Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[F:19])[CH:14]=O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[F:19])[CH:14]=[N:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1
Reactant: N#Cc1ccc(N)cn1
Reactant: O=Cc1ccc(F)c(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: N#Cc1ccc(N=Cc2ccc(F)c(Cl)c2)cn1
Temperature: 25 °C
Yield: 93.1 %

Procedure:
A mixture of 5-amino-2-cyanopyridine (2.86 g, 24 mmol), 3-chloro-4-fluoro-benzaldehyde (3.79 g, 24 mmol) and p-toluenesulfonic acid (92 mg, 0.5 mmol) in toluene (150 mL) was heated to reflux for 12 hours. Then the reaction mixture was cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 5-[(3-chloro-4-fluoro-benzylidene)-amino]-pyridine-2-carbonitrile (5.8 g, 93.6%) as a light yellow solid. MS (ESI+) [(M+H)+] 260.1.
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][C:13](Br)=[CH:14][CH:15]=2)[O:10][C:9]([C:18]2[N:19]=[CH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:8]1)(C)(C)C.[NH2:28][C:29]1[CH:30]=[C:31]([C:35]#[CH:36])[CH:32]=[CH:33][CH:34]=1>>[NH2:28][C:29]1[CH:30]=[C:31]([C:35]#[C:36][C:13]2[CH:12]=[C:11]3[C:16]([C:7](=[N:6][OH:5])[CH:8]=[C:9]([C:18]4[N:19]=[CH:20][C:21]5[C:26]([CH:27]=4)=[CH:25][CH:24]=[CH:23][CH:22]=5)[O:10]3)=[CH:15][CH:14]=2)[CH:32]=[CH:33][CH:34]=1
Reactant: C#Cc1cccc(N)c1
Reactant: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2cc(Br)ccc12
Product: Nc1cccc(C#Cc2ccc3c(=NO)cc(-c4cc5ccccc5cn4)oc3c2)c1

Procedure:
7-(3-aminophenyl)ethynyl-2-isoquinolin-3-yl-chromen-4-one oxime was prepared in 17% overall yield using the method described in example 24, starting from 7-bromo-2-isoquinolin-3-yl-chromen-4-one O-tert-butyl oxime (example 2B) and 3-aminophenylacetylene. The title compound was isolated as a yellow solid and as a 95/5 mixture of Z/E oxime isomers.
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:8]=[C:9]([O:13][CH3:14])[CH:10]=[CH:11][CH:12]=1.CN(C)[CH:17]=[O:18].O>O1CCCC1>[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:8]=1[CH:17]=[O:18]
Reactant: COc1cccc(F)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(F)c1C=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of butyllithium in hexanes (2.5 M; 15.9 ml) was added to a stirring solution of 3-fluoroanisole (5.0 g) in dry tetrahydrofuran (100 ml) at -78° C. and the mixture stirred at that temperature for 30 min. Dry dimethylformamide (3.1 ml) was added and the mixture stirred and allowed to warm to ambient temperature during one hour. Water (150 ml) was added and the mixture extracted with ethyl acetate (3×100 ml). The combined extracts were washed with brine (100 ml), dried over magnesium sulphate, and the solvent removed in vacuo. Distillation of the residue under reduced pressure gave 2-fluoro-6-methoxybenzaldehyde (4.6 g) as an oil b.p. 120° C. at 10.66 mbar.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:22][CH2:21][CH2:20][C@H:9]1[C:10]([NH:12][C@H:13]([C:16]([O:18][CH3:19])=[O:17])[CH2:14]O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C1(C)C(S(Cl)(=O)=O)=CC=CC=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:22][CH2:21][CH2:20][C@H:9]1[C:10]([NH:12][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH2:14])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@H](CO)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: Cc1ccccc1S(=O)(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C=C(NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(=O)OC

Procedure:
31.6 g of methyl t-butoxycarbonylprolylserinate are dissolved in 300 ml methylene chloride. 20.2 g of N-methylmorpholine are added to the solution followed by the addition of 19.1 g toluenesulfonyl chloride. The reaction mixture is chromatographed on silica gel to obtain pure product, methyl t-butoxycarbonylprolyldehydroalaninate.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:7][CH3:8])=[N:5][N:6]=1.[I:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][Br:15])=[CH:12][CH:11]=1>C(O)C>[BrH:15].[CH2:7]([C:4]1[S:3][C:2](=[NH:1])[N:6]([CH2:14][C:13]2[CH:16]=[CH:17][C:10]([I:9])=[CH:11][CH:12]=2)[N:5]=1)[CH3:8]
Reactant: CCc1nnc(N)s1
Reactant: BrCc1ccc(I)cc1
Solvent: CCO
Product: Br
Product: CCc1nn(Cc2ccc(I)cc2)c(=N)s1
Yield: 64.9 %

Procedure:
A solution of 2-amino-5-ethyl-1,3,4-thiadiazole (42.6 g) and 4-iodobenzyl bromide (89.1 g) in ethanol (500 ml) was heated under reflux for 20 hours. After the reaction mixture was cooled, the crystals so precipitated were collected by filtration and then dried, whereby 83 g of the title compound was obtained.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:13])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[OH:12])[CH2:3][CH2:2]1.[O:14]1[CH2:16][C@H:15]1[CH2:17]OS(C1C=CC=C([N+]([O-])=O)C=1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH:1]1([NH:4][C:5](=[O:13])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:12][CH2:17][C@@H:15]2[CH2:16][O:14]2)[CH2:2][CH2:3]1
Reactant: O=C(NC1CC1)c1ccccc1O
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(NC1CC1)c1ccccc1OC[C@@H]1CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
A mixture of N-cyclopropyl-2-hydroxybenzamide (270 mg, 1.52 mmol), (2S)-oxiran-2-ylmethyl-3-nitrobenzenesulfonate (378 mg, 1.68 mmol) and cesium carbonate (645 mg, 1.98 mmol) in DMF (4 mL) was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography (40% heptane in ethyl acetate) to give the subtitled compound (354 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH2:9](Br)[CH:10]=[CH2:11].[OH-].[Na+]>CC(C)=O>[CH2:11]([O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH:10]=[CH2:9]
Reactant: Oc1ccc(F)cc1
Reactant: C=CCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: C=CCOc1ccc(F)cc1

Procedure:
This compound was prepared from 4-fluorophenol and allyl bromide according to the process described in Example 5, stage A. The solvent used is acetone and the reaction was carried out in the presence of sodium hydroxide.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH2:16][CH2:15]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[OH:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1>O1CCOCC1.O.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>[CH2:23]([S:20]([N:17]1[CH2:18][CH2:19][CH:14]([C:5]2[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=[C:2]([C:38]4[CH:39]=[CH:40][C:35]([CH2:34][OH:33])=[CH:36][CH:37]=4)[CH:3]=3)[NH:7][CH:6]=2)[CH2:15][CH2:16]1)(=[O:22])=[O:21])[CH3:24]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: OCc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CO)cc4)cc23)CC1
Temperature: 160 °C
Yield: 30.2 %

Procedure:
To a solution of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (20.0 mg, 0.048 mmol), K3PO4 (21.0 mg, 0.096 mmol) and [4-(hydroxymethyl)phenyl]boronic acid (30.0 mg, 0.193 mmol) in dioxane/H2O (2 mL/0.7 mL) was bubbled argon for 5 minutes prior to addition of Pd(PPh3)4 (5.0 mg, 0.0048 mmol). The reaction mixture was heated in a microwave reactor (Smith synthesizer) for 20 minutes at 160° C. The solvent was evaporated, and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine (10 mL), dried over MgSO4, filtered, concentrated, and purified by reverse phase HPLC method A (water/CH3CN, 0.1% TFA 10-90%) to give the title compound (6.4 mg, 30%).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Cl:5][CH2:6][C:7](Cl)=[O:8].[CH2:10]([OH:18])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCl>[Cl:5][CH2:6][C:7]([C:15]1[CH:16]=[CH:17][C:12]([CH2:11][CH2:10][OH:18])=[CH:13][CH:14]=1)=[O:8]
Reactant: OCCc1ccccc1
Reactant: O=C(Cl)CCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(CCl)c1ccc(CCO)cc1
Temperature: -10 °C
Yield: 81.9 %

Procedure:
Finely ground AlCl3 (92.0 g, 0.69 mol) was mixed with dichloromethane (120 ml) in a flask and cooled to -10° C. Chloracetyl chloride (37.3 g, 0.33 mol) was added to the mixture as it was kept cool. Phenethyl alcohol (36.6 g, 0.30 mol) was dissolved in dichloromethane (20 ml) and charged to a dropping funnel. The phenethyl alcohol solution was added slowly dropwise to the mixture over 2 hours while stirring and keeping the temperature at about 10° C. At the end of the addition, the mixture was allowed to warm to room temperature and stirred overnight. The red color solution was poured into a large quantity of ice (about 300 g). The organic layer was separated and the aqueous layer was extracted with dichloromethane (200 ml), and the dichloromethane portions were washed with water until neutral. The organic phase was then dried (magnesium sulfate), concentrated, recrystallized (ether), and dried to give 48.8 g (81.9%) of compound 5. Analysis of the products gave the following results: mp 41°-45° C.; NIR (KBr) 3477, 3355, 2947, 1702, 1693, 1606, 1218, 1044, 818 cm-1 ; 1H NMR (60 MHz) δ 1.96 (s, 1H), 2.92 (t, 2H, J=6.5 Hz), 3.90 (t, 2H, J=6.5 Hz), 4.67 (s,2H), 7.2-7.4 (m, 2H), 7.8-8.0 (m, 2H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([CH2:12][CH3:13])[C:10]#[N:11].[CH2:14](N)[CH2:15][NH2:16]>>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([C:10]1[NH:16][CH2:15][CH2:14][N:11]=1)[CH2:12][CH3:13]
Reactant: NCCN
Reactant: CCC(C#N)c1cccc(F)c1F
Product: CCC(C1=NCCN1)c1cccc(F)c1F

Procedure:
rac-2-[1-(2,3-Difluoro-phenyl)-propyl]-4,5-dihydro-1H-imidazole was prepared from rac-2-(2,3-difluoro-phenyl)-butyronitrile and ethylene diamine in analogy to Example 22: colourless powder; MS (ISP): 225.0 ((M+H)+.).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)=[CH:10][CH:9]=1.[CH3:25][CH:26]1[NH:30][C:29](=O)[CH2:28][CH2:27]1.C(N(CC)CC)C>ClCCCl>[ClH:3].[CH3:25][CH:26]1[N:30]=[C:29]([N:14]([CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)[C:11]2[CH:12]=[CH:13][C:8]([O:7][CH3:6])=[CH:9][CH:10]=2)[CH2:28][CH2:27]1
Reactant: CC1CCC(=O)N1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(NCc2c[nH]c3ccccc23)cc1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COc1ccc(N(Cc2c[nH]c3ccccc23)C2=NC(C)CC2)cc1
Product: Cl
Reaction time: 5 h

Procedure:
Phosphorus oxychloride (3.06 g., 0.02 mole) in 10 ml. of 1,2-dichloroethane is added dropwise in 20 min. to a solution of 3-(p-anisidinomethyl)indole (5.04 g., 0.02 mole), 5-methyl-2-pyrrolidinone (1.98 g., 0.02 mole) and triethylamine (2.02 g., 0.02 mole) held at a temperature of about 3° C. When the addition is complete, the mixture is stirred at 3° to 4° C. for 5 hr. and then filtered to provide 2.4 g. solid which is crystallized from water affording 1.02 g., m.p. 184°-187° C. This fraction is combined with an additional 1.81 g. fraction obtained as hereinabove described and crystallized from ethanol to furnish analytically pure 3-[[N-(5-methyl-1-pyrrolin-2-yl)-p-anisidino]methyl]indole hydrochloride, m.p. 181.5°-183.5° C. (corr.)
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][CH2:15]O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.C(S(F)(=O)=O)(F)(F)F.[CH:30]1([Li])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31]1>C1(C)C=CC=CC=1.CCCCCC.C(OCC)C>[CH:1]1[C:13]2[CH:12]([CH2:14][CH2:15][CH:30]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:32]=[CH:31]3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: OCCC1c2ccccc2-c2ccccc21
Reactant: [Li]C1C=Cc2ccccc21
Agent: O=S(=O)(F)C(F)(F)F
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: CCCCCC
Product: C1=CC(CCC2c3ccccc3-c3ccccc32)c2ccccc21
Reaction time: 6 h

Procedure:
To a solution of 21.0 g 2-(9-fluorenyl)ethanol, in 495 mL toluene was added dropwise with stirring 40 mL of a 2.5M solution of n-butyllithium in hexane. The resulting solution of Li{flu-CH2—CH2—O} was cooled to below −25° C. Then, 16.7 g CF3SO2F was condensed into the reaction mixture. Tile temperature was allowed to rise to 25° C. and the reaction mixture was stirred for 6 h. Unreacted CF3SO2F was removed by pumping about 10 mL of liquid into a dry ice-cooled trap. To the solution of flu-CH2—CH2—OSO2CF3 thus obtained was added a solution of 0.1 mole indenyllithium in 100 mL diethyl ether. After stirring for 12 h, solvents were removed under vacuum and the residue recrystallized in air from boiling heptane. The yield of white microcrystalline solid, mp 79-80° C., was 8.9 g (29%). Spectroscopic and chemical analysis confirmed the identity of the desired compound.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([C:17]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:12])[CH:18]=3)=[CH:3][N:4]=2)[N:7]=1
Reactant: Clc1ccc2ncc(Br)n2n1
Reactant: OB(O)c1cccc(Cl)c1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Clc1cccc(-c2cnc3ccc(Cl)nn23)c1
Temperature: 110 °C
Reaction time: 3 h
Yield: 52.8 %

Procedure:
To a solution of 3-bromo-6-chloroimidazo[1,2-b]pyridazine (2 g, 8.6 mmol) and 3-(chloro)phenylboronic acid (1.35 g, 8.6 mmol) in dioxane/H2O (100 mL, 4:1) was added K2CO3 (2.4 g, 17.2 mmol) and Pd(PPh3)4 (0.19 g, 0.172 mmol), the mixture was stirred at 110° C. for 3 h. The solution was concentrated, partitioned in EtOAc/H2O. The aqueous layer was washed with EtOAc (50 mL) for 3 times. The collected organic layers were dried over Na2SO4, concentrated and purified by column chromatography to give compound 6-chloro-3-(3-chlorophenyl)imidazo[1,2-b]pyridazine (1.2 g, 4.54 mmol, 53% yield) as a brown solid.
Reaction SMILES: [C:1]1([Si:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([OH:9])[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16](O)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OC(C)C)=O)=O)(C)C>O1CCCC1>[C:1]1([Si:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([O:9][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[OH:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCCCCCC/C=C\CCCCCCCCO
Reactant: O[Si](O)(c1ccccc1)c1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCC/C=C\CCCCCCCCO[Si](O)(c1ccccc1)c1ccccc1

Procedure:
Diphenyl-cis-9-octadecenyloxysilanol is prepared under Mitsunobu conditions from 2 g (9.25 mmol) of diphenylsilanediol, 2.08 ml (4.62 mmol) of cis-9-octadecen-1-ol, 2.45 g (9.25 mmol) of triphenylphosphine and 1.88 ml (9.25 mmol) of azodicarboxylic acid diisopropyl ester in 40 ml of tetrahydrofuran analogously to Step 1.3, Variant a.
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:12]1[S:15][CH:13]1[CH3:14]>>[CH3:1][S:2]([O-:5])(=[O:4])=[O:3].[SH:15][CH:13]([CH3:14])[CH2:12][N+:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC1CS1
Reactant: c1ccncc1
Reactant: CS(=O)(=O)O
Product: CC(S)C[n+]1ccccc1
Product: CS(=O)(=O)[O-]
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 15.2 %

Procedure:
Methanesulfonic acid (1.95 mL, 0.030 mol) was added slowly to cold pyridine (7.83 mL, 0.097 mol) and the resulting mixture was stirred at 40° C. for 15 min, treated with dl-propylenesulfide (2.59 mL, 0.033 mol) and stirred at 60° C. under a nitrogen atmosphere for 90 h. Pyridine was removed under vacuum; the residue was mixed with water and purified by chromatography (hplc, Prep. Bondapak C-18). The appropriate fractions were combined and lyophilized giving dl-1-(2-mercapto-2-methylethyl)pyridinium methanesulfonate 1.14 g (15%) as a colorless syrup; ir (film) νmax : 2520 (SH), 1640 (pyridinium), 1180 (s, CH3SO3-), 1040 (CH3SO3-)cm-1, 1Hmr (DMSO d6) δ: 1.35 (d, J=6.8 Hz, 3H, CH3CHS), 2.30 (s, 3H, CH3SO3-), 2.90 (d, J =8.5 Hz, 1H, SH), 3.2-3.7 (m, CHSH), 4.52 (dd, Jgem =12.9 Hz, J=8.4 Hz, CHCH2N+), 4.87 (dd, Jgem =12.9 Hz, J=6.0 Hz, CHCH2N+), 8.0-8.4 (m, 2H, Hm of pyridinium), 8.5-8.8 (m, 1H, Hp of pyridinium), 9.04 (dd, J=1.4 Hz, J=6.7 Hz, 2H, Ho of pyridinium), uv (H2O) λmax : 208 (ε5267), 259 (ε3338), Anal. calcd. for C9H15NO3S2.2H2O; C 37.88, H 6.71, N 4.91, S 22.47; found: C 37.49, H 6.85, N 4.86, S 22.09 and dl-1-(2-mercapto-1-methylethyl) pyridinium methanesulfonate 0.82 g (11%) as a colourless syrup: ir (film) νmax : 2500 (SH), 1628 (pyridinium), 1180 (sulfonate, 1035 (sulfonate) cm-1, 1Hmr (DMSO d6) δ: 1.69 (d, J=6.8 Hz, 3H, CH3CHN30), 2.31 (s, 3H, CH3SO3-), 3.0-3.3 (m, 2H, CH2S), 4.2-5.2 (m, 1H, CHN+), 8.0-8.4 (m, 2H, Hm of pyridinium), 8.5-8.8 (m, 1H, Hp of pyridinium), 9.0-9.2 (m, 2H, Ho of pyridinium), uv (H2O) λmax : 209 (ε4987), 258 (ε3838). Anal. calcd. for C9H15NO3S2.1.5H2O: C 39.11, H 6.56, N, 5.07; found: C 39.13, H, 5.92, N 5.20.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:8]=[S:9]1[CH:15]2[N:12]([C:13](=[O:17])[C:14]2=O)[CH:11]([C:18]([OH:20])=[O:19])[C:10]1([CH3:22])[CH3:21].[CH3:23][CH:24]([CH3:47])[C:25]([CH:27]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:26]>C1C=CC=CC=1>[C:1]([OH:7])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:8]=[S:9]1[C@H:15]2[N:12]([C:13](=[O:17])[C:14]2=[CH:27][C:25](=[O:26])[CH:24]([CH3:47])[CH3:23])[C@@H:11]([C:18]([OH:20])=[O:19])[C:10]1([CH3:22])[CH3:21]
Reactant: C=S1C2C(=O)C(=O)N2C(C(=O)O)C1(C)C
Reactant: CC(C)C(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)C(=O)O
Solvent: c1ccccc1
Product: C=S1[C@@H]2C(=CC(=O)C(C)C)C(=O)N2[C@@H](C(=O)O)C1(C)C
Reaction time: 0.17 h

Procedure:
A solution of 5.4 g of methylene-6,7-dioxo-3,3-dimethyl-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate pivalate in 100 ml of benzene is treated at room temperature with 8.8 g of dimethylacetylmethylenetriphenylphosphorane. After 10 minutes, the reaction mixture is evaporated. The residue is chromatographed on silica gel while eluting with cyclohexane/ethyl acetate (6:4). There is obtained methylene-(2S,5R)-3,3-dimethyl-6-(3-methyl-2-oxobutylidene)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate pivalate as a yellow oil [Rf: 0.35; cyclohexane/ethyl acetate (6:4); NMR (CDCl3), δ (ppm): 1.12 (6H); 1.25 (9H); 1.51 (3H); 1.6 (3H); 2.77 (2H); 4.6 (1H); 5.89 (2H); 6.05 (1H); 6.72 (1H)].
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[C:13](Cl)(=[O:16])[CH2:14][CH3:15].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[NH2:23]>>[CH3:30][O:29][C:25]1[CH:24]=[C:22]([NH:23][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:2]=2[NH:1][C:13](=[O:16])[CH2:14][CH3:15])[CH:21]=[C:20]([O:19][CH3:18])[C:26]=1[O:27][CH3:28]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: CCC(=O)Cl
Reactant: COc1ccc(C(=O)O)c(N)c1
Product: CCC(=O)Nc1cc(OC)ccc1C(=O)Nc1cc(OC)c(OC)c(OC)c1

Procedure:
Compound 63 is synthesized following a similar method as in Example 1 and using 2-amino-4-methoxybenzoic acid, propionyl chloride and 3,4,5-trimethoxyaniline as materials. Total yield of the two steps: 64%.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][SH:7])(=[O:3])[CH3:2].C1CCN2C(=NCCC2)CC1.[CH3:19][C@H:20]1[CH2:25][O:24][CH2:23][CH2:22][N:21]1[C:26]1[CH:31]=[C:30]([CH2:32]OS(C)(=O)=O)[N:29]=[C:28]([C:38]2[CH:43]=[CH:42][C:41]([NH:44][C:45]([NH:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[O:46])=[CH:40][CH:39]=2)[N:27]=1>C(#N)C>[CH3:19][C@H:20]1[CH2:25][O:24][CH2:23][CH2:22][N:21]1[C:26]1[N:27]=[C:28]([C:38]2[CH:39]=[CH:40][C:41]([NH:44][C:45](=[O:46])[NH:47][C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=3)=[CH:42][CH:43]=2)[N:29]=[C:30]([CH2:32][S:7][CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])[CH:31]=1
Reactant: CC(=O)NCCS
Reactant: C[C@H]1COCCN1c1cc(COS(C)(=O)=O)nc(-c2ccc(NC(=O)Nc3ccccc3)cc2)n1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(=O)NCCSCc1cc(N2CCOC[C@@H]2C)nc(-c2ccc(NC(=O)Nc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
N-Acetylcysteamine (0.086 mL) was dissolved in acetonitrile (5 mL). DBU (0.120 mL) was then added to the solution and was allowed to stir at RT for 15 minutes. 1-[4-[4-[(3S)-3-Methylmorpholin-4-yl]-6-(methylsulfonyloxymethyl)pyrimidin-2-yl]phenyl]-3-phenyl-urea (228 mg) in acetonitrile (5 mL) was added to the reaction and stirred for 30 minutes. The reaction was concentrated in vacuo and the crude residue purified on silica, eluting with 5% methanol in DCM, to give the desired compound (100 mg) as a white solid.
Reaction SMILES: N[C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N:13]1[CH:18]=CC=CC=1.ClC(Cl)([O:22]C(=O)OC(Cl)(Cl)Cl)Cl>C(#N)C.ClCCl>[CH3:12][O:11][C:10]1[CH:9]=[CH:8][C:7]2[NH:13][C:18](=[O:22])[O:6][C:4](=[O:5])[C:3]=2[CH:2]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: c1ccncc1
Reactant: COc1cccc(C(=O)O)c1N
Solvent: CC#N
Solvent: ClCCl
Product: COc1ccc2[nH]c(=O)oc(=O)c2c1
Temperature: 52.5 °C
Reaction time: 2 h

Procedure:
To a solution of 2-amino-3-methoxy-benzoic acid (2.50 g, 14.9 mmol) in anhydrous acetonitrile (25 mL) at 50-55° C. were simultaneously added pyridine (2.36 g, 29.8 mmol) and a solution of triphosgene (1.46 g, 4.90 mmol) in anhydrous dichloromethane (10 mL) over 20 minutes, the reaction was stirred at 50-55° C. for 2 hours. The solvent was removed and the residue was mixed with water (100 mL), the solid was filtered and rinsed with cold water (30 mL) and dried. The crude was further washed with ether (20 mL) to give 6-methoxy-1H-benzo[d][1,3]oxazine-2,4-dione. Yield: 2.56 g (89%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])(C)C.Cl[CH2:15][C:16]#[N:17].[CH3:18][CH2:19]N(C(C)C)C(C)C.CCOCC>ClCCl>[C:16]([CH2:15][N:11]1[CH2:10][CH2:9][N:8]([C:6]([O:5][CH2:1][CH2:4][CH2:18][CH3:19])=[O:7])[CH2:13][CH2:12]1)#[N:17]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCN(C(C)C)C(C)C
Reactant: N#CCCl
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCOC(=O)N1CCN(CC#N)CC1
Reaction time: 8 h

Procedure:
A solution of N-t-butoxycarbonylpiperazine (10 g, 53.8 mmol), chloroacetonitrile (4 mL, 1.05 equiv.) and DIEA (10 mL, 1.1 equiv.) in dichloromethane (300 mL) was refluxed overnight. The reaction mixture was evaporated to give a thick oil, which was tritiated with ether (30 mL) and the organic layer was separated and stored in freezer overnight and filtered. The ether solution was evaporated to give the product as a white solid (12.7 g).