.33 (m, 1H), 5.92 (tt, 1H), 4.67 (ABq, 2H), 4.37 (m, 1H), 3.91 (dd, 1H), 3.59 (dd, 1H), 2.48 (d, 1H). 19F NMR (CDCl3) δ-79.2 (d, 3F), -88.5 (m, 2F), -120.33 (m, 1F), -137.2 (dt, 2F). HRMS calcd. for C24H19F8NO3: 522.1315 [M+H]+, found: 522.1297.
Reaction SMILES: [C:1]([N:9]1[C:26](=[O:27])[CH2:25][CH2:24][C@@:23]2([CH3:28])[C:10]1=[CH:11][CH2:12][C@@H:13]1[C@@H:22]2[CH2:21][CH2:20][C@@:18]2([CH3:19])[C@H:14]1[CH2:15][CH2:16][C@@H:17]2[OH:29])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[N-]>C(Cl)Cl.CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O.[Rh+2].[Rh+2]>[CH2:36]([O:35][C:33](=[O:34])[CH2:32][O:29][C@H:17]1[CH2:16][CH2:15][C@H:14]2[C@H:13]3[C@H:22]([CH2:21][CH2:20][C@:18]12[CH3:19])[C@:23]1([CH3:28])[C:10]([N:9]([C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:26](=[O:27])[CH2:25][CH2:24]1)=[CH:11][CH2:12]3)[CH3:37]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4N(C(=O)c5ccccc5)C(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: CCOC(=O)CO[C@H]1CC[C@H]2[C@@H]3CC=C4N(C(=O)c5ccccc5)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To the alcohol product from Step B, above and ethyl diazoacetate (0.5 ml) in methylene chloride (6.5 ml) was added rhodium diacetate dimer (15 mg) intermittently during 2 hours. The mixture was stirred at room temperature for 18 hours. The mixture was concentrated and the residue was purified via preparative TLC using two silica gel plates (2000μ) developed with 40% EtOAc in hexanes to afford the title compound (Rf =0.33).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][N:10]2[CH2:13][C:14]2[CH:15]=[C:16]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26]O)=[CH:22][CH:21]=3)[CH:17]=[CH:18][CH:19]=2)=[CH:5][CH:4]=1.[CH3:30][O:31][C:32](=[O:44])[CH:33]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:34][SH:35].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.N1C=CN=C1.CP(C)C>ClCCl.CCCCCCC>[CH3:30][O:31][C:32](=[O:44])[CH:33]([NH:36][C:37]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38])[CH2:34][S:35][CH2:26][C:23]1[CH:24]=[CH:25][C:20]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([CH2:13][N:10]3[C:11]4[C:6](=[CH:5][CH:4]=[C:3]([C:2]([F:29])([F:1])[F:28])[CH:12]=4)[CH2:7][CH2:8][CH2:9]3)[CH:15]=2)=[CH:21][CH:22]=1
Reactant: OCc1ccc(-c2cccc(CN3CCCc4ccc(C(F)(F)F)cc43)c2)cc1
Reactant: COC(=O)C(CS)NC(=O)OC(C)(C)C
Agent: CP(C)C
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1c[nH]cn1
Solvent: CCCCCCC
Solvent: ClCCl
Product: COC(=O)C(CSCc1ccc(-c2cccc(CN3CCCc4ccc(C(F)(F)F)cc43)c2)cc1)NC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere, a solution of [3′-(7-trifluoromethyl-3,4-dihydro-2H-quinolin-1-ylmethyl)-biphenyl-4-yl]-methanol (0.257 g, 0.65 mmol), 2-tert-butoxycarbonylamino-3-mercapto-propionic acid methyl ester (0.304 g, 1.29 mmol), 1,1′-(azodicarbonyl)dipiperidine (0.343 g, 1.36 mmol), and imidazole (0.92 g, 1.36 mmol) in dichloromethane (10 mL, 0.07 M) was treated with trimethylphosphine (1 M in toluene; 1.4 mL, 1.36 mmol) in a dropwise manner at room temperature. After stirring for 1 hour, an equal volume of heptane was added and the resulting precipitate was removed by filtration. The filtrate was concentrated and purified by flash chromatography (20% ethyl acetate in heptane) to give 2-tert-butoxycarbonylamino-3-[3′-(7-trifluoromethyl-3,4-dihydro-2H-quinolin-1-ylmethyl)-biphenyl-4-ylmethylsulfanyl]-propionic acid methyl ester as a white solid.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([N:18]2[C:27]3[C:22](=[CH:23][CH:24]=[N:25][CH:26]=3)[C:21]3=[N:28][O:29][C:30]([CH3:31])=[C:20]3[C:19]2=[O:32])[CH2:13]1)C1C=CC=CC=1.[I:34][Si](C)(C)C>ClCCl>[IH:34].[NH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([N:18]2[C:27]3[C:22](=[CH:23][CH:24]=[N:25][CH:26]=3)[C:21]3=[N:28][O:29][C:30]([CH3:31])=[C:20]3[C:19]2=[O:32])[CH2:13]1
Reactant: Cc1onc2c1c(=O)n(C1CCCC(CNC(=O)OCc3ccccc3)C1)c1cnccc21
Reactant: C[Si](C)(C)I
Solvent: ClCCl
Product: Cc1onc2c1c(=O)n(C1CCCC(CN)C1)c1cnccc21
Product: I

Procedure:
Dissolve [3-(3-methyl-4-oxo-5H-2-oxa-1,5,7-triaza-cyclopenta[a]naphthalen-5-yl)-cyclohexylmethyl]-carbamic acid benzyl ester (0.42 g, 0.00093 mol) in dry dichloromethane. Add iodotrimethylsilane (0.33 mL, 0.0023 mol) and stir overnight at ambient temperature. Quench the mixture with methanol (5 mL) and concentrate in vacuo. Take up the resulting residue in minimal dichloromethane and add diethyl ether. Concentrate and titrate from dichloromethane/diethyl ether to form a dark solid. Decant the solvent and the dry in vacuo to give a near quantitative amount of the crude amine salt as a dark solid and used directly without purification. MS(ES): (M+1)+ 313.2, 314.2 m/z.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[C:12]([C:18]#[C:19][C:20]([C:22]3[N:23](C(OC(C)(C)C)=O)[CH:24]=[CH:25][CH:26]=3)=O)[C:13]([F:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[O:34]C(OC(C)(C)C)=O)=O)(C)(C)C.[OH:42][CH2:43][CH:44]1[CH2:49][CH2:48][CH2:47][NH:46][CH2:45]1.[H-].[Na+]>CN(C=O)C.C(OCC)(=O)C.O>[F:17][C:13]1[C:12]2[C:11]3[C:16](=[CH:15][CH:14]=1)[NH:8][C:9](=[O:34])[C:10]=3[C:20]([C:22]1[NH:23][CH:24]=[CH:25][CH:26]=1)=[CH:19][C:18]=2[N:46]1[CH2:47][CH2:48][CH2:49][CH:44]([CH2:43][OH:42])[CH2:45]1
Reactant: OCC1CCCNC1
Reactant: CC(C)(C)OC(=O)Oc1cc2c(C#CC(=O)c3cccn3C(=O)OC(C)(C)C)c(F)ccc2n1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1Nc2ccc(F)c3c(N4CCCC(CO)C4)cc(-c4ccc[nH]4)c1c23
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-tert-butoxycarbonyloxy-4-[3-(1-tert-butoxycarbonyl-1H-pyrrol-2-yl)-3-oxo-prop-1-ynyl]-5-fluoro-indole-1-carboxylic acid tert-butyl ester (from Example 4 above) (230 mg, 0.40 mmol) and 3-hydroxymethyl-piperidine (Aldrich, 1.20 g, 12.10 mmol) in DMF (6 ml) was treated with NaH (Aldrich, 146 mg, 6.08 mmol). After stirring for 30 minutes at room temperature and then 30 hours at 120° C. the mixture was cooled and poured in a mixture of ethyl acetate and water. The aqueous layer was extracted a few more times with ethyl acetate and the combined organic layer was dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by flash chromatography (silica gel,0-50% ethyl acetate in hexanes gradient) and then further purified by HPLC (silica gel, 30% ethyl acetate in hexanes) and precipitation out of THF with excess of pentane to give 6-fluoro-5-(3-hydroxymethyl-piperidin-1-yl)-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one as a yellow solid. (Yield 12 mg, 8%).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[CH3:5][N:6]([N:8]=[N:9][C:10]1[CH:14]=[CH:13][S:12][C:11]=1[C:15](OC)=[O:16])[CH3:7].O>C1COCC1>[CH3:7][N:6]([N:8]=[N:9][C:10]1[CH:14]=[CH:13][S:12][C:11]=1[C:15]([NH:4][CH2:3][CH2:1][OH:2])=[O:16])[CH3:5]
Reactant: COC(=O)c1sccc1N=NN(C)C
Reactant: NCCO
Solvent: O
Solvent: C1CCOC1
Product: CN(C)N=Nc1ccsc1C(=O)NCCO
Temperature: 25 °C
Reaction time: 20 h
Yield: 77 %

Procedure:
To an ice cold (0-5° C.) solution of ethanol amine (5 mL) in THF (5 mL) was added a solution of methyl 3-[(dimethylamino)diazenyl]thiophene-2-carboxylate (500 mg) in THF (5 mL) for 5 min and stirred at rt for 20 h. The solution was poured into ice cooled water and the solution was extracted with ethyl acetate (3×50 mL). The combined EtOAc layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using chloroform-methanol (95:5) as eluents to give the product, which was recrystallized from chloroform-hexane gave the product as a pale orange color solid (430 mg, 77%), mp 118-122° C. IR (neat) νmax, 3397, 3278, 2926, 1621, 1353, 1298, 1220, 1083, 1007, 882, 775 cm−1;
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[Li]CCCC.CN([CH:17]=[O:18])C.Cl>C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:17]=[O:18])=[CH:4][N:3]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=Cc1ccc(Br)nc1
Temperature: -80 °C

Procedure:
To a suspension of 2,5-dibromopyridine (2.00 g, 8.44 mmol) in dry diethyl ether (25 mL) was added n-BuLi (3.55 mL, 8.87 mmol, 2.5 M solution in hexane) at −80° C. under a nitrogen atmosphere. After stirring for 1 h at −80° C. dry DMF (0.68 mg, 9.28 mmol) was added. After stirring for an additional hour at −80° C. the reaction mixture was allowed to warm to 0° C. and HCl (18.0 mL, 1 M) was added. After stirring for 15 minutes the phases were separated and aqueous layer was extracted twice with diethyl ether. The combined organic layers were washed with water (50 mL), brine (50 mL) and dried over MgSO4. The organic phase was concentrated under reduced pressure and the crude product was purified by flash chromatography on silica-gel using a mixture of hexane/ethyl acetate (8:1) as eluent. White solid. Yield: 1.03 g, 66%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=7.67-7.71 ppm (m, 1H), 8.02 (dd, J=8.2, 2.5 Hz, 1H), 8.84 (dd, J=2.5, 0.6 Hz, 1H), 10.10 (s, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=129.0, 130.6, 137.5, 148.3, 152.5, 189.4; MS (ESI): m/z=187.19 [M+H]+.
Reaction SMILES: C1(=O)NC(=O)CC1.[C:8]([OH:27])(=O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[NH2:28][CH2:29][CH:30]([OH:33])[CH2:31][OH:32]>C(#N)C.O>[OH:33][CH:30]([CH2:31][OH:32])[CH2:29][NH:28][C:8](=[O:27])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: NCC(O)CO
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: O=C1CCC(=O)N1
Solvent: CC#N
Solvent: O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)NCC(O)CO
Yield: 87 %

Procedure:
To a solution of cis-9-octadecenoic acid succinimide (18.3 g, 48.2 mmol) in 50 ml of acetonitrile is added 1-amino-2,3-propanediol (4.4 g, 48.2 mmol) in 50 ml of H2O. After stirring for 12 hours at room temperature the acetonitrile is distilled off and the residue is extracted with ethyl acetate. The combined organic phases are extracted with saturated NaCl solution. The organic phase is dried with MgSO4, filtrated and concentrated. The residue is crystallized from isohexane. Yield: 87% of a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:27]([CH:29]([CH3:31])[CH3:30])[CH3:28])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23]O)=[CH:21][N:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1.S(Cl)(Cl)=O.[Cl-].[CH2:37]([NH:41][CH3:42])[CH:38]([CH3:40])[CH3:39]>ClCCl.CN(C=O)C>[Cl:1][C:2]1[C:3]([N:27]([CH:29]([CH3:30])[CH3:31])[CH3:28])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23][N:41]([CH2:37][CH:38]([CH3:40])[CH3:39])[CH3:42])=[CH:21][N:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1
Reactant: CC(C)N(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2
Reactant: CNCC(C)C
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CC(C)CN(C)Cc1cnnn1-c1cccc(C2=Nc3cc(N(C)C(C)C)c(Cl)cc3NC(=O)C2)c1

Procedure:
The title compound was prepared from 8-chloro-4-[3-(5-hydroxymethyl-[1,2,3]triazol-1-yl)-phenyl]-7-(isopropyl-methyl-amino)-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 96) (220 mg, 0.50 mmol) by reaction with thionylchloride in dichloromethane and subsequent treatment of the corresponding chloride with N-isobutylmethylamine in DMF according to the method described in Example 45. Obtained as a light yellow solid (190 mg, 75%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C@@H:11](O)[C:10]2[CH:16]=[C:17]([CH2:24][CH3:25])[C:18]([C:20]([F:23])([F:22])[F:21])=[CH:19][C:9]1=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P([N:40]=[N+:41]=[N-:42])(C2C=CC=CC=2)=O)C=CC=CC=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:11]([N:40]=[N+:41]=[N-:42])[C:10]2[CH:16]=[C:17]([CH2:24][CH3:25])[C:18]([C:20]([F:23])([F:22])[F:21])=[CH:19][C:9]1=2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCC[C@H]2O
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: CCc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCC[C@@H]2N=[N+]=[N-]
Yield: 71.3 %

Procedure:
Heat a mixture of (R)-7-ethyl-5-hydroxy-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid tert-butyl ester (7.59 g, 21.12 mmol), diphenylphosphoryl azide (DPPA, 5.50 mL, 25.64 mmol) and DBU (3.95 mL, 26.41 mmol) in toluene (200 mL) at 65° C. under nitrogen for 12 h. Add silica gel to the cooled mixture and remove the solvents under reduced pressure. Purify the residue by column chromatography, eluting with ethyl acetate/hexanes (1:2), to provide the title compound as a colorless oil (5.79 g, 71%): 1H NMR (CDCl3, 300 MHz) δ 1.21-2.30 (m, 18H), 2.83-2.89 (m, 2H), 4.78-4.80 (m, 1H), 7.31-7.45 (m, 2H); APCI MS m/z 356 (M−N2)−.
Reaction SMILES: [CH3:1][C@@:2]12[C:17]([CH3:19])([CH3:18])[C@@H:5]([C:6]3[C:7](=[O:16])[N:8]([CH2:11][C:12]([F:15])([F:14])[F:13])[NH:9][C:10]=31)[CH2:4][CH2:3]2.Br[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.ClCCl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[CH3:1][C@@:2]12[C:17]([CH3:19])([CH3:18])[C@@H:5]([C:6]3[C:7](=[O:16])[N:8]([CH2:11][C:12]([F:13])([F:14])[F:15])[N:9]([CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:10]=31)[CH2:4][CH2:3]2
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(CC(F)(F)F)c(=O)c12
Reactant: BrCCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1c2c(=O)n(CC(F)(F)F)n1CCc1ccccc1
Temperature: 100 °C
Yield: 11.5 %

Procedure:
A mixture of (4S,7R)-7,8,8-trimethyl-2-(2,2,2-trifluoro-ethyl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 47; 150 mg, 0.55 mmol), tetrabutylammonium iodide (220 mg, 0.60 mmol) and (2-bromoethyl)benzene (660 μL, 4.8 mmol) in dimethylformamide (2 mL) was heated in a pressure tube in an oil-bath at 100° C. for 24 h. Dichloromethane (75 mL) was added and the solution was washed with water (5×25 mL) and aqueous sodium thiosulfate (25 mL), dried (magnesium sulfate), filtered, evaporated and purified using an ISCO 40 g column, eluting with 20-100% ethyl acetate/hexanes. Fractions homogeneous for the product were evaporated, co-evaporated with methanol, and dried under high vacuum at 90° C. for 3 h to give (4S,7R)-7,8,8-trimethyl-1-phenethyl-2-(2,2,2-trifluoro-ethyl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (24 mg, 12%) as a yellow gum. ES(+)-MS (M+H) 379.
Reaction SMILES: Cl.F[C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:28])[NH:8][C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N:19]4[CH2:24][CH2:23][N:22]([CH:25](C)C)[CH2:21][CH2:20]4)[N:14]=3)=[N:10]2)=[C:5]([O:29][CH3:30])[CH:4]=1.[CH2:31]([O:38]C1C=CC(OC)=C(C=1)C=O)C1C=CC=CC=1.[OH-:49].[Li+]>C1OCCOCCOCCOCCOC1>[CH3:30][O:29][C:5]1[CH:4]=[C:3]([O:38][CH3:31])[CH:12]=[C:11]2[C:6]=1[C:7](=[O:28])[NH:8][C:9]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N:19]3[CH2:20][CH2:21][N:22]([CH3:25])[C:23](=[O:49])[CH2:24]3)[N:14]=1)=[N:10]2
Reactant: COc1ccc(OCc2ccccc2)cc1C=O
Reactant: COc1cc(F)cc2nc(-c3cccc(N4CCN(C(C)C)CC4)n3)[nH]c(=O)c12
Reactant: [OH-]
Agent: C1COCCOCCOCCOCCO1
Agent: Cl
Agent: [Li+]
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cccc(N4CCN(C)C(=O)C4)n3)nc2c1
Temperature: 100 °C
Yield: 18.2 %

Procedure:
A mixture of 2-(6-bromopyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (5 Scheme 21, 0.100 g, 0.278 mmol), 1-methylpiperazin-2-one (7, 0.100 g, 0.667 mmol) and anhydrous lithium hydroxide (0.020 g, 0.83 mmol) in 15-crown-5 (0.9 mL) was heated at 100° C. for 18 h. The mixture was cooled to room temperature and purified by reverse phase HPLC eluting with 10% to 90% CH3CN in H2O to afford the title compound (0.02 g, 18%) as an off-white solid: 1H NMR (500 MHz, DMSO-d6) δ 11.33 (s, 1H), 7.78 (t, J=7.5 Hz, 1H), 7.73 (d, J=7.1 Hz, 1H), 7.08 (d, J=8.3 Hz, 1H), 6.78 (d, J=2.2 Hz, 1H), 6.58 (d, J=2.2 Hz, 1H), 4.25 (s, 2H), 3.97 (t, J=5.5 Hz, 2H), 3.91 (s, 3H), 3.87 (s, 3H), 3.47 (t, J=5.3 Hz, 2H), 2.93 (s, 3H); ESI MS m/z 396 [M+H]+.
Reaction SMILES: Cl.[NH2:2][CH2:3][C@@H:4]([NH:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C:5]([O:7][CH3:8])=[O:6].CCN(CC)CC.[Cl:27][CH2:28][CH2:29][CH2:30][C:31](Cl)=[O:32]>CO>[CH2:13]([O:12][C:10]([NH:9][C@H:4]([CH2:3][NH:2][C:31](=[O:32])[CH2:30][CH2:29][CH2:28][Cl:27])[C:5]([O:7][CH3:8])=[O:6])=[O:11])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(Cl)CCCCl
Reactant: COC(=O)[C@@H](CN)NC(=O)OCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)[C@@H](CNC(=O)CCCCl)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.1 %

Procedure:
A solution of (R)-methyl 3-amino-2-(benzyloxycarbonylamino)propanoate hydrochloride (4.0 g, 0.014 mol) in methanol (80 mL) was cooled to 0° C. To this mixture was added Et3N (3.3 g, 31 mmol), followed by 4-chlorobutanoyl chloride (2.3 g, 15.0 mmol). The reaction mixture was allowed to warm to rt and stirred for 4 h. The reaction was quenched with saturated brine (200 mL), the organic layer extracted with CH2Cl2, washed with 1N HCl, saturated brine, dried over MgSO4 and concentrated to give crude (R)-methyl 2-(benzyloxycarbonylamino)-3-(4-chlorobutanamido)propanoate (5.0 g) that was used in the next step without further purification. 1H NMR (CDCl3, 400 MHz) δ 7.45-7.35 (m, 5H) 6.01 (s, 1H), 5.84 (d, 1H), 5.11 (d, 2H), 4.42 (t, 5H), 3.68-3.50 (m, 6H), 2.32 (t, 2H), 2.08 (t, 2H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:13][C:12](=[O:14])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-]#N.[Na+].[C:18](=[O:21])([O-])[O-].[NH4+:22].[NH4+:23]>O.C(O)C>[NH:22]1[CH2:13][C:12](=[O:14])[NH:23][C:18]1=[O:21].[CH2:1]([O:8][CH2:9][CH:10]1[CH2:13][C:12](=[O:14])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: O=C([O-])[O-]
Agent: O=C1CC(COCc2ccccc2)C1
Agent: [C-]#N
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C1CNC(=O)N1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
3-(Benzyloxymethyl)cyclobutanone 4.0 g (21 mmol), sodium cyanide 2.1 g (42 mmol) and ammonium carbonate 10.1 g (105 mmol) were added into a 100-ml eggplant-shaped flask, and the mixture was dissolved in 50 ml of 50% water/ethanol. This eggplant-shaped flask was sealed and the mixture was stirred overnight at 60° C. After opening this flask with caution in a draft chamber, the reaction solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and filtered to remove insoluble inorganic salts. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography (hexane:ethyl acetate=50:50). Thus, 3-(benzyloxymethyl)cyclobutanone hydantoin was obtained as a white crystal (cis-form 2.8 g, 11 mmol, 50%; trans-form 1.1 g, 4.3 mmol, 21%).
Reaction SMILES: C(NCC)C.C(O)(C)(C)C.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][C:13]=1[N+:21]([O-:23])=[O:22].Br[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][CH:29]=1)=[O:27].S(=O)(=O)(O)O>[Cl-].[Zn+2].[Cl-].C1C=CC=CC=1>[Br:34][C:31]1[CH:32]=[CH:33][C:28]([C:26](=[O:27])[CH2:25][CH2:19][C:18]([C:15]2[CH:16]=[CH:17][C:12]([Cl:11])=[C:13]([N+:21]([O-:23])=[O:22])[CH:14]=2)=[O:20])=[CH:29][CH:30]=1
Reactant: CC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: O=C(CBr)c1ccc(Br)cc1
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCNCC
Solvent: c1ccccc1
Solvent: CC(C)(C)O
Product: O=C(CCC(=O)c1ccc(Cl)c([N+](=O)[O-])c1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1.75 h

Procedure:
Zinc chloride (2.73 g, 20 mmole)was treated with anhydrous benzene (10 mL) followed by diethylamine (1.55 mL, 15 mmole) and tert-butanol (1.4 mL, 15 mmole) and the resulting slurry was stirred at room temperature for 1.75 hr until all solids had dissolved. To the cloudy suspension was added 4′-chloro-3′-nitroacetophenone followed by 2,4′-dibromoacetophenone and the resulting light yellow slurry was stirred at room temperature for 68 hours. The resulting thick white slurry was treated with 25 mL 5% aqueous sulfuric acid with stirring and the resulting slurry was filtered. The solid was washed with water (50 mL), MeOH (50 mL) and CH2Cl2 (50 mL), then dried in vacuo at room temperature for 1 hr and at 55° C. for 5 hr. giving the title compound as a white solid, 3.4 g, 86%.