Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[CH:3]([C@:6]1([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][N:21]=3)[CH2:16][CH2:15]2)=[O:13])[CH2:10][CH2:9][C@@H:8]([NH2:11])[CH2:7]1)([CH3:5])[CH3:4].[CH3:30][O:31][CH:32]1[C:37](=O)[CH2:36][CH2:35][O:34][CH2:33]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH:3]([C@:6]1([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=[CH:22][N:21]=3)[CH2:16][CH2:15]2)=[O:13])[CH2:10][CH2:9][C@@H:8]([NH:11][CH:37]2[CH2:36][CH2:35][O:34][CH2:33][CH:32]2[O:31][CH3:30])[CH2:7]1)([CH3:5])[CH3:4]
Reactant: COC1COCCC1=O
Reactant: CC(C)[C@]1(C(=O)N2CCN(c3nccc(C(F)(F)F)n3)CC2)CC[C@@H](N)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1COCCC1N[C@@H]1CC[C@@](C(=O)N2CCN(c3nccc(C(F)(F)F)n3)CC2)(C(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.6 %

Procedure:
To a solution of (1R,3S)-3-isopropyl-3-({4-[4-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl}carbonyl)cyclopentanamine dihydrochloride (135.0 mg, 0.2945 mmol), 3-methoxytetrahydro-4H-pyran-4-one (110 mg, 0.88 mmol) and triethylamine (0.16 mL, 1.2 mmol) in methylene chloride (8 mL) was added sodium triacetoxyborohydride (190 mg, 0.88 mmol). After being stirred at room temperature overnight, the reaction was quenched with saturated NaHCO3. The resulting solution was extracted with EtOAc three times. The combined organic layers were dried (MgSO4), concentrated. The residue was purified by flash chromatography on silica gel (EtOAc to EtOAc/Et3N=10:0.1) to give 123 mg of desired product as a mixture of two isomers. The two isomers were separated by chiral HPLC to give isomer 1 (65 mg after converting to TFA salt) and isomer 2 (45 mg after converting to TFA salt). LCMS calculated for C24H36F3N5O3: (M+1) 500; found 500.1 for both isomers.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5](Br)[CH:6]=[CH:7][CH:8]=1.[Mg].II.[O:15]=[C:16]([CH3:22])[CH2:17][CH2:18][CH2:19][C:20]#[N:21].Cl>O1CCCC1.O>[OH:15][C:16]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:11])([F:10])[F:1])[CH:4]=1)([CH3:22])[CH2:17][CH2:18][CH2:19][C:20]#[N:21]
Reactant: CC(=O)CCCC#N
Reactant: FC(F)(F)c1cccc(Br)c1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: CC(O)(CCCC#N)c1cccc(C(F)(F)F)c1
Temperature: 35 °C
Yield: 49 %

Procedure:
A mixture of 7.0 mL (0.05 mole) of 3-trifluoromethylphenyl bromide, 1.2 grams (0.05 mole) of magnesium and a crystal of iodine in about 70 mL of tetrahydrofuran was warmed to 35° C. to initiate the formation of the Grignard reagent. Upon formation of the Grignard reagent, the reaction mixture was cooled to ambient temperature and, with stirring, a solution of 5.8 mL (0.05 mole) of 5-oxohexanenitrile in 10 mL of tetrahydrofuran was added dropwise. The reaction mixture temperature increased to about 35° C., at which time the rate of addition was slowed to keep the reaction mixture temperature at about 35°-40° C. The complete addition required about 15 minutes. Upon completion of the addition, the reaction mixture was allowed to warm to ambient temperature, where it was stirred for 2 hours. After this time, the reaction mixture was poured into 200 mL of water and was acidified with aqueous 2N hydrochloric acid. The mixture was then extracted with two 150 mL portions of diethyl ether. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The oil was subjected to column chromatography on silica gel. Elution was accomplished using methylene chloride. The product-containing fractions were combined and concentrated under reduced pressure, yielding 6.3 grams of 5-hydroxy-5-(3-trifluoromethylphenyl)hexanenitrile. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:5][CH:4]=1)#[N:2].CO.C1COCC1>[C].[Pd].C(O)(=O)C>[NH2:2][CH2:1][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(C#N)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)CCc1ccc(CN)cc1
Reaction time: 3 h
Yield: 77.3 %

Procedure:
To 223 mg of tert-butyl (2E)-3-(4-cyanophenyl)acrylate were added 12 mL of methanol, 5 ml of THF, 1 ml of an acetic acid solution, and 90 mg of 10% palladium-carbon in this order, followed by stirring for 3 hours under hydrogen at 3 atm. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. To the residue were added a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate to carry out a layer separation operation. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to obtain 177 mg of tert-butyl 3-[4-(aminomethyl)phenyl]propanoate.
Reaction SMILES: CN(C)C=O.Cl.Cl[CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][N:11]([CH3:15])[CH2:10]1.C(=O)([O-])[O-].[K+].[K+].[NH2:22][C:23]1[CH:42]=[CH:41][C:26]([O:27][C:28]2[C:37]3[C:32](=[CH:33][C:34]([OH:40])=[C:35]([C:38]#[N:39])[CH:36]=3)[N:31]=[CH:30][CH:29]=2)=[CH:25][C:24]=1[F:43]>C(OCC)(=O)C.O>[NH2:22][C:23]1[CH:42]=[CH:41][C:26]([O:27][C:28]2[C:37]3[C:32](=[CH:33][C:34]([O:40][CH2:8][CH:9]4[CH2:14][CH2:13][CH2:12][N:11]([CH3:15])[CH2:10]4)=[C:35]([C:38]#[N:39])[CH:36]=3)[N:31]=[CH:30][CH:29]=2)=[CH:25][C:24]=1[F:43]
Reactant: N#Cc1cc2c(Oc3ccc(N)c(F)c3)ccnc2cc1O
Reactant: CN1CCCC(CCl)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CN1CCCC(COc2cc3nccc(Oc4ccc(N)c(F)c4)c3cc2C#N)C1
Temperature: 20 °C
Reaction time: 3 h
Yield: 10.9 %

Procedure:
After adding dimethylformamide (4 ml), 3-chloromethyl-1-methylpiperidine hydrochloride (621 mg) and potassium carbonate (840 mg) to 4-(4-amino-3-fluorophenoxy)-6-cyano-7-hydroxyquinoline (400 mg), the mixture was stirred at 20° C. for 3 hours. Water was added to the reaction solution, extraction was performed with ethyl acetate, the organic layer was washed with water and saturated saline in that order and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by NH silica gel column chromatography (ethyl acetate) to obtain the title compound (60 mg).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:20]([O-:22])=[O:21])[CH:8]=2)[N:3]=1.[CH2:23]([NH2:26])[CH:24]=[CH2:25]>O>[ClH:1].[CH2:23]([NH:26][C:2]1[N:11]=[C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:20]([O-:22])=[O:21])[CH:8]=2)[N:3]=1)[CH:24]=[CH2:25]
Reactant: C=CCN
Reactant: CCCCCCCNc1nc(Cl)nc2ccc([N+](=O)[O-])cc12
Solvent: O
Product: C=CCNc1nc(NCCCCCCC)c2cc([N+](=O)[O-])ccc2n1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 150 mg (0.46 mmol) of 2-chloro-4-heptylamino-6-nitroquinazoline was added 1.14 g (20.00 mmol) of allylamine, followed by stirring at room temperature overnight. To the reaction solution was water added, followed by extraction with ethyl acetate, washing with brine and drying over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 140 mg (yield: 88.6%) of a free compound base of the title compound.
Reaction SMILES: CN(C)[C:3]1[S:4][C:5]2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:6]=2[C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:12][CH:11]=1)=[O:9].[CH:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][C:33]=1[Mg]Br.CO>C1COCC1.C(Cl)Cl>[CH:40]1[C:41]2[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:37]=[CH:38][C:39]=1[C:3]1[S:4][C:5]2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:6]=2[C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][N:19]2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]2)=[CH:12][CH:11]=1)=[O:9]
Reactant: Br[Mg]c1ccc2ccccc2c1
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(N(C)C)sc2c1
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3ccc4ccccc4c3)sc2c1
Yield: 75.1 %

Procedure:
By the method described in Example 1, [2-dimethylamino-6-methoxybenzothien-3-yl][4-[2-(1-piperdinyl)ethoxy]phenyl]methanone (1.58 g, 3.6 mmol) in THF (12 mL) was reacted with a 0.65M THF solution of 2-naphthylmagnesium bromide (15 mL, 9.8 mmol) to provide, after chromatography (silica gel, 5% methanol in methylene chloride) 1.41 g (75%) of the title compound as a green/yellow foam: 1H NMR (300 MHz, CDCl3) δ1.43 (m, 2H), 1.59 (m, 4H), 2.45 (m, 4H), 2.70 (t, J=6.0 Hz, 2H), 3.91 (s, 3H), 4.02 (t, J=6.0 Hz, 2H), 6.72 (d, J=8.7 Hz, 2H), 7.01 (dd, J=2.1 Hz, 8.8 Hz, 1H), 7.38 (d, J=2.3 Hz, 1H), 7.44-7.47 (m, 2H), 7.53 (d, J=8.4 Hz, 1H), 7.60 (d, J=9.3 Hz, 1H), 7.67-7.79 (m, 4H), 7.82 (d, J=8.7 Hz, 2H), 7.94 (d, J=1.6 Hz, 1H); MS (FD) m/e 521 (M+); Anal. calc'd. for C33H31NO3S: C, 75.98; H, 5.99; N, 2.68. Found: C, 76.27; H, 6.10; N, 2.74.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]1[O:8][CH2:7][CH2:6][O:5]1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C(=O)C.[F:21][C:22]1[N:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1>C(OCC)(=O)C.O>[O:5]1[CH2:6][CH2:7][O:8][CH:4]1[CH2:3][CH2:2][O:28][C:25]1[CH:24]=[CH:23][C:22]([F:21])=[N:27][CH:26]=1
Reactant: Oc1ccc(F)nc1
Reactant: BrCCC1OCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: Fc1ccc(OCCC2OCCO2)cn1
Temperature: 100 °C
Reaction time: 12 h
Yield: 85.7 %

Procedure:
2-(2-Bromoethyl)-1,3-dioxolane (2.49 ml, 19.9 mmol) and cesium carbonate (15.1 g, 46.4 mmol) were added to an N,N-dimethylacetamide solution (25 ml) of 6-fluoropyridin-3-ol (1.5 g, 13.3 mmol), and stirred under a nitrogen atmosphere at 100° C. for 12 hours. The reaction solution was cooled with ice, water and ethyl acetate were added, and the organic layer was washed with water and saturated saline water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Biotage, hexane:ethyl acetate=5:1 to 1:1) to obtain 5-[2-(1,3-dioxolan-2-yl)ethoxy]-2-fluoropyridine (2.43 g, yield: 86%) as a colorless oil.
Reaction SMILES: [NH3:1].Cl[C:3]1[C:8]([CH3:9])=[N:7][N:6]2[C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[N:11][N:12]=[C:5]2[N:4]=1>CO>[NH2:1][C:3]1[C:8]([CH3:9])=[N:7][N:6]2[C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[N:11][N:12]=[C:5]2[N:4]=1
Reactant: Cc1nn2c(Cc3ccc(O)cc3)nnc2nc1Cl
Reactant: N
Solvent: CO
Product: Cc1nn2c(Cc3ccc(O)cc3)nnc2nc1N
Temperature: 70 °C

Procedure:
NH3 gas was bubbled through a solution of 4-(7-chloro-6-methyl-[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-ylmethyl)-phenol (70 mg, 0.25 mmol) in methanol (5 mL) at 0° C. The saturated solution was stirred at 70° C. until the starting material disappeared. After evaporation of solvent, the residue was purified on a silica gel column eluting with 10% methanol in dichloromethane to provide 4-(7-amino-6-methyl-[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-ylmethyl)-phenol (35 mg). 1H-NMR (400 MHz, DMSO-d6) δ 9.22 (s, 1H), 7.05 (d, 2H), 6.65 (d, 2H), 4.12 (s, 2H), 2.35 (s, 3H). MS (m/z) 257 [M+1].
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]#[N:5].C(N(C(C)C)CC)(C)C.[CH:15]([N:18]([CH:22]([CH3:24])[CH3:23])[P:19](Cl)[Cl:20])([CH3:17])[CH3:16]>C1COCC1>[CH:15]([N:18]([CH:22]([CH3:24])[CH3:23])[P:19]([Cl:20])[O:1][CH2:2][CH2:3][C:4]#[N:5])([CH3:17])[CH3:16]
Reactant: CC(C)N(C(C)C)P(Cl)Cl
Reactant: N#CCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)N(C(C)C)P(Cl)OCCC#N
Reaction time: 0.42 h

Procedure:
FIG. 15 illustrates the synthesis of bifunctional diphosphitylating, triphosphitylating, and tetraphosphitylating reagents (66, 69, 72). For the preparation of 66, phosphorus trichloride (21, 875 μL, 10 mmol) and diisopropylethylamine (1,747 μL, 10 mmol) were added to anhydrous THF. Diisopropylamine (1,400 μL, 10 mmol) was added dropwise in 10 min to the solution mixture and the mixture was stirred for 45 min at 0° C. to yield diisopropylphosphoramidodichloridite (29). Then 3-hydroxypropionitrile (22, 683 μL, 10 mmol) and diisopropylethylamine (1,747 μL, 10 mmol) were added dropwise to the solution of 29 in anhydrous THF during 10 min period. The stirring was continued for 25 min at 0° C. to afford 2-cyanoethyl diisopropylphosphoramidochloridite (24). Water (180 μL, 10 mmol) and diisopropylethylamine (1,747 μL, 10 mmol) were added dropwise in 10 min period to the solution. The mixture was stirred for 10 min at 0° C. to yield 2-cyanoethyl diisopropylamine hydroxyphosphite (25). Then 29 (1 eq, 10 mmol) that was prepared at the same time in a separate reaction vessel, was added dropwise in 10 min period to the solution containing 25. The mixture was stirred for 25 min at 0° C. to yield diisopropylphosphoramidochloridite-O-2-cyanoethyl diisopropylphosphoramidite 66 (bifunctional diphosphitylating reagent). The reaction mixture containing diphosphitylating reagent 66 was immediately used in coupling reactions with polymer-bound p-acetoxybenzyl alcohol 78. Further stability studies on 66 using mass spectrometry methods showed that the compound remained stable after 2 months storage at −20° C.
Reaction SMILES: [C:1](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[N:22]=[CH:23][C:24]([C:27]([O:29][CH3:30])=[O:28])=[N:25][CH:26]=2)[CH2:17][CH2:16]1.C=O.C(O)(=O)C>CO>[CH3:1][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[N:22]=[CH:23][C:24]([C:27]([O:29][CH3:30])=[O:28])=[N:25][CH:26]=2)[CH2:17][CH2:16]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COC(=O)c1cnc(C2CCNCC2)cn1
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1cnc(C2CCN(C)CC2)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 101.6 %

Procedure:
Sodium triacetoxyborohydride (530 mg, 2.50 mmol) was added to methyl 5-(piperidin-4-yl)pyrazine-2-carboxylate (221 mg, 1.00 mmol), formaldehyde (37% aqueous solution, 1.50 ml, 20.00 mmol) and acetic acid (0.11 ml, 2.00 mmol) in methanol (5.00 ml) at 25° C. The resulting solution was stirred at ambient temperature for 18 h. The reaction mixture was quenched with water (5 mL) and the crude product was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH and evaporated to dryness to afford methyl 5-(1-methylpiperidin-4-yl)pyrazine-2-carboxylate (239 mg, 100%) as a yellow waxy solid. This was used directly with no further purification.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][C:4]([N+:10]([O-:12])=[O:11])=[N:3]1.S(Cl)([Cl:15])=O.Cl.Cl.[CH3:19][N:20]1[CH:24]=[C:23]([NH:25][C:26]([C:28]2[N:29]([CH3:34])[CH:30]=[C:31]([NH2:33])[CH:32]=2)=[O:27])[CH:22]=[C:21]1[C:35]([NH:37][CH2:38][CH2:39][C:40]([NH2:42])=[NH:41])=[O:36].C(=O)(O)[O-].[Na+].Cl>C1C=CC=CC=1.O1CCOCC1.O>[ClH:15].[CH3:19][N:20]1[CH:24]=[C:23]([NH:25][C:26]([C:28]2[N:29]([CH3:34])[CH:30]=[C:31]([NH:33][C:7]([C:6]3[N:2]([CH3:1])[N:3]=[C:4]([N+:10]([O-:12])=[O:11])[CH:5]=3)=[O:9])[CH:32]=2)=[O:27])[CH:22]=[C:21]1[C:35]([NH:37][CH2:38][CH2:39][C:40]([NH2:42])=[NH:41])=[O:36]
Reactant: O=S(Cl)Cl
Reactant: Cn1nc([N+](=O)[O-])cc1C(=O)O
Reactant: Cn1cc(NC(=O)c2cc(N)cn2C)cc1C(=O)NCCC(=N)N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(NC(=O)c2cc(NC(=O)c3cc([N+](=O)[O-])nn3C)cn2C)cc1C(=O)NCCC(=N)N
Reaction time: 1 h

Procedure:
To a solution of 0.55 g of 1-methyl-3-nitropyrazole-5-carboxylic acid (prepared as in reported in Example 8) in 10 ml of benzene were added 2 ml of thionyl chloride. The mixture was refluxed for one hour and the solvent evaporated in vacuo to yield a solid residue which was dissolved in 10 ml of dioxane and added in small portions to a solution of 1 g of β-[1-methyl-4-[1-methyl-4-aminopyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine, dihydrochloride (prepared as reported in J. Med. Chem. 32,774-778,1989) and 0.2 g of sodium bicarbonate in 10 ml of water. The mixture was stirred for one hour and then brought to pH 4-5 with 10% hydrochloric acid. The Solvent was evaporated in vacuo and the solid residue chromatographed on silica gel eluting whit a mixture methylene chloride-methanol (80:20 by volume), yielding 0.7 g of β-[1-methyl-4-[1-methyl-4-[1-methyl-3-nitropyrazole-5-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine, hydrochloride.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]3[O:13][C:14]([CH3:17])=[CH:15][CH:16]=3)=[N:9][C:8]=2[CH:18]=1)([O-])=O.CCO.[C:22](Cl)(Cl)=[S:23].C(=O)([O-])[O-].[Ca+2]>C(Cl)(Cl)Cl.[Pd].O>[CH3:17][C:14]1[O:13][C:12]([C:10]2[O:11][C:7]3[CH:6]=[CH:5][C:4]([N:1]=[C:22]=[S:23])=[CH:18][C:8]=3[N:9]=2)=[CH:16][CH:15]=1
Reactant: Cc1ccc(-c2nc3cc([N+](=O)[O-])ccc3o2)o1
Reactant: S=C(Cl)Cl
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: O
Product: Cc1ccc(-c2nc3cc(N=C=S)ccc3o2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 420.2 %

Procedure:
3.32 g (0.0013 mole) of 5-nitro-2-(5-methyl-2-furyl)-benzoxazole and 0.65 g of 10% Pd are suspended in 100 ml of abs. EtOH and hydrogenated at 65 psi over a period of 4 hr. The catalyst is removed and the EtOH evaporated under vacuum yielding a dark brown residue. The residue is dissolved in 150 ml of CHCl3 and added dropwise to the following cold suspension: 1.5 g (0.013 mole) of thiophosgene, 1.3 g (0.013 mole) of calcium carbonate, 150 ml of CHCl3 and 30 ml of water. After the addition is complete the mixture is warmed to room temperature and allowed to stir overnight. The CHCl3 layer is then separated and evaporated to dryness yielding 1.4 g of a light brown solid (43%) mp 110°-121°. This material is then extracted with petroleum ether and the extracts then evaporated yielding a tan solid. This material is recrystallized from petroleum ether yielding 0.540 g of white powder, mp 130°-132°(16%).
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][C:16]([F:19])([F:18])[F:17])[C:5]=2[CH2:20]O)[CH2:3][CH2:2]1.P(Br)(Br)[Br:23]>C(Cl)Cl>[Br:23][CH2:20][C:5]1[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][C:16]([F:19])([F:18])[F:17])=[N:7][O:8][C:4]=1[CH:1]1[CH2:3][CH2:2]1
Reactant: BrP(Br)Br
Reactant: OCc1c(-c2ccccc2OC(F)(F)F)noc1C1CC1
Solvent: ClCCl
Product: FC(F)(F)Oc1ccccc1-c1noc(C2CC2)c1CBr
Temperature: 0 °C
Reaction time: 3 h
Yield: 79.2 %

Procedure:
To a solution of (5-cyclopropyl-3-(2-trifluormethoxy-phenyl)-isoxazol-4-yl)-methanol (2.19 g, 7.32 mmol) in anhydrous methylene chloride (50 mL) at 0° C. is added PBr3 (0.83 mL, 8.7 mmol) and the mixture is stirred for 3 hours. The mixture is then poured into 100 mL of ice water and extracted with DCM (2×). The combined DCM layers are washed with brine, dried (MgSO4) and concentrated under reduced pressure to provide crude residue. The residue is purified via flash chromatography (120 g silica) eluting with a gradient of 0 to 60% ethyl acetate in heptane to provide the title compound (2.1 g, 79%) as an oil.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[O:11][CH3:12])=O.[S:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[CH2:22][C:23]([CH3:25])=O.[NH2:26]/[C:27](/[CH3:31])=[CH:28]\[C:29]#[N:30]>C(O)(C)C>[S:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[C:22]1[CH:1]([C:3]2[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=2[O:11][CH3:12])[C:28]([C:29]#[N:30])=[C:27]([CH3:31])[NH:26][C:23]=1[CH3:25]
Reactant: COc1cc(C#N)ccc1C=O
Reactant: CC(=O)Cc1nc2ccccc2s1
Reactant: C/C(N)=C/C#N
Solvent: CC(C)O
Product: COc1cc(C#N)ccc1C1C(C#N)=C(C)NC(C)=C1c1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
150 mg (0.931 mmol) of the compound from example 3A, 178 mg (0.931 mmol) of 1-(1,3-benzo-thiazol-2-yl)acetone [Costa et al., J. Heterocycl. Chem. 28, 1541-1544 (1991)] and 76 mg (0.931 mmol) of 3-aminocrotononitrile are dissolved in 6 ml of isopropanol and stirred at the reflux temperature overnight. After cooling to room temperature, the volatile components are removed in a rotary evaporator. The crude product obtained in this way is recrystallized from acetonitrile. 40 mg (11% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([O:16][CH2:17][CH:18]([OH:21])[CH2:19][OH:20])[CH:13]=[C:12]([C:22](O)=[O:23])[CH:11]=1)#[N:2].Cl.Cl.[CH3:27][C:28]1[N:33]=[CH:32][C:31]([C@H:34]([NH2:36])[CH3:35])=[CH:30][CH:29]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([O:16][CH2:17][CH:18]([OH:21])[CH2:19][OH:20])[CH:13]=[C:12]([C:22]([NH:36][C@@H:34]([C:31]2[CH:32]=[N:33][C:28]([CH3:27])=[CH:29][CH:30]=2)[CH3:35])=[O:23])[CH:11]=1)#[N:2]
Reactant: Cc1ccc([C@@H](C)N)cn1
Reactant: Cc1ccc(-c2cc(OCC(O)CO)cc(C(=O)O)c2)c(C#N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(OCC(O)CO)cc(C(=O)N[C@H](C)c3ccc(C)nc3)c2)c(C#N)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2′-cyano-5-(2,3-dihydroxypropoxy)-4′-methylbiphenyl-3-carboxylic acid (30 mg, 0.092 mmol) in N,N-dimethylformamide (1 mL) were added (R)-1-(6-methylpyridin-3-yl)ethanamine dihydrochloride (60 mg, 0.29 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (100 mg, 0.26 mmol), and N,N-diisopropylethylamine (400 μL, 2.3 mmol). The reaction mixture was stirred for 16 hours at 25° C., and then purified by preparative HPLC to afford the final product as a light color solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][N:9]=[C:10]([C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])[NH2:11])=[CH:4][CH:3]=1.C(Cl)(Cl)Cl.[S:24](Cl)(Cl)=[O:25]>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[N:9]=[C:10]([C:12]3[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[NH:11][S:24]2=[O:25])=[CH:6][CH:7]=1
Reactant: NC(=NNc1ccc(Br)cc1)c1c(F)cccc1Cl
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=S1NC(c2c(F)cccc2Cl)=NN1c1ccc(Br)cc1

Procedure:
The title compound was prepared according to the procedure described in step-4 of Intermediate-1 using N′-(4-bromophenyl)-2-chloro-6-fluorobenzenecarbohydrazonamide (step-3 of Intermediate-1, 0.100 g, 0.292 mmol), CHCl3 (10 mL), pyridine (2.0 mL) and thionyl chloride (1.0 mL). The obtained product was purified with column chromatography on silica gel eluting with 0.5% MeOH:DCM to afford 0.050 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 7.45 (t, J=6.9 Hz, 3H), 7.51-7.68 (m, 4H), 12.05 (br s, 1H); MS (m/z): 388.02 (M)−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH2:10][CH2:11][S:12][CH2:13][CH:14]=1.N1C=CC=CC=1.Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([NH:8][C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH:5]=[CH:4][C:3]=1[C:9]1[CH2:14][CH2:13][S:12][CH2:11][CH:10]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccc(C2=CCSCC2)c(F)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc(C2=CCSCC2)c(F)c1)OCc1ccccc1
Temperature: 25 °C

Procedure:
4-(2-Fluoro-4-aminophenyl)-3,6-dihydro-2H-thiopyran (9.8 g, 46.8 mM) was dissolved in dry dichloromethane (196 ml), pyridine (6.23 g, 79.1 mM) added, and the mixture stirred under nitrogen at −20°. A solution of benzyl chloroformate (9.54 g, 53.9 mM) dissolved in dry dichloromethane (25 ml) was added dropwise, and the mixture left to warm to ambient temperature over 18 hours. The mixture was washed with 1M hydrochloric acid (200 ml), then brine (100 ml), dried (magnesium sulfate), filtered and evaporated to a small volume. The addition of isohexane (300 ml) precipitated the desired product (15.5 g).