Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH:19](=[O:27])[C:20]1[C:21](=[CH:23][CH:24]=[CH:25][CH:26]=1)[OH:22].[Cl:28][CH2:29]/[CH:30]=[CH:31]\[CH2:32]Cl.[OH-].[Na+]>O>[Cl:28][CH2:29]/[CH:30]=[CH:31]\[CH2:32][O:22][C:21]1[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=1[CH:19]=[O:27]
Reactant: O=Cc1ccccc1O
Reactant: ClC/C=C\CCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=Cc1ccccc1OC/C=C\CCl

Procedure:
To 1.2 lt of refluxing water, 1 ml of 40% aqueous tetrabutylammonium hydroxide, 125 ml of salicylaldehyde and 150 ml of cis-1,4-dichloro-2-butene are added while vigorously stirring, followed by the dropwise addition of the solution of 42 g of sodium hydroxide in 200 ml of water at such a rate that the pH of the mixture is kept between 7 and 8. Thereafter the mixture is refluxed until the pH is about 7, cooled and extracted with methylene chloride. The extract is washed with 5% aqueous sodium hydroxide, dried, evaporated, the residue distilled and the fraction boiling at 137°-140°/0.1 mmHg collected, to yield the 2-(4-chloro-cis-2-butenyloxy)-benzaldehyde.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:10][CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[C:5]([NH2:9])=[N:6][C:7]=1[Cl:8].[Cl:18][C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[S:26](Cl)(=[O:28])=[O:27]>>[Cl:18][C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[S:26]([NH:9][C:5]1[C:4]([O:10][CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:3][C:2]([Cl:1])=[C:7]([Cl:8])[N:6]=1)(=[O:28])=[O:27]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Reactant: Nc1nc(Cl)c(Cl)nc1OCc1cccnc1
Product: O=S(=O)(Nc1nc(Cl)c(Cl)nc1OCc1cccnc1)c1cccc(Cl)c1Cl

Procedure:
Prepared by the method of Example 1 (reaction performed at room temperature) using 5,6-dichloro-3-(3-pyridinylmethoxy)-2-pyrazinamine (Example 121a) (0.27 g) and 2,3-dichlorobenzenesulphonyl chloride (0.27 g). Yield 0.17 g.
Reaction SMILES: S1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.ClC1C=CC=C(C(OO)=O)C=1.[S:21]([O-:25])([O-])(=[O:23])=S.[Na+].[Na+]>O1CCCC1>[S:21]1(=[O:25])(=[O:23])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: O=S([O-])([O-])=S
Reactant: c1ccc2sccc2c1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S1(=O)C=Cc2ccccc21
Reaction time: 1 h
Yield: 74 %

Procedure:
To a solution (120 mL) of 1-benzothiophene (11.2 g) in tetrahydrofuran was added m-chloroperbenzoic acid (70% containing, 43.1 g) at 0° C. and the mixture was stirred at the same temperature for 1 hr, further stirred at room temperature for 1 hr. An aqueous sodium thiosulfate solution (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with 1 mol/L aqueous sodium hydroxide solution, saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound as a white solid (yield 10.3 g, 74%).
Reaction SMILES: Br[C:2]1[C:3]([O:15][CH3:16])=[CH:4][C:5]([O:13][CH3:14])=[C:6]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[CH:7]=1.CCN(CC)CC.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.[CH3:49][C:50]1([CH3:57])[C:54]([CH3:56])([CH3:55])[O:53][BH:52][O:51]1.[NH4+].[Cl-]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2].O>[O:9]1[CH2:10][CH2:11][O:12][CH:8]1[C:6]1[C:5]([O:13][CH3:14])=[CH:4][C:3]([O:15][CH3:16])=[C:2]([B:52]2[O:53][C:54]([CH3:56])([CH3:55])[C:50]([CH3:57])([CH3:49])[O:51]2)[CH:7]=1
Reactant: CC1(C)OBOC1(C)C
Reactant: COc1cc(OC)c(C2OCCO2)cc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(OC)c(C2OCCO2)cc1B1OC(C)(C)C(C)(C)O1
Yield: 92.6 %

Procedure:
Ex-46B: 2-(5-Bromo-2,4-dimethoxy-phenyl)-[1,3]dioxolane (Ex-46A, 4.78 g, 10.5 mmol) was dissolved in dioxane (75 mL) and the solution was purged with nitrogen for 15 min. Pd(OAc)2 (188 mg, 0.84 mmol), Et3N (6.91 mL, 49.6 mmol), and 2-(dicyclohexylphosphino)biphenyl (1.16 g, 3.31 mmol) were added. 4,4,5,5-Tetramethyl-[1,3,2]dioxaborolane (3.6 mL, 24.8 mmol) was added slowly, accompanied by gas evolution and the darkening of the reaction solution. The solution was heated at reflux for 2.5 h and then cooled. Saturated, aqueous NH4Cl (60 mL) and water (20 mL) were added and the solution extracted with EtOAc (1×100 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated to a dark oil. The oil was purified via silica gel chromatography (1:1 EtOAc/hexanes after a column pre-wash of 5% Et3N in 1:1 EtOAc/hexanes) to provide 3.27 g of 2-(5-[1,3]dioxolan-2-yl-2,4-dimethoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane as a yellow solid (with some starting borolane present), 59% yield. 1H-NMR (CDCl3) δ 7.85 (s, 1H), 6.39 (s, 1H), 6.07 (s, 1H), 4.13–4.18 (m, 2H), 3.98–4.02 (m, 2H), 3.89 (s, 3H), 3.84 (s, 3H), 1.33 (s, 9H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH2:18])[CH3:17])[CH2:3][CH2:2]1.Cl[C:20]1[N:28]=[CH:27][N:26]=[C:25]2[C:21]=1[N:22]=[CH:23][N:24]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[O:1]1[CH2:2][CH2:3][CH:4]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH:18][C:20]2[N:28]=[CH:27][N:26]=[C:25]3[C:21]=2[N:22]=[CH:23][NH:24]3)[CH3:17])[CH2:5][CH2:6]1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: C[C@H](N)c1nc2ccccc2n1C1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccccc2n1C1CCOCC1
Temperature: 120 °C
Reaction time: 72 h

Procedure:
A mixture of (S)-1-[1-(tetrahydropyran-4-yl)-1H-benzoimidazol-2-yl]ethylamine from Example 17 (195 mg, 0.796 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (266 mg, 1.11 mmol) and DIPEA (0.25 mL, 1.43 mmol) in n-butanol (2 mL) was stirred in a sealed vial for 3 days at 120° C. After cooling to RT, volatiles were removed under reduced pressure and the resulting residue was loaded into an Isolute® SCX-2 which was washed with MeOH and the product eluted with 2M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo and the resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) and then triturated with a mixture EtOAc and MeOH affording 127 as an off-white solid (148 mg, 51%). LCMS: RT 2.29 min [M+H]+ 364.0. 1H NMR (DMSO, 400 MHz): δ 12.93 (1H, bs), 8.30-7.81 (3H, m), 7.61-7.59 (2H, m), 7.17-7.03 (2H, m), 5.96 (1H, bs), 4.81-4.63 (1H, m), 3.94 (1H, d, J=11.07 Hz), 3.74 (1H, d, J=11.25 Hz), 3.35 (1H, bs), 2.84 (1H, bs), 2.47-2.35 (1H, m), 2.30-2.17 (1H, m), 1.75 (1H, bd), 1.64 (3H, d, J=6.71 Hz), 1.50 (1H, bs)
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:12][C@H:13]2[C@@H:17]([O:18][CH2:19][CH3:20])[CH2:16][N:15]([C:21]([O:23][CH3:24])=[O:22])[CH2:14]2)=[N:5][C:6]([CH2:10][CH3:11])=[C:7](I)[N:8]=1)[CH3:2].[CH3:25][O:26][C:27]1[CH:35]=[C:34]2[C:30]([CH2:31][CH2:32][CH2:33]2)=[CH:29][C:28]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>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.COCCOC>[CH2:1]([C:3]1[C:4]([NH:12][C@H:13]2[C@@H:17]([O:18][CH2:19][CH3:20])[CH2:16][N:15]([C:21]([O:23][CH3:24])=[O:22])[CH2:14]2)=[N:5][C:6]([CH2:10][CH3:11])=[C:7]([C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][C:27]=2[O:26][CH3:25])[CH2:33][CH2:32][CH2:31]3)[N:8]=1)[CH3:2]
Reactant: COc1cc2c(cc1B(O)O)CCC2
Reactant: CCO[C@H]1CN(C(=O)OC)C[C@H]1Nc1nc(CC)c(I)nc1CC
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: O=C([O-])[O-]
Solvent: COCCOC
Product: CCO[C@H]1CN(C(=O)OC)C[C@H]1Nc1nc(CC)c(-c2cc3c(cc2OC)CCC3)nc1CC
Temperature: 80 °C
Reaction time: 18 h
Yield: 92.8 %

Procedure:
A 7 ml vial was charged with methyl (3R,4S)-3-[(3,6-diethyl-5-iodopyrazin-2-yl)amino]-4-ethoxypyrrolidine-1-carboxylate (100 mg), 6-methoxy-2,3-dihydro-1H-inden-5-ylboronic acid (82 mg) (Preparation 2), tetrakis(triphenylphosphine)palladium (20 mg), 2 M Na2CO3 (0.4 mL), and ethylene glycol dimethyl ether (1.6 mL). The reaction was stirred for 18 hours at 80° C. The reaction was poured into sat. aq. NaHCO3 and extracted with ethyl ether. The organic phases were combined, dried with MgSO4, filtered, and concentrated. The crude was purified with flash column chromatography (silica, a gradient of 10-25% EtOAc in heptane) to give 97 mg, 95% of methyl (3R,4S)-3-{[3,6-diethyl-5-(6-methoxy-2,3-dihydro-1H-inden-5-yl)pyrazin-2-yl]amino}-4-ethoxypyrrolidine-1-carboxylate. IR (diffuse reflectance) 2967, 2934, 2876, 2350, 2335, 2224, 2063, 1940, 1710, 1568, 1482, 1466, 1451, 1392, 1348 cm−1 HRMS (ESI) calcd for C26H36N4O4+H1 469.2815. found 469.2805. Anal. Calcd for C26H36N4O4: C, 66.64; H, 7.74; N, 11.96. Found: C, 66.27; H, 7.61; N, 11.75.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:33])[CH2:11][N:12]([CH2:19][C:20]1[CH:32]=[CH:31][C:23]([O:24][C:25]([CH3:30])([CH3:29])[C:26]([OH:28])=[O:27])=[CH:22][CH:21]=1)[CH2:13][C:14]1[O:15][CH:16]=[CH:17][CH:18]=1.[OH-].[Na+:35]>C(O)C>[Na+:35].[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:33])[CH2:11][N:12]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:24][C:25]([CH3:30])([CH3:29])[C:26]([O-:28])=[O:27])=[CH:31][CH:32]=1)[CH2:13][C:14]1[O:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cc1ccc(NC(=O)CN(Cc2ccc(OC(C)(C)C(=O)O)cc2)Cc2ccco2)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(NC(=O)CN(Cc2ccc(OC(C)(C)C(=O)[O-])cc2)Cc2ccco2)c(C)c1
Reaction time: 0.08 h

Procedure:
0.015 g (0.03 mmol) of the compound from Example 3-4 is dissolved in 0.5 ml of ethanol and treated with 0.3 ml of 1N aqueous sodium hydroxide solution. The reaction mixture is stirred for another 5 min and then concentrated using a rotary evaporator. The residue is taken up in a little toluene and the solvent is removed under reduced pressure. The product is then dried under reduced pressure for 20 hours. This gives 0.015 g (95.5% of theory) of the title compound.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:11]2[C:20]3[C:15](=[CH:16][C:17]([CH3:21])=[CH:18][CH:19]=3)[CH2:14][NH:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9]C.[BrH:22]>>[BrH:22].[OH:2][C:3]1[CH:4]=[C:5]([CH:11]2[C:20]3[C:15](=[CH:16][C:17]([CH3:21])=[CH:18][CH:19]=3)[CH2:14][NH:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[OH:9]
Reactant: COc1ccc(C2CNCc3cc(C)ccc32)cc1OC
Agent: Br
Product: Cc1ccc2c(c1)CNCC2c1ccc(O)c(O)c1

Procedure:
850 mg of 4-(3,4-dimethoxyphenyl)-7-methyl-1,2,3,4-tetrahydroisoquinoline was dissolved in 17 ml of 48% hydrobromic acid, and the mixture was heated under reflux under an argon gas stream for 3 hours. The reaction solution was cooled, and the crystals obtained were collected by filtration, giving 620 mg of 4-(3,4-dihydroxyphenyl)-7-methyl-1,2,3,4-tetrahydroisoquinoline hydrobromide.
Reaction SMILES: [CH3:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].O[CH2:13][CH:14]([CH2:16]O)O.[OH-].[NH4+].C(O)(=O)C>O>[CH3:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[C:5]2[C:3]=1[N:4]=[CH:16][CH:14]=[CH:13]2
Reactant: Cc1c(N)cccc1[N+](=O)[O-]
Reactant: OCC(O)CO
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1c([N+](=O)[O-])ccc2cccnc12
Temperature: 150 °C
Reaction time: 6 h

Procedure:
A mixture of 2-methyl-3-nitroaniline (10 g), glycerin (20.57 g) and As2O5.xH2O (Baker, 88% As2O5, 8.5 g) is heated slowly to 150° C. in an open round-bottom flask, then stirred for 6 hrs at 150° C. The resulting mixture is cooled to room temperature and diluted with water (200 mL), then basified with ammonium hydroxide (28-30%, 100 mL). After about 10 minutes, the solution is acidified to pH=5 with glacial acetic acid and extracted with CH2Cl2 (3×200 mL). The combined extracts are washed with H2O (200 mL), sat. NaHCO3 (200 mL), then dried over MgSO4 and rotary evaporated. The crude quinoline is filtered through a short pad of silica gel, using CH2Cl2 as solvent. The filtrate is rotary evaporated and the residue recrystallized from hexane/CH2Cl2 to afford 8-methyl-7-nitroquinoline as a tan solid.
Reaction SMILES: C([O:3][C:4](=[O:29])[C:5]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)(=[O:20])=[O:19])([CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])C>CO.[OH-].[Na+]>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([S:18]([C:5]([CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)([CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])[C:4]([OH:29])=[O:3])(=[O:20])=[O:19])=[CH:22][CH:23]=1
Reactant: CCOC(=O)C(CC=C(C)C)(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(S(=O)(=O)C(CC=C(C)C)(Cc2cccnc2)C(=O)O)cc1

Procedure:
2-(4-Methoxy-benzenesulfonyl)-5-methyl-2-pyridin-3-ylmethyl-hex-4-enoic acid was prepared starting from 2-(4-methoxy-benzenesulfonyl)-5-methyl-2-pyridin-3-ylmethyl-hex-4-enoic acid ethyl ester (4.0 g, 9.5 mmol) dissolved in methanol (50 ml) and 10 N NaOH (30 ml). The resulting reaction mixture was worked up as outlined in Example 9. Yield 3.2 g, 87%; ivory solid; mp 117-119° C.; MS: 390 (M+H)+.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH:7]([N:10]1[CH2:15][CH2:14][CH:13]([C:16]([NH2:18])=O)[CH2:12][CH2:11]1)([CH3:9])[CH3:8].O.[OH-].[Na+]>C1COCC1>[CH:7]([N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][NH2:18])[CH2:12][CH2:11]1)([CH3:9])[CH3:8]
Reactant: CC(C)N1CCC(C(N)=O)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)N1CCC(CN)CC1
Yield: 23.3 %

Procedure:
To a suspension of 10.0 g of LAH in 500 mL of dry THF, at room temperature, was added portionwise 39.7 g of 1-isopropylpiperidine-4-carboxamide and the mixture was refluxed 18 h. The cooled reaction mixture was diluted with 150 mL THF and treated dropwise with 10 mL H2O and 10 mL 5 N NaOH, respectively. The resulting gray mixture was refluxed 18 h, filtered and evaporated. The residue partially dissolved in hexane to give 25.5 g of crude yellow liquid and 6.9 g hexane insoluble starting carboxamide. HPLC purification on silica gel of the 25.5 g liquid, eluting with 20% MeOH-EtOAc gave 1-isopropylpiperidine-4-methylamine (8.5 g, 28%).
Reaction SMILES: [CH2:1]([CH:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[Cl:14]C(Cl)(Cl)C(OCC)=O>O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(=O)([O-])[O-].[K+].[K+]>[Cl:14][C:3]([CH2:1][CH3:2])([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(CC)C(=O)OCC
Reactant: CCOC(=O)C(Cl)(Cl)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [F-]
Solvent: O
Product: CCOC(=O)C(Cl)(CC)C(=O)OCC
Yield: 70.1 %

Procedure:
In a 10 mL round-bottom flask, 1.88 g of diethyl ethylmalonate (10 mmol), 2.10 g of ethyl trichloroacetate (11 mmol), 158 mg of tetra-n-butylammonium fluoride trihydrate (0.5 mmol), and 69 mg of potassium carbonate (0.5 mmol) were stirred at 24° C. for 5 h. After filtration, the solution was found to contain 1.56 g (70% yield) of diethyl α-chloro-α-ethylmalonate.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([I:13])[CH:8]=2)[N:3]=1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[F:22])[NH2:18].C([O-])(=O)C.[Na+]>C1COCC1.O>[Cl:1][C:2]1[N:11]=[C:10]([NH:18][C:17]2[CH:19]=[CH:20][C:21]([F:22])=[C:15]([Cl:14])[CH:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([I:13])[CH:8]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2cc(I)ccc2n1
Reactant: Nc1ccc(F)c(Cl)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Fc1ccc(Nc2nc(Cl)nc3ccc(I)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 144 h
Yield: 73.4 %

Procedure:
In a 50 mL round-bottomed flask was added 2,4-dichloro-6-iodoquinazoline (0.52 g, 1.6 mmol), 3-chloro-4-fluoroaniline (0.30 g, 2.1 mmol), and sodium acetate (0.20 g, 2.4 mmol) in THF (6 mL) and water (2 mL) to give a brown suspension. After being stirred at room temperature for 6 days, the reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (2×10 mL). The organic layers were combined and washed with brine (1×20 mL), dried over Na2SO4, filtered and concentrated. The resulting product, was washed with CH2Cl2 and dried to give 0.51 g of 2-chloro-N-(3-chloro-4-fluorophenyl)-6-iodoquinazolin-4-amine as a tight brown solid in a 73% yield, 1H NMR (300 MHz, DMSO) δ 10.29 (s, 1H), 8.95 (s, 1H), 8.14 (dd, J=1.5, 9.0 Hz, 1H), 8.06 (dd, J=2.7, 6.6 Hz, 1H), 7.81-7.76 (m, 1H), 7.52-7.46 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:31]([O-])=O)=[C:6]([NH:8][C:9]2[N:17]=[C:16]3[C:12]([N:13]=[C:14]([CH3:24])[N:15]3[CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:11]([C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)[N:10]=2)[CH:7]=1.C(O)(=O)C.O.[OH-].[NH4+]>[Fe].C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[N:17]=[C:16]3[C:12]([N:13]=[C:14]([CH3:24])[N:15]3[CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:11]([C:25]3[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=3)[N:10]=2)[C:5]([NH2:31])=[CH:4][CH:3]=1
Reactant: Cc1nc2c(-c3ccncc3)nc(Nc3cc(Cl)ccc3[N+](=O)[O-])nc2n1C1CCOCC1
Agent: [Fe]
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: Cc1nc2c(-c3ccncc3)nc(Nc3cc(Cl)ccc3N)nc2n1C1CCOCC1
Temperature: 90 °C
Reaction time: 0.17 h

Procedure:
To a vial containing N-(5-chloro-2-nitrophenyl)-8-methyl-6-(pyridin-4-yl)-9-(tetrahydro-2H-pyran-4-yl)-9H-purin-2-amine (16.3 mg, 0.035 mmol) was added glacial acetic acid (1 mL), water (2.5 mL) and ethanol (5 mL), followed by iron powder (20 mg, 0.35 mmol, 10 equiv.) and the resulting mixture heated at 90° C. for 15 min (HPLC monitoring). The reaction mixture was left to cool down to room temperature, concentrated ammonium hydroxide solution was added to bring the pH to basic, and the mixture was stirred for 10 min. The aqueous layer was extracted with ethyl acetate, the combined organic layers were washed with brine, dried (anhydrous Na2SO4), and the solvent removed in vacuo to give the desired product as a pale yellow solid (yield quantitative). This material was used in the next step without further purification. MS (EI) m/z 436.4 (MH)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[OH:1][C:2]1[C:7]([N+:12]([O-:14])=[O:13])=[CH:6][C:5]([C:8]([F:9])([F:11])[F:10])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])O
Reactant: Oc1ccc(C(F)(F)F)cn1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc(C(F)(F)F)cnc1O
Temperature: 80 °C
Reaction time: 1 h
Yield: 41.6 %

Procedure:
To a mixture of 9.84 g of 2-hydroxy-5-(trifluoromethyl)pyridine and 40 ml of concentrated sulfuric acid, 10.9 g of 70% nitric acid was dropped at 80° C. This mixture was stirred at 80° C. for 1 hour. The reaction mixture was cooled down to room temperature, then, the reaction mixture was poured into ice water. The deposited solid was collected by filtration. This solid was washed with ice water, then, dissolved in ethyl acetate, and washed with saturated saline. The organic layer was dried over magnesium sulfate, then, concentrated under reduced pressure, to obtain 5.22 g of 2-hydroxy-3-nitro-5-(trifluoromethyl)pyridine.
Reaction SMILES: [NH2:1][CH2:2]/[CH:3]=[CH:4]\[CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].[OH-].[Na+].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>O.C(Cl)(Cl)Cl>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:1][CH2:2]/[CH:3]=[CH:4]\[CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: NC/C=C\CCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(O)CCC/C=C\CNS(=O)(=O)c1ccc(Cl)cc1
Reaction time: 24 h
Yield: 29.5 %

Procedure:
A rapidly stirred solution of (Z)-7-aminohept-5-enoic acid (0.61 g), sodium hydroxide (0.51 g) in water (5 ml) was treated with 4-chlorobenzenesulphonyl chloride (0.9 g) in chloroform (2.5 ml). The solution was stirred for 24 hours then evaporated with chloroform (4×15 ml). The aqueous layer was treated with hydrochloric acid to pH=1 and extracted with chloroform (4×40 ml). These chloroform extracts were combined, dried over magnesium sulphate and evaporated to dryness. The residue was recrystallised from isopropanol to give the title compound (0.4 g). N.M.R; 250 MHz; δ(CDCl3) (ppm): 1.7 (m, 2H) 2.05 (m, 2H), 2.35 (m, 2H), 3.6 (t, 2H), 4.9 (t, 1H) 5.3 (m, 1H), 5.45 (m, 1H) 7.45 (m, 2H), 7.8 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH:10]3[C:9]3[CH:16]=[CH:17][CH:18]=[CH:19][C:8]=3[CH2:7][C:6]=2[CH:20]=1.Cl[CH2:22][CH2:23][O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH2:12][CH2:13][N:14]([CH2:22][CH2:23][O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH2:15][CH:10]3[C:9]3[CH:16]=[CH:17][CH:18]=[CH:19][C:8]=3[CH2:7][C:6]=2[CH:20]=1
Reactant: Brc1ccc2c(c1)Cc1ccccc1C1CNCCN21
Reactant: COC(=O)COCCCl
Product: COC(=O)COCCN1CCN2c3ccc(Br)cc3Cc3ccccc3C2C1
Yield: 38 %

Procedure:
Following a procedure similar to that described in Example 1, but using 8-bromo-1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrazino[1,2-a]azepine and methyl 2-chloroethoxyacetate, the title compound was obtained in a yield of 38%.
Reaction SMILES: [OH:1][CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].S([O-])([O-])(=O)=O.[Na+].[Na+].[F:20][C:21]([F:29])(S(F)(=O)=O)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>CC#N>[F:20][CH:21]([F:29])[O:1][CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4]
Reactant: O=C(CO)OCc1ccccc1
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: O=C(COC(F)F)OCc1ccccc1
Temperature: 45 °C

Procedure:
Benzyl 2-hydroxyacetate (3.2 ml, 22.2 mmol), sodium sulfate (0.63 g, 4.4 mmol), and MeCN (34 ml) were placed in a 100 ml two-necked RBF fitted with a magnetic stirrer, a dropping funnel and a refluxing condenser. 2,2-Difluoro-2-(fluorosulfonyl)acetic acid (9.18 ml, 89 mmol) was then added with stirring at 45° C. After addition, the mixture was further stirred for 1 h at this temperature. The reaction mixture was poured into 10% aqueous sodium carbonate and was extracted with diethyl ether, the combined extracts were washed with 10% aqueous sodium carbonate, water, brine, dried over sodium sulfate, and concentrated. The crude material was purified by column chromatography (4:1 Hexanes/EtOAc) to afford the intermediate benzyl 2-(difluoromethoxy)acetate which was dissolved in EtOAc (34 mL). N-Ethyl-N-isopropylpropan-2-amine (0.561 ml, 3.2 mmol) was added and after degassing with nitrogen, palladium on carbon (0.680 g, 0.64 mmol) was added. The reaction was purged with hydrogen and stirred under 50 PSI of hydrogen for 24 hours. The degassed reaction was filtered through a pad of Celite and concentrate to afford the titled product as the amine salt which was used directly for subsequent reaction steps without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:12](=[O:13])[CH2:11][CH2:10][C:9]2=[O:14])=[CH:3][CH:2]=1.[ClH:15]>C(O)C.[Pt]=O>[ClH:15].[NH:1]1[CH2:2][CH2:3][CH:4]([CH2:7][N:8]2[C:12](=[O:13])[CH2:11][CH2:10][C:9]2=[O:14])[CH2:5][CH2:6]1
Reactant: O=C1CCC(=O)N1Cc1ccncc1
Agent: O=[Pt]
Agent: Cl
Solvent: CCO
Product: O=C1CCC(=O)N1CC1CCNCC1

Procedure:
A suspension of platinum oxide (0.3 g), in a solution of XVII (16.71 g, 88 mmol) in ethanol (100 mL) and concentrated HCl (17.6 g, 176 mmol), was hydrogenated in a 500 mL Parr bottle at 60 psi and room temperature for 24 hr. The mixture was then filtered. The filtrate was concentrated in vacuo to give the product as a white powder which was used in the next step without further purification.