Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[OH:9])=[CH:4][CH:3]=1.O[CH:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[N+:33]([O-:35])=[O:34])[CH2:19][CH2:18]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[O:9][CH:17]2[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][CH2:25][O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[N+:33]([O-:35])=[O:34])[CH2:21][CH2:22]2)=[CH:4][CH:3]=1
Reactant: OC(c1ccc(Cl)cc1)c1ccccn1
Reactant: O=[N+]([O-])c1ccccc1OCCCN1CCC(O)CC1
Product: O=[N+]([O-])c1ccccc1OCCCN1CCC(OC(c2ccc(Cl)cc2)c2ccccn2)CC1

Procedure:
The procedure of Example 32 (a) was repeated except for using (4-chlorophenyl)-2-pyridylmethanol and 4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine instead of phenyl-2-pyridylmethanol and 4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give oily 4-[(4-chlorophenyl)-2-pyridylmethoxy]-1-[3-(2-nitrophenoxy)propyl]piperidine.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=1.[CH3:9][N:10]([CH3:14])[CH2:11][CH2:12][NH2:13]>C(OCCO)C.CCOC(C)=O>[CH3:9][N:10]([CH3:14])[CH2:11][CH2:12][NH:13][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=1
Reactant: Clc1ccc(I)cn1
Reactant: CN(C)CCN
Solvent: CCOC(C)=O
Solvent: CCOCCO
Product: CN(C)CCNc1ccc(I)cn1
Yield: 34.7 %

Procedure:
A stirred solution of 2-chloro-5-iodopyridine (0.50 g, 2.18 mmol) and N,N-dimethylethylenediamine (0.81 g, 1.00 mL, 9.20 mmol) in 2-ethoxyethanol (5 mL) was heated in a sealed tube under microwave irradiation at 125° C. for 1 h. The reaction mixture was then diluted with EtOAc (50 mL), washed with water (3×20 mL), dried (MgSO4), filtered and concentrated in vacuo. The residual oil was purified by column chromatography (SiO2, 3:1 EtOAc/MeOH) to give the title compound (0.22 g, 36%) as a viscous oil which solidified on standing. δH (CDCl3) 8.19 (1H, br. s), 7.53 (1H, m), 6.23 (1H, m), 3.29 (2H, m), 2.52 (2H, m), 2.24 (6H, s). Exchangeable proton not observed. LCMS (ES+) 292.0 (M+H)+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([NH:17][C@H:18]3[CH2:23][CH2:22][C@H:21]([OH:24])[CH2:20][CH2:19]3)=[CH:12][CH:13]=[N:14]2)=[CH:9][CH:8]=1.C(N(CC)CC)C>ClCCl>[Cl:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([NH:17][C@H:18]3[CH2:19][CH2:20][C@H:21]([O:24][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:22][CH2:23]3)=[CH:12][CH:13]=[N:14]2)=[CH:9][CH:8]=1
Reactant: O[C@H]1CC[C@H](Nc2ccnc3cc(Cl)ccc23)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)O[C@H]1CC[C@H](Nc2ccnc3cc(Cl)ccc23)CC1

Procedure:
447 ml of methanesulphonyl chloride were added portionwise within 20 minutes while cooling with an ice bath to a mixture of 1157 g of trans-N-(7-chloro-quinolin-4-yl)-4-aminocyclohexanol and 868 ml of triethylamine in 6.1 l of dichloromethane. After a clear solution formed transiently the product began to separate. After 2 hours the mixture was filtered and the filtrate was evaporated to dryness. Filter residue and evaporation residue were combined and triturated. in 8 l of water. The mixture was again filtered, washed with a further 8 l of water and thereafter with 4 l of isopropanol and the product obtained was dried at 50° C./12 mbar. Yield: 2028 g (90%) of trans-N-(7-chloro-quinolin-4-yl)-4-methanesulphonyloxy-cyclohexylamine, m.p.: 154-159° C.
Reaction SMILES: [CH2:1]([C:3]1[O:7][C:6]([NH2:8])=[N:5][N:4]=1)[CH3:2].N1C=CC=CC=1.Cl[C:16]([O:18][CH2:19][C:20]([Cl:23])([Cl:22])[Cl:21])=[O:17].O>O1CCCC1>[CH2:1]([C:3]1[O:7][C:6]([NH:8][C:16](=[O:17])[O:18][CH2:19][C:20]([Cl:23])([Cl:22])[Cl:21])=[N:5][N:4]=1)[CH3:2]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CCc1nnc(N)o1
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCOC1
Product: CCc1nnc(NC(=O)OCC(Cl)(Cl)Cl)o1
Yield: 29.9 %

Procedure:
To a solution of 5-ethyl-1,3,4-oxadiazol-2-ylamine (1.00 g, 8.84 mmol) and pyridine (2.10 ml, 26.5 mmol) in tetrahydrofuran (29 ml) was added, under ice-cooling, 2,2,2-trichloroethyl chloroformate (2.45 ml, 17.7 mmol), and the mixture was stirred at room temperature for 1.5 hour. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give 763 mg (29.9%) of the desired product as a solid.
Reaction SMILES: [Br:1]Br.[O:3]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[O:6][CH:5]([CH2:13][OH:14])[CH2:4]1>C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+].[O-]S([O-])=O.[Na+].[Na+]>[Br:1][C:10]1[CH:11]=[C:12]2[O:3][CH2:4][CH:5]([CH2:13][OH:14])[O:6][C:7]2=[N:8][CH:9]=1
Reactant: BrBr
Reactant: OCC1COc2cccnc2O1
Agent: O=C([O-])[O-]
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: OCC1COc2cc(Br)cnc2O1
Temperature: 25 °C
Yield: 40.6 %

Procedure:
Bromine (0.009 mol) was added dropwise to a solution of 2,3-dihydro-1,4-dioxino[2,3-b]pyridine-3-methanol (0.009 mol) in DCM (100 ml) and Na2CO3 saturated solution (50 ml), stirred at room temperature. The reaction mixture was stirred for 16 hours at room temperature. More bromine (0.009 mol) was added and the reaction mixture was stirred for 3 more days at room temperature. A few drops of Na2SO3 were added and the mixture was stirred for 15 minutes. The separated organic layer was dried, filtered and the solvent evaporated. The residue was purified by short open column chromatography over silica gel (eluent: CH2Cl2/CH3OH 100/0; 98/2). The desired fractions were collected and the solvent was evaporated, yielding 0.9 g of 7-bromo-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-3-methanol (intermediate 35).
Reaction SMILES: B(Cl)([C@H]1[C@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1)[C@H]1[C@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][CH2:31][C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([CH:40]=[CH:41][C:42]2[CH:51]=[CH:50][C:49]3[C:44](=[CH:45][C:46]([F:53])=[C:47]([F:52])[CH:48]=3)[N:43]=2)[CH:35]=1)=[O:33].N(CCO)CCO>C(Cl)Cl>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][CH2:31][C@@H:32]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([CH:40]=[CH:41][C:42]2[CH:51]=[CH:50][C:49]3[C:44](=[CH:45][C:46]([F:53])=[C:47]([F:52])[CH:48]=3)[N:43]=2)[CH:35]=1)[OH:33]
Reactant: O=C(CCc1ccccc1Cl)c1cccc(C=Cc2ccc3cc(F)c(F)cc3n2)c1
Agent: C[C@@H]1[C@H]2C[C@@H](C[C@H]1B(Cl)[C@@H]1C[C@@H]3C[C@H]([C@H]1C)C3(C)C)C2(C)C
Solvent: OCCNCCO
Solvent: ClCCl
Product: O[C@@H](CCc1ccccc1Cl)c1cccc(C=Cc2ccc3cc(F)c(F)cc3n2)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
At -20° C., a solution of (-)-B-chlorodiisopinocampheylborane (1.74 g, 1.5 equiv.) in 9 mL of CH2Cl2 was added dropwise to a suspension of the ketone of Step 4 (1.52 g, 3.5 mmol) in 18 mL of CH2Cl2 and the mixture was stirred at 0° C. for an hour and at room temperature for 2 hours. At 0° C., 10% aq. diethanolamine was added and the mixture was stirred at r.t. for 30 min. The product was extracted in EtOAc:THF 1:1, washed with brine, dried over Na2SO4, and concentrated. The oil was dissolved in ether and conc. HCl (5 ml) was added. The precipitated hydrochloride was filtered, washed with ether, and dissolved in THF:0.1 N NaOH. The product was extracted in EtOAc:THF 1:1, washed with brine, dried over Na2SO4 and purified by flash chromatography with EtOAc:toluene 10:90. Yield 1.125 g, 74%.
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[CH:15][C:5]2[NH:6][C:7]([C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.Br/[CH:19]=[CH:20]\[CH3:21].II.[Mg]>C1COCC1.C(Cl)Cl>[Cl:17][C:16]1[C:2]([Cl:1])=[CH:3][C:4]2[NH:8][C:7]([C:9]([OH:14])(/[CH:19]=[CH:20]\[CH3:21])[C:10]([F:13])([F:11])[F:12])=[N:6][C:5]=2[CH:15]=1
Reactant: C/C=C\Br
Reactant: O=C(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Agent: II
Agent: [Mg]
Solvent: ClCCl
Solvent: C1CCOC1
Product: C/C=C\C(O)(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 1-(5,6-dichloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (510 mg) in THF (5 mL) at 0° C. was added Grignard reagent, which was freshly prepared from cis-1-bromo-1-propene (1.07 mL), a small iodine flake, and magnesium powder (306 mg) in THF (5 mL). The resulting mixture was then stirred at room temperature for 3 hr. The reaction was quenched with NH4Cl (sat. aq), filtered through a pad of Celite®, rinsed with EtOAc, the layers were separated, the aqueous layer extracted with EtOAc, dried over Na2SO4, filtered, and concentrated to yield a residue. The residue was purified by flash chromatography with Biotage 40s+ column and elution with 10%-40% EtOAc/hexanes to yield a yellow solid. The yellow solid was dissolved in a minimal amount of CH2Cl2 and triturated with hexanes to yield the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([C:4]1[N:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[N:35]([C:36]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[C:7]2[CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:9][CH2:10][CH2:11][C:6]=2[N:5]=1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH2:61](Br)[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1.CN(C)C=O>C(OCC)(=O)C>[CH2:61]([N:9]1[CH2:10][CH2:11][C:6]2[N:5]=[C:4]([CH2:1][CH2:2][CH3:3])[N:17]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]4[N:35]([C:36]([C:43]5[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=5)([C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=5)[C:49]5[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=5)[N:34]=[N:33][N:32]=4)=[CH:23][CH:24]=3)[C:7]=2[CH:8]1[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1
Reactant: CCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc1)C(C(=O)OCC)NCC2
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc1)C(C(=O)OCC)N(Cc1ccccc1)CC2
Yield: 66.6 %

Procedure:
A mixture of ethyl 2-n-propyl-3-[2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (2.00 g), potassium carbonate (1.16 g), benzyl bromide (0.72 g) and dimethylformamide (10 ml) is stirred under ice-cooling for two hours. The mixture is diluted with ethyl acetate, and the solution is washed with water, dried and evaporated. The residue is purified by silica gel column chromatography (solvent; n-hexane/ethyl acetate) to give ethyl 5-benzyl-2-n-propyl-3-[2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (1.50 g) as a white foam.
Reaction SMILES: [F:1][C:2]([F:25])([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=1)[C:3]1[N:12]=[C:11](O)[C:10]2[C:5](=[C:6]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.P(Br)(Br)(Br)=O.CCN(C(C)C)C(C)C.[CH3:40][C:41]1[NH:45][N:44]=[C:43]([NH2:46])[CH:42]=1>CN(C=O)C.C1(C)C=CC=CC=1>[F:1][C:2]([F:25])([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=1)[C:3]1[N:12]=[C:11]([NH:46][C:43]2[CH:42]=[C:41]([CH3:40])[NH:45][N:44]=2)[C:10]2[C:5](=[C:6]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: CS(=O)(=O)c1cccc2c(O)nc(C(F)(F)c3ccc(F)cn3)nc12
Reactant: Cc1cc(N)n[nH]1
Agent: O=P(Br)(Br)Br
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nc(C(F)(F)c3ccc(F)cn3)nc3c(S(C)(=O)=O)cccc23)n[nH]1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 59.5 %

Procedure:
To 2-(difluoro(5-fluoropyridin-2-yl)methyl)-8-(methylsulfonyl)quinazolin-4-ol (100 mg, 0.27 mmol) were added phosphoryl tribromide (1.25 g) and toluene (0.5 mL) and DIEA (0.094 mL, 0.54 mmol), and the mixture was heated at 100° C. for 20 min. The mixture was cooled and partitioned between EtOAc and saturated aq sodium bicarbonate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. To the residue was added a solution of 5-methyl-1H-pyrazol-3-amine (67 mg, 0.69 mmol) in DMF (3 mL) and the mixture was stirred at rt for 0.5 h. The crude mixture was purified by preparative HPLC (Phenomenex C-18 reverse phase column, eluting with a gradient of solvent B=0.05% HOAc/ACN and solvent A=0.05% HOAc/H2O) to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-N-(5-methyl-1H-pyrazol-3-yl)-8-(methylsulfonyl)quinazolin-4-amine (72 mg, 69%). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.21 (s, 3H) 3.47 (s, 3H) 6.14 (s, 1H) 7.83 (t, J=7.91 Hz, 1H) 7.97-8.09 (m, 2H) 8.44 (d, J=7.35 Hz, 1H) 8.68 (s, 1H) 9.03 (d, J=8.10 Hz, 1H) 11.11 (s, 1H) 12.24-12.36 (m, 1H); LC-MS (ESI) m/z 449 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:9][C:7](=O)[CH2:6][C:4](=[O:5])[CH2:3]1.C(Cl)(=O)C([Cl:14])=O>C(Cl)(Cl)Cl>[Cl:14][C:7]1[CH2:9][C:2]([CH3:10])([CH3:1])[CH2:3][C:4](=[O:5])[CH:6]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC1(C)CC(=O)CC(=O)C1
Solvent: ClC(Cl)Cl
Product: CC1(C)CC(=O)C=C(Cl)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
The title compound was prepared using the method of Clark and Heathcock. J. Org. Chem., 1976, 41, 636. To a suspension of dimedone (15.0 g, 107 mmol) in chloroform (40 ml) was added slowly oxalyl chloride (27.2 g, 214 mmol). The addition was accompanied by vigorous evolution of gas. After stirring at room temperature for 10 minutes, the slurry was refluxed for 20 minutes to give a yellow solution which was evaporated and distilled to give 15.7 g (92%) of chloroenone as a colorless liquid, bp 72° (5 mm). ##STR5##
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].C(=O)([O-])[O-].[Ca+2].[CH2:10]([O:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>ClCCl.O>[CH2:10]([O:17][C:18]1[CH:19]=[CH:20][C:21]([N:22]=[C:1]=[S:2])=[CH:23][CH:24]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: S=C(Cl)Cl
Reactant: Nc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: ClCCl
Solvent: O
Product: S=C=Nc1ccc(OCc2ccccc2)cc1
Temperature: 15 °C
Reaction time: 4 h

Procedure:
Thiophosgene (12.63 g) was added at 0° C. to a stirred suspension of calcium carbonate (11.05 g) in a mixture of dichloromethane (100 ml) and water (100 ml). A solution of p-benzyloxyaniline (16.5 g) in dichloromethane (100 ml) was added dropwise at 0° C. over 30 minutes. The mixture was stirred for four hours at 15° C. The organic layer was separated, dried and the solvent removed by evaporation to give a residue which was extracted into boiling hexane to give 4-benzyloxyphenylisothiocyanate (m.p. 69° C.).
Reaction SMILES: [F:1][C:2]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:3]=1[CH2:4][N:5]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH3:34])=[CH:29][CH:28]=1)[C:6](=[O:25])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([O:22][CH2:23][CH3:24])[C:17]([O:19]CC)=[O:18])=[CH:11][CH:10]=1.[Li+].[OH-].Cl>C(#N)C>[F:1][C:2]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:3]=1[CH2:4][N:5]([CH2:26][C:27]1[CH:28]=[CH:29][C:30]([CH2:33][CH3:34])=[CH:31][CH:32]=1)[C:6](=[O:25])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([O:22][CH2:23][CH3:24])[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)N(Cc2ccc(CC)cc2)Cc2ccc(F)cc2F)cc1)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Product: CCO[C@@H](Cc1ccc(OCC(=O)N(Cc2ccc(CC)cc2)Cc2ccc(F)cc2F)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
To a solution of ethyl(2S)-3-(4-{2-[(2,4-difluorobenzyl)(4-ethylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoate (1.13 g, 2.1 mmol) in acetonitrile (100 mL) was added aqueous 0.10 M LiOH (52 mL) and the solution was stirred at room temperature overnight. After neutralisation with 5% HCl, the solvent volume was reduced in vacuo and the remaining aqueous phase was acidified with 5% HCl and extracted with ethyl acetate (3×100 mL). The combined organic phase was washed with brine (100 mL), dried over Na2SO4, and concentrated in vacuo to afford 1.01 g (94%) of a colourless oil.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:21][C@@H:20]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[C@H:19](/[CH:30]=[CH:31]/[C@@H:32]([O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[CH2:33][C@H:34]([CH3:39])[CH2:35][CH2:36][CH2:37][CH3:38])[C:8]=1[S:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])(=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)=O.[CH3:72][OH:73].[O-][Si]([O-])=O.[Mg+2]>O1CCCC1.CN(C)C=O.[C]=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[CH:72]([C:7]1[CH2:21][C@@H:20]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[C@H:19](/[CH:30]=[CH:31]/[C@@H:32]([O:40][Si:41]([C:44]([CH3:45])([CH3:46])[CH3:47])([CH3:43])[CH3:42])[CH2:33][C@H:34]([CH3:39])[CH2:35][CH2:36][CH2:37][CH3:38])[C:8]=1[S:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[O:73]
Reactant: CCCC[C@@H](C)C[C@@H](/C=C/[C@@H]1C(SCCCCCC(=O)OC)=C(OS(=O)(=O)C(F)(F)F)C[C@H]1O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Reactant: CO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=[Si]([O-])[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O=CO
Product: CCCC[C@@H](C)C[C@@H](/C=C/[C@@H]1C(SCCCCCC(=O)OC)=C(C=O)C[C@H]1O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Temperature: 80 °C
Reaction time: 15 h

Procedure:
Methyl (11R,12S,13E,15S,17R)-9-trifluoromethanesulfonyloxy-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethyl-7-thiaprosta-8,13-dienoate (120 mg, 0.154 mmol), palladium acetate (11.2 mg, 0.05 mmol), triphenylphosphine (26 mg, 0.1 mmol), formic acid (12 μl, 0.309 mmol), and triethylamine (65 μl, 063 mmol) in tetrahydrofuran (6 mL) were placed in an autoclave into which carbon monoxide gas was pumped under pressure to give the internal pressure of 17 atmospheres. The solution was heated and agitated at 80° C. for 15 hours. This was dissolved in dimethylformamide (2 ml). Methanol (810 μl, 20 mmol) and triethylamine (139 μl, 1 mmol) were added. This was agitated in carbon monoxide atmosphere (1 atmosphere) at room temperature for further 18 hours. The reaction vessel was cooled to room temperature, then carbon monoxide in the reaction vessel was removed, the reaction solution thus obtained was passed through Florisil column, was concentrated under reduced pressure, and was purified by silica gel column chromotography (2 to 5% ethyl acetate/hexane) to obtain methyl (11R,12S,13E,15S,17R)-9-formyl-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethyl-7-thiaprosta-8,13-dienoate as a crude (21 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:16]#[N:17])[CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.[N-:18]=[N+:19]=[N-:20].[Na+].[Cl-].[NH4+].Cl>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13]([S:12][C:11]3[CH:10]=[C:9]([C:16]4[NH:20][N:19]=[N:18][N:17]=4)[CH:8]=[CH:7][C:6]=3[CH2:5]2)=[CH:14][CH:15]=1
Reactant: N#Cc1ccc2c(c1)Sc1ccc(Cl)cc1C2
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Clc1ccc2c(c1)Cc1ccc(-c3nnn[nH]3)cc1S2
Temperature: 130 °C

Procedure:
A mixture of 2-chloro-6-cyanothioxanthene (1.38g.), sodium azide (0.71g.), ammonium chloride (0.59g.) and dimethylformamide (20 ml.) was heated at 130° C. for 7 hr. The mixture was cooled, poured into cold dilute hydrochloric acid, and the precipitated product filtered off. Recrystallisation from acetic acid yielded 7-chloro-3(5-tetrazolyl)thioxanthene, which was dired at 154° C./20mm Hg., m.pt. 257° C. with decomposition.
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([N:8]2[CH2:11][CH:10](OS(C)(=O)=O)[CH2:9]2)[O:6][CH:7]=1)#[N:2].[C:17]([O-:20])(=[S:19])[CH3:18].[K+]>CN(C)C=O>[C:17]([S:19][CH:10]1[CH2:9][N:8]([C:5]2[O:6][CH:7]=[C:3]([C:1]#[N:2])[N:4]=2)[CH2:11]1)(=[O:20])[CH3:18]
Reactant: CS(=O)(=O)OC1CN(c2nc(C#N)co2)C1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CN(c2nc(C#N)co2)C1
Temperature: 80 °C
Reaction time: 5 h
Yield: 55.4 %

Procedure:
To a solution of 1-(4-cyano-1,3-oxazol-2-yl)-3-methanesulfonyloxyazetidine (309 mg, 1.27 mmol) (obtained as described in Reference Example 23(3)) in dimethylformamide (15 ml) was added potassium thioacetate (0.87 g, 7.62 mmol) at room temperature. The reaction mixture was stirred in an oil bath (80° C.) for 5 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The obtained organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (2:1) as the eluant to afford 3-acetylthio-1-(4-cyano-1,3-oxazol-2-yl)azetidine (157 mg, yield 55%) as a colorless oil.
Reaction SMILES: C(N(CC)CC)C.[N:8]1([C:14]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=2[C:16]([NH2:25])=[N:17][C:18]([NH2:24])=[N:19]3)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.Br[CH2:27][C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=1.[ClH:38].O1CCOCC1>CN(C)C=O>[ClH:38].[CH:29]1[C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:36]=[CH:37][C:28]=1[CH2:27][N:11]1[CH2:12][CH2:13][N:8]([C:14]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=2[C:16]([NH2:25])=[N:17][C:18]([NH2:24])=[N:19]3)[CH2:9][CH2:10]1
Reactant: Nc1nc(N)c2c(N3CCNCC3)cccc2n1
Reactant: BrCc1ccc2ccccc2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1nc(N)c2c(N3CCN(Cc4ccc5ccccc5c4)CC3)cccc2n1
Temperature: 60 °C
Yield: 71 %

Procedure:
In a 20 mL vial with stir bar, triethylamine (40 mg; 0.4 mmol) was added to a mixture of 5-piperazin-1-yl-quinazoline-2,4-diamine (50 mg; 0.2 mmol) and 2-(bromomethyl)naphthalene (59 mg; 0.26 mmol) in N,N-dimethylformamide and heated to 60° C. for 72 hours. Mixture was quenched with 1 mL of 1N NaOH and after 1.5 hours solids were collected by filtration and triturated with ethanol. Solids were stirred at room temperature with 4M HCl in Dioxane (2 eq). Solids were collected and dried to 60 mg of title compound. (71% yield). 1H NMR (500 MHz, DMSO-d6) δ 12.8 (s, 1H), 11.7 (s, 1H), 9.38 (s, 1H), 9.07 (s, 1H), 8.16 (s, 1H), 8.00 (m, 3H), 7.85 (dd, J=8.5, 1.0 Hz, 1H), 7.75 (t, J=8.0 Hz, 1H), 7.61 (m, 2H), 7.27 (d, J=8.5 Hz, 1H), 7.18 (d, J=8.5 Hz, 1H), 4.54 (s, 2H), 3.58 (m, 2H), 3.43 (d, J=11.5 Hz, 2H), 3.32 (t, J=12.0 Hz, 2H), 3.25 (d, J=12.0 Hz, 2H). ESIMS+385.8 m/z
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1N.C(O)C.Cl.N([O-])=O.[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: Nc1c(Cl)cc(Cl)cc1C(=O)O
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc(Cl)cc(Cl)c1
Temperature: 75 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
206 parts of 3,5-dichloroanthranilic acid are introduced into 400 parts of ethanol and 400 parts of 36 percent strength by weight hydrochloric acid are then added. A solution of 100 parts of NaNO2 in 150 parts of water is run in at 75° C., resulting in the evolution of nitrogen. The mixture is stirred for one hour at 75° C. and is then cooled, 1,500 parts of water are added and the product is filtered off. 183 parts (89% of theory) of 3,5-dichlorobenzoic acid of melting point 170°-175° C. are obtained.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][N:5]1[C:9]2[C:10]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][S:6]1(=[O:19])=[O:18].O.FC(F)(F)C(O)=O>C(Cl)Cl>[O:2]=[CH:3][CH2:4][N:5]1[C:9]2[C:10]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][S:6]1(=[O:18])=[O:19]
Reactant: COC(=O)c1cccc2c1N(CC(OC)OC)S(=O)(=O)N2
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cccc2c1N(CC=O)S(=O)(=O)N2
Yield: 148 %

Procedure:
The solution of methyl 3-(2,2-dimethoxyethyl)-1,3-dihydro-2,1,3-benzothiadiazole-4-carboxylate 2,2-dioxide (0.2 g, 0.5 mmol) from Step D above in methylene chloride (10 mL) with water (1 mL) and trifluoroacetic acid (0.5 mL) was stirred at room temperature for 3.5 h. The reaction mixture was concentrated under reduced pressure and dried overnight under high vacuum to remove the excess trifluoroacetic acid, providing methyl 3-(2-oxoethyl)-1,3-dihydro-2,1,3-benzothiadiazole-4-carboxylate 2,2-dioxide (0.2 g): 1H NMR (500 MHz, DMSO-d6) δ 9.56 (s, 1H), 7.42 (dd, J=7.5, 1.5 Hz, 1H), 7.19-6.99 (m, 2H), 4.71 (s, 2H), 3.78 (s, 3H).