Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH:4]1[CH2:10][CH2:9][N:8]([C:11]2[N:15]([CH3:16])[N:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])[CH2:7][CH:6]([OH:20])[CH2:5]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[NH2:1][CH:4]1[CH2:10][CH2:9][N:8]([C:11]2[N:15]([CH3:16])[N:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])[CH2:7][CH:6]([OH:20])[CH2:5]1
Reactant: Cn1ncc([N+](=O)[O-])c1N1CCC(N=[N+]=[N-])CC(O)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cn1ncc([N+](=O)[O-])c1N1CCC(N)CC(O)C1
Temperature: 65 °C

Procedure:
To a solution of 5-azido-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-3-ol, Intermediate 18 (3.4 g, 16 mmol) in THF (40 mL) and water (8 mL), was added triphenylphosphine (1.89 g, 7.2 mmol) and the mixture was heated at 65° C. for 16 hr. The solvents were removed under reduced pressure to afford 5-amino-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-3-ol (contaminated with triphenylphosphine oxide) as a viscous oil. To this amine in DCM (40 mL), di-tert-butyl dicarbonate (4.49 g, 20.6 mmol) and DIPEA (4.78 mL, 27.4 mmol) were added and the mixture stirred at room temperature for 60 hr. The solvent was removed under reduced pressure and the residue purified by silica gel column chromatography (0-100% EtOAc/isohexane) to give tert-butyl 6-hydroxy-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-ylcarbamate as a yellow oil (2.6 g). To a solution of this oil (2.6 g, 10.2 mmol) in DCM (50 mL) was added deoxo-Fluor® (50% in THF, 6.7 mL, 18.6 mmol) and the mixture was stirred at room temperature for 16 hr. The mixture was diluted with DCM (30 mL), cooled in an ice/water bath and quenched by the dropwise addition of saturated aqueous NaHCO3 (30 mL). The resulting mixture was stirred for 10 min. The organic layer was separated, dried over Na2SO4 and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-50% EtOAc/isohexane) gave tert-butyl 6-fluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-ylcarbamate (1.07 g, 66% over three steps) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.14-7.97 (m, 1H), 5.04-4.46 (m, 3H), 3.96-2.99 (m, 6H), 2.42-1.64 (m, 5H), 1.70-1.22 (m, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([O:13][CH3:14])[CH:9]=[CH:10][CH:11]=2)[CH:6]=[C:5]([C:15](OC)=[O:16])[CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([O:13][CH3:14])[CH:9]=[CH:10][CH:11]=2)[CH:6]=[C:5]([CH2:15][OH:16])[CH:4]=1
Reactant: COC(=O)c1cc(OC)c2cccc(OC)c2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: COc1cc(CO)cc2c(OC)cccc12

Procedure:
In an analogous manner to that described in Example 5b), by reducing methyl 4,8-dimethoxy-naphthalene-2-carboxylate (J.Chem.Soc. 1959, 1024) by means of lithium aluminium hydride there was obtained (4,8-dimethoxy-naphthalen-2-yl)-methanol, MS: 218 (M)+, as a colourless solid.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][N:9]([CH:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=2)[CH2:31][CH2:30]1)[C:10]([C:12]1[CH:20]=[C:19]2[C:15]([CH2:16][CH2:17][C@H:18]2[NH:21]C(=O)OC(C)(C)C)=[CH:14][CH:13]=1)=[O:11]>ClCCl>[NH2:21][C@H:18]1[C:19]2[C:15](=[CH:14][CH:13]=[C:12]([C:10]([N:9]([CH3:8])[CH:29]3[CH2:30][CH2:31][N:32]([C:35]4[CH:36]=[CH:37][N:38]=[CH:39][CH:40]=4)[CH2:33][CH2:34]3)=[O:11])[CH:20]=2)[CH2:16][CH2:17]1
Reactant: CN(C(=O)c1ccc2c(c1)[C@H](NC(=O)OC(C)(C)C)CC2)C1CCN(c2ccncc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)c1ccc2c(c1)[C@H](N)CC2)C1CCN(c2ccncc2)CC1
Reaction time: 1 h

Procedure:
TFA (1 ml) was added dropwise at 0° C. to a solution of (R)-tert-butyl 6-(methyl(1-(pyridin-4-yl)piperidin-4-yl)carbamoyl)-2,3-dihydro-1H-inden-1-ylcarbamate (0.2 g, 0.44 mmol, 1 eq) in dichloromethane (5 ml), and stirring was carried out for 1 h at RT. Then the solvent was concentrated under reduced pressure. The residue was taken up in dichloromethane and concentrated again. Then the TFA salt was stirred for 1 h with Amberlyst-21 in MeOH (10 ml) and filtered. The filtrate was concentrated under reduced pressure and used in the next stage without being purified further.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][CH2:9][O:10][C:11]([C:13]2([C:44]([O:46][CH2:47][CH:48]=[CH:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[O:45])[O:17][C:16]3[CH:18]=[CH:19][C:20]([CH2:22][C@H:23]([N:25]([CH2:34][C@@H:35]([C:37]4[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=4)[OH:36])C(OCC(Cl)(Cl)Cl)=O)[CH3:24])=[CH:21][C:15]=3[O:14]2)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(Cl)(Cl)Cl.CO>[C:1]1([CH:7]=[CH:8][CH2:9][O:10][C:11]([C:13]2([C:44]([O:46][CH2:47][CH:48]=[CH:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[O:45])[O:17][C:16]3[CH:18]=[CH:19][C:20]([CH2:22][C@H:23]([NH:25][CH2:34][C@@H:35]([C:37]4[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=4)[OH:36])[CH3:24])=[CH:21][C:15]=3[O:14]2)=[O:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@H](Cc1ccc2c(c1)OC(C(=O)OCC=Cc1ccccc1)(C(=O)OCC=Cc1ccccc1)O2)N(C[C@H](O)c1cccc(Cl)c1)C(=O)OCC(Cl)(Cl)Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: C[C@H](Cc1ccc2c(c1)OC(C(=O)OCC=Cc1ccccc1)(C(=O)OCC=Cc1ccccc1)O2)NC[C@H](O)c1cccc(Cl)c1
Yield: 59 %

Procedure:
The fide compound was prepared as a colorless oil according to the procedure of Example 4, Step 6 except that 5-{(2R)-2-[[(2R)2-(3-chloro-phenyl)-2-hydroxy-ethyl]-(2,2,2-trichloro-ethoxycarbonyl)-amino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(3-phenyl-allyl) ester was used in place of 5-{(2R)-2-[[(2R)-2-(3-chloro-phenyl)-2-hydroxy-ethyl]-(2,2,2-trichloro-ethoxycarbonyl)-amino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid diallyl ester; yield 59%; Rf =0.35 (10/1 CHCl3 /MeOH); 1H NMR (300 MHz, CDCl3): δ 1.15 (d, J=6.3 Hz, 3H), 2.50-3.70 (brs, 2H), 2.60-2.71 (m, 1H), 2.80-2.92 (m, 2H), 2.95-3.15 (m, 2H), 4.83-4.95 (m, 5H), 5.25-5.40 (m, 4H), 6.08-6.30 (complex m, 2H), 6.66-6.91 (m, 5H), 7.15-7.40 (m, 14H); MS (ES) m/z (relative intensity): 654 (M+, 100).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[C:9]([CH2:11][CH2:12]OS(C3C=CC(C)=CC=3)(=O)=O)[CH:10]=[C:5]2[O:4][C:3]1=[O:24].[C:25]1([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>O1CCOCC1>[CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[C:9]([CH2:11][CH2:12][N:34]3[CH2:35][CH2:36][N:31]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:32][CH2:33]3)[CH:10]=[C:5]2[O:4][C:3]1=[O:24]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2cnc3c(c2)oc(=O)n3C)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cn1c(=O)oc2cc(CCN3CCN(c4ccccc4)CC3)cnc21
Temperature: 25 °C

Procedure:
3-methyl-6-[2-(p-toluenesulfonyloxy)ethyl]oxazolo[4,5-b]pyridin-2(3H)-one of Preparation 15 (210 mg, 1.2 mmol) is dissolved in 1,4-dioxane (8 ml). N-phenylpiperazine (0.10 ml, 1.38 mmol) and triethylamine (0.18 ml, 1.3 mmol) are added in succession to the reaction mixture. Stirring is maintained at room temperature for 24 hours. After the solvent has been evaporated off under reduced pressure, the residue is taken up in water. Extraction is carried out with dichloromethane and the organic phase is dried over magnesium sulfate and filtered, and then the solvent is evaporated off. The title product is purified by chromatography on silica gel (eluant: dichloromethane/methanol: 95/5). The yield obtained is 91%. ##STR66##
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[C:6]2[CH3:18].[H-].[Na+].[CH:21]([O:24][C:25](Cl)=[O:26])([CH3:23])[CH3:22]>CN(C=O)C>[CH:21]([O:24][C:25]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([F:2])=[CH:11][CH:10]=2)[C:6]([CH3:18])=[C:7]1[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[O:26])([CH3:23])[CH3:22]
Reactant: Cc1c(-c2cccnc2)[nH]c2ccc(F)cc12
Reactant: CC(C)OC(=O)Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(-c2cccnc2)n(C(=O)OC(C)C)c2ccc(F)cc12
Reaction time: 8 h

Procedure:
5-Fluoro-3-methyl-2-pyridin-3-yl-indole (Example 3, 0.246 g, 1.044 mmol) is dissolved in DMF (9 mL). NaH (60%, 0.054 g, 1.357 mmol) is added and the mixture is stirred for 1 h, whereupon isopropylchloroformate (1.0M in toluene 2.1 mL, 2.1 mmol) is added. The mixture is stirred overnight, quenched with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic phase is dried over MgSO4 and concentrated in vacuo to give a residue, which is purified by silica gel flash chromatography (ethyl acetate-heptane, 1:4 to 2:3) to give 5-fluoro-3-methyl-2-pyridin-3-yl-indole-1-carboxylic acid isopropyl ester as a pale yellow solid. 1H NMR (400 MHz, MeOD) δ ppm 1.07 (d, J=6.3 Hz, 6H), 2.12 (s, 3H), 4.93-5.04 (m, 1H), 7.09-7.17 (m, 1H), 7.30 (dd, J=8.8, 2.3 Hz, 1H), 7.54-7.59 (m, 1H), 7.84-7.89 (m, 1H), 8.23 (dd, J=9.1, 4.5 Hz, 1H), 8.53-8.56 (m, 1H), 8.61 (dd, J=4.5, 1.6 Hz, 1H). HRMS (ESI) m/z 313.1353 [(M+H)+ Calcd for C18H18FN2O2: 313.1352].
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11](B2OC(C)(C)C(C)(C)O2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:22].[Na+].OO.O.Cl>C1COCC1>[CH2:1]([N:8]1[CH:12]=[C:11]([OH:22])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: CC1(C)OB(c2cnn(Cc3ccccc3)c2)OC1(C)C
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Oc1cnn(Cc2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 116.7 %

Procedure:
1-Benzyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (Aldrich, 700 mg, 2.46 mmol) was dissolved in THF (6 mL) and cooled to 0° C. NaOH 2.5 M (2 mL, 4.93 mmol) and H2O2 30% solution in water (503 μl, 4.93 mmol) were added and the reaction mixture was stirred at room temperature for 45 min. Then the pH was adjusted to 2 by the addition of aqueous HCl 2 M and the mixture was extracted with dichloromethane. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using cyclohexane/EtOAc as eluant. The expected fractions were combined and evaporated under reduced pressure to give the title compound 1-benzyl-1H-pyrazol-4-ol (500 mg, quantitative yield). LCMS: (M+H)+=175; Rt=0.61 min.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([SH:17])=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([S:17][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[CH:13][CH:12]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(Sc2ccc(Cl)cc2)cc1
Temperature: 90 °C
Yield: 63.8 %

Procedure:
A mixture of 4-fluorobenzaldehyde (12.6 mmol, 1.57 g), 4-chlorobenzenethiol (12.6 mmol, 1.81 g), K2CO3 (15.1 mmol, 2.09 g) in DMF (5.00 mL) was heated at 90° C. for 10 h. After cooling to room temperature, the reaction mixture was poured into a separatory funnel with water (100 mL). The phases were separated and the aqueous layer was extracted with CH2Cl2 (3×50 mL). The combined organic layers were washed with water (2×100 mL), brine (50 mL) and dried over MgSO4. Removal of the solvents in vacuo gave a light yellow liquid. Purification by flash column chromatography (eluent: 5% EtOAc in Hexane) provided 4-(4-chlorophenylthio)benzaldehyde (2.00 g, 76.0% yield) as a light yellow liquid. 1H NMR (CDCl3) δ 9.93 (s, 1H), 7.72 (d, J=8.3 Hz, 2H), 7.46-7.39 (m, 4H), 7.25 (d, J=8.3 Hz, 2H).
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C@H:8]([C:12]([N:14]1[CH2:36][CH2:35][CH2:34][C@H:15]1[C:16]([NH:18][C@@H:19]([CH:31]([CH3:33])[CH3:32])[CH:20]([C:22]1[O:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1)[OH:21])=[O:17])=[O:13])[CH:9]([CH3:11])[CH3:10].[C:37]([O:41][C:42]([CH2:44][N:45]1[C:50](=[O:51])[CH:49]=[CH:48][N:47]([CH2:52][C:53](O)=[O:54])[C:46]1=[O:56])=[O:43])([CH3:40])([CH3:39])[CH3:38].Cl.N=C=N>O>[C:37]([O:41][C:42]([CH2:44][N:45]1[C:50](=[O:51])[CH:49]=[CH:48][N:47]([CH2:52][C:53]([NH:7][C@H:8]([C:12]([N:14]2[CH2:36][CH2:35][CH2:34][C@H:15]2[C:16]([NH:18][C@@H:19]([CH:31]([CH3:32])[CH3:33])[CH:20]([C:22]2[O:23][C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=3[N:26]=2)[OH:21])=[O:17])=[O:13])[CH:9]([CH3:11])[CH3:10])=[O:54])[C:46]1=[O:56])=[O:43])([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)(C)OC(=O)Cn1c(=O)ccn(CC(=O)O)c1=O
Reactant: CC(C)[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)C(C)C)C(O)c1nc2ccccc2o1
Agent: Cl
Agent: N=C=N
Solvent: c1ccncc1
Solvent: O
Product: CC(C)[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)Cn1ccc(=O)n(CC(=O)OC(C)(C)C)c1=O)C(C)C)C(O)c1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 15 h
Yield: 91.5 %

Procedure:
To pyridine (20 ml) containing L-valyl-N-[(1S)-2-(2-benzoxazolyl)-1-isopropyl-2-hydroxyethyl]-L-prolinamide (1.0 g) are added 2-(3-tert-butoxycarbonylmethyl-2,4-dioxo-1-pyrimidinyl)acetic acid (0.7 g) obtained in Example 4 and 1-ethyl-3-dimethylaminopropyl)carbodiimide hydrochloride (0.6 g), and the mixture is stirred at room temperature for 15 hours. The reaction solution is poured into water, and the mixture is extracted with ethyl acetate. The extract is washed successively with 1 mol/liter hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution, and a saturated brine, and dried over anhydrous magnesium sulfate. The solvent is removed by evaporation under reduced pressure to give the desired 2-(3-tert-butoxycarbonylmethyl-2,4-dioxo-1-pyrimidinyl)acetyl-L-valyl-N-[(1S)-2-(2-benzoxazolyl)-1-isopropyl-2-hydroxyethyl]-L-prolinamide (1.5 g) as powders.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1.[OH-].[NH4+:12]>CO>[N:7]1[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH2:3][CH2:2][NH2:12])[CH:6]=1
Reactant: ClCCOc1cccnc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CO
Product: NCCOc1cccnc1
Temperature: 125 °C
Yield: 36.2 %

Procedure:
The 2-chloro-1-(3-pyridyloxy)ethane (1.23 g, 7.80 mmol) was dissolved in methanol (25 mL) and added to concentrated ammonium hydroxide solution (29.7%, 14.8 M, 55 mL) in a heavy-walled glass pressure-tube apparatus. The tube was sealed and the mixture was stirred and heated at 125° C. (oil bath temperature) for 42 h. After cooling, the mixture was concentrated by rotary evaporation. Saturated NaCl solution (10 mL) was added to the residue, and the solution (pH 6) was extracted with ether (3×25 mL) to remove impurities. The aqueous layer was diluted with saturated NaCl solution (15 mL) and basified to pH 12 with 10% NaOH solution (5 mL). The mixture was extracted with chloroform (4×50 mL). The combined light-yellow chloroform extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation to a residue that was dried briefly under high vacuum to give 0.390 g (36.2%) of a light-yellow oil.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:19]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([S:29][Si](C(C)C)(C(C)C)C(C)C)[CH:24]=1)(=[O:21])[CH3:20].Br[CH2:41][C:42](=[O:50])[CH2:43][CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46]>C1COCC1>[C:19]([O:22][C:23]1[CH:24]=[C:25]([S:29][CH2:41][C:42](=[O:50])[CH2:43][CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH:26]=[CH:27][CH:28]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)Oc1cccc(S[Si](C(C)C)(C(C)C)C(C)C)c1
Reactant: CCOC(=O)CCC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)CCC(=O)CSc1cccc(OC(C)=O)c1
Reaction time: 0.25 h
Yield: 63.1 %

Procedure:
Tetrabutylammonium fluoride (7 ml, 7.0 mmol, 1M in THF) was added to a solution of 3-[1,1-bis(Methylethyl)-2-methyl-1-silapropylthio]phenyl acetate (1.53 g, 4.7 mmol) in THF (10 ml) under argon at room temperature. The reaction was stirred for 15 minutes followed by addition of a solution of ethyl 5-bromo-4-oxopentanoate (1.15 g, 5.17 mmol) in THF (5 ml). After stirring for 3 hours, the solvent was removed under vacuum and the crude product was chromatographed over silica gel to yield 920 mg (73%) of ethyl 5-(3-acetyloxyphenylthio)-4-oxopentanoate. NMR 1H Cl3CD δ: 7.29 (t, 1H, J=8.0 Hz), 7.18 (dd, 1H, J=0.8, 7.6 Hz), 7.07 (t, 1H, J=1.6 Hz), 6.94 (dd, 1H, J=1.2, 8.0 Hz), 4.12 (c, 2H, J=7.2 Hz), 3.75 (s, 2H), 2.89 (t, 2H, J=6.8 Hz), 2.60 (t, 2H, J=6.8 Hz), 2.29 (s, 3H), 1.24 (t, 1H, J=7.2 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([NH2:11])=[C:4]([O:12][CH3:13])[CH:3]=1.OS(O)(=O)=O.[CH3:19][C:20](O)=[O:21]>CC(OC(C)=O)=O>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([NH:11][C:20](=[O:21])[CH3:19])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: COc1cc(Br)cc([N+](=O)[O-])c1N
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Product: COc1cc(Br)cc([N+](=O)[O-])c1NC(C)=O
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
To a solution of 4-bromo-2-methoxy-6-nitrobenzenamine (27.85 g) in HOAc (150 mL) and Ac2O (17 mL) was added conc. H2SO4 at 70° C. and the mixture was stirred at 70° C. for 30 min and kept at rt overnight. The formed precipitate was collected by filtration and washed with hexane to afford the desired product as a light yellow solid (24.45 g, 75%). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.01 (s, 3H), 3.92 (s, 3H), 7.61 (d, 1H, J=1.8 Hz), 7.65 (d, 1H, J=1.8 Hz), 9.91 (s, 1H); LC-MS: m/e=289 [M+1]+
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[CH2:12][CH2:11][C:10]3([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:9]2=[O:18])[CH2:4][CH2:3]1.Cl[C:20]1[C:25]([CH3:26])=[CH:24][C:23]([N+:27]([O-:29])=[O:28])=[CH:22][N:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[OH:1][C@@H:2]1[CH2:3][CH2:4][C@H:5]([N:8]2[CH2:12][CH2:11][C:10]3([CH2:17][CH2:16][N:15]([C:20]4[C:25]([CH3:26])=[CH:24][C:23]([N+:27]([O-:29])=[O:28])=[CH:22][N:21]=4)[CH2:14][CH2:13]3)[C:9]2=[O:18])[CH2:6][CH2:7]1
Reactant: Cc1cc([N+](=O)[O-])cnc1Cl
Reactant: O=C1N([C@H]2CC[C@@H](O)CC2)CCC12CCNCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])cnc1N1CCC2(CC1)CCN([C@H]1CC[C@@H](O)CC1)C2=O
Temperature: 90 °C

Procedure:
A mixture of 2-(cis-4-hydroxycyclohexyl)-2,8-diazaspiro[4.5]decan-1-one (0.10 g, 0.40 mmol), 2-chloro-3-methyl-5-nitropyridine (0.0718 g, 0.416 mmol) and potassium carbonate (0.11 g, 0.79 mmol) in N,N-dimethylformamide (2.0 mL) was heated at 90° C. overnight. After cooled to room temperature, the mixture was diluted with ethyl acetate, washed with water and brine. The organic phase was dried over Na2SO4, filtered, and concentrated. The residue was used directly in next step without further purification.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:29]=1)[NH:5][CH2:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=1[C:17]1[CH:22]=[C:21]([CH:23]([CH3:25])[CH3:24])[CH:20]=[CH:19][C:18]=1[O:26][CH3:27]>CCOCC.[H-].[H-].[H-].[H-].[Li+].[Al+3]>[F:35][C:34]([F:36])([F:37])[C:32]1[CH:33]=[C:28]([CH:4]([NH:5][CH2:6][C:7]2[CH:12]=[C:11]([C:13]([F:14])([F:15])[F:16])[CH:10]=[CH:9][C:8]=2[C:17]2[CH:22]=[C:21]([CH:23]([CH3:24])[CH3:25])[CH:20]=[CH:19][C:18]=2[O:26][CH3:27])[CH2:3][OH:2])[CH:29]=[C:30]([C:38]([F:39])([F:40])[F:41])[CH:31]=1
Reactant: COC(=O)C(NCc1cc(C(F)(F)F)ccc1-c1cc(C(C)C)ccc1OC)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CNC(CO)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of methyl[3,5-bis(trifluoromethyl)phenyl]({[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)acetate (13.2 mg, 0.0217 mmol) was dissolved in Et2O (1.5 mL) and cooled to 0° C. LAH (108.5 μL of a 1 M solution in LAH, 0.1085 mmol) was added dropwise by syringe. The reaction was warmed to room temperature and stirred at room temperature for 1 hour. The reaction was then quenched by addition of H2O (100 μL) followed by 1 N NaOH (100 μL), followed by H2O (300 mL). The gelatinous precipitate was washed several times with CH2Cl2. The organic washes were filtered through a plug of silica gel with 2% MeOH/CH2Cl2 and the filtrate was concentrated. Purification of the residue by PTLC with 25% EtOAc/hexanes afforded 2-[3,5-bis(trifluoromethyl)phenyl]-2-({[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)ethanol. Rf=0.27 (25% EtOAc/hexanes). LCMS=580.4 (M+1)+. 1H NMR (CD2Cl2, 500 MHz) δ 7.79 (s, 1H), 7.75 (s, 2H), 7.63-7.68 (m, 1H), 7.55 (d, J=7.8 Hz, 1H), 7.31 (d, J=7.8 Hz, 1H), 7.23 (m, 1H), 6.94 (m, 1H), 6.89 (m, 1H), 3.43-3.76 (m, 9H), 2.86 (m, 1H), 1.90 (bs, 1H), 1.20 (d, J=6.8 Hz, 6H).
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([CH:15]=[O:16])[N:5]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=1.[CH3:17][N:18]1[CH2:21][CH:20]([CH2:22]O)[CH2:19]1>>[I:1][C:2]1[N:3]=[C:4]2[N:5]([CH2:7][CH2:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[CH:15]2[O:16][CH2:22][CH:20]2[CH2:21][N:18]([CH3:17])[CH2:19]2)[CH:6]=1
Reactant: CN1CC(CO)C1
Reactant: O=Cc1nc(I)cn1CCc1ccccc1
Product: CN1CC(COC2c3ccccc3CCn3cc(I)nc32)C1

Procedure:
Compound 7A is obtained following the procedure already described in example 2A starting from compound 4-iodo-1-phenethyl-imidazole-2-carbaldehyde (example 2B) and (1-methylazetidin-3-yl)-methanol to give 2-iodo-4-(1-methylazetidin-3-ylmethoxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene melting at 100° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH2:7])=[C:3]([NH2:8])[CH:2]=1.[CH3:9][C:10]([CH:12]=O)=O.C(OCC)(=O)C>CO>[CH3:12][C:10]1[N:8]=[C:3]2[CH:2]=[N:1][CH:6]=[CH:5][C:4]2=[N:7][CH:9]=1
Reactant: Nc1ccncc1N
Reactant: CC(=O)C=O
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cnc2ccncc2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.1 %

Procedure:
Pyridine-3,4-diamine (2.00 g, 18.3 mmol) was dissolved in methanol (100 mL) and cooled in an ice bath. Pyruvic aldehyde (40% wt., 3.36 mL, 22.0 mmol) was added, dropwise, and the solution was allowed to warm to ambient temperature where it was stirred, under nitrogen, for 18 h. The reaction was monitored by LC-MS and pyruvic aldehyde (2.5 mL, 16.4 mmol) was added and the solution stirred at room temperature, under nitrogen for an additional 5 h. The solvent was removed, in vacuo, to give a black liquid which solidified to a black solid (3.58 g) upon standing. This material was adsorbed onto silica gel and purified by column chromatography, eluting with a solution of 1:1 hexane:ethyl acetate to give a brown solid (2.18 g, 82% Yield). 1H NMR 400 MHz (DMSO): δ=9.43 (s, 1H), 9.00 (s, 1H), 8.81 (d, 1H, J=5.9 Hz), 7.91 (dd, 1H, J=5.7 Hz, J=0.8 Hz), 2.79 (s, 3H). HPLC (Column; Xterra RP18, 3.5 μm, 4.6×150 mm, Column temp.=40° C.), Flow=1.2 mL/min., 85/15-5/95, 10 min., 5/95, 5.0 min., (25 mM HCO2NH4 buffer, pH=3.5/AcN/MeOH), No impurities @ 210-370 nM, and no impurities @ 306 nM, retention time =3.5 min. Calculated mass=145.06, [M+H]+=146.