Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:26]=[CH:25][C:7]2[C:8]3[C:9](=[C:20]([CH:23]=[O:24])[NH:21][CH:22]=3)[CH2:10][N:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:6]=2[CH:5]=1.O.[CH3:28]O>>[Cl:3][C:4]1[CH:26]=[CH:25][C:7]2[C:8]3[C:9](=[C:20]([CH2:23][OH:24])[NH:21][C:22]=3[CH3:28])[CH2:10][N:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:6]=2[CH:5]=1
Reactant: CO
Reactant: O=Cc1[nH]cc2c1CN=C(c1ccccc1Cl)c1cc(Cl)ccc1-2
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: Cc1[nH]c(CO)c2c1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Reaction time: 0.5 h

Procedure:
In one portion 0.2 g (5.2 mmol) of sodium borohydride was added to 0.9 g of 8-chloro-6-(2-chlorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine-3-carboxaldehyde in 20 ml of methanol which was cooled to 0°. After stirring at 0° for 30 min, water was added and the resulting precipitate was collected by filtration to give a tan amorphous solid (mp 170°-180° dec.). All attempts to purify this product led to the introduction of impurities by decomposition.
Reaction SMILES: Cl[C:2](OC(Cl)(Cl)Cl)=[O:3].[CH3:9][O:10][C:11]1[CH:27]=[CH:26][C:14]([CH2:15][NH:16][C:17]2[N:25]=[CH:24][CH:23]=[CH:22][C:18]=2[C:19]([OH:21])=[O:20])=[CH:13][CH:12]=1>O1CCOCC1>[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][N:16]2[C:17]3[N:25]=[CH:24][CH:23]=[CH:22][C:18]=3[C:19](=[O:21])[O:20][C:2]2=[O:3])=[CH:26][CH:27]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: COc1ccc(CNc2ncccc2C(=O)O)cc1
Solvent: C1COCCO1
Product: COc1ccc(Cn2c(=O)oc(=O)c3cccnc32)cc1
Yield: 67.7 %

Procedure:
Trichloromethyl chloroformate (3.36 mL, 27.8 mmol) was added slowly to a suspension of 2-(4-methoxy-benzylamino)-nicotinic acid (11) (6 g, 23.23 mmol) in dioxane and refluxed for 18 h under nitrogen atmosphere. The solution was cooled and the solvent was removed under vacuum. The residue was dissolved in dichloromethane and washed by saturated NaHCO3 solution. The organic phase was dried over Na2SO4 and evaporated to yield a residue. The residue was recrystallized by ether to yield 4.47 g (67%) of 1-(4-methoxy-benzyl)-1H-pyrido[2,3-d][1,3]oxazine-2,4-dione (12) as white solids. MP: 160° C.; 1H-NMR (DMSO-d6): δ 3.71 (s, 1H), 5.27 (s, 2H), 6.85 (d, J=7.0 Hz, 2H), 7.33 (m, 3H), 8.40 (dd, J=1.5, 7.5 Hz, 1H), 8.75 (dd, J=1.5, 7.5 Hz, 1H); EIMS: 286 (M+23).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]([CH2:39][CH3:40])([CH3:38])[CH3:37])=[CH:32][C:31]=2[C:41]([CH2:44][CH3:45])([CH3:43])[CH3:42])=[C:4]([C:22]([NH2:24])=[O:23])[C:5]2[C:10]([C:11]=1[N:12]=NC1C=CC(OC)=CC=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[NH2:12][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:22]([NH2:24])=[O:23])=[C:3]([CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]([CH2:39][CH3:40])([CH3:37])[CH3:38])=[CH:32][C:31]=2[C:41]([CH2:44][CH3:45])([CH3:43])[CH3:42])[C:2]=1[OH:1]
Reactant: CCC(C)(C)c1ccc(OCCCCc2c(O)c(N=Nc3ccc(OC)cc3)c3ccccc3c2C(N)=O)c(C(C)(C)CC)c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CCC(C)(C)c1ccc(OCCCCc2c(O)c(N)c3ccccc3c2C(N)=O)c(C(C)(C)CC)c1
Yield: 59.9 %

Procedure:
To a solution of 21 g (0.034 mole) crude 3-hydroxy-4-(p-methoxyphenylazo)-2-[4'-(2,4-di-t-pentylphenoxy)-n-butyl]-naphthamide in 400 ml alcohol was added a solution of 13.9 g (0.08 mole) 90% sodium dithionite in 75 ml water. The mixture was refluxed for 0.5 hrs, then cooled and diluted with 400 ml H2O. The product was extracted into hexane, crystallized, and was collected and recrystallized from hexane to give 10 g yellow green solid, m.p. 93°-96° C.
Reaction SMILES: [O:1]1[C:5]2=[CH:6][CH:7]=[CH:8][C:9]([NH2:10])=[C:4]2[CH2:3][CH2:2]1.CO.[CH:13](I)([CH3:15])[CH3:14]>C(N(CC)CC)C>[CH:13]([NH:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[O:1][CH2:2][CH2:3][C:4]=12)([CH3:15])[CH3:14]
Reactant: Nc1cccc2c1CCO2
Reactant: CC(C)I
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)Nc1cccc2c1CCO2

Procedure:
To a solution of 19.7 g. of 2,3-dihydro-4-benzofuranamine in 150 ml. of methanol is added 11 ml. of isopropyliodide and 15.5 ml. of triethylamine. The solution is refluxed for 40 hours and then concentrated in vacuo. The resultant oil is extracted and combined, filtered through Celite, and the ether removed in vacuo to give an oil of N-isopropyl-2,3-dihydro-4-benzofuranamine.
Reaction SMILES: [NH:1]([CH3:20])[C:2]([C:5]([NH:7][C@H:8]([C:16]([O:18][CH3:19])=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6])([CH3:4])[CH3:3].Cl.[N+:22]([C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1)([O-:24])=[O:23]>C(Cl)Cl>[N+:22]([C:25]1[CH:33]=[CH:32][C:28]([C:29]([N:1]([CH3:20])[C:2]([C:5]([NH:7][C@H:8]([C:16]([O:18][CH3:19])=[O:17])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:6])([CH3:3])[CH3:4])=[O:30])=[CH:27][CH:26]=1)([O-:24])=[O:23]
Reactant: CNC(C)(C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)C(C)(C)N(C)C(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 24 %

Procedure:
To a stirred solution of H—NMeAib—Phe—OMe, HCl salt (0.3 g, 1.0 mmol) in CH2Cl2 (3mL) was added TEA (0.28 mL, 2.0 mmol). After stirring for 5 min at room temperature p-nitrobenzoyl chloride (0.15 g, 1 mmol) was added. The resulting solution was stirred at room temperature for 24 h. The solvent was removed in vacuo and redissolved in ethyl acetate (30 mL). The ethyl acetate layer was washed with 1M HCl (3×10 mL) brine (10 mL), 10% aq. Na2CO3 (3×10 mL), brine (10 mL), and dried over Na2SO4. Evaporation of the solvent was followed by column chromatography of the product with CHCl3—MeOH-Acetic Acid (90:10:0.1 v:v:v) provided 7a (see Table 1) (100 mg 24%) as a pale yellow amorphous solid: mp.65-70° C.; 1H NMR (360 MHz CDCl3 δ) 1.54 &1.52 (2s, 6H, β-MeAib), 2.87 (s, 3H, N—CH3), 3.15 (d, 2H, J=5.04 Hz, β-H), 3.69 (s, 3H, O—CH3), 4.86 (m, 1H, α-H); 6.35 (d, 1H, J=6.35 Hz, N—H), 7.20 (m, 5H, Aromatic Phe), 7.55 (d, 2H, J=8.64 Hz, Benzyl-H), 8.64 (d, 2H, J=8.64 Hz, Benzyl-H), FAB-MS m/z (relative intensity) 428 (35%), 450 (40%), 249 (100%); [α]D20−16.15° (c 0.014, MeOH).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][O:4][CH2:3]1.[H-].[Na+].[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12](Br)[N:11]=1>C1COCC1>[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:1][CH:2]2[CH2:6][CH2:5][O:4][CH2:3]2)[N:11]=1
Reactant: O[C@H]1CCOC1
Reactant: Brc1cccc(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Brc1cccc(OC2CCOC2)n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of (S)-(+)-3-hydroxy-tetrahydrofuran (0.34 mL, 4.2 mmol) and dry THF (20 mL) was added NaH (0.17 g, 4.2 mmol, 60%) under N2 at RT. After 5 min, added 2,6-dibromopyridine. Stirred at RT for 4 h. Quenched with H2O and extracted with EtOAc. Washed organic layer with saturated NH4Cl, brine, dried (MgSO4) and concentrated in vacuo to give 2-bromo-6-(tetrahydro-furan-3-yloxy)-pyridine as a clear, colorless oil. MS m/z: 245.2 (M+H). Calc'd for C9H10BrNO2—244.09.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH:8]1[N:12]=[CH:11][N:10]([C:13](N2C=NC=C2)=[O:14])[CH:9]=1>O1CCCC1>[N:10]1([C:13]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[O:14])[CH:9]=[CH:8][N:12]=[CH:11]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCCCCCO
Solvent: C1CCOC1
Product: CCCCCCOC(=O)n1ccnc1
Temperature: 30 °C

Procedure:
A solution of n-hexanol (30.6 g) in tetrahydrofuran (400 ml) was slowly added to solution of N,N-carbonyldiimidazole (55.08 g) in tetrahydrofuran (100 ml) and stirred for 2½ hour at 25-35° C. to provide hexyl 1H-imidazole-1-carboxylate compound of formula-4. 1-methyl-2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide compound of formula-5 (100 g), tetrahydrofuran (700 ml), water (800 ml) and potassium carbonate (138 g) were added to the reaction mixture and stirred for 20 hours at 25-30° C. After completion of the reaction, filtered the solid, washed with tetrahydrofuran and then dried to get title compound.
Reaction SMILES: O1CC1COC1C2C(C)=NOC=2C=CC=1.Cl.[CH2:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH:18]1[NH:27]CC(O)COC1C2C(C)=NOC=2C=CC=1>C(O)C>[NH2:27][CH:18]1[CH2:19][CH2:20][C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:17]1
Reactant: Cc1noc2cccc(OCC(O)CNC3CCc4ccccc4C3)c12
Agent: Cc1noc2cccc(OCC3CO3)c12
Agent: Cl
Solvent: CCO
Product: NC1CCc2ccccc2C1

Procedure:
Following the procedure of Example 27, but starting from 4-(2,3-epoxypropoxy)-3-methyl-1,2-benzisoxazole (20.5 g) (DE-2,711,382) and 2-aminotetralin (14.82 g) in absolute ethanol (150 ml), N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(3-methyl-1,2-benzisoxazol-4-yloxy)propanamine hydrochloride is obtained ((i), R=H, Ar=radical 59, and the chain is attached to position 2 of the tetralin moiety).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[F:13][C:14]1[C:22]([O:23][C:24]2[C:33]3[C:28](=[CH:29][C:30]([O:35][CH3:36])=[C:31]([OH:34])[CH:32]=3)[N:27]=[CH:26][N:25]=2)=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[CH:17][NH:18]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:56]([N:59]1[CH2:64][CH2:63][N:62]([CH2:65][CH2:66][CH2:67]O)[CH2:61][CH2:60]1)(=[O:58])[CH3:57]>C(Cl)Cl>[C:56]([N:59]1[CH2:64][CH2:63][N:62]([CH2:65][CH2:66][CH2:67][O:34][C:31]2[CH:32]=[C:33]3[C:28](=[CH:29][C:30]=2[O:35][CH3:36])[N:27]=[CH:26][N:25]=[C:24]3[O:23][C:22]2[C:14]([F:13])=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][CH:17]=[CH:16]3)[CH2:61][CH2:60]1)(=[O:58])[CH3:57]
Reactant: CC(=O)N1CCN(CCCO)CC1
Reactant: COc1cc2ncnc(Oc3ccc4[nH]ccc4c3F)c2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2ncnc(Oc3ccc4[nH]ccc4c3F)c2cc1OCCCN1CCN(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.8 %

Procedure:
Diethyl azodicarboxylate (117 μl, 0.738 mmol) was added dropwise to a solution of 4-(4-fluoroindol-5-yloxy)-6-hydroxy-7-methoxyquinazoline (0.2 g, 0.615 mmol), triphenylphosphine (0.242 g, 0.92 mmol) and 3-(4-acetylpiperazin-1-yl)propan-1-ol (0.137 g, 0.738 mmol), (prepared as described for the starting material in Example 1 or Example 7), in methylene chloride (5 ml). After stirring at ambient temperature for 1 hour, triphenylphosphine (0.032 g), 3-(4-acetylpiperazin-1-yl)propan-1-ol (0.022 g) and diethyl azodicarboxylate (20 μl) were added. The mixture was stirred for 1 hour at ambient temperature and evaporated under vacuum. The residue was purified by column chromatography, eluting with increasingly polar mixtures of methylene chloride and ethyl acetate followed by methylene chloride and methanol. The fractions containing the expected product were combined and evaporated. The residue was repurified by preparative LC/MS eluting with increasingly polar mixtures of acetonitrile and water (containing 1% acetic acid). The fractions containing the expected product were combined and evaporated. The residue was triturated under diethyl ether and pentane and the residue was filtered, washed with diethyl ether and dried under vacuum to give 6-(3-(4-acetylpiperazin-1-yl)propoxy)-4-(4-fluoroindol-5-yloxy)-7-methoxyquinazoline (0.057 g, 19%).
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:23](=[O:26])[CH2:24]Br)[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2].[C:27]([O-:30])(=[O:29])[CH3:28].[K+]>CC(C)=O.O>[CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:23](=[O:26])[CH2:24][O:30][C:27](=[O:29])[CH3:28])[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2]
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)CBr
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)COC(C)=O
Yield: 35.1 %

Procedure:
A mixture of 2.1 g of 16β-ethyl-17β-bromoacetoxy-4-estren-3-one and 1.0 g of potassium acetate is stirred in a mixture of 50 ml of acetone and 3 ml of water for 20 hours. The acetone is distilled off under reduced pressure and the residue is extracted with 150 ml of ethyl acetate. The organic layer is separated, washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure and the residue is subjected to column chromatography. Following passage of 700 ml of diisopropyl ether-n-hexane (1:1), elution is carried out with 600 ml of a 3:2 mixture and 300 ml of a 5:1 mixture of the same solvents. The eluates are combined and evaporated under reduced pressure to remove the solvent, giving 0.7 g of the above-identified compound as colorless crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([CH2:10][S:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][C:13]=2[CH3:21])[CH:5]=1)[CH3:2]>C(O)(=O)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([CH2:10][S:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][C:13]=2[CH3:21])[CH:5]=1)[CH3:2]
Reactant: CCOc1ccnc(CSc2ccc([N+](=O)[O-])cc2C)c1
Solvent: CC(=O)O
Product: CCOc1ccnc(CSc2ccc(N)cc2C)c1
Temperature: 25 °C
Reaction time: 420 h
Yield: 79.9 %

Procedure:
4-ethoxy-2-[[(2-methyl-4-nitrophenyl)sulfanyl]methyl]pyridine (2.5 g) was dissolved in acetic acid (25 ml), reduced iron (7.5 g) was added to the mixture, and the mixture was stirred for 420 hours at room temperature. The mixture was filtered with Celite, and washed with ethyl acetate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 4-[[(4-ethoxy-2-pyridinyl)methyl]sulfanyl]-3-methylaniline (1.8 g).
Reaction SMILES: Cl.[CH:2](=[C:9]1[NH:13][C:12](=[O:14])[NH:11][C:10]1=[O:15])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C].[C].C[OH:19]>[Zn]>[C:12]([NH:13][C@H:9]([C:10]([OH:15])=[O:19])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)(=[O:14])[NH2:11]
Reactant: CO
Reactant: O=C1NC(=O)C(=Cc2ccccc2)N1
Agent: Cl
Agent: [C]
Agent: [Zn]
Product: NC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reaction time: 0.5 h

Procedure:
This Example shows the process in which hydrochloric acid is added first and then the zinc is added. A round bottom flask fitted with a stirrer, thermometer and condenser was charged with 10 grams of 5-benzalhydantoin (0.053 mole), 100 milliliters of methanol and then 21.0 grams of concentrated (37 weight percent) hydrochloric acid (0.213 mole of hydrogen chloride, 400 mole percent based on 5-benzalhydantoin) was added. To this was added very slowly with stirring 6.93 grams of zinc powder (0.106 mole, 200 mole percent based on 5-benzalhydantoin) over a period of 45 minutes. After 30 minutes of additional stirring, some of the zinc powder remained unreacted and so 5 grams more of concentrated hydrochloric acid was added. After about 60 minutes more of stirring, no unreacted zinc powder remained. The reaction was stirred an additional 2 hours. By UV analysis, the reaction mixture showed 98% reduction of the carbon-carbon double bond of the 5-benzalhydantoin. By workup of the reaction mixture N-carbamylphenylalanine was isolated. The melting point was determined to be 186°-188° C. corresponding to the literature melting point of 190° C., reported in Am. Chem. J. 45, 368 (1911) (compound referred to as 4-benzylhydantoic acid).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:22][C:23](O)=[O:24])[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:26]([NH:28][CH2:29][C:30]1[N:31]([CH3:35])[CH:32]=[CH:33][CH:34]=1)[CH3:27]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH2:22][C:23]([N:28]([CH2:26][CH3:27])[CH2:29][C:30]2[N:31]([CH3:35])[CH:32]=[CH:33][CH:34]=2)=[O:24])(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Reactant: CCNCc1cccn1C
Product: CCN(Cc1cccn1C)C(=O)CN(c1ccc(C)cc1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with ethyl-(1-methyl-1H-pyrrol-2-ylmethyl)-amine
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:27]3[CH2:30][C:29](CO)([OH:31])[CH2:28]3)=[N:9][C:10]=2[C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1>C1COCC1.O.C(Cl)Cl>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:27]3[CH2:28][C:29](=[O:31])[CH2:30]3)=[N:9][C:10]=2[C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Nc1nccn2c(C3CC(O)(CO)C3)nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c12
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: Nc1nccn2c(C3CC(=O)C3)nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-[8-amino-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-1-hydroxymethyl-cyclobutanol (7.282 g, 17.69 mmol) in THF-water mixture (200 mL, 3:1) was added NaIO4 (4.542 g, 21.23 mmol) and the reaction was stirred at rt overnight. The reaction mixture was diluted with DCM (500 mL) and the DCM layer was separated, washed with brine, dried over anhydrous Na2SO4 and evaporated in vacuo. The crude product was purified by chromatography on silica gel using DCM: MeOH as eluent (0%→2%) yielded the desired compound as a yellow solid. MS (ES+): m/z 406.15 [MH+]. HPLC: tR=2.23 min (OpenLynx, polar—5 min). 1H NMR (400 MHz, CDCl3) δ 3.60-3.36 (m, 2H), 3.82-3.92 (m, 3H), 5.31 (br, 2H), 7.21 (dd, J=12.8, 4.8 Hz, 2H), 7.48-7.56 (m, 3H), 7.91-7.98 (m, 3H), 8.18-8.20 (m, 2H), 8.28 (d, J=8.0 Hz, 1H), 8.42 (s, 1H).
Reaction SMILES: [F:1][C:2]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:10](Cl)(Cl)=[S:11].C(N(CC)CC)C.C(OCC)(=O)C>C1(C)C=CC=CC=1.O>[F:1][C:2]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:3]=1[N:4]=[C:10]=[S:11]
Reactant: S=C(Cl)Cl
Reactant: Nc1cccc(Cl)c1F
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: Fc1c(Cl)cccc1N=C=S
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.7 %

Procedure:
Into a solution of 2-fluoro-3-chloroaniline (1.0 g, 6.87 mmol) in 30 mL of toluene at room temperature, thiophosgene (0.8 mL, 10.3 mmol) and triethylamine (1.12 mL, 8.24 mmol) were added. The mixture was stirred at room temperature for 16 hours. The mixture was parationed between ethyl acetate and water. The combined organic layer was then concentrated to give the desired product (950 mg, 74%). 1H NMR (CDCl3) δ 7.09 (m, 2H), 7.30 (m, 1H).
Reaction SMILES: [OH-].[Na+].Cl.C([CH:7]([C:29]([O:31]C)=[O:30])[C:8]1[CH:9]=[C:10]([C:17](C)([C:23](OCC)=O)[C:18]([O:20]CC)=[O:19])[CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])(=O)C>CO>[C:29]([CH2:7][C:8]1[CH:9]=[C:10]([CH:17]([CH3:23])[C:18]([OH:20])=[O:19])[CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])([OH:31])=[O:30]
Reactant: CCOC(=O)C(C)(C(=O)OCC)c1ccc([N+](=O)[O-])c(C(C(C)=O)C(=O)OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C(=O)O)c1ccc([N+](=O)[O-])c(CC(=O)O)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 65 %

Procedure:
In methanol (1 mL) was dissolved diethyl 2-[3-[acetyl(methoxycarbonyl)methyl]-4-nitrophenyl]-2-methylmalonate (obtained in (1) above, 50.9 mg, 0.124 mmol.). The resulting solution was stirred for 15 hours at room temperature after addition of 2M aqueous sodium hydroxide solution (1.5 mL, 3 mmol.). The reaction mixture was then stirred at 60° C. for 3 hours after addition of 6M hydrochloric acid (1 mL, 3 mmol.). The mixture was cooled and extracted with ethyl acetate. The ethyl acetate portion was washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The dried organic portion was concentrated and purified by silica gel column chromatography (Wako Gel C-200, available from Wako Jyunyaku Industry Co., Ltd., hexane/ethyl acetate/acetic acid=7/3/1, v/v/v), to give 20.3 mg (yield: 65%) of the desired compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]2[O:20][C:19]([C@@:21]([OH:27])([CH3:26])[C:22]([F:25])([F:24])[F:23])=[N:18][N:17]=2)=[N:4][C:5]([O:14][CH3:15])=[C:6]([C:10]([F:13])([F:12])[F:11])[C:7]=1[CH:8]=[CH2:9].[CH3:28][C:29]1(C)[C:33](C)([CH3:34])OB(C2C=CC=CC=2)O1>>[NH2:1][C:2]1[C:3]([C:16]2[O:20][C:19]([C@@:21]([OH:27])([CH3:26])[C:22]([F:25])([F:24])[F:23])=[N:18][N:17]=2)=[N:4][C:5]([O:14][CH3:15])=[C:6]([C:10]([F:12])([F:13])[F:11])[C:7]=1[C:8]1[CH:34]=[CH:33][CH:29]=[CH:28][CH:9]=1
Reactant: CC1(C)OB(c2ccccc2)OC1(C)C
Reactant: C=Cc1c(N)c(-c2nnc([C@](C)(O)C(F)(F)F)o2)nc(OC)c1C(F)(F)F
Product: COc1nc(-c2nnc([C@](C)(O)C(F)(F)F)o2)c(N)c(-c2ccccc2)c1C(F)(F)F

Procedure:
The title compound was prepared analogously to (S)-2-(5-(3-Amino-6-methoxy-5-(trifluoromethyl)-4-vinylpyridin-2-yl)-1,3,4-oxadiazol-2-yl)-1,1,1-trifluoropropan-2-ol (Example 14.0 step 1) by replacing 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane with 4,4,5,5-tetramethyl-2-phenyl-1,3,2-dioxaborolane;
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[F:11][C:12]([F:16])([F:15])[CH2:13][NH2:14]>CS(C)=O>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:14][CH2:13][C:12]([F:16])([F:15])[F:11])([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: NCC(F)(F)F
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccccc1NCC(F)(F)F
Temperature: 120 °C

Procedure:
A mixture of 1-fluoro-2-nitro-benzene (1.55 g, 11.0 mmol), 2,2,2-trifluoro-ethylamine (3.27 g, 33.0 mmol) and DMSO (4.5 mL) was heated at 120° C. for 24 h. The resulting mixture was poured onto ice/H2O and the resultant precipitate was collected by filtration, washed with H2O and hexanes to yield (2-nitro-phenyl)-(2,2,2-trifluoro-ethyl)-amine MS 221 (M+1)+.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([F:19])[CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][C:22]=1[C:30]([F:33])([F:32])[F:31]>C1(C)C=CC=CC=1>[CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:28]([NH:27][C:24]3[CH:25]=[CH:26][C:21]([Cl:20])=[C:22]([C:30]([F:32])([F:31])[F:33])[CH:23]=3)=[O:29])=[C:14]([F:19])[CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CNC(=O)c1cc(Oc2ccc(N)c(F)c2)ccn1
Solvent: Cc1ccccc1
Product: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)c(F)c2)ccn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 47.1 %

Procedure:
To a solution of 4-(4-amino-3-fluorophenoxy)pyridine-2-carboxylic acid methylamide (177 mg, 0.68 mmol) in toluene (3 mL) was added 4-chloro-3-(trifluoromethyl)phenyl isocyanate (150 mg, 0.68 mmol). The mixture was stirred at rt for 72 h. The reaction was concentrated under reduced pressure and the residue was triturated with diethylether. The resulting solid was collected by filtration and dried in vacuo for 4 h to afford the title compound (155 mg, 0.32 mmol; 47% yield); 1H-NMR (DMSO-d6) 2.78 (d, J=4.9, 3H), 7.03-7.08 (m, 1H), 7.16 (dd, J=2.6, 5.6, 1H), 7.32 (dd, J=2.7, 11.6, 1H), 7.39 (d, J=2.5, 1H), 7.60 (s, 2H), 8.07-8.18 (m, 2H), 8.50 (d, J=5.7, 1H), 8.72 (s, 1H), 8.74-8.80 (m, 1H), 9.50 (s, 1H); MS (HPLC/ES) 483.06 m/z=(M+1).