Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-:1].[Ca+2:2].[OH-].[C:4]([OH:12])(=[O:11])[CH:5]([CH2:7][C:8]([OH:10])=[O:9])[OH:6]>O>[C:4]([O:12][OH:1])(=[O:11])[CH:5]([CH2:7][C:8]([O-:10])=[O:9])[OH:6].[Ca+2:2].[Ca+2:2].[OH:1][O:11][C:4](=[O:12])[CH:5]([CH2:7][C:8]([O-:10])=[O:9])[OH:6].[OH:1][O:11][C:4](=[O:12])[CH:5]([CH2:7][C:8]([O-:10])=[O:9])[OH:6].[OH:1][O:11][C:4](=[O:12])[CH:5]([CH2:7][C:8]([O-:10])=[O:9])[OH:6]
Reactant: O=C(O)CC(O)C(=O)O
Reactant: [OH-]
Agent: [Ca+2]
Solvent: O
Product: O=C([O-])CC(O)C(=O)OO

Procedure:
A dicalciumhydroxy malate granular product is prepared by mixing two molar equivalents of particulate calcium hydroxide with one molar equivalent of particulate malic acid (totaling 45 kg for the entire composition) in a ribbon blender for 15 minutes at normal speeds. To ensure that the product does not over react when small amounts of water are added to the batch a water jacket is used. Next, about 1 L of water is slowly sprayed into the particulate mixture product. After about 10 minutes of reaction time (the product becomes spongy and rises, and then drops back to a more granular state), an additional 1 L of water is added. This is repeated several times until no further reaction appeared to be occurring upon addition of water. The end result is a granular product. Once a fully reacted granular product is formed, no additional water is added. The resulting composition is then dried in a cool room and ground to a predetermined particle size.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[O:4][N:3]=1.[C:14]([O:18][C:19]([NH:21][CH2:22][CH2:23]O)=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19]([NH:21][CH2:22][CH2:23][O:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[O:4][N:3]=1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: Oc1ccc(-c2cc(O)no2)cc1
Reactant: CC(C)(C)OC(=O)NCCO
Product: CC(C)(C)OC(=O)NCCOc1cc(-c2ccc(O)cc2)on1
Yield: 66.4 %

Procedure:
3-Hydroxy-5-(4-hydroxyphenyl)isoxazole (0.1 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.1 g) were subjected to reaction and post-treatment in a similar manner to that described in Example 9(a) to obtain the title compound (0.12 g, 67%) as a colorless powder.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:34][CH2:33][CH2:32][C@H:12]1[C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[CH:20]([OH:31])[CH2:21][S@@:22]([C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=1)=[O:23])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(C)=O.C1CCC(N=C=NC2CCCCC2)CC1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:34][CH2:33][CH2:32][C@H:12]1[C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20](=[O:31])[CH2:21][S@@:22]([C:24]1[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=1)=[O:23])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc([S@@](=O)CC(O)[C@@H]2CCCN2C(=O)[C@@H]2CCCN2C(=O)OCc2ccccc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CS(C)=O
Product: Cc1ccc([S@@](=O)CC(=O)[C@@H]2CCCN2C(=O)[C@@H]2CCCN2C(=O)OCc2ccccc2)cc1
Yield: 45.6 %

Procedure:
(2S)-1-(N-Benzyloxycarbonyl-L-prolyl)-2-{1-hydroxy-2-[(S)-p-tolylsulfinyl]ethyl}pyrrolidine (357 mg) was subjected to DMSO-DCC oxidation as in Example 1-D), and the reaction product was purified by medium pressure liquid chromatography (silica gel, eluate; chloroform:methanol=99:1) to give 162 mg of the title compound (See Table 4).
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([N+:19]([O-:21])=[O:20])[CH:14]=3)[C:9](=[O:22])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.COCCOC.N>O>[NH2:1][C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([N+:19]([O-:21])=[O:20])[CH:14]=3)[C:9](=[O:22])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=C1c2ccc([N+](=O)[O-])cc2C(=O)c2c1cccc2[N+](=O)[O-]
Agent: N
Solvent: COCCOC
Solvent: O
Product: Nc1cccc2c1C(=O)c1cc([N+](=O)[O-])ccc1C2=O
Yield: 93 %

Procedure:
A mixture of 301 g of 1,7-dinitroanthraquinone (99%) and 1 liter of ethyleneglycol dimethylether was reacted with 510 g of ammonia in an autoclave over a period of 4 hours at a temperature of 130° C. (molar ratio 30 : 1; pressure 60 atms). After cooling, the reaction mixture was poured into 5 litres of water and the deposit which precipitated was filtered off under suction, washed with water and dried. Yield: 264 g of a 93% 1-amino-7-nitroanthraquinone (91% of the theoretical yield).
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.[OH-].[Na+].Cl>C1COCC1>[CH:22]1([C:15]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:13]([S:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:27])=[O:2])=[CH:5][CH:6]=3)(=[O:12])=[O:11])[CH:14]=2)[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: COC(=O)c1ccc(S(=O)(=O)n2cc(C3CCCC3)c3ccccc32)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(S(=O)(=O)n2cc(C3CCCC3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 12 L RBF, charge 4-(3-cyclopentyl-indole-1-sulfonyl)-benzoic acid methyl ester (465 g 1.213 mol) and THF (4.7 L). Add 5N NaOH (485 ml) dropwise at ambient temperature. Stir the solution at room temperature overnight. Bring the pH of the reaction to 1 with c.HCl. Separate the layers and extract the aqueous layer with ethyl acetate (4 L). Dry the combined organic layers over sodium sulfate, filter and rinse with ethyl acetate. Concentrate the organics under vacuum to give an off-white solid (401 g, yield=89.5%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.[O:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[O:15][CH2:16][CH2:17][N:18]1[CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=[N:19]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:8][C:5]1[CH:4]=[CH:3][C:2]([C:21]2[CH:20]=[N:19][N:18]([CH2:17][CH2:16][O:15][CH:10]3[CH2:11][CH2:12][CH2:13][CH2:14][O:9]3)[CH:22]=2)=[CH:7][N:6]=1
Reactant: CC1(C)OB(c2cnn(CCOC3CCCCO3)c2)OC1(C)C
Reactant: Fc1ccc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Fc1ccc(-c2cnn(CCOC3CCCCO3)c2)cn1
Temperature: 85 °C
Reaction time: 6 h
Yield: 70.7 %

Procedure:
A mixture of 5-bromo-2-fluoropyridine (176 mg, 1.00 mmol), 1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (322 mg, 1.00 mmol), Pd(PPh3)4 (115 mg, 0.100 mmol) and Na2CO3 (212 mg, 2.00 mmol) in 1,4-dioxane (5 ml) was bubbled with N2 for 10 min and then stirred at 85° C. for 6 h. After being cooled to rt, the reaction mixture was filtered through celite and the filtrate was diluted with EA. The organic phase was washed with water, brine and dried over anhydrous MgSO4. Filtered and concentrated to afford the title compound (0.206 g, yield 63.6%), which was used in next step without further purification. 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.48 (s, 1H), 8.27 (s, 1H), 8.17 (dd, 1H), 7.98 (s, 1H), 7.19 (d, 1H), 4.53 (s, 1H), 4.30 (t, 2H), 3.95 (m, 1H), 3.75 (m, 1H), 3.53 (m, 1H), 3.35 (t, 1H), 1.65 (m, 1H), 1.57 (m, 1H), 1.40 (m, 4H). LCMS (method B): [M+H]+=292, tR=2.16 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][S:9]([C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15](O)=[O:16])(=[O:11])=[O:10].B.C1COCC1.Cl.O>C1COCC1>[OH:16][CH2:15][C:14]1[CH:13]=[C:12]([S:9]([NH:8][CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)(=[O:11])=[O:10])[CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)c1cccc(S(=O)(=O)NCc2ccccn2)c1
Agent: B
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(NCc1ccccn1)c1cccc(CO)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To solution of 3-[(Pyridin-2-ylmethyl)-sulfamoyl]-benzoic acid (840 mg, 2.87 mmol) in THF (5 ml) was added BH3.THF (1M, 14.4 ml, 14.4 mmol) dropwise. After the addition, the reaction mixture was allowed to stir for 18 h at room temperature, and 5 N HCl (8 ml) was carefully added, resulting in the evolution of H2. Upon heating to 70° C. for 2 h, a clear solution was obtained. Water (30 ml) was added, and the resulting solution was extracted with diethyl ether (3×20 ml). The aqueous phase was cooled to 0° C., neutralized with solid NaOH, and then solid NaHCO3 and extracted with CHCl3 (6×20 ml). The combined organic extracts were dried over MgSO4, and concentrated under reduced pressure. The crude material was used without further purification in the next reaction.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:32])[C:24]2[C:29]([Cl:30])=[CH:28][N:27]=[CH:26][C:25]=2[Cl:31])=[CH:18][CH:17]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=O)(C)(C)C.Cl>CCOC(C)=O.O1CCOCC1>[ClH:30].[NH2:8][C@@H:9]([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:23](=[O:32])[C:24]2[C:29]([Cl:30])=[CH:28][N:27]=[CH:26][C:25]=2[Cl:31])=[CH:20][CH:21]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cncc2Cl)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H](N)Cc1ccc(NC(=O)c2c(Cl)cncc2Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 194 %

Procedure:
A solution of the compound of Intermediate 2 (70 g, 0.146 mol) in EtOAc (500 ml) and 1,4-dioxan (50 ml) was treated with a solution of HCl in EtOAc (500 ml, 3M), and stirred at room temperature for 4 h. The reaction was concentrated in vacuo to give a yellow solid which was triturated with Et2O then recrystallised (EtOAc/hexane) to give the title compound (59.3 g, 92%). δH (DMSO d6), 11.10 (1H, s), 8.70 (2H, s), 7.55 (2H, d, J 8.4 Hz), 7.25 (2H, d, J 8.4 Hz), 4.10 (3H, m), 3.10 (2H, m), 1.10 (3H, m); m/z (ES+, 70V) 382 (MH+).
Reaction SMILES: [C:1]1([O:11][CH2:12][C:13]([O:15]CC)=O)[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:18][CH2:19][CH:20]([OH:32])[CH2:21][N:22]1[CH2:31][CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23]1>CCO>[CH2:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:30][CH2:31][N:22]1[CH2:21][CH:20]([OH:32])[CH2:19][NH:18][C:13](=[O:15])[CH2:12][O:11][C:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)COc1cccc2c1CCCC2
Reactant: NCC(O)CN1CCc2ccccc2C1
Solvent: CCO
Product: O=C(COc1cccc2c1CCCC2)NCC(O)CN1CCc2ccccc2C1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 5.5 %

Procedure:
To a stirred mixture of ethyl 2-((5,6,7,8-tetrahydronaphthalen-1-yl)oxy)acetate (150 mg, 0.641 mmol) in EtOH (2 mL) was added 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (132 mg, 0.641 mmol). The mixture was stirred at 120° C. for 0.5 hours under microwave heating. After evaporation of the solvent, the residue was purified by prep-HPLC to afford the desired target product N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2-((5,6,7,8-tetrahydronaphthalen-1-yl)oxy)acetamide (14 mg, Yield 6%). 1H NMR (400 MHz, MeOD) δ=7.13-7.00 (m, 5H), 6.74 (d, J=7.8 Hz, 1H), 6.65 (d, J=8.3 Hz, 1H), 4.53 (s, 2H), 4.02 (quin, J=5.9 Hz, 1H), 3.72-3.63 (m, 2H), 3.53-3.45 (m, 1H), 3.39 (d, J=6.3 Hz, 1H), 2.96-2.86 (m, 2H), 2.83-2.69 (m, 6H), 2.56 (d, J=6.3 Hz, 2H), 1.84-1.74 (m, 4H). LCMS (m/z): 395.1 (M+1).
Reaction SMILES: [N:1]([C:4]1[CH:19]=[CH:18][C:7]([S:8]/[C:9](=[C:13](\O)/[C:14]([OH:16])=[O:15])/[C:10](O)=[O:11])=[CH:6][CH:5]=1)=[C:2]=[S:3].FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)(Cl)Cl>[N:1]([C:4]1[CH:19]=[CH:18][C:7]([S:8][C:9]2[C:10]([O:15][C:14](=[O:16])[CH:13]=2)=[O:11])=[CH:6][CH:5]=1)=[C:2]=[S:3]
Reactant: O=C(O)/C(O)=C(/Sc1ccc(N=C=S)cc1)C(=O)O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: O=C1C=C(Sc2ccc(N=C=S)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 6.5 h

Procedure:
The 2-[4'-(Isothio-cyanato)thiophenoxy]-3-hydroxymaleic acid (4.510 g, 15.07 mmol) was slurried in 140 mL of CHCl3 under nitrogen, treated with trifluoroacetic anhydride (5.30 mL, 7.88 g, 37.5 mmol), and heated to reflux. After 6.5 hours, the homogeneous reaction mixture was allowed to cool to room temperature, concentrated, taken up in hot CCl4 (80 mL), filtered hot, concentrated to one third volume, and diluted with 10 mL of hexane. Crystallization occurred upon standing at room temperature over 30 minutes. After storing at 0° C. an additional 2 hours, the light orange crystals of 2-[4'-(isothiocyanato)thiophenoxy] maleic anhydride (the titled compound) were collected by filtration, washed twice with 30 mL portions of hexane and dried overnight under vacuum (0.05 mm Hg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=O)[CH3:11])=[CH:5][CH:4]=1.[C:13]1([CH:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:20][CH2:21][NH2:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>[Pt]=O.C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([NH:22][CH2:21][CH2:20][CH:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH3:11])=[CH:5][CH:4]=1
Reactant: NCCC(c1ccccc1)c1ccccc1
Reactant: COc1ccc(CC(C)=O)cc1
Agent: O=[Pt]
Solvent: CCO
Product: COc1ccc(CC(C)NCCC(c2ccccc2)c2ccccc2)cc1

Procedure:
The starting material is prepared as follows: the mixture of 246.3 g of p-methoxyphenylacetone, 317 g of 3,3-diphenylpropylamine and 1,000 ml of anhydrous ethanol is hydrogenated at 20° and 3.4 atm. over 5 g of platinum oxide. After the theoretical amount of hydrogen has been absorbed (ca 4,000 ml), the mixture is filtered and the filtrate evaporated at 60°, to yield the 1-(4-methoxyphenyl)-2-(3,3-diphenylpropylamino)-propane as an oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.C([Mg]Br)C.[CH2:18]=[O:19].Cl>C1COCC1.CCN(CC)CC.C(OCC)C>[OH:13][C:9]1[CH:8]=[C:7]([N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)[CH:12]=[CH:11][C:10]=1[CH:18]=[O:19]
Reactant: Oc1cccc(N2CCOCC2)c1
Reactant: C=O
Agent: CC[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=Cc1ccc(N2CCOCC2)cc1O
Temperature: 30 °C
Reaction time: 1.5 h

Procedure:
After slowly adding a solution of 3-morpholinophenol (5.0 g) in THF (100 ml) to a 3 M diethyl ether solution (10 ml) of ethylmagnesium bromide, the mixture was stirred at 30° C. for 1.5 hours. Paraformaldehyde (3.0 g) and Et3N (3.0 g) were added to the reaction solution and the mixture was stirred at 80° C. for 4 hours. After cooling, a 6 N hydrochloric acid aqueous solution (20 ml) was added, the mixture was stirred for an hour, and then the organic layer and aqueous layer were separated and the aqueous layer was rendered weakly alkaline prior to extraction with AcOEt. The organic layers were combined and dried with MgSO4, and then filtered and concentrated. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=3/1) to obtain 2-hydroxy-4-morpholinobenzaldehyde.
Reaction SMILES: [C:1]([C:9]1[C:13]([CH3:14])=[C:12]([CH3:15])[S:11][C:10]=1[N:16]1[C:20]([CH2:21][Cl:22])=[N:19][C:18]([C:23]([O:25]CC)=[O:24])=[N:17]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[OH-].[Na+].Cl>O>[C:1]([C:9]1[C:13]([CH3:14])=[C:12]([CH3:15])[S:11][C:10]=1[N:16]1[C:20]([CH2:21][Cl:22])=[N:19][C:18]([C:23]([OH:25])=[O:24])=[N:17]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nc(CCl)n(-c2sc(C)c(C)c2C(=O)c2ccccc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1sc(-n2nc(C(=O)O)nc2CCl)c(C(=O)c2ccccc2)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 0.3 g. of ethyl 1-(3-benzoyl-4,5-dimethyl-2-thienyl)-5-chloromethyl-1H-1,2,4-triazole-3-carboxylate in 5 ml. of methanol is added 1 ml. of 2N-sodium hydroxide. After the mixture is stirred for 1 hour at room temperature, the resulting solution is neutralized with 2N-hydrochloric acid, then diluted with water and extracted with chloroform. After the chloroform layer is washed with water and dried over sodium sulfate, the solvent is evaporated. Recrystallization of the residue from methanol yields 1-(3-benzoyl-4,5-dimethyl-2-thienyl)-5-chloromethyl-1H-1,2,4-triazole-3-carboxylic acid as crystals melting at 162° to 163° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:34][C:35]([C:37]2[C:42](=[O:43])[N:41]([C:44]3[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=3)[CH:40]=[CH:39][N:38]=2)=[O:36])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[N:15]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[N:16]=[C:17]([CH2:18][CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[C:10]=12.[CH:51](=O)[CH3:52].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1>[CH3:33][O:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][N:15]2[C:11]3=[N:12][CH:13]=[CH:14][C:9]([O:8][C:7]4[CH:6]=[CH:5][C:4]([NH:34][C:35]([C:37]5[C:42](=[O:43])[N:41]([C:44]6[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=6)[CH:40]=[CH:39][N:38]=5)=[O:36])=[CH:3][C:2]=4[F:1])=[C:10]3[C:17]([CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([CH2:51][CH3:52])[CH2:21][CH2:20]3)=[N:16]2)=[CH:31][CH:30]=1
Reactant: CC=O
Reactant: COc1ccc(Cn2nc(CC3CCNCC3)c3c(Oc4ccc(NC(=O)c5nccn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCN1CCC(Cc2nn(Cc3ccc(OC)cc3)c3nccc(Oc4ccc(NC(=O)c5nccn(-c6ccc(F)cc6)c5=O)cc4F)c23)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
N-(4-(1-(4-methoxybenzyl)-3-(piperidin-4-ylmethyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-4-(4-fluorophenyl)-3-oxo-3,4-dihydropyrazine-2-carboxamide (17 mg, 0.025 mmol; prepared as in Example 152, Step B) was added to a small round bottom flask and dissolved in dry THF (1.5 mL). Acetaldehyde (5.56 mg, 0.126 mmol) and a drop of acetic acid (d 1.049) were added. The reaction mixture was stirred for 10 minutes under N2(g) at room temperature. NaBH(OAc)3 (53.5 mg, 0.252 mmol) was added and stirred at room temperature for 1 hour. The reaction mixture was partitioned between water and DCM and extracted with a second portion of DCM (10 mL). The combined organics were dried over sodium sulfate and evaporated to afford desired product, used as crude in next step. Yield 18.6 mg, 90% purity by HPLC, 94%. LRMS (APCI pos) m/e 706.3 (M+H).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:23]2[CH2:27][CH2:26][C:25]([F:29])([F:28])[CH2:24]2)[C:8]2[NH:13][N:12]([C@@H](C3C=CC=CC=3Cl)C)[NH:11][C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.[Cl:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[C@H:57](O)[CH3:58]>>[C:1]([C:5]1[N:6]=[C:7]([N:23]2[CH2:27][CH2:26][C:25]([F:28])([F:29])[CH2:24]2)[C:8]2[N:13]=[N:12][N:11]([C@H:57]([C:52]3[CH:53]=[CH:54][CH:55]=[CH:56][C:51]=3[Cl:50])[CH3:58])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](O)c1ccccc1Cl
Reactant: C[C@H](c1ccccc1Cl)N1Nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2N1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: C[C@@H](c1ccccc1Cl)n1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-2-[(R)-1-(2-chloro-phenyl)-ethyl]-7-(3,3-difluoro-pyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 87), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (R)-1-(2-chlorophenyl)ethanol and isolated as light-yellow gum (3.8 mg, 21%). MS (m/e): 421.4 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([CH2:30][CH2:31][NH2:32])[C:6]=2[CH:33]=1.[C:34](OC(=O)C)(=[O:36])[CH3:35].O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([CH2:30][CH2:31][NH:32][C:34](=[O:36])[CH3:35])[C:6]=2[CH:33]=1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(CCN)c3cc(Cl)ccc32)cn1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)NCCC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)nc2)c2ccc(Cl)cc21
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 7-chloro-5-(2-aminoethyl)-1-[6-(2-methylbenzoyl-amino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.42 g) in pyridine (10 ml) is added acetic anhydride (0.13 ml), and the mixture is stirred at 80° C. for 2 hours, and then stirred at room temperature overnight. Water is added to the reaction solution, and the mixture is extracted with dichloromethane. The extract is washed successively with diluted hydrochloric acid, water, and aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography to give 7-chloro-5-(2-acetylamino-ethyl)-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (91 mg) as white powder.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.O[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:8]=1>>[Cl:3][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cc(O)c2ccccc2n1
Product: CCOC(=O)c1cc(Cl)c2ccccc2n1

Procedure:
Phosphorous oxychloride (5 ml) was added to ethyl 4-hydroxyquinoline-2-carboxylate (1.01 g). The reaction mixture was subjected to single-mode microwave at 100° C. for 30 min using a Smith Microwave Synthesizer. The solvent was removed in vacuo and recrystallized with acetone to gave the title compound as a white solid (1.90 g). MS (ES) MH+: 235, 237 for C12H10ClNO2; NMR (CDCl3): 1.44 (t, 3H, J=7.16), 4.51 (q, 2H, J=7.16), 7.19 (s, 1H), 7.71 (m, 1H), 7.81 (m, 1H), 8.22 (m, 1H), 8.36 (d, 1H, J=8.29).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[C:13]3[CH:14]=[C:15]([C:17]4[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=4)[S:16][C:12]=3[S:11](=[O:24])(=[O:23])[NH:10][CH2:9]2)=[CH:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)S(O)(=O)=O.C([O-])(O)=O.[Na+]>ClCCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]3[CH:14]=[C:15]([C:17]4[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=4)[S:16][C:12]=3[S:11](=[O:24])(=[O:23])[NH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=S1(=O)NCC(O)(c2ccc(Cl)cc2)c2cc(-c3ccncc3)sc21
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCCl
Product: O=S1(=O)NC=C(c2ccc(Cl)cc2)c2cc(-c3ccncc3)sc21
Temperature: 90 °C
Yield: 41.7 %

Procedure:
4-(4-chlorophenyl)-6-pyridin-4-yl-3,4-dihydro-2H-thieno[3,2-e][1,2]thiazin-4-ol 1,1-dioxide (25 mg, 0.064 mmol) was suspended in 1,2-Dichloroethane (1.0 mL) and triethylsilane (0.1016 mL, 0.6363 mmol) and Trifluoromethanesulfonic acid (0.02815 mL, 0.3182 mmol) were added to a pressure tube and the resulting yellowish solution was heated at 90° C. overnight. At that time, LCMS indicated mainly the product of elimination. Mixture was cooled to room temperature, solid NaHCO3 (20 mg) was added, mixture was filtered and the filtrate was absorbed on silica gel (1 g). The material was purified by ISCO using DCM to 10% MeOH in DCM over 10 minutes to afford the title compound (10 mg, 42%). LCMS: (FA) ES+ 375, 377. 1H NMR (400 MHz, d6-DMSO) δ: 8.63 (dd, J=4.60, 1.62 Hz, 2H), 7.79 (dd, J=4.58, 1.63 Hz, 2H), 7.64 (s, 1H), 7.51 (s, 4H), 7.06 (s, 1H).