Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:18])[CH:15]=2)[CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl[C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH2:26])=[O:25])=[CH:22][N:21]=1.C([O-])([O-])=O.[K+].[K+].CC(N(C)C)=O>C1(C)C=CC=CC=1>[C:4]([O:3][C:1](=[O:2])[NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:18][C:20]3[CH:28]=[CH:27][C:23]([C:24](=[O:25])[NH2:26])=[CH:22][N:21]=3)[CH:15]=2)[CH2:10]1)([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)NC1Cc2ccc(O)cc2C1
Reactant: NC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC1Cc2ccc(Oc3ccc(C(N)=O)cn3)cc2C1
Temperature: 25 °C

Procedure:
Combine N-Boc-5-hydroxy-2-aminoindane (2.50 g, 10.0 mmol), 6-chloronicotinamide (1.49 g, 9.55 mmol, K2CO3 (1.90 g, 14.3 mmol), DMA (25 ml) and toluene (20 ml) in a round bottom flask, equipped with Dean-Stark trap, condenser, and nitrogen inlet. Reflux the suspension for two hours before cooling to ambient temperature. Remove the solids via filtration, wash solids with EtOAc, and concentrate the filtrate/wash on a rotary evaporator. Dissolve the remaining oil in EtOAc, wash with water (2×) and brine, dry (MgSO4) and concentrate. Purify the material on silica gel (20% THF/DCM) to give [5-(5-carbamoyl-pyridin-2-yloxy)-indan-2-yl]-carbamic acid tert-butyl ester (870 mg) as a light yellow solid.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:8]1[C:9]([N+:18]([O-:20])=[O:19])=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH2:30][C:31]([OH:33])=[O:32])[CH:26]=[CH:27][C:28]=1[OH:29].Cl>CS(C)=O.CCOC(C)=O.O>[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH2:30][C:31]([OH:33])=[O:32])[CH:26]=[CH:27][C:28]=1[O:29][C:8]1[C:9]([N+:18]([O-:20])=[O:19])=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2
Reactant: COc1cc(CC(=O)O)ccc1O
Reactant: O=[N+]([O-])c1c(Cl)ccc2ncccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(CC(=O)O)ccc1Oc1ccc2ncccc2c1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 4 h

Procedure:
Cs2CO3 (15.5 g, 47.5 mmol) was added to (24.1) (3 g, 14.4 mmol) and 3-methoxy-4-hydroxyphenylacetic acid (2.63 g, 14.4 mmol) in DMSO (30 mL) at room temperature. The mixture was then stirred at 80° C. for 4 h. After cooling, the reaction mixture was treated with water (50 mL), 3N HCl (35 mL) and EtOAc (100 mL). The product was insoluble in EtOAc, but stayed in the organic layer. So the organic layer was washed with water 4 times to get rid of all the salts, and the organic layer was separated, concentrated and dried under vacuum to afford 24.2. MS ESI (pos.) m/z: 355.1 (M+H). 1H NMR (DMSO-d6) δ 8.99 (dd, 1H); 8.24 (m, 2H); 7.77 (dd, 1H); 7.29 (d, 1H); 7.21 (d, 1H); 7.18 (d, 1H); 6.96 (dd, 1H); 3.73 (s, 3H); 3.65 (s, 2H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4]([NH2:12])=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1.C(N(CC)CC)C.[C:20](Cl)(Cl)=[S:21]>C1COCC1>[CH3:1][N:2]1[C:3]2[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=2[NH:12][C:20]1=[S:21]
Reactant: S=C(Cl)Cl
Reactant: CNc1ccc([N+](=O)[O-])cc1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1c(=S)[nH]c2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.3 %

Procedure:
To a solution of N1-Methyl-4-nitro-benzene-1,2-diamine (1.0 g, 6.0 mmol) and triethylamine 2.5 ml (18 mmol) in THF (60 ml) was added thiophosgene (0.46 ml, 6.0 mmol) at 0° C. After 1 h, the reaction mixture was warmed up to rt and was stirred at room temperature for 3 h. After the starting material was consumed, the reaction was filtered. The collected solid was washed with EtOAc:Hexane=1:1 (10 ml×2) and water. The resulting yellow solid was dried to give the title compound (0.82 g, 66%). MS (ESI) m/z=209 [M+H].
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[OH:15].[CH2:16]([O:18][C:19](=[O:24])[CH:20]=[C:21](Cl)[CH3:22])[CH3:17]>O1CCCC1>[CH2:16]([O:18][C:19](=[O:24])/[CH:20]=[C:21](/[O:15][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([CH3:14])[C:8]=1[CH3:7])\[CH3:22])[CH3:17]
Reactant: Cc1cccc(O)c1C
Reactant: CCOC(=O)C=C(C)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)Oc1cccc(C)c1C
Temperature: 23 °C
Yield: 35 %

Procedure:
Potassium t-butoxide (11.2 g, 0.100 mol) was added to a stirred solution of 2,3-dimethyl-phenol (6.18 g, 0.051 mol) in tetrahydrofuran (40 mL) at 23° C. under nitrogen and the reaction mixture was heated to reflux for 0.75 h. The reaction mixture was cooled to 23° C. and a solution of 3-chloro-but-2-enoic acid ethyl ester (prepared as in Example 191, 7.50 g, 0.050 mol) in tetrahydrofuran (40 mL) was added to the reaction mixture. The reaction mixture was refluxed for an additional 3 h. After this time, the mixture was concentrated in vacuo and the residue was diluted with water and extracted with diethyl ether. The organic layer was then washed with 5% aqueous sodium hydroxide solution followed by a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo to afford (E)-3-(2,3-dimethyl-phenoxy)-but-2-enoic acid ethyl ester (4.10 g, 35%) as a yellow oil.
Reaction SMILES: [NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:2]([C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH2:28]([O:30][P:31](Cl)(=[O:35])[O:32][CH2:33][CH3:34])[CH3:29].[H-].[Na+]>O1CCOCC1>[NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:2]([C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][P:31]([O:32][CH2:33][CH3:34])([O:30][CH2:28][CH3:29])=[O:35])=[CH:8][CH:9]=1
Reactant: CCOP(=O)(Cl)OCC
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOP(=O)(OCC)Oc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OCc2ccccc2)cc1

Procedure:
The title compound was prepared by reaction of BocTyrOBzl (371 mg, 1 mmol) and diethylphosphorochloridate (258 mg, 1.5 mmol) with an excess of NaH (60% in mineral oil) in dry dioxane for 3.5 h at 50° C. under argon atmosphere The solvent was concentrated in vacuo and the residue was dissolved in EtOAc and washed several times with a 5% solution of NaHCO3, a 10% solution of citric acid and a solution of satured NaCl. The organic phase was dried (Na2SO4) and concentrated, giving an oil 254 mg (50% yield), that was used without purification for the next step. FAB mass spectroscopy: m/z 508 [MH]+, 530 [MNa]+. H1NMR (200 Mhz, CDCl3) d (ppm)=7.4-6.85 (m, 9H, aromatics), 5.1 (d, 2H, COOCH2—F), 4.6 (m, 1H, N—CH—CO), 4.3-4 (m, 4H, P—O—CH2—CH3), 3 (t, 2H, CH—CH2—F), 1.4 (m, 15H, CH3− CH2+ tBu).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:25]=[CH:24][C:15]3[N:16]([CH:21]([CH3:23])[CH3:22])[C:17](=[O:20])[N:18]([CH3:19])[C:14]=3[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.ClC1[C:28](C2C=CC3N(C(C)C)C(=O)NC=3C=2)=[N:29]C=C(C(F)(F)F)C=1.BrCC#N>>[Cl:1][C:2]1[C:3]([C:12]2[CH:25]=[CH:24][C:15]3[N:16]([CH:21]([CH3:22])[CH3:23])[C:17](=[O:20])[N:18]([CH2:19][C:28]#[N:29])[C:14]=3[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: CC(C)n1c(=O)n(C)c2cc(-c3ncc(C(F)(F)F)cc3Cl)ccc21
Reactant: CC(C)n1c(=O)[nH]c2cc(-c3ncc(C(F)(F)F)cc3Cl)ccc21
Agent: N#CCBr
Product: CC(C)n1c(=O)n(CC#N)c2cc(-c3ncc(C(F)(F)F)cc3Cl)ccc21
Yield: 50 %

Procedure:
In a similar manner to the preparation of 5-(3-chloro-5-trifluoromethylpyridin-2-yl)-3-methyl-1-(1-methylethyl)benzimidazol-2-one described above, 2.5 g of 5-(3-chloro-5-trifluoromethylpyridin-2-yl)-1-(1-methylethyl)benzimidazol-2-one and 0.9 g of bromoacetonitrile gave, after chromatography on silica gel, 1.4 g of colorless crystals. Yield: 50%; m.p.: 158-159° C.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([C:19]1[C:27]([N+:28]([O-])=O)=[CH:26][C:22]3[O:23][CH2:24][O:25][C:21]=3[CH:20]=1)[CH2:13][CH2:12]2)C1C=CC=CC=1>C(O)(=O)C.[OH-].[Pd+2].[OH-]>[NH2:28][C:27]1[C:19]([CH:14]2[CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([OH:8])[CH:18]=[CH:17][C:16]=3[CH2:15]2)=[CH:20][C:21]2[O:25][CH2:24][O:23][C:22]=2[CH:26]=1
Reactant: O=[N+]([O-])c1cc2c(cc1C1=Cc3ccc(OCc4ccccc4)cc3CC1)OCO2
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Product: Nc1cc2c(cc1C1CCc3cc(O)ccc3C1)OCO2
Temperature: 25 °C
Reaction time: 13 h
Yield: 40.9 %

Procedure:
To a solution of 5-(6-benzyloxy-3,4-dihydronaphthalen-2-yl)-6-nitrobenzo[1,3]dioxole (832 mg) in acetic acid (10 ml) was added 20% palladium hydroxide-activated charcoal (200 mg), and the solution was stirred for 13 hours at room temperature under a hydrogen atmosphere at 4 atmospheric pressures. After filtration through celite pad, the solution was concentrated, neutralized with aqueous ammonia, extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (240 mg).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:14])[CH:7]=[C:8]([CH2:12][OH:13])[O:9]2)=[CH:4][CH:3]=1.Br[CH2:16][CH2:17][CH2:18][Cl:19].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O.CN(C)C=O.C(OCC)C>[Cl:19][CH2:18][CH2:17][CH2:16][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:14])[CH:7]=[C:8]([CH2:12][OH:13])[O:9]2)=[CH:4][CH:3]=1
Reactant: ClCCCBr
Reactant: O=c1cc(CO)oc2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: O=c1cc(CO)oc2cc(OCCCCl)ccc12
Yield: 50.4 %

Procedure:
A mixture of 6 g (31 mmoles) of the compound obtained in Example 4, 6 mL (61 mmoles) of 1-bromo-3-chloropropane, 4.3 g (31 mmoles) of anhydrous potassium carbonate in 100 mL of acetone and 25 mL of N,N-dimethylformamide was heated at reflux for 16 hours. The reaction mixture was poured onto 100 mL of water and extracted with 100 mL of ethyl acetate. The organic extracts were washed with two portions of 100 mL of water, dried over sodium sulphate and evaporated at vaccum. The residue obtained was suspended in 25 mL of ethyl ether, filtered and dried at vaccum to give 4.2 g of 7-(3-chloropropoxy)-2-(hydroxymethyl)-chromen-4-one in 50% yield, mp 110-112° C.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:7][CH2:6]2.[Cl-:13].[Al+3].[Cl-].[Cl-].Cl.C(=O)(O)[O-].[Na+]>CSC.O.ClCCl>[ClH:13].[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:7][CH2:6]2
Reactant: [Cl-]
Reactant: COc1ccc2c(c1)CCNC2
Agent: Cl
Agent: O=C([O-])O
Agent: [Al+3]
Solvent: O
Solvent: ClCCl
Solvent: CSC
Product: Oc1ccc2c(c1)CCNC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In dimethylsulfide (20 ml), 6-methoxy-1,2,3,4-tetrahydroisoquinoline (7.75 g) was dissolved, followed by the addition of aluminum chloride (19.0 g) under ice cooling. The resulting mixture was stirred at room temperature for 3 hours. Dichloromethane and dilute hydrochloric acid were added to the reaction mixture. A saturated aqueous solution of sodium bicarbonate was added to the water layer so separated to make it weakly alkaline, followed by the extraction with dichloromethane. After drying over anhydrous sodium sulfate, the solvent was then distilled off under reduced pressure. The residue was dissolved in saturated ethanol hydrochloride (100 ml) and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the residue and the solid so precipitated was collected by filtration, whereby the title compound (7.91 g, 90%) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:25][CH2:24][C:11]2([C:15](=[O:16])[N:14]([C:17]3[CH:22]=[N:21][C:20](Br)=[CH:19][N:18]=3)[CH2:13][CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][C@H:27]1[CH2:31][CH2:30][CH2:29][N:28]1[C@H:32]1[CH2:36][CH2:35][NH:34][CH2:33]1.CC(C)([O-])C.[Na+]>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].C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:25][CH2:24][C:11]2([C:15](=[O:16])[N:14]([C:17]3[CH:22]=[N:21][C:20]([N:34]4[CH2:35][CH2:36][C@H:32]([N:28]5[CH2:29][CH2:30][CH2:31][C@@H:27]5[CH3:26])[CH2:33]4)=[CH:19][N:18]=3)[CH2:13][CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H]1CCCN1[C@H]1CCNC1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(c1cnc(Br)cn1)C2=O
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: C[C@H]1CCCN1[C@H]1CCN(c2cnc(N3CCC4(CCN(C(=O)OC(C)(C)C)CC4)C3=O)cn2)C1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
A mixture of 2-(5-bromo-pyrazin-2-yl)-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (0.06 g, 0.146 mmol), (2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl (0.045 g, 0.292 mmol), R-(−)-BINAP (0.007 g, 0.011 mmol), and anhydrous toluene (3 mL) was de-gassed and refilled with N2 in three cycles. Pd2(dba)3 (0.0034 g, 0.0037 mmol,), and sodium t-butoxide (0.021 g, 0.212 mmol) was then added to the mixture and de-gassed and refilled with N2 in three additional cycles. The reaction mixture was heated and stirred at 90° C. for 16 hours. The reaction mixture was allowed to cool to room temperature and quenched with water (1 mL). The aqueous phase was extracted with dichloromethane (3×10 mL). The combined organics were washed with sodium bicarbonate (5 mL), and brine (10 mL), dried over Na2SO4, concentrated under vacuum. Purification by column chromatography on silica gel (0-10%) methanol in dichloromethane afforded 0.0257 (37%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]([OH:15])=O)=[CH:8][CH:7]=[CH:6]2.S(Cl)([Cl:18])=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]([Cl:18])=[O:15])=[CH:8][CH:7]=[CH:6]2
Reactant: COc1ccc2c(C(=O)O)cccc2c1
Reactant: O=S(Cl)Cl
Product: COc1ccc2c(C(=O)Cl)cccc2c1
Temperature: 25 °C

Procedure:
Under an argon atmosphere, 6-methoxy-1-naphthoic acid (synthesized by the process of J. D. Moseley and J. P. Gilday, Tetrahedron, 62, 4690-4697 (2006)) (1.20 g, 5.93 mmol) was dissolved in thionyl chloride (5.00 mL, 68.8 mmol) and the solution was heated to reflux for 3 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure to give the crude product of 6-methoxy-1-naphthoyl chloride (22) as a colorless oil. The product was used in the following reaction without further purification.
Reaction SMILES: FC1C=CC(OC2C=C(C=CC=2)N)=CC=1.FC(F)(OC1C=C(C=CC=1)C=O)C(F)F.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].Cl.[OH-].[Na+].[F:52][C:53]1[CH:80]=[CH:79][C:56]([O:57][C:58]2[CH:59]=[C:60]([NH:64][CH2:65][C:66]3[CH:71]=[CH:70][CH:69]=[C:68]([O:72][C:73]([F:78])([F:77])[CH:74]([F:76])[F:75])[CH:67]=3)[CH:61]=[CH:62][CH:63]=2)=[CH:55][CH:54]=1.[F:81][C:82]([F:87])([F:86])[CH:83]1[O:85][CH2:84]1>ClC(Cl)C.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:52][C:53]1[CH:54]=[CH:55][C:56]([O:57][C:58]2[CH:59]=[C:60]([N:64]([CH2:65][C:66]3[CH:71]=[CH:70][CH:69]=[C:68]([O:72][C:73]([F:77])([F:78])[CH:74]([F:75])[F:76])[CH:67]=3)[CH2:84][CH:83]([OH:85])[C:82]([F:87])([F:86])[F:81])[CH:61]=[CH:62][CH:63]=2)=[CH:79][CH:80]=1
Reactant: Fc1ccc(Oc2cccc(NCc3cccc(OC(F)(F)C(F)F)c3)c2)cc1
Reactant: FC(F)(F)C1CO1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: Nc1cccc(Oc2ccc(F)cc2)c1
Solvent: CC(=O)O
Solvent: CC#N
Solvent: CC(Cl)Cl
Product: OC(CN(Cc1cccc(OC(F)(F)C(F)F)c1)c1cccc(Oc2ccc(F)cc2)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
Ex-634C) The 3-(4-fluorophenoxy)aniline (812 mg, 4 mmol) from EX-634B and 3-(1,1,2,2-tetrafluoroethoxy)benzaldehyde (888 mg, 2 mmol) were dissolved in dichloroethane (15 mL) and acetic acid (0.25 mL, 4.2 mmol), then solid NaBH(OAc)3 (1.01 g, 5 mmol) was added. The mixture was stirred at room temperature for 3 h, then acidified with 1 N HCl. After neutralizing to pH 7.5 with 2.5 N sodium hydroxide, the mixture was extracted with methylene chloride. The organic layer was washed with brine and water, then dried over anhydrous MgSO4, and evaporated to give 1.32 g (78%) of the desired of N-[3-(4-fluorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amine product as a brown oil, which was greater than 90% pure by reverse phase HPLC analysis. MS m/z=410 [M+H]+. 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: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]([C:27]2[CH:32]=[CH:31][C:30]([CH2:33][NH2:34])=[CH:29][CH:28]=2)[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#[N:26])[CH:20]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[C:42](OC(=O)C)(=[O:44])[CH3:43]>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]([C:27]2[CH:32]=[CH:31][C:30]([CH2:33][NH:34][C:42](=[O:44])[CH3:43])=[CH:29][CH:28]=2)[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#[N:26])[CH:20]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: N#Cc1cccc(CN(c2ccc(CN)cc2)C2CCN(C(=O)OCc3ccccc3)CC2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCc1ccc(N(Cc2cccc(C#N)c2)C2CCN(C(=O)OCc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
To a solution of the above amine (462 mg, 1.02 mmol) in CH2Cl2 (10 mL) were added Et3N (0.45 mL, 3.23 mmol) followed by acetic anhydride (0.20 mL, 2.12 mmol) and the mixture was stirred at room temperature overnight to afford 4-[[4-(acetylamino-methyl)-phenyl]-(3-cyano-benzyl)-amino]-piperidine-1-carboxylic acid benzyl ester as a white solid (463 mg, 91%) following work-up and purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][N+:7]([O-:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].CO[NH2:13].CC(C)([O-])C.[K+].[Cl-].[NH4+]>CN(C=O)C.[Cl-].[Zn+2].[Cl-]>[NH2:13][C:5]1[CH:6]=[N+:7]([O-:10])[CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1
Reactant: CON
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1c[n+]([O-])ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.4 %

Procedure:
4-Nitropyridine N-oxide (140 mg, 1 mmol) and O-methylhydroxylamine (71 mg, 1.5 mmol) were dissolved in DMF (2 ml), and a resulting solution was added dropwise to a DMF solution (3 ml) containing potassium tert-butoxide (336 mg, 3 mmol) and zinc (II) chloride (136 mg, 1 mmol) at 25° C. After completion of the addition, the resulting mixture was stirred at 25° C. for one hour and an aqueous saturated ammonium chloride solution (50 ml) was added, followed by extraction with ethyl acetate (80 ml). A resulting organic layer was dried over anhydrous magnesium sulfate, and then isolated and purified by subjecting to silica gel thin layer chromatography [eluent: ethyl acetate] to obtain 58 mg of 3-amino-4-nitropyridine N-oxide (yield: 38%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:11](=O)([O-])[O-].[Cs+].[Cs+].IC.C(OCC)(=O)C>CN(C=O)C>[CH3:11][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[N:10][C:2]=1[Cl:1]
Reactant: O=C(O)c1cccnc1Cl
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: COC(=O)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-chloronicotinic acid (2.00 g, 12.69 mmol) in DMF (40 mL) at 0° C. is added cesium carbonate (4.96 g, 15.23 mmol) followed by iodomethane (0.95 mL, 15.23 mmol). The reaction mixture is warmed to room temperature and stirred 16 h. Dilution with ethyl acetate is followed by washing with water, 8% NaHCO3 solution and brine. The organic layer is dried (MgSO4) and concentrated under reduced pressure to give 2-chloronicotinic acid methyl ester as an oil: 1H NMR (CDCl3, 300 MHz): δ 8.55 (1H, dd), 8.18 (1H, dd), 7.33 (1H, dd), 3.97 (3H, s).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[C:13]2[C:14]3[CH2:15][CH2:16][CH2:17][C:18]=3[C:19]([CH3:21])=[CH:20][C:12]=2[CH:11]([N:22]([C:38](=[O:40])[CH3:39])[CH2:23][C:24]2[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=2)[CH2:10][CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].COC(C1C=C2C(=CC=1N)CCC2)=O>>[CH:1]([O:4][C:5]([N:7]1[C:13]2[C:12](=[CH:20][C:19]3[CH2:21][CH2:16][CH2:17][C:18]=3[C:14]=2[CH3:15])[CH:11]([N:22]([C:38](=[O:40])[CH3:39])[CH2:23][C:24]2[CH:29]=[C:28]([C:30]([F:32])([F:33])[F:31])[CH:27]=[C:26]([C:34]([F:35])([F:37])[F:36])[CH:25]=2)[CH2:10][CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2c1cc(C)c1c2CCC1
Agent: COC(=O)c1cc2c(cc1N)CCC2
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2c1cc1c(c2C)CCC1

Procedure:
The titled compound was prepared following the procedures described for the preparation of (+/−)-6-[Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-4-methyl-2,3,6,7,8,9-hexahydro-1H-10-aza-cyclohepta[e]indene-10-carboxylic acid isopropyl ester (example 137) by replacing 4-amino-indan-5-carboxylic acid methyl ester by 6-amino-indan-5-carboxylic acid methyl ester in example 136 step 1.
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[CH2:17][C:16]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[C:7]=3[NH:8][C:9](=[O:10])[C:4]2=[N:3][CH:2]=1.[OH-].[Na+].[C:20]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])(=[O:23])[CH:21]=O.C(O)(=O)C>CS(C)=O.CN(C)C=O.O>[C:25]([O:24][C:20]([CH:21]=[C:17]1[C:6]2[N:5]3[CH:1]=[CH:2][N:3]=[C:4]3[C:9](=[O:10])[NH:8][C:7]=2[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:16]1=2)=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: O=c1[nH]c2c(n3ccnc13)Cc1ccccc1-2
Reactant: CC(C)(C)OC(=O)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)C=c1c2ccccc2c2[nH]c(=O)c3nccn3c12
Reaction time: 0.58 h
Yield: 25.1 %

Procedure:
to a solution, cooled to 19° C. and under cover of nitrogen, of 9 g of 5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one in 180 ml of dimethyl sulphoxide are added 4 g of 60% sodium hydroxide portionwise with stirring. The stirring is continued for 35 minutes and 7.8 g of tert-butyl glyoxylate are added dropwise. After stirring for 18 hours the reaction mixture is treated with 9 ml of acetic acid and 150 ml of water. The suspension is filtered and the insoluble material is washed with water (2×200 ml) and then with acetone (3×100 ml) and dried at 80° C. under reduced pressure. The crude product obtained (5.85 g) is heated to about 90°-10° C. in 300 ml of dimethylformamide and filtered immediately, and 150 ml of methanol and 200 ml of water are added to the filtrate, which is left in the ice compartment of a refrigerator overnight. The crystals formed are filtered off, washed with 20 ml of water and dried at 80° C. under vacuum (2 mmHg; 0.26 kPa) to give 3.4 g of 10-(tert-butoxycarbonylmethylene)-5H,10H-imidazo-[1,2-a]indeno[1,2-e]pyrazin-4-one, in the form of a red solid melting above 260° C. (Analysis % calculated C: 68.05, H: 5.11, N: 12.53, O: 14.31, % found C: 68.0, H: 5.6, N: 12.5, O: 14.3).