Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:6]([N:8]([CH2:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[O:21][CH2:22][CH2:23][OH:24])[C:9](=[O:11])[CH3:10])[CH:7]=1.C(N(C(C)C)CC)(C)C.[S:41](Cl)([CH3:44])(=[O:43])=[O:42]>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[C:6]([N:8]([CH2:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[O:21][CH2:22][CH2:23][O:24][S:41]([CH3:44])(=[O:43])=[O:42])[C:9](=[O:11])[CH3:10])[CH:7]=1
Reactant: COc1ccc(OCCO)c(CN(C(C)=O)c2cc(F)ccc2Oc2ccccc2)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(OCCOS(C)(=O)=O)c(CN(C(C)=O)c2cc(F)ccc2Oc2ccccc2)c1
Yield: 88 %

Procedure:
To a solution of 300 mg (0.71 mmol) 1e and 139 mg (1.06 mmol) diisopropyl ethyl amine in 5 ml dichloromethane was added 97 mg (0.85 mmol) mesyl chloride in 0.5 ml dichloromethane drop wisely at −10° C. The stirred reaction mixture was warmed over a period of 4 h to room temperature and diluted with dichloromethane. The organic phase was washed with saturated sodium hydrogen carbonate solution, water and brine. The organic phase was dried with magnesium sulfate. The crude product was purified by silica column chromatography (ethyl acetate:hexane gradient 1:6→1:2). The desired product 1f was obtained in 88% yield (346 mg, 0.62 mmol) as yellow oil.
Reaction SMILES: [C:1]([O-:4])([O-])=[O:2].[K+].[K+].[C:7]1(O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(#N)C>[CH3:11][CH2:12][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:7]([CH2:12][C:1]([OH:4])=[O:2])[CH3:8]
Reactant: Oc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCC(=O)O
Product: CCCCCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
O-methyl(ethyl) O-aryl chlorothiophosphate, which was obtained by reacting O-methyl(ethyl) dichlorothiophosphate with phenol, was reacted with aminocarboxylic acid to give a hapten for immunoassay of phosphorothioate pesticides: to 46 mmol of O-methyl(ethyl) dichlorothiophosphate (10) dissolved in 30 mL of acetonitrile was added 45 g of ground K2CO3 and 42 mmol of phenol (11) dissolved in 30 mL of acetonitrile, and the mixture was stirred for 1 hour at room temperature. Then, the reaction mixture was filtered with cellite, the solvent was evaporated from the filtrate, and the remnant was subject to silica-gel column chromatography equilibrated with benzene/hexane (1:1, v/v) or hexane/ethylacetic acid (10:1, v/v), to obtain oily compound of O-methyl(ethyl) O-aryl chlorothiophosphate (12).
Reaction SMILES: [OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=[O:4].[CH3:13]O>>[CH3:13][O:4][C@:3]1([CH2:2][OH:1])[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@@H:5]1[OH:6]
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CO
Product: CO[C@]1(CO)O[C@H](CO)[C@@H](O)[C@@H]1O
Temperature: 160 °C
Reaction time: 0.03 h

Procedure:
A mixture of methanol and fructose was initially charged in a stirred vessel A. The fraction of fructose was 30% of the methanol fraction. The mixture was conveyed by a suitable pump B at a pressure of 120 bar continuously through the reactor C. The tubular reactor C was heated to a temperature of 160° C. by the heater D. A carrier stream comprising pure methanol from the reservoir F was heated to approx. 300° using the preheater G. At the mixing point H, the carrier stream was mixed with the reactant stream and fed to the reactor. The preheating temperature was sufficiently high that reaction temperature was already present at the mixing point, so that the temperature gradient in the reactor was sufficiently low to prevent carbonization at the wall. The residence time in the tubular reactor was approx. 2 min. With the aid of the control valve E, the pressure was kept at the target value mentioned. At the outlet of the system, the reacted product mixture was collected. According to HPLC, the product mixture contained 4% product.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:12]([O-])=O)=[C:4]([CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10])[NH2:5].C(O)C.O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+]>O>[NH2:12][C:3]1[C:4]([NH2:5])=[CH:6][CH:7]=[C:8]([N+:9]([O-:11])=[O:10])[C:2]=1[CH3:1]
Reactant: Cc1c([N+](=O)[O-])ccc(N)c1[N+](=O)[O-]
Agent: [Na+]
Agent: [S-2]
Solvent: O
Solvent: CCO
Product: Cc1c([N+](=O)[O-])ccc(N)c1N
Temperature: 0 °C

Procedure:
To a solution 3-methyl-2,4-dinitroaniline (30 g) in boiling ethanol (750 mL) is added dropwise over 90 minutes a solution of sodium sulfide nonahydrate (109.6 g) in water (750 mL). At the end of the addition, the mixture is refluxed for 30 minutes then poured into ice (2000 g) and allowed to stand until all the ice has melted. The mixture is then extracted with methylene chloride and the organic layer is dried over magnesium sulfate and rotary evaporated. The residue is purified by flash chromatography on silica gel, eluting with methylene chloride to afford 2,3-diamino-6-nitrotoluene as an orange solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:18]3=[N:19][C:20]4[C:25]([Cl:26])=[CH:24][CH:23]=[C:22]([CH:27]([O:32][CH:33]([F:35])[F:34])[C:28]([F:31])([F:30])[F:29])[C:21]=4[N:17]3[CH2:16][CH2:15][CH2:14]2)=[C:9]([CH3:36])[N:8]=1)(=O)=O.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>CN(C)C=O.O>[Cl:26][C:25]1[C:20]2[N:19]=[C:18]3[N:13]([C:10]4[C:9]([CH3:36])=[N:8][C:7]([N:39]5[CH2:44][CH2:43][O:42][CH2:41][CH2:40]5)=[CH:12][CH:11]=4)[CH2:14][CH2:15][CH2:16][N:17]3[C:21]=2[C:22]([CH:27]([O:32][CH:33]([F:35])[F:34])[C:28]([F:29])([F:30])[F:31])=[CH:23][CH:24]=1
Reactant: C1COCCN1
Reactant: Cc1nc(OS(=O)(=O)C(F)(F)F)ccc1N1CCCn2c1nc1c(Cl)ccc(C(OC(F)F)C(F)(F)F)c12
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(N2CCOCC2)ccc1N1CCCn2c1nc1c(Cl)ccc(C(OC(F)F)C(F)(F)F)c12
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 82.8 %

Procedure:
To a solution of 5-{9-chloro-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-3,4-dihydropyrimido[1,2-a]benzimidazol-1(2H)-yl}-6-methylpyridin-2-yl trifluoromethanesulfonate (100.4 mg, 0.169 mmol) in N,N-dimethylformamide (1.5 mL) was added morpholine (73.6 μL, 0.844 mmol). The reaction mixture was stirred, at 80° C. for 1.5 hrs. The starting material wasn't consumed completely. To the mixture was added morpholine (73.6 μL, 0.844 mmol). The reaction mixture was stirred at 80° C. for 3.5 hrs. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The combined organic layer was washed with water (×2) and brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-60% ethyl acetate/n-hexane gradient mixture. The resulting solid was recrystallized from ethyl acetate/n-hexane to give a title compound as a colorless powder (74.6 mg, 0.140 mmol, 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][CH2:6][CH2:7]Br.[CH2:14]([NH2:17])[C:15]#[CH:16]>CC#N.O>[Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][NH:17][CH2:14][C:15]#[CH:16]
Reactant: C#CCN
Reactant: Clc1ccc(OCCCBr)c(Cl)c1
Solvent: O
Solvent: CC#N
Product: C#CCNCCCOc1ccc(Cl)cc1Cl

Procedure:
2.3 ml of 87% pure 3-(2,4-dichlorophenoxyl) propylbromide (2.99 g; 0.011 mole) and 1.6 ml propargylamine (1.38 g; 0.025 mole) in 30 ml CH3CN and 1.65 g k2CO3 in 3 ml H2O were stirred at room temperature for 5 days.
Reaction SMILES: [S:1]([N:17](S(C1C2C=CC=C(N(C)C)C=2C=CC=1)(=O)=O)[CH2:18][CH2:19][S:20][S:21][CH2:22][CH2:23][NH2:24])([C:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:9]([N:10]([CH3:12])[CH3:11])[C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])=[O:2].C(C(O)=O)CP(CCC(O)=O)CCC(O)=O.[Br:57][C:58]1[C:63](=[O:64])[NH:62][C:60](=[O:61])[C:59]=1Br>CO>[Br:57][N:17]([S:1]([C:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:9]([N:10]([CH3:12])[CH3:11])[C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])=[O:2])[CH2:18][CH2:19][S:20][S:21][CH2:22][CH2:23][NH2:24].[C:60]1(=[O:61])[NH:62][C:63](=[O:64])[CH:58]=[CH:59]1
Reactant: CN(C)c1cccc2c(S(=O)(=O)N(CCSSCCN)S(=O)(=O)c3cccc4c(N(C)C)cccc34)cccc12
Reactant: O=C1NC(=O)C(Br)=C1Br
Agent: O=C(O)CCP(CCC(=O)O)CCC(=O)O
Solvent: CO
Product: CN(C)c1cccc2c(S(=O)(=O)N(Br)CCSSCCN)cccc12
Product: O=C1C=CC(=O)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 37.8 %

Procedure:
A round bottomed flask was charged with di-dansyl cystamine (48 mg, 0.08 mmol), TCEP (23 mg, 1 eq), and MeOH (10 ml). The reaction mixture was stirred at ambient temperature under argon for 3 hrs. Dibromomaleimide (41 mg, 2 eq) in MeOH (10 ml), was added to the reaction mixture. After 16 hrs, the reaction mixture was concentrated in vacuo. The residue was worked up with DCM and brine. The organic layers were combined, dried (MgSO4) and purified by flash chromatography (silica gel, 0-15% EtOAC-DCM) to yield the desired compound (17 mg, 22%). 1HNMR (CDCl3, 600 MHz), δ8.5 (1H, d J 8.5 Hz aromatic H's), δ8.2 (2H, m aromatic H's), δ7.6 (1H, s CONH), δ7.53 (2H, m, aromatic H's), δ7.15 (1H, d, J=7.4 Hz aromatic H's), δ5.30 (1H, t, J 5.6 SO2NH), δ3.38 (2H, t, J 6.3 SCH2), δ3.26 (2H, q, J 6.3 NHCH2), δ2.88 (6H, s NCH3); 13CNMR (CDCl3, 150 MHz), δ165.5, 162.9, 152.2, 142.5, 134.5, 130.95, 129.94, 129.92, 129.5, 128.7, 123.3, 119.0, 118.5, 115.4, 45.5, 43.7, 30.5; IR (cm−1) 3295 (br) 1726 (s) MS (ES+) m/z relative intensity: 485 (M, 100); Exact mass calculated for [C18H19N3O4S2Br] requires m/z 484.0000. Found 783.9982.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:28]=[CH:27][C:8]([NH:9]/[C:10](=[C:13]2\[C:14](=[O:26])[NH:15][C:16]3[C:21]\2=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=3)/[CH2:11][CH3:12])=[CH:7][CH:6]=1)([OH:3])=O.Cl.[CH3:30][NH:31][CH3:32]>>[CH3:30][N:31]([CH3:32])[C:1]([CH2:4][C:5]1[CH:28]=[CH:27][C:8]([NH:9]/[C:10](=[C:13]2\[C:14](=[O:26])[NH:15][C:16]3[C:21]\2=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=3)/[CH2:11][CH3:12])=[CH:7][CH:6]=1)=[O:3]
Reactant: CC/C(Nc1ccc(CC(=O)O)cc1)=C1/C(=O)Nc2cc(OC)c(OC)cc21
Reactant: CNC
Agent: Cl
Product: CC/C(Nc1ccc(CC(=O)N(C)C)cc1)=C1/C(=O)Nc2cc(OC)c(OC)cc21

Procedure:
Prepared from 3-(Z)-{1-[4-(carboxymethyl)-anilino]-1-ethyl-methylidene}-5,6-dimethoxy-2-indolinone and dimethylamine-hydrochloride
Reaction SMILES: [CH2:1]([CH2:13]N)[CH2:2][C:3](P([O-])(O)=O)(P(O)(O)=O)[OH:4].[Na+:15].[OH-].[Na+].[N+:18]([C:21]1C=CC=[CH:26][C:22]=1C(Cl)=O)([O-])=O.[CH2:30]([CH2:42][NH2:43])[CH2:31][C:32]([P:38]([OH:41])([OH:40])=[O:39])([P:34]([OH:37])([OH:36])=[O:35])[OH:33]>O.C1COCC1>[NH2:18][C:21]1[CH:13]=[CH:1][C:2]([C:3]([NH2:43])=[O:4])=[CH:26][CH:22]=1.[CH2:30]([CH2:42][NH2:43])[CH2:31][C:32]([P:34]([O-:36])([OH:37])=[O:35])([P:38]([OH:41])([OH:40])=[O:39])[OH:33].[Na+:15]
Reactant: NCCCC(O)(P(=O)(O)O)P(=O)(O)O
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Agent: NCCCC(O)(P(=O)([O-])O)P(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The 4-aminobenzamide of alendronate sodium was prepared as follows. In a 500 mL beaker, 54 g (166 mmol) of sodium alendronate was dissolved in 150 mL of DI water with a pH adjusted to 11 with concentrated NaOH. Nitrobenzoyl chloride, 28 g (150 mmol), dissolved in 100 mL of THF, was added dropwise into the aqueous alendronate solution. The pH was kept at 11 with additional NaOH solution during the addition. After the addition was complete, the solution was stirred for another 2 hours at room temperature. THF was removed in vacuo, and the pH of the solution was adjusted to 4. The resulting precipitate, which was collected by filtration at room temperature, was primarily nitrobenzoic acid and was discarded. The solution was kept at 4° C. overnight, and the resulting precipitate was collected by filtration, washed with DI water, and dried. The resulting solid weighted approximately 56 g (86%).
Reaction SMILES: [CH2:1]([CH:4]([CH2:15][CH:16]=[CH2:17])[CH2:5][O:6][SiH2:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][CH:9]=1)[CH:2]=[CH2:3].C([Mg]Cl)(C)C.C(C(CC=C)CO[SiH2]C1C=CC([Mg]Cl)=CC=1)C=C.C(O[B:45]1[O:49][C:48]([CH3:51])([CH3:50])[C:47]([CH3:53])([CH3:52])[O:46]1)(C)C>O.C1COCC1>[CH2:1]([CH:4]([CH2:15][CH:16]=[CH2:17])[CH2:5][O:6][SiH2:7][C:8]1[CH:13]=[CH:12][C:11]([B:45]2[O:49][C:48]([CH3:51])([CH3:50])[C:47]([CH3:53])([CH3:52])[O:46]2)=[CH:10][CH:9]=1)[CH:2]=[CH2:3]
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: C=CCC(CC=C)CO[SiH2]c1ccc(I)cc1
Agent: C=CCC(CC=C)CO[SiH2]c1ccc([Mg]Cl)cc1
Agent: CC(C)[Mg]Cl
Solvent: O
Solvent: C1CCOC1
Product: C=CCC(CC=C)CO[SiH2]c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
A THF solution (2 mL) of the 4-(diallylethoxysilyl)iodobenzene (171 mg, 0.48 mmol) obtained in Example 2 was added dropwise with 2 mol/L of i-PrMgCl (0.50 mL (solvent: THF), 1.0 mmol) at −30° C. Then, the resultant solution was stirred under a nitrogen atmosphere at −30° C. for 1.5 hours to obtain a THF solution containing 4-(diallylethoxysilyl)phenylmagnesium chloride (Grignrad solution). Subsequently, the obtained Grignrad solution was cooled to −78° C., and added dropwise with 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (204 μL, 1.0 mmol) to obtain a reaction mixture. Thereafter, the obtained reaction mixture was stirred under a nitrogen atmosphere at −78° C. for one hour, and further stirred at room temperature for 14 hours. After that, the reaction mixture was added with distilled water to terminate the reaction, and 10% by mass of an HCl solution was further added thereto until the salt thus formed disappeared. Then, the organic layer was separated therefrom, and the aqueous layer was extracted with ether to collect the organic layer. Subsequently, the organic layer thus collected was washed with sat.NaHCO3 and sat.NaCl, dried with MgSO4, filtered, and concentrated to obtain a crude product. Thereafter, the crude product thus obtained was separated and purified by silica gel column chromatography (hexane/EtOAc=5/1), and thereby 1-(diallylethoxysilyl)-4-(4,4,5,5-tetramethyl-1,3,2-di oxaborolan-2-yl)benzene was obtained (128.3 mg, 75% yield).
Reaction SMILES: [CH3:1][CH:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH2:21][N:22]1[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]2[C:23]1=[O:32].O>CN(C=O)C>[CH3:1][CH:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:20][CH2:21][N:22]2[C:26](=[O:27])[C:25]3=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]3[C:23]2=[O:32])=[CH:10][CH:11]=1)[CH2:3][CH3:4]
Reactant: CCC(C)Oc1ccc(O)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(C)Oc1ccc(OCCN2C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 4-(1-methylpropoxy)phenol (44.3 mmol) in 25 ml of DMF is added, under N2, potassium carbonate (51.0 mmol) followed by dropwise addition of N-(bromoethyl)phthalimide (51.0 mmol) in 30 ml of DMF. The mixture is stirred at RT overnight. Water is then added and the aqueous phase is extracted with ether. The combined organic layers are washed with 5% sodium hydroxide, with water and with brine, dried and the solent removed to give N-{2-[4-(1-methylpropoxy)phenoxy]ethyl}phthalimide. Following the procedures of Example 7, the above phthalimide (5.7 mmol) is reacted with hydrazine hydrate (5.7 mmol) to give 2-[4-(1-methylpropoxy)phenoxy]ethylamine.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[C:4]([CH2:12]Br)[CH:3]=1.[NH2:14][CH2:15][CH2:16][C:17]([CH3:20])([OH:19])[CH3:18].CCN(CC)CC>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:10][CH:11]=1)[C:6](=[O:8])[N:14]([CH2:15][CH2:16][C:17]([OH:19])([CH3:20])[CH3:18])[CH2:12]2
Reactant: COC(=O)c1ccc(Br)cc1CBr
Reactant: CC(C)(O)CCN
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(O)CCN1Cc2cc(Br)ccc2C1=O
Temperature: 85 °C

Procedure:
To methyl 4-bromo-2-(bromomethyl)benzoate (0.220 g, 0.714 mmol) suspended in MeOH (6.0 mL) were added 4-amino-2-methylbutan-2-ol (0.077 g, 0.750 mmol) and Et3N (0.156 mL, 1.107 mmol). The mixture was heated to reflux (85° C.) for 24 hours, then cooled to RT, and concentrated in vacuo to give the title compound, which was used without further purification.
Reaction SMILES: [CH3:1][NH:2]C[C@H](C1C=CC=CN=1)O.Cl[CH2:13][C:14]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)=[O:15]>>[CH3:1][NH:2][CH2:13][C@H:14]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)[OH:15]
Reactant: O=C(CCl)c1cccnc1
Reactant: CNC[C@@H](O)c1ccccn1
Product: CNC[C@@H](O)c1cccnc1

Procedure:
As described for the preparation of (1R)-2-(methylamino)-1-pyridin-2-ylethanol (Preparations 27-28), 3-chloroacetylpyridine (Chem. Ber. 1951, 84, 147-149) is converted to the title compound, isolated as a pale yellow amorphous solid.
Reaction SMILES: C([N:5]1[CH:13](O)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:15])[CH:11]=2)[C:6]1=[O:16])(C)(C)C.O.[NH2:18]N>CC(O)=O.O>[CH3:15][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[C:6](=[O:16])[NH:18][N:5]=[CH:13]2
Reactant: Cc1ccc2c(c1)C(O)N(C(C)(C)C)C2=O
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc2c(=O)[nH]ncc2c1
Temperature: 80 °C

Procedure:
To a solution of 2-tert-butyl-3-hydroxy-5-methylisoindolin-1-one (10.54 g, 48.1 mmol) in AcOH (250 ml) charged to a 500 mL round bottom and stirred at 80° C., hydrazine hydrate (3.51 ml, 72.1 mmol) was added. The reaction mixture was stirred at 80° C. for 90 min. The reaction mixture was then cooled and diluted with water and extracted with 4 L DCM. The organics were washed with brine, dried over magnesium sulfate and concentrated under vacuum to give 6-methylphthalazin-1(2H)-one. MS (M+H)+ 161.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]2[S:7][CH:8]=[CH:9][C:5]=2[CH:4]=1)=[O:2].[C:12]1([CH3:18])C=CC=CC=1.C1(C)C=CC(S(O)(=O)=[O:26])=CC=1>C(O)CO>[O:2]1[CH2:18][CH2:12][O:26][CH:1]1[C:3]1[CH:11]=[CH:10][C:6]2[S:7][CH:8]=[CH:9][C:5]=2[CH:4]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=Cc1ccc2sccc2c1
Reactant: Cc1ccccc1
Solvent: OCCO
Product: c1cc2cc(C3OCCO3)ccc2s1
Reaction time: 6 h
Yield: 79 %

Procedure:
A solution of product from Step A (16.4 g, 0.1 mol), toluene (300 ml), p-toluenesulfonic acid (1.0 g) and ethylene glycol (20 ml) was heated at reflux with the aid of a Dean-Stark trap. After 6 hours, the organic layer was cooled, washed with saturated Na2CO3. The Na2CO3 layer was extracted with ethyl acetate (2x). The combined organic extracts were dried, filtered and concentrated to dryness. The residue was distilled at 149°-153° C. at 0.3 mm Hg to yield 16.4 g (79%) of product.
Reaction SMILES: [Br:1][C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[C:5](Br)=[N:4][CH:3]=1.[O:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][N:20]2[CH:24]=[CH:23][N:22]=[C:21]2[NH2:25])[CH2:14][CH2:13]1>>[Br:1][C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:25][C:21]2[N:20]([CH2:19][CH2:18][N:15]3[CH2:14][CH2:13][O:12][CH2:17][CH2:16]3)[CH:24]=[CH:23][N:22]=2)=[N:4][CH:3]=1
Reactant: Nc1nccn1CCN1CCOCC1
Reactant: Brc1ncc(Br)n2ncnc12
Product: Brc1cnc(Nc2nccn2CCN2CCOCC2)c2ncnn12

Procedure:
Prepared using Intermediate 3 and Intermediate 10 in a manner analogous to the procedure of Example 1, Step 1. 1H NMR (400 MHz, CDCl3) 2.55 (brs, 4H), 2.71-2.80 (m, 2H), 3.68-3.83 (m, 4H), 4.15-4.26 (m, 2H), 6.92 (s, H), 7.05 (s, H), 7.71 (s, H), 8.31 (s, H), 8.58 (s, 1H).
Reaction SMILES: OC([C:5]1[CH:6]=[C:7]2[C:24](=[CH:25][CH:26]=1)[C:11]1=[N:12][O:13][C:14]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH3:23])=[CH:17][CH:16]=3)=[C:10]1[CH2:9][CH2:8]2)C#N.Cl.[OH2:28].[CH3:29][C:30]([OH:32])=[O:31]>>[OH:28][CH:29]([C:5]1[CH:6]=[C:7]2[C:24](=[CH:25][CH:26]=1)[C:11]1=[N:12][O:13][C:14]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH3:23])=[CH:17][CH:16]=3)=[C:10]1[CH2:9][CH2:8]2)[C:30]([OH:32])=[O:31]
Reactant: CCCc1ccc(-c2onc3c2CCc2cc(C(O)C#N)ccc2-3)cc1
Reactant: O
Reactant: CC(=O)O
Agent: Cl
Product: CCCc1ccc(-c2onc3c2CCc2cc(C(O)C(=O)O)ccc2-3)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 13 %

Procedure:
To a solution of 2-hydroxy-2-(3-(4-propylphenyl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)acetonitrile (Preparation 127A, 120 mg, 0.35 mmol) in glacial AcOH (1.5 mL) was added concentrated HCl (0.5 mL). The reaction mixture was stirred at 70° C. for 8 h. After cooling, the solution was poured into water and was extracted with ethyl acetate. The organic layer was dried (over magnesium sulfate), filtered, and concentrated. The resulting residue was purified by preparative HPLC (Phenomenex Luna 5 u C18 21.2×100 mm, Solvent A: 90% water with 10% MeOH and 0.1% TFA, Solvent B: 90% MeOH with 10% water and 0.1% TFA, Gradient: 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention time=12.1 min) to give 2-hydroxy-2-(3-(4-propylphenyl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)acetic acid (20 mg, 0.049 mmol, 13% yield): product HPLC ret. time=9.59 min. (condition G); LC/MS M+1=364.1; 1H NMR (400 MHz, CD3OD) δ ppm 7.87 (1H, d, J=7.92 Hz), 7.70 (2H, d, J=8.14 Hz), 7.41-7.57 (2H, m), 7.35 (2H, d, J=8.14 Hz), 5.19 (1H, s), 3.04 (4H, s), 2.66 (2H, t, J=7.59 Hz), 1.60-1.77 (2H, m), 0.97 (3H, t, J=7.26 Hz).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:15]1[N:16]=[C:17]([CH2:45][CH2:46][CH3:47])[N:18]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]3[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=3)=[CH:33][CH:32]=2)[C:19](=[O:29])[C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[CH3:14]>O>[CH2:13]([C:15]1[N:16]=[C:17]([CH2:45][CH2:46][CH3:47])[N:18]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[C:43]3[NH:3][C:4](=[O:7])[O:5][N:44]=3)=[CH:33][CH:32]=2)[C:19](=[O:29])[C:20]=1[C:21]1[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)[CH3:14]
Reactant: O=C([O-])O
Reactant: CCCc1nc(CC)c(-c2ccc(OC)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCc1nc(CC)c(-c2ccc(OC)cc2)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 81.3 %

Procedure:
A mixture of hydroxylammonium chloride (1.2 g), sodium hydrogen carbonate (1.7 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[4-ethyl-5-(4-methoxyphenyl)-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (0.48 g) was added, and the mixture was stirred at 90° C. for 24 hr. The reaction mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the precipitated solid was collected by filtration. The obtained solid was dissolved in ethyl acetate. The solution was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.25 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.23 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.44 g, 81%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].Cl.[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[C:23]([C:25]3[CH:34]=[C:33]4[C:28]([CH2:29][CH2:30][NH:31][CH2:32]4)=[CH:27][CH:26]=3)[N:22]=[C:21]([NH2:35])[N:20]=2)[CH2:15][CH2:14]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([N:31]1[CH2:30][CH2:29][C:28]2[C:33](=[CH:34][C:25]([C:23]3[CH:24]=[C:19]([N:16]4[CH2:15][CH2:14][N:13]([CH3:12])[CH2:18][CH2:17]4)[N:20]=[C:21]([NH2:35])[N:22]=3)=[CH:26][CH:27]=2)[CH2:32]1)=[O:6]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)c3cccc(Cl)c3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 2 starting from 3-chlorobenzoyl chloride (Lancaster, Cat. #L01191) and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=463.3/465.3.