Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[N:6]([CH3:7])[C:5]([CH3:8])=[N:4][C:3]=1[C:9]#[N:10].N(OC(C)(C)C)=O.C(Br)(Br)[Br:19]>>[Br:19][C:2]1[N:6]([CH3:7])[C:5]([CH3:8])=[N:4][C:3]=1[C:9]#[N:10]
Reactant: BrC(Br)Br
Reactant: Cc1nc(C#N)c(N)n1C
Agent: CC(C)(C)ON=O
Product: Cc1nc(C#N)c(Br)n1C
Yield: 42 %

Procedure:
A solution of 5-amino-1,2-dimethyl-1H-imidazole-4-carbonitrile (8.5 g, 62 mmol) in bromoform (51 mL) was cooled with an ice water bath, and tert-butyl nitrite (12.87 g, 124.8 mmol) was added dropwise. The reaction was heated on a steam bath for 30 minutes, allowed to cool, and then refrigerated. The solution was decanted to separate it from a precipitate, and then the solution was purified by column chromatography on silica gel (eluting with ethyl acetate) to provide 5.2 g (42%) of 5-bromo-1,2-dimethyl-1H-imidazole-4-carbonitrile as a bright orange solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([O:23][CH3:24])[O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si](C(C)(C)C)(C)C)(=O)=O.[NH4+].[Cl-]>C(Cl)Cl>[CH3:24][O:23][CH:14]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: COC(OCc1ccccc1)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: COC(OCc1ccccc1)C1CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
410 mg (1.2 mmol) of 1-t-butoxycarbonyl-4-(methoxybenzyloxymethyl)piperidine and 0.28 mL (2.4 mmol) of 2,6-lutidine were combined in 2.5 mL of CH2Cl2. 0.42 mL (1.8 mmol) of t-butyldimethylsilyl trifluoromethane sulfonate were added and the mixture was stirred for 1 h at rt. 10 mL of sat'd NH4Cl-solution were added and the mixture was extracted with CH2Cl2. The combined organic fractions were washed with sat'd NaCl solution, dried over MgSO4, filtered and the filtrate was concentrated. The residue was redissolved in 3 mL of THF. 2 mL of a solution of tetrabutylammonium fluoride (1M in THF) were added and the mixture was stirred for 2 h at rt. 10 mL of sat'd NaHCO3-solution were added and the mixture was extracted with CH2Cl2. The combined organic fractions were washed with sat'd NaCl solution, dried over MgSO4, filtered and the filtrate was concentrated to give the title compound which was used without further purification.
Reaction SMILES: [C:1]1([C@:7]2([C:16]([O:18]C)=[O:17])[CH2:9][C@@H:8]2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC([O-])(C)C.[K+]>CS(C)=O>[C:1]1([C@:7]2([C:16]([OH:18])=[O:17])[CH2:9][C@@H:8]2[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)[C@@]1(c2ccccc2)C[C@@H]1c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(O)[C@@]1(c2ccccc2)C[C@@H]1c1ccccc1
Yield: 59.8 %

Procedure:
To a round-bottom flask at room temperature was added (1S,2R)-methyl 1,2-diphenylcyclopropanecarboxylate (11.5 mmol, 2.91 g, 1.0 equiv.) in dry DMSO (24 mL). t-BuOK (25.4 mmol, 2.85 g, 2.2 equiv.) was added in several portions over 30 minutes under argon. The reaction was monitored by TLC technique until the starting material was consumed completely. The reaction mixture was cooled with ice bath and acidified by careful addition of saturated ammonium chloride (10 mL), followed by a slow addition of 1 N HCl aqueous (35 mL) with vigorous stirring until the pH value reached 3-4. Light yellow solid precipitate was collected by filtration, washed with water (3×5 mL), dissolved in ethyl acetate (100 mL), washed with brine (3×5 mL), dried over MgSO4, and concentrated in vacuo. The crude material was purified using flash column chromatography eluting with a 10:1 mixture of hexanes/ethyl acetate to provide the desired product as a white solid (1.64 g, 60% yield, >99% ee). 1H NMR (400 MHz, CDCl3) δ 7.15-7.14 (m, 3H), 7.08-7.03 (m, 5H), 7.06-6.79 (m, 2H), 3.18 (dd, J=9.4, 7.4 Hz, 1H), 2.21 (dd, J=9.4, 4.9 Hz, 1H), 1.97 (dd, J=7.4, 4.9 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 179.8, 136.1, 134.2, 132.1, 128.3, 127.99, 127.97, 127.5, 126.7, 37.4, 34.1, 20.9; HPLC (to improve the separation, the product was converted to the corresponding methyl ester prepared using dimethylsulfate/KOH in tetrahydrofuran under reflux), (S,S-Whelk, 1.5% isopropanol in hexane, 0.7 mL/min, 1 mg/mL, 30 min, UV 254 nm) retention times of 12.5 min (major) and 15.5 min (minor), >99% ee.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:17].[F:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[C:29]([F:31])[CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>O.C(COC)OC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:24][C:25]1[CH:26]=[C:27]([C:2]2[C:11]3[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:17])[CH:28]=[C:29]([F:31])[CH:30]=1
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1Cl
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCO
Product: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cc(F)cc(F)c1
Yield: 47.5 %

Procedure:
To (4-chloro-8-trifluoromethyl-quinoline-3-yl)-phenyl-methanone (150 mg, 0.448 mmol), 3,5-difluorophenyl boronic acid (141 mg, 0.895 mmol), tetrakis(triphenylphosphine) palladium (52 mg, 0.045 mmol), sodium carbonate (50 mg, 1.41 mmol) in water (750 ml), glyme (2 ml), and ethanol (350 ml), was subjected to micro wave conditions (140° C., 300 watts, 300 sec.). The resulting dark red-brown mixture was filtered concentration in vacuo. Reverse phase gradient HPLC (CH3CN, H2O) afforded the title compound as a yellow powder (88 mg, 48%). MS (ESI) m/z 414; HRMS: calcd for C23H12F5NO, 413.0839; found (ESI, [M+H]+), 414.0911.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:23][C:24]#[C:25][CH3:26].C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:23][C:24]#[C:25][CH3:26])=[CH:17][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC#CCBr
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC#CCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
Under a nitrogen atmosphere, at room temperature, a commercially available reagent of methyl (S)-2-tert-butoxycarbonylamino-3-(4-hydroxy-phenyl)-propionate (199 g, 673 mmol) was dissolved in DMF (795 mL), and a commercially available reagent of 1-bromo-2-butyne (100 g, 752 mmol) and potassium carbonate (112 g, 807 mmol) were added. The mixture was stirred at room temperature for 19 hours. To the reaction solution were added a saturated aqueous solution of ammonium chloride and ethyl acetate and the mixture was extracted. The organic layer was washed with water and a saturated brine in order, dried over anhydrous magnesium sulfate, and filtered. The solvent was distilled off. The residue was then dried under reduced pressure to obtain methyl (S)-2-tert-butoxycarbonylamino-3-(4-but-2-ynyloxy-phenyl)-propionate (ESI (LC/MS positive mode) m/z 348 (M+H); Rt 2.50 min.; No. 4935047; 233 g, quant.).
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[CH2:3][CH2:4]N.[OH:7][CH2:8][C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[CH2:14][CH:15]([N:17]1[C:30]2[CH:29]=[C:28]([C:31](=[S:33])[NH2:32])[CH:27]=[CH:26][C:25]=2[S:24][C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH3:16].S>C(O)C.C(OC(C)C)(C)C>[OH:7][CH2:8][C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[CH2:14][CH:15]([N:17]1[C:30]2[CH:29]=[C:28]([C:31](=[S:33])[NH:32][CH2:4][CH2:3][CH:2]([CH3:6])[CH3:1])[CH:27]=[CH:26][C:25]=2[S:24][C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH3:16]
Reactant: CC(CN1CCC[C@@H]1CO)N1c2ccccc2Sc2ccc(C(N)=S)cc21
Reactant: CC(C)CCN
Agent: S
Solvent: CC(C)OC(C)C
Solvent: CCO
Product: CC(C)CCNC(=S)c1ccc2c(c1)N(C(C)CN1CCC[C@@H]1CO)c1ccccc1S2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-Methylbutylamine (8.5 cc) is added to a solution of 10-{1-[(2R)-2-hydroxymethyl-1-pyrrolidinyl]-2-propyl}-2-phenothiazinecarbothioamide, L series (5.86 g) in absolute ethanol (135 cc). The mixture is saturated with hydrogen sulphide and then brought to 150° C. for 16 hours. The reaction mixture is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 50° C. The residue is diluted with ethyl acetate (150 cc), washed with distilled water (3×100 cc) and with saturated sodium chloride solution (100 cc), dried over magnesium sulphate and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 50° C. before being purified by chromatography on a column (height: 32 cm; diameter: 4 cm) of silica gel (0.06-0.2 mm), eluting with pure ethyl acetate (1000 cc), collecting 60-cc fractions. Fractions 6 to 12 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) to give a residue which is dissolved in isopropyl ether (80 cc). Crystallization is primed by scratching, and the mixture is stirred for 12 hours at 25° C. The crystals are filtered off to give 10-{1-[(2R)-2-hydroxymethyl-1-pyrrolidinyl]-2-propyl}-N-(3-methylbutyl)-2-phenothiazinecarbothioamide, L series (4.3 g) in the form of yellow crystals, m.p. 140° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:36])[NH:15][C:16]2[S:17][C:18]3[CH:24]=[C:23]([O:25][S:26]([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)(=[O:28])=[O:27])[CH:22]=[CH:21][C:19]=3[N:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH:15][C:16]2[S:17][C:18]3[CH:24]=[C:23]([O:25][S:26]([C:29]4[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=4)(=[O:28])=[O:27])[CH:22]=[CH:21][C:19]=3[N:20]=2)=[O:36])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2nc3ccc(OS(=O)(=O)c4ccc(F)cc4)cc3s2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1)C1CCNCC1
Yield: 67.5 %

Procedure:
A solution of 4-[6-(4-fluorobenzenesulfonyloxy)benzothiazol-2-ylcarbamoyl]-piperidine-1-carboxylic acid tert-butyl ester (intermediate 3) (100 mg, 0.187 mmol) and of TFA (0.5 ml) in dichloromethane (4.5 ml) is stirred at room temperature for 1 hour. The reaction medium is evaporated to dryness. The residue is taken up in a minimum amount of water, neutralized by addition of aqueous 10% Na2CO3 solution and extracted with ethyl acetate to give 55 mg of 4-fluorobenzenesulfonic 2-[(piperidine-4-carbonyl)amino]benzo-thiazol-6-yl ester (white solid).
Reaction SMILES: FC(F)(F)C([NH:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][OH:14])=O.C(O)COCCOCCO.[N-:27]=[N+:28]=[N-]>CO.[Pd]>[N:5]([CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][OH:14])=[N+:27]=[N-:28]
Reactant: O=C(NCCOCCOCCO)C(F)(F)F
Reactant: [N-]=[N+]=[N-]
Agent: [Pd]
Solvent: OCCOCCOCCO
Solvent: CO
Product: [N-]=[N+]=NCCOCCOCCO
Reaction time: 12 h

Procedure:
8-Trifluoroacetamido-3,6-dioxa-1-octanol (1f: 8-azido-3,6-dioxa-1-octanol (Amvamzollo, P. H.; Sinay, P. Carbohydr. Res. 1986, 150, 199-212) (0.7 g, 4.0 mmol) was synthesized from triethylene glycol following the reported procedure (Bertozzi, C. R.; Bednarski, M. D. J. Org. Chem. 1991, 56, 4326-4329). The azide was combined with Pd/C (150 mg) in MeOH (8.0 mL) and stirred 12 h under H2 (1 atm). The suspension was filtered over celite, and the filtrate was concentrated to afford the amine (0.590 g, 4.0 mmol) in quantitative yields (Sato, H.; Hayashi, E.; Yamada, N.; Yatagai, M.; Takahara, Y. Bioconjugate Chem. 2001, 12, 701-710.). Following general procedure 1, 2-[2-(2-aminoethoxy)ethoxy]ethanol (0.590 g, 3.95 mmol) was combined with triethylamine (1.378 mL, 9.89 mmol) and trifluoroacetic anhydride (0.782 mL, 5.54 mmol) in MeOH (5 mL). Purification by silica gel chromatography (EtOAc) yielded 0.576 g (60%) of if as a white solid. 1H (300 MHz, CD3OD): δ 7.87 (br s, 1H), 3.73 (m, 2H), 3.68-3.60 (m, 10H), 3.55 (t, 2H, J=4.5 Hz), 3.32 (br s, 1H); 13C (75 mHz, CD3OD): δ 157.6 (q, J=36.6 Hz), 116.1 (q, J=286.1 Hz), 72.68, 70.35, 70.24, 68.90, 61.52, 39.84; ESI-MS calcd for C8H14F3NO4 [M−H]−: 244.0797. found 244.0795.
Reaction SMILES: [C:1]([S:11][CH2:12][CH2:13][NH:14][C:15](=[O:58])[CH2:16][CH2:17][NH:18][C:19](=[O:57])[C@H:20]([OH:56])[C:21]([CH3:55])([CH3:54])[CH2:22][O:23][P:24]([OH:53])(=[O:52])[O:25][P:26]([OH:51])(=[O:50])[O:27][CH2:28][C@H:29]1[O:33][C@@H:32]([N:34]2[C:43]3[N:42]=[CH:41][N:40]=[C:38]([NH2:39])[C:37]=3[N:36]=[CH:35]2)[C@H:31]([OH:44])[C@@H:30]1[O:45][P:46]([OH:49])([OH:48])=[O:47])(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=O.OC(CCCC(O)=O)CC(SCCNC(=O)CCNC(=O)[C@H](O)C(C)(C)COP(O)(=O)OP(O)(=O)OC[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2)[C@H](O)[C@@H]1OP(O)(O)=O)=O.C(SCCNC(=O)CCNC(=O)[C@H](O)C(C)(C)COP(O)(=O)OP(O)(=O)OC[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2)[C@H](O)[C@@H]1OP(O)(O)=O)(=O)CC(C)=O>>[CH3:55][C:21]([CH:20]([OH:56])[C:19]([NH:18][CH2:17][CH2:16][C:15]([NH:14][CH2:13][CH2:12][S:11][C:1]([C:2]1[C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH:3]=1)=[O:10])=[O:58])=[O:57])([CH2:22][O:23][P:24]([O:25][P:26]([O:27][CH2:28][C@H:29]1[O:33][C@@H:32]([N:34]2[C:43]3[N:42]=[CH:41][N:40]=[C:38]([NH2:39])[C:37]=3[N:36]=[CH:35]2)[C@H:31]([OH:44])[C@@H:30]1[O:45][P:46]([OH:48])([OH:49])=[O:47])([OH:51])=[O:50])([OH:53])=[O:52])[CH3:54]
Reactant: CC(C)(COP(=O)(O)OP(=O)(O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1OP(=O)(O)O)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)CCCCCC(=O)O
Agent: CC(=O)CC(=O)SCCNC(=O)CCNC(=O)[C@H](O)C(C)(C)COP(=O)(O)OP(=O)(O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1OP(=O)(O)O
Agent: CC(C)(COP(=O)(O)OP(=O)(O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1OP(=O)(O)O)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)CC(O)CCCC(=O)O
Product: CC(C)(COP(=O)(O)OP(=O)(O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1OP(=O)(O)O)C(O)C(=O)NCCC(=O)NCCSC(=O)C1=CCCCC1=O

Procedure:
Alternative routes for producing a cyclic compound from 3-hydroxypimeloyl-CoA that do not proceed through pimeloyl-CoA are shown in FIG. 3. This route is found in Geobacter metallireducens and Thauera aromatica, among others, in the direction of beta-oxidation. In the route, the biosynthesis of 3-hydroxypimelyl-CoA proceeds from acetoacetyl-CoA, as described above. 3-Hydroxypimeloyl-CoA is dehydrated to form a cyclic product, 6-oxocylohex-1-ene-1-carboxyl-CoA (6-KCH-CoA). 6-KCH-CoA is then converted to cyclohexanone in three enzymatic steps: removal of the CoA moiety, decarboxylation and reduction. With a reversible PEP carboxykinase, this pathway is predicted to achieve a theoretical yield of cyclohexanone (0.75 mol/mol) and is able to achieve an ATP yield of 0.56 mol/mol if a transferase or ATP synthase is utilized in step 2.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-])=O)[C:5]=1[NH2:6])([O-])=O>C1COCC1>[NH2:1][C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([NH2:11])[C:5]=1[NH2:6]
Reactant: Nc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Solvent: C1CCOC1
Product: Nc1cccc(N)c1N

Procedure:
15.0 g (82 mmol) of 2,6-dinitroaniline was dissolved in 150 g of THF and the reaction system was satisfactorily purged with nitrogen, to which 7.6 g of 5% Pd/C (hydrous) was added. Thereafter, the system was purged with hydrogen, followed by reaction at room temperature for 15 hours. After completion of the reaction, the reaction solution was filtered to remove Pd therefrom, and the resulting filtrate was condensed as it is to obtain the intended product. The thus obtained product was instable and was used as it is in a subsequent reaction.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](I)[C:3]=1[C:4]#[N:5].C([Li])CCC.[Br:16][C:17]1[CH:18]=[C:19]2[C:26](=[CH:27][CH:28]=1)[O:25][CH2:24][C:21]1([CH2:23][CH2:22]1)[C:20]2=[N:29]S(C(C)(C)C)=O.[NH4+].[Cl-]>C1COCC1>[Br:16][C:17]1[CH:18]=[C:19]2[C:20]3([C:6]4[C:3](=[C:2]([F:1])[CH:9]=[CH:8][CH:7]=4)[C:4]([NH2:5])=[N:29]3)[C:21]3([CH2:22][CH2:23]3)[CH2:24][O:25][C:26]2=[CH:27][CH:28]=1
Reactant: N#Cc1c(F)cccc1I
Reactant: CC(C)(C)S(=O)N=C1c2cc(Br)ccc2OCC12CC2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: NC1=NC2(c3cc(Br)ccc3OCC23CC3)c2cccc(F)c21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 29.8 %

Procedure:
To a solution of 2-fluoro-6-iodobenzonitrile (1560 mg, 6.32 mmol) in THF (16 mL) at −78° C. was added n-butyllithium (2.64M solution in n-hexane, 2.39 ml, 6.32 mmol) dropwise. The mixture was stirred for 0.5 hour at −78° C. and to the solution was added a solution of N-(6-bromo-4H-spiro[chromene-3,1′-cyclopropan]-4-ylidene)-2-methylpropane-2-sulfinamide (1500 mg, 4.21 mmol) in THF (5 mL). The mixture was stirred for 1 hour at −78° C. and overnight at room temperature. To the mixture was added saturated aqueous NH4Cl. The mixture was extracted with EtOAc and the organic layer was concentrated in vacuo. The residue was purified by silica gel chromatography(hexane/AcOEt=100:0-0:100, then CHCl3:MeOH=85:15) to give 6′-bromo-4″-fluorodispiro[cyclopropane-1,3′-chromene-4′,1″-isoindol]-3″-amine (469 mg).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[F:10][C:11]([F:22])([F:21])[C:12]([N:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1)=[O:13].C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][CH:17]2[CH2:18][CH2:19][N:14]([C:12](=[O:13])[C:11]([F:10])([F:21])[F:22])[CH2:15][CH2:16]2)=[CH:4][CH:3]=1
Reactant: NCc1ccc(F)cc1
Reactant: O=C1CCN(C(=O)C(F)(F)F)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(N1CCC(NCc2ccc(F)cc2)CC1)C(F)(F)F
Reaction time: 0.08 h
Yield: 36.9 %

Procedure:
4-Fluorobenzylamine (3.14 g, 25.9 mmol) was dissolved in methanol (150 mL). 1-(trifluoroacetyl)-4-piperidone (5.07 g, 25.9 mmol) was added, and the pH was adjusted to ˜5 with acetic acid. The reaction mixture was stirred for 5 min and NaBH3CN (2.46 g, 38.9 mmol) was added slowly under stirring. After 20 h at room temperature the reaction was concentrated. 2 M NaOH (100 mL) was added and the aqueous phase was extracted with dichloromethane (2×100 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated to give N-(4-fluorobenzyl)-1-(trifluoroacetyl)piperidin-4-amine (50ELH85, 2.91 g, 37%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:13][CH:12]([NH:14][C:15](=[O:17])[CH3:16])[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].I[CH3:19]>>[CH3:19][N:14]([CH:12]1[CH2:11][N:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:13]1)[C:15](=[O:17])[CH3:16]
Reactant: CC(=O)NC1CN(c2ccc([N+](=O)[O-])cc2)C1
Reactant: CI
Product: CC(=O)N(C)C1CN(c2ccc([N+](=O)[O-])cc2)C1

Procedure:
N-[1-(4-nitrophenyl)azetidin-3-yl]acetamide was alkylated with iodomethane by method F. This resulted in the product with the molecular weight of 249.27 (C12H15N3O3); MS (ESI): 250 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([NH:11][C:12]1[O:13][CH2:14][C:15]3[CH:21]=[C:20]([NH2:22])[CH:19]=[CH:18][C:16]=3[N:17]=1)[CH2:6][CH2:5]2.[Cl:23][CH2:24][C:25](Cl)=[O:26]>>[Cl:23][CH2:24][C:25]([NH:22][C:20]1[CH:19]=[CH:18][C:16]2[N:17]=[C:12]([NH:11][CH:7]3[C:8]4[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=4)[CH2:5][CH2:6]3)[O:13][CH2:14][C:15]=2[CH:21]=1)=[O:26]
Reactant: Nc1ccc2c(c1)COC(NC1CCc3cc(F)ccc31)=N2
Reactant: O=C(Cl)CCl
Product: O=C(CCl)Nc1ccc2c(c1)COC(NC1CCc3cc(F)ccc31)=N2
Yield: 98 %

Procedure:
Prepared from rac-N2-(5-fluoro-indan-1-yl)-4H-benzo[d][1,3]oxazine-2,6-diamine (Example 11) (300 mg, 1.01 mmol) and chloroacetyl chloride (85 ul, 1.06 mmol) according to the procedure described for Example 3 step A. Obtained the title compound as a light brown foam (370 mg, 98%), MS (ISP) m/e=374.2 [(M+H)+] and 376 [(M+2+H)+].
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]2[C:15]=1[CH2:14][N:13]([C:16](=[O:37])[CH2:17][CH:18]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:19][C:20]1[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:21]=1[F:28])[CH2:12][C:11]1[CH:38]=[CH:39][CH:40]=[CH:41][C:10]2=1)=[O:5])C.[OH-].[Li+].Cl>C1COCC1.O>[C:33]([O:32][C:30]([NH:29][CH:18]([CH2:19][C:20]1[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:21]=1[F:28])[CH2:17][C:16]([N:13]1[CH2:14][C:15]2[N:9]([CH:8]=[N:7][C:6]=2[C:4]([OH:5])=[O:3])[C:10]2[CH:41]=[CH:40][CH:39]=[CH:38][C:11]=2[CH2:12]1)=[O:37])=[O:31])([CH3:36])([CH3:34])[CH3:35]
Reactant: CCOC(=O)c1ncn2c1CN(C(=O)CC(Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C)Cc1ccccc1-2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(CC(=O)N1Cc2ccccc2-n2cnc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.8 %

Procedure:
To a solution of 5-[3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-5,6-dihydro-4H-2,5,10b-triaza-benzo[e]azulene-3-carboxylic acid ethyl ester (100 mg, 0.17 mmol) in THF (5 mL) and water (5 mL), was added lithium hydroxide (43 mg, 1.03 mmol). The reaction mixture was stirred at r.t. overnight. After the completion of the reaction as confirmed by TLC, the reaction mixture was cooled to 0° C. and neutralized with 10% HCl solution to pH˜4. The compound was extracted with ethylacetate (15 mL). The organic layer was washed with water, separated, dried over Na2SO4 and concentrated in vacuo to afford 5-[3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-5,6-dihydro-4H-2,5,10b-triaza-benzo[e]azulene-3-carboxylic acid (85 mg, 89%) as a viscous gel which was used without further purification for the next step.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:15][C:16]([NH:28][C:29]1[C:30](=[O:51])[N:31]([C:40]2[CH:45]=[CH:44][C:43]([O:46][C:47]([F:50])([F:49])[F:48])=[CH:42][CH:41]=2)[C@@H:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:33]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]=1)[CH3:17].FC(F)(F)C(O)=O.O>C1(C)C=CC=CC=1>[CH3:17][C:16]([NH:28][C@@H:29]1[CH2:33][C@H:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:31]([C:40]2[CH:41]=[CH:42][C:43]([O:46][C:47]([F:48])([F:50])[F:49])=[CH:44][CH:45]=2)[C:30]1=[O:51])([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]=1)[CH3:15]
Reactant: CC(C)(NC1=C[C@H](c2ccccc2)N(c2ccc(OC(F)(F)F)cc2)C1=O)c1cccc(C(F)(F)F)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)(N[C@@H]1C[C@H](c2ccccc2)N(c2ccc(OC(F)(F)F)cc2)C1=O)c1cccc(C(F)(F)F)n1
Reaction time: 3 h
Yield: 99 %

Procedure:
Add sodium triacetoxyborohydride (98 g, 465 mmol) in two portions to a solution of (R)-3-[1-methyl-1-(6-trifluoromethyl-pyridin-2-yl)-ethylamino]-1-(4-trifluoromethoxy-phenyl)-5-phenyl-1,5-dihydro-pyrrol-2-one (173 g, 332 mmol) and trifluoroacetic acid (50 mL, 664 mmol) in toluene (1.7 L). Stir for 3 hours and cannulate the mixture into water (2.5 L) over a period of 20 minutes. Extract the water with MTBE (2 L) and wash with water and sodium bicarbonate and concentrate to obtain the title compound as a tan oil (172 g, 98%). 1H NMR (400 MHz, DMSO-d6) δ 8.07 (m, 2H), 7.71 (d, J=8 Hz, 1H), 7.39 (d, J=12 Hz, 2H), 7.21 (m, 8H), 5.16 (m, 1H), 3.42 (m, 1H), 2.68 (m, 1H), 1.63 (m, 1H), 1.38 (s, 3H), 1.43 (s, 3H).