Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(CCN(C)C)C.C([Li])(CC)C.[F:14][C:15]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=[O:18].CN([CH:28]=[O:29])C>C1COCC1>[F:14][C:15]1[C:23]([CH:28]=[O:29])=[C:22]([F:24])[CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=[O:18]
Reactant: CN(C)C=O
Reactant: O=C(O)c1ccc(F)cc1F
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: O=Cc1c(F)ccc(C(=O)O)c1F
Temperature: -75 °C
Yield: 11 %

Procedure:
A solution of TMEDA (10.5 mL, 70 mmol) in THF (50 mL) was cooled to <−80° C. and treated with sec-butyllithium (50 mL, 70 mmol). A solution of 2,4-difluorobenzoic acid (5.0 g, 31.6 mmol) in THF was added dropwise maintaining the temperature below −80° C. The reaction mixture was allowed to warm to −75° C. and treated with DMF (15 mL), the mixture then allowed to warm to 0° C. before quenching the reaction with water. The aqueous layer was separated, acidified to pH ˜2 (concentrated HCl) and extracted twice with diethyl ether. The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to give a yellow oil. The crude product was crystallized from cyclohexane/diethyl ether to give the title compound as a yellow solid (670 mg, 11%). 1H NMR (CDCl3, 400 MHz) 10.40 (1 H, s), 8.31 (1 H, ddd, J=8.96, 8.02, 6.08 Hz), 7.12 (1 H, td, J=9.09, 1.42 Hz).
Reaction SMILES: BrCC1[CH:4]=[C:5]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:6]#[N:7].C(=O)(O)[O-].[Na+].Cl.[C:18]([O:22][C:23](=[O:32])[C@@H:24]([CH2:28][CH:29]([CH3:31])[CH3:30])[NH:25][CH2:26][CH3:27])([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C.O>[C:6]([C:5]1[CH:4]=[C:27]([CH:10]=[C:9]([F:11])[CH:8]=1)[CH2:26][NH:25][CH:24]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:23]([O:22][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:32])#[N:7]
Reactant: CCN[C@H](CC(C)C)C(=O)OC(C)(C)C
Reactant: N#Cc1cc(F)cc(CBr)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)CC(NCc1cc(F)cc(C#N)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 3-(bromomethyl)-5-fluorobenzonitrile (4.0 g, 0.02 mol) in dry DMF (40 mL) were added sodium bicarbonate (3.9 g, 0.046 mol) and ethyl D-leucine tert-butyl ester hydrochloride (4.2 g, 0.019 mol). The reaction mixture was stirred at RT for 16 hours. It was diluted with water and extracted with ethyl acetate. The organic phase was washed with water, brine, dried and concentrated. The crude product was purified by chromatography using petroleum ether/ethyl acetate as eluent, affording the title compound as a colorless liquid. 1H NMR (DMSO-d6, 400 MHz): δ 7.68 (d, J=9.5 Hz, 1H), 7.63 (s, 1H), 7.53 (d, J=9.8 Hz, 1H), 3.78 (d, 1H), 3.64 (d, 1H), 2.97 (d, 1H), 2.60 (brs, 1H), 1.97-1.71 (m, 1H), 1.36 (m, 11H), 0.86 (d, 3H), 0.80 (d, 3H).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:7]=[CH:6][C:5]=1[OH:15])[CH:2]=[CH2:3]>[Pd].C(OCC)(=O)C>[CH3:12][C:11]([CH3:13])([CH3:14])[CH2:10][C:8]1[CH:7]=[CH:6][C:5]([OH:15])=[C:4]([CH2:1][CH2:2][CH3:3])[CH:9]=1
Reactant: C=CCc1cc(CC(C)(C)C)ccc1O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCc1cc(CC(C)(C)C)ccc1O
Reaction time: 1 h

Procedure:
A mixture of 2-allyl-4-(2,2-dimethyl-propyl)phenol (0.70 g, 3.4 mmol) and 10% palladium on carbon (0.14 g) in ethyl acetate was stirried under hydrogen (1 atm) for 1 h. The reaction mixture was filtered and the filtrate was concentrated to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]3[O:18][C:17](=[O:19])[C:16]([CH3:21])([CH3:20])[O:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[H][H]>[Pd].C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][O:15][C:16]([CH3:21])([CH3:20])[C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC1(C)OC(c2ccc(-c3ccc(Cl)cc3)cc2)OC1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(OCc1ccc(-c2ccc(Cl)cc2)cc1)C(=O)O
Reaction time: 1.5 h

Procedure:
Palladium on carbon (5% w/w, 0.1 g.) was added to a solution of 2-[4-(4-chlorophenyl)-phenyl]-5,5-dimethyl-1,3-dioxolan-4-one (0.3 g.) in ethanol (50 ml.). The suspension was treated with hydrogen gas at 25° C. and atmospheric pressure for 1.5 hours. The catalyst was removed by filtration and the filtrate evaporated. The residue was dissolved in toluene (10 ml.) and the solution obtained was extracted with 1 M sodium hydroxide solution (10 ml.). The aqueous extracts were acidified with 2 M hydrochloric acid and extracted with toluene (2×10 ml.). By evaporation of the toluene extracts, there may thus be obtained 2-[4-(4-chlorophenyl)benzyloxy]-2-methylpropionic acid, as a waxy solid equivalent to that obtained in Example 12.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:13][CH2:12][C@@H:11]([O:14][C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[C:22]([N:24]2[CH2:38][C:27]3=[C:28]4[N:33]([N:34]=[C:26]3[CH2:25]2)[C:32]([CH3:35])=[C:31]([Cl:36])[C:30]([CH3:37])=[N:29]4)=[O:23])[CH2:10]1)=O)(C)(C)C>O1CCOCC1>[Cl:36][C:31]1[C:30]([CH3:37])=[N:29][C:28]2[N:33]([N:34]=[C:26]3[CH2:25][N:24]([C:22]([C:16]4[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=4[O:14][C@@H:11]4[CH2:12][CH2:13][NH:9][CH2:10]4)=[O:23])[CH2:38][C:27]3=2)[C:32]=1[CH3:35]
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccc(F)cc1O[C@@H]1CCN(C(=O)OC(C)(C)C)C1)C3
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccc(F)cc1O[C@@H]1CCNC1)C3
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.9 %

Procedure:
HCl (1.3 mL) was added to a solution of (R)-3-[2-(6-chloro-5,7-dimethyl-1H,3H-2,4,7a,8-tetraaza-cyclopenta[a]indene-2-carbonyl)-5-fluoro-phenoxy]-pyrrolidine-1-carboxylic acid tert-butyl ester (700 mg; 1.32 mmol; 1 eq.) in 1,4-dioxane (10 mL) was stirred at room temperature for 16 hours then concentrated in vacuo. The reaction mixture was diluted with DCM, washed with 0.1M NaOH, dried over magnesium sulfate and concentrated in vacuo to afford the title compound (550 mg, 97%) as yellow foam. 1H NMR (DMSO-d6) δ 7.40-7.31 (m, 1H), 7.09-7.01 (m, 1H), 6.93-6.83 (m, 1H), 5.03-4.93 (m, 1H), 4.86-4.76 (m, 2H), 4.62-4.43 (m, 2H), 3.13-3.02 (m, 1H), 2.84 (s, 1.5H), 2.81 (s, 1.5H), 2.78-2.69 (m, 2H), 2.62 (s, 1.5H), 2.57 (s, 1.5H), 2.07-1.89 (m, 1H), 1.79-1.61 (m, 2H). HPLC (max plot) 97.2%, Rt 2.74 min. UPLC/MS: (MS+) 430.4 ([M+H]+).
Reaction SMILES: [OH-].[Na+].[CH2:3]([N:10]1[CH2:15][CH2:14][CH:13]([CH3:16])[CH:12]([N:17]([CH3:37])[C:18]2[C:19]3[CH:26]=[CH:25][N:24](S(C4C=CC(C)=CC=4)(=O)=O)[C:20]=3[N:21]=[CH:22][N:23]=2)[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O>[CH2:3]([N:10]1[CH2:15][CH2:14][C@@H:13]([CH3:16])[C@@H:12]([N:17]([CH3:37])[C:18]2[C:19]3[CH:26]=[CH:25][NH:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(N(C)C4CN(Cc5ccccc5)CCC4C)ncnc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C[C@@H]1CCN(Cc2ccccc2)C[C@@H]1N(C)c1ncnc2[nH]ccc12
Temperature: 100 °C
Reaction time: 1 h
Yield: 123.2 %

Procedure:
To a clean, nitrogen-purged reactor were charged 50% sodium hydroxide solution (210 ml) and (1-benzyl-4-methyl-piperidin-3-yl)-methyl-[7-(toluene-4-sulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine (30.0 g, 0.061 mol). The mixture was heated to 95-105° C. for a minimum of 5 hours then cooled to 70-90° C. and water (300 ml) was added. The slurry was cooled to room temperature over a minimum of 1.5 hours and held at room temperature for 1 hour. The solids were isolated by filtration and washed with water (120.0 ml) to obtain 25.2 g of the title compound, water wet.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13](F)[CH:14]=1)[O:11][C:7]1([CH2:10][CH2:9][CH2:8]1)[CH2:6][CH:5]2[NH2:16].[F:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22]([CH2:27][C:28](O)=[O:29])=[C:21]2[CH3:31].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[O:11][C:7]1([CH2:10][CH2:9][CH2:8]1)[CH2:6][CH:5]2[NH:16][C:28](=[O:29])[CH2:27][C:22]1[NH:23][C:24]2[C:20]([C:21]=1[CH3:31])=[CH:19][C:18]([F:17])=[CH:26][CH:25]=2
Reactant: Cc1c(CC(=O)O)[nH]c2ccc(F)cc12
Reactant: NC1CC2(CCC2)Oc2c(F)cc(F)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(CC(=O)NC2CC3(CCC3)Oc3ccc(F)cc32)[nH]c2ccc(F)cc12

Procedure:
The title compound was prepared from Intermediate 6 (200 mg, 0.963 mmol) and (5-fluoro-3-methyl-1H-indol-2-yl)acetic acid (200 mg, 0.963 mmol) in presence of EDCI.HCl (276 mg, 1.145 mmol), HOBt (221 mg, 1.145 mmol) and triethylamine (401 μl, 3.003 mmol) in dichloromethane (10 ml) as described in Example 1 to give 18 mg of the product as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.52-1.74 (m, 4H), 1.88-1.95 (m, 2H), 2.08-2.25 (m, 2H), 2.40 (s, 3H), 3.70 (s, 2H), 5.23 (q, J=8.7 Hz, 1H), 5.68 (d, J=9.0 Hz, 1H), 6.61-6.66 (m, 2H), 6.72-6.89 (m, 2H), 7.07-7.18 (m, 2H), 8.01 (s, 1H); ESI-MS (m/z) 397.33 (M+H)+.
Reaction SMILES: [C:1]1([CH2:11][CH:12]([CH2:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)[C:13](O)=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.Cl.[CH2:29]([O:31][C:32](=[O:41])[C@H:33]([CH2:35][C:36]1[N:40]=[CH:39][NH:38][CH:37]=1)[NH2:34])[CH3:30].ON1C2C=CC=CC=2N=N1.CCN(CC)CC.C1(N=C=NC2CCCCC2)CCCCC1>C1COCC1>[NH:38]1[CH:37]=[C:36]([CH2:35][C@H:33]([NH:34][C:13](=[O:14])[CH:12]([CH2:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)[CH2:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[C:32]([O:31][CH2:29][CH3:30])=[O:41])[N:40]=[CH:39]1
Reactant: O=C(O)C(Cc1cccc2ccccc12)Cc1cccc2ccccc12
Reactant: CCOC(=O)[C@@H](N)Cc1c[nH]cn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](Cc1c[nH]cn1)NC(=O)C(Cc1cccc2ccccc12)Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.8 %

Procedure:
A solution of 0.5 g (1.5 mmol) of bis-(1-naphthylmethyl)-acetic acid, 0.77 g (3.0 mmol) of histidine ethyl ester dihydrochloride (His-OEt·2 HCl), and 0.22 g (1.6 mmol) of 1-hydroxybenzotriazole (HOBt) in 20 mL of THF was treated with 0.85 mL (6.0 mmol) of Et3N followed by 0.33 g (1.6 mmol) of N,N'-dicyclo hexylcarbodiimide (DCC) and the solution allowed to stir at room temperature overnight. The mixture was filtered and the solvent removed under reduced pressure. The residue was taken up in EtOAc and washed with a saturated solution of NaHCO3, then with a saturated solution of NaCl. Drying over MgSO4 and removal of the solvent under reduced pressure gave the crude product. Chromatography on silica gel, eluting with a gradient of methylene chloride (CH2Cl2) to CH2Cl2 /MeOH (96/4) gave 0.15 g of the product as a white foam. The structure was confirmed by NMR and mass spectroscopy; (m+H)+ =506.
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH:5]=1)(=O)[CH3:2].[CH2:22]([NH2:25])[CH2:23][NH2:24].[BH4-].[Na+].O>C(O)C.O1CCOCC1.CCOCC>[C:16]1([S:13]([N:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:4]([CH:1]3[CH2:2][NH:25][CH2:22][CH2:23][NH:24]3)=[CH:5]2)(=[O:15])=[O:14])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(=O)c1cn(S(=O)(=O)c2ccccc2)c2ccccc12
Reactant: NCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: O=S(=O)(c1ccccc1)n1cc(C2CNCCN2)c2ccccc21
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 25.4 %

Procedure:
The 19.1 g of the above indole derivative in 500 ml of ethanol and 200 ml of dioxane was stirred and cooled to 0°-5° C. under argon. A solution of 3.46 g of ethylenediamine in 100 ml of ethanol was added dropwise. The temperature was maintained at 0°-5° C. until solution was complete, then the mixture was stirred at room temperature for 3.5 hours, recooled to 0°-5° C. and 4.37 g of sodium borohydride added. This mixture was stirred for 18 hours, water was added and the mixture evaporated to dryness in vacuo. The residue was dissolved in dichloromethane, washed with water, dried, filtered and evaporated giving an oil, which solidified. The solid was dissolved in cold ether, filtered and concentrated in vacuo at 40° C. The solid was collected, washed with cold ether and dried, giving 5 g of 1-(phenylsulfonyl)-3-(2-piperazinyl)-1H-indole.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.[CH3:14][C:15]1[S:19][C:18]([SH:20])=[N:17][N:16]=1>CO>[CH3:13][C:4]1[CH:3]=[C:2]([S:20][C:18]2[S:19][C:15]([CH3:14])=[N:16][N:17]=2)[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: Cc1cc(Cl)c2cccc(O)c2n1
Reactant: Cc1nnc(S)s1
Solvent: CO
Product: Cc1cc(Sc2nnc(C)s2)c2cccc(O)c2n1
Temperature: 80 °C

Procedure:
A mixture of 4-chloro-2-methyl-quinolin-8-ol (10 mg, 52 μmol) and 5-methyl-[1,3,4]thiadiazole-2-thiol (6.9 mg, 52 μmol) in MeOH (0.3 mL) was heated to 80° C. for 1.5 h. The solvent was removed in vacuo to give title compound. MS (m/z): 289.9 [M+H+].
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:7]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C.[Pd]>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:15][CH:16]=1
Reactant: CCOC(=O)c1ccc(C2=NCCN2)cc1
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(-c2ncc[nH]2)cc1

Procedure:
500 mg (2.3 mmol) of ethyl 4-(2-imidazoline-2-yl)benzoate and 500 mg of 10% palladium/carbon were heated in 20 ml of toluene under reflux in argon atmosphere for 9 hours. The reaction liquid was diluted with ethyl acetate and filtered through Celite. The filtrate was concentrated to obtain the title compound.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]([CH2:21]OS(C3C=CC=CC=3)(=O)=O)[CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-:32]>CC(C)=O>[C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]([CH2:21][I:32])[CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [I-]
Reactant: O=S(=O)(OCC1CN(S(=O)(=O)c2ccccc2)CC1c1ccccc1)c1ccccc1
Solvent: CC(C)=O
Product: O=S(=O)(c1ccccc1)N1CC(CI)C(c2ccccc2)C1
Yield: 96.8 %

Procedure:
A solution of 234 mg (0.51 mmol) of 1-(benzenesulfonyl)-3-(SR)-benzenesulfonyloxymethyl-4-(SR)-phenylpyrrolidine (from Example 1, Step D) and 1.1 g (7.7 mmol) of sodiuim iodide in 8 mL of acetone was heated at reflux for 20 h. The reaction mixture was partitioned between 50 mL of ether and 30 mL of H2O and the layers were separated. The organic layer was washed with 30 mL of sat'd NaCl and dried over MgSO4. The aqueous layers were combined and extracted with 30 mL of ether. The extract was dried; the organic layers were combined. and concentrated in vacuo. Flash chromatography on 25 g of silica gel using 3:2 v/v hexanes/ether as the eluant afforded 211 mg (96%) of the title compound as an oil. 1H NMR (500 MHz, CDCl3): δ2.43 (t, J=9.8, 1H), 2.64-2.74 (m, 2H), 3.30 (dd, J=2.5, 7.8, 1H), 3.47 (q, J=6.7, 1H), 3.67-3.74 (3H), 7.05-7.95 (1OH). Mass Spectrum (NH3-CI): m/z 428 (M+1).
Reaction SMILES: C([O-])(=O)C.[Na+].Cl.[NH2:7][OH:8].[F:9][C:10]([F:24])([F:23])[CH2:11][NH:12][C:13]([C:15]1[S:16][C:17]([CH:21]=O)=[CH:18][C:19]=1[CH3:20])=[O:14]>C1COCC1.O.CS(C)=O>[F:9][C:10]([F:24])([F:23])[CH2:11][NH:12][C:13]([C:15]1[S:16][C:17]([CH:21]=[N:7][OH:8])=[CH:18][C:19]=1[CH3:20])=[O:14]
Reactant: NO
Reactant: Cc1cc(C=O)sc1C(=O)NCC(F)(F)F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(C=NO)sc1C(=O)NCC(F)(F)F
Reaction time: 3 h

Procedure:
Sodium acetate (90 mg) is added to a solution of hydroxylamine hydrochloride (60 mg) and 5-formyl-3-methyl-thiophene-2-carboxylic acid (2,2,2-trifluoro-ethyl)-amide (190 mg) in THF (5 ml), water (1 ml) and DMSO (1 ml). After 3 hours at room temperature, the reaction is quenched with water. The reaction mixture is extracted three times with ethyl acetate. The combined organic phases are dried over Na2SO4 and concentrated in vacuo to yield 5-(hydroxyimino-methyl)-3-methyl-thiophene-2-carboxylic acid (2,2,2-trifluoro-ethyl)-amide. The crude product obtained (206 mg, yellowish oil) is used without further purification. MS (HPLC/MS): 267 (MH+). Retention time: 2.56 min and 2.64 min (two diastereoisomers).
Reaction SMILES: [ClH:1].C(OCC)(=O)C.C([NH:15][C@@H:16]1[CH2:18][C@H:17]1[C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:41])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:28]=2)=[CH:21][CH:20]=1)C1C=CC=CC=1.C(=O)C1C=CC=CC=1>>[ClH:1].[NH2:15][C@@H:16]1[CH2:18][C@H:17]1[C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:41])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH2:34][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:28]=2)=[CH:21][CH:20]=1
Reactant: O=C(Nc1ccc([C@@H]2C[C@H]2NCc2ccccc2)cc1)c1cccc(OCc2ccccc2)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O=Cc1ccccc1
Product: N[C@@H]1C[C@H]1c1ccc(NC(=O)c2cccc(OCc3ccccc3)c2)cc1

Procedure:
By a method similar to Example 1, Step C, 4N hydrochloric acid/ethyl acetate solution was added to N-{4-[trans-2-(benzylamino)cyclopropyl]phenyl}-3-(benzyloxy)benzamide obtained from N-[4-(trans-2-aminocyclopropyl)phenyl]-3-(benzyloxy)benzamide hydrochloride (109 mg) and benzaldehyde (29.3 μL), and the resulting solid was collected by filtration to give the title compound (96.1 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C@H:7]2[C@H:15]3[C@@H:11]([N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:19]=4)[C:13](=[O:16])[O:14]3)[CH2:10][S:9](=[O:29])(=[O:28])[CH2:8]2)=[CH:4][C:3]=1[F:32].[CH3:33][N:34]1[CH2:39]C[O:37][CH2:36][CH2:35]1.CN(C)CC(O)=O>CN(C=O)C.CCOC(C)=O>[C:24]([C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][N:12]1[C@@H:11]2[C@H:15]([C@H:7]([CH2:6][C:5]3[CH:30]=[CH:31][C:2]([NH:1][C:36](=[O:37])[CH2:35][N:34]([CH3:39])[CH3:33])=[C:3]([F:32])[CH:4]=3)[CH2:8][S:9](=[O:28])(=[O:29])[CH2:10]2)[O:14][C:13]1=[O:16])([CH3:26])([CH3:27])[CH3:25]
Reactant: CC(C)(C)c1cccc(CN2C(=O)O[C@H]3[C@H](Cc4ccc(N)c(F)c4)CS(=O)(=O)C[C@@H]32)c1
Reactant: CN1CCOCC1
Agent: CN(C)CC(=O)O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)CC(=O)Nc1ccc(C[C@@H]2CS(=O)(=O)C[C@H]3[C@H]2OC(=O)N3Cc2cccc(C(C)(C)C)c2)cc1F

Procedure:
A mixture of (3aR*,7S*,7aS*)-7-(4-amino-3-fluoro-benzyl)-3-(3-tert-butyl-benzyl)-5,5-dioxo-hexahydro-1oxa-5lambda*6*-thia-3-aza-inden-2-one (example 1j), 1.06 g, 2.3 mmol), N-methylmorpholine (0.507 mL, 4.6 mmol), N,N-dimethylglycine (0.356 g, 3.45 mmol) and propylphosphoric acid anhydride (50% in DMF, 2.68 mL, 4.6 mmol) was stirred in DMF (9.2 mL) at 25° C. for 19 h. The reaction mixture was diluted with EtOAc and washed with saturated NaHCO3 solution, water and brine. The organic layer was dried over Na2SO4, filtered and evaporated to leave the title compound as a colorless, amorphous powder: TLC (toluene-ETA 85:15) Rf=0.36; HPLC RtA=1.84 min; ESIMS [M+H]+=546; 1H NMR (600 MHz, DMSO-d6): δ 9.46 (s, 1H), 7.85 (t, 1H), 7.39 (s, 1H), 7.32 (d, 1H), 7.28 (t, 1H), 7.17-7.11 (m, 2H), 7.0 (d, 1H), 4.42 (d, 1H), 4.23 (d, 1H), 4.16 (t, 1H), 3.74-3.65 (m, 2H), 3.45 (t, 1H), 3.08 (m, 3H), 3.01 (m, 1H), 2.93 (m, 1H), 2.58 (m, 1H), 2.52 (m, 1H), 2.30 (s, 6H), 1.25 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]3[C:10](=[CH:11][CH:12]=2)[CH:9]=[CH:8][C:7]([CH3:16])=[N:6]3)[N:3]=1.[N+:17]([O-])([OH:19])=[O:18].S(=O)(=O)(O)O>>[N+:17]([C:11]1[CH:12]=[C:13]2[C:4]([N:3]=[C:2]([CH3:1])[CH:15]=[CH:14]2)=[C:5]2[C:10]=1[CH:9]=[CH:8][C:7]([CH3:16])=[N:6]2)([O-:19])=[O:18]
Reactant: Cc1ccc2ccc3ccc(C)nc3c2n1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1ccc2cc([N+](=O)[O-])c3ccc(C)nc3c2n1

Procedure:
Specifically, 2,9-dimethyl-1,10-phenanthroline shown by the formula (A) in FIG. 1 is reacted with an acid mixture composed of nitric acid and sulfuric acid to give 5-nitro-2,9-dimethyl-1,10-phenanthroline shown by the formula (B) in FIG. 1. The 5-nitro-2,9-dimethyl-1,10-phenanthroline is then reacted with selenium dioxide to give a dialdehyde compound shown by the formula (C) in FIG. 1. This dialdehyde compound is then oxidized to obtain the compound of the formula (1).
Reaction SMILES: [CH2:1]([C:8]1([CH3:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]1=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:20][CH2:21][O:22]C1CCCCO1>>[CH2:1]([C:8]1([CH3:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:20][CH2:21][OH:22])[C:9]1=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCCOC1CCCCO1
Reactant: CC1(Cc2ccccc2)C(=O)Nc2ccccc21
Product: CC1(Cc2ccccc2)C(=O)N(CCO)c2ccccc21

Procedure:
Prepared from 3-benzyl-3-methylindol-2(3H)-one and 2-(2-chloroethoxy)tetrahydro-2H-pyran.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C@@H:9]1[C:14]([NH:16][CH:17]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:18]([OH:22])[C:19](O)=[O:20])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:30]([O:33][NH2:34])([CH3:32])[CH3:31]>>[CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C@@H:9]1[C:14]([NH:16][CH:17]([CH:18]([OH:22])[C:19]([NH:34][O:33][CH:30]([CH3:32])[CH3:31])=[O:20])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)ON
Reactant: O=C(O)C(O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccccc1
Product: CC(C)ONC(=O)C(O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccccc1

Procedure:
The reaction can be carried out in analogy to reaction step 1.3 by reacting 3-((R)-1-benzyl-5-oxopyrrolidine-2-carboxamido)-2-hydroxy-4-phenylbutanoic acid with O-isopropylhydroxylamine.
Reaction SMILES: C([NH:8][C@H:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C@H:10]1[O:22][CH2:23][C:24]([CH3:26])=[CH2:25])C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].CO>[NH2:8][C@H:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:11][C@H:10]1[O:22][CH2:23][CH:24]([CH3:26])[CH3:25]
Reactant: C=C(C)CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NCc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Yield: 92.5 %

Procedure:
The same operation as in Example (90d) was performed using tert-butyl cis(±)-4-(benzylamino)-3-[(2-methyl-2-propen-1-yl)oxy]piperidine-1-carboxylate obtained in Example (117c) (1.8 g, 5 mmol), 10% Pd/C (wet, 0.5 g), ammonium formate (2.52 g, 40 mmol) and methanol (20 mL), to obtain 1.26 g of the title compound as a colorless oily substance (93%).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:8]=[CH:7][C:6]([OH:9])=[CH:5][N:4]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1F)[CH:16]=[O:17].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[O:9][C:6]1[CH:7]=[N:8][C:3]([C:2]([F:1])([F:10])[F:11])=[N:4][CH:5]=1)[CH:16]=[O:17]
Reactant: Oc1cnc(C(F)(F)F)nc1
Reactant: O=Cc1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(Oc2cnc(C(F)(F)F)nc2)c(F)c1
Temperature: 130 °C
Yield: 83.4 %

Procedure:
To a solution of 2-(trifluoromethyl)pyrimidin-5-ol (1.5 g, 9.14 mmol) and 3,4-difluorobenzaldehyde (1.299 g, 9.14 mmol) in DMF (18 mL), was added K2CO3 (1.642 g, 11.88 mmol). The mixture was heated with a microwave condition at 130° C. for 1 h. After cooling, the reaction mixture was diluted in water, extracted with EA. The organic phase was washed with water and brine, dried over Na2SO4, concentrated to afford the title compound (2.18 g, 7.62 mmol, 83% yield) as a brown oil. LCMS: rt=3.08 min, [M+H+]=287