Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:24])[C:7]([C:21]([OH:23])=[O:22])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[C:13]=2[F:20])=[CH:4][C:3]=1[F:25].[N+:26]([O-])([O-:28])=[O:27].[K+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:24])[C:7]([C:21]([OH:23])=[O:22])=[CH:8][N:9]2[C:12]2[CH:17]=[C:16]([N+:26]([O-:28])=[O:27])[C:15]([F:18])=[C:14]([F:19])[C:13]=2[F:20])=[CH:4][C:3]=1[F:25]
Reactant: O=[N+]([O-])[O-]
Reactant: O=C(O)c1cn(-c2ccc(F)c(F)c2F)c2nc(Cl)c(F)cc2c1=O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C(O)c1cn(-c2cc([N+](=O)[O-])c(F)c(F)c2F)c2nc(Cl)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 86.2 %

Procedure:
To 10 ml of conc. sulfuric acid was added 890 mg of 7-chloro-6-fluoro-1,4-dihydro-4-oxo-1-(2,3,4-trifluorophenyl)-1,8-naphthyridine-3-carboxylic acid. Potassium nitrate (730 mg) was added in portions to the solution, which was stirred at room temperature for 2 days. The reaction solution was allowed to cool, poured into ice water, and stirred overnight. The precipitated solid was collected by filtration, washed with water, ethanol and diethyl ether to give 860 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[C:24](O)(=[O:27])[CH2:25][CH3:26]>>[CH3:1][O:2][C:3]([N:5]1[C@H:13]2[C@H:8]([C@:9]([O:23][C:24](=[O:27])[CH2:25][CH3:26])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: CCC(=O)O
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Product: CCC(=O)O[C@@]1(C#Cc2cccc(C)c2)CCC[C@@H]2[C@H]1CCN2C(=O)OC

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and propionic acid to yield (3aR,4S,7aR)-4-propionyloxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester. MS [M+H] 296 (ester elimination ion); RT=1.34 min; UPLC Method I
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][CH2:10][CH:11]=[O:12])=[CH:4][C:3]=1[CH3:13].[CH3:14][Mg]Br>O1CCCC1.O1CCCC1.C1(C)C=CC=CC=1>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][CH2:10][CH:11]([OH:12])[CH3:14])=[CH:4][C:3]=1[CH3:13]
Reactant: Cc1cc(CCC=O)cc(C)c1Br
Reactant: C[Mg]Br
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1cc(CCC(C)O)cc(C)c1Br
Reaction time: 0.5 h

Procedure:
To a solution of 3-(4-bromo-3,5-dimethylphenyl)propanal (120 mg) in tetrahydrofurane (2 mL) is added at 0° C. methylmagnesium bromide (800 μL of a 1.4 M solution in tetrahydrofurane/toluene 1:3). After stirring for 30 minutes the mixture is partitioned between saturated aqueous NH4Cl solution and diethylether. The organic phase is dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 99:1→70:30) to give the title compound. Yield: 130 mg; LC (method 8): tR=0.37 min; Mass spectrum (ESI+): m/z=274 [M+NH4]+.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:30]=[CH:29][C:13]([CH2:14][C@H:15]2[CH2:19][O:18]C(C)(C)[N:16]2C(OC(C)(C)C)=O)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CO.C(OCC)(=O)C>[NH2:16][C@H:15]([CH2:19][OH:18])[CH2:14][C:13]1[CH:12]=[CH:11][C:10]([NH:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2ccc(NC(=O)c3ccccc3)cc2)COC1(C)C
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: N[C@H](CO)Cc1ccc(NC(=O)c2ccccc2)cc1
Reaction time: 4 h
Yield: 55 %

Procedure:
To a solution of tert-butyl (S)-4-[4-(benzoylamino)benzyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (690 mg) in methanol (20 ml) was added 4N hydrogen chloride in ethyl acetate (5 ml) at room temperature, and the solution was stirred at the same temperature for 4 hours. The mixture was evaporated in vacuo, and the residue was partitioned between chloroform and saturated sodium bicarbonate solution. The organic layer was separated, washed with brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated to give (S)-N-[4-(2-amino-3-hydroxypropyl)phenyl]benzamide (250 mg) as a colorless solid.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][O:3][CH2:2]1.[C:9]12([NH2:19])[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]3)[CH2:10]1)[CH2:16]2>ClCCl>[C:9]12([NH:19][C:5](=[O:6])[CH2:4][O:3][CH2:2][C:1]([OH:7])=[O:8])[CH2:16][CH:15]3[CH2:14][CH:13]([CH2:12][CH:11]([CH2:17]3)[CH2:10]1)[CH2:18]2
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: O=C1COCC(=O)O1
Solvent: ClCCl
Product: O=C(O)COCC(=O)NC12CC3CC(CC(C3)C1)C2
Reaction time: 3.67 h

Procedure:
In a similar operation, a solution of 11.56g (0.100 mole) of diglycolic anhydride in 1 liter of dichloromethane was added with stirring to a solution of 15.11 grams (0.100 mole) of 1-adamantanamine in 700 milliliters of dichloromethane during about 24 minutes at about 15° to 25° C., whereupon a reaction took place with the formation of heterogeneous milky white mixture. The mixture was stirred for 3.67 hours at temperatures of about 23°-25° C. to complete the reaction with the formation of the desired product in the reaction mixture. The mixture was then concentrated on a rotary evaporator to recover 32.7 grams of a white solid which after recrystallization from 1:1 isopropanol-water mixture yielded the desired [2-(1-adamantylamino)-2-oxoethoxy]acetic acid as white plates, m.p. 181°-183° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:21])=[O:20])[N:9]=2)[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[N:34]#CBr.O>CS(C)=O>[CH3:18][O:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]([S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20])[N:9]=[C:8]2[N:5]1[CH2:4][CH2:3][N:2]([C:1]#[N:34])[CH2:7][CH2:6]1
Reactant: COc1ccc2c(c1)c(N1CCN(C)CC1)nn2S(=O)(=O)c1ccccc1
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc2c(c1)c(N1CCN(C#N)CC1)nn2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 6.3 %

Procedure:
To a stirred mixture of 3-(4-methyl-1-piperazinyl)-5-methoxy-1-phenylsulfonyl-1H-indazole (55.0 g, 0.14 mol) of Example 5d, potassium carbonate (22.0 g, 0.16 mol) and dimethylsulfoxide (DMSO) [500 ml] under N2 was added dropwise, cyanogen bromide (16.0 g, 0.15 mol) dissolved in DMSO (125 ml). The reaction was stirred at room temperature for 4 hours and was then poured into H2O (2.5 l). The solid which formed was collected and washed well with H2O. The solid was dried and weighed to yield 41.0 g. A 5.0 sample was recrystallized twice from ethanol (utilizing decolorizing carbon) to afford 3.5 g (50%) of 4-(5-methoxy-1-phenylsulfonyl-1H-indazol-3-yl)-1-piperazinecarbonitrile. m.p. 171°-173° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][C:14]([O:16][CH3:17])=[O:15].[Na]>C(=O)(OC)OC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]([C:14]([O:16][CH3:17])=[O:15])[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)Cc1ccccc1Oc1cccc(OC)c1
Agent: [Na]
Solvent: COC(=O)OC
Product: COC(=O)C(C(=O)OC)c1ccccc1Oc1cccc(OC)c1

Procedure:
Methyl 2-(3-methoxyphenoxy)phenylacetate (6.81 g) was dissolved in 11 mL of dimethyl carbonate and 600 mg of sodium was added. The mixture was heated at reflux for 10 h, then cooled. The reaction mixture was quenched with water, acidified with concentrated aqueous HCl and extracted with dichloromethane. The combined organic extracts were dried (MgSO4), filtered and concentrated under reduced pressure to give an oil. The desired material was separated from unreacted starting material by flash chromatography (4:1 hexane:ethyl acetate as eluant) to yield after concentration, 3.54 g (43%) of the title compound of Step B. 1H NMR (CDCl3): δ 7.46 (dd,J=1.5, 7.5 Hz, 1H), 7.29 (t,J=8 Hz, 1H), 7.2 (m,2H), 6.92 (d,J=8 Hz, 1H), 6.65 (td,J=1.5, 7.5 Hz, 1H), 6.5 (m,2H), 5.14 (s,1H), 3.77 (s,3H), 3.73 (s,6H).
Reaction SMILES: [C:1]([C:9]1([OH:18])[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[C:15]([OH:17])=[O:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[CH:21]1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH3:21][O:16][C:15]([CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][C:9]1([C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[OH:18])=[O:17]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(O)C1CCCCC1(O)C(=O)c1ccccc1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C1CCCCC1(O)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67 %

Procedure:
9.93 g (0.04 mol) of 2-benzoyl-2-hydroxy-cyclohexanecarboxylic acid prepared according to the method of example 1 and 1.4 g of methanol (0.044 mol) are dissolved in 200 ml of dichloromethane. 9.91 g (0.044 mol) dicyclohexylcarbodiimide are added to the solution and the resulting suspension is stirred for 3 hours at room temperature. After this time, no more carboxylic acid is detected by TLC analysis. The reaction mixture is filtered and the solid dicyclohexylurethane is washed with dichloromethane. The organic solution is washed with sodium bicarbonate and water, dried over MgSO2 and evaporated in vacuum. The residual crude product is purified by chromatography on silica gel (eluant: petroleum ether/ethyl acetate 9:1) to give 7.03 g (71%) 2-benzoyl-2-hydroxy-cyclohexanecarboxylic acid methyl ester as a viscous resin.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH2:8][S:9]([O-:12])(=O)=[O:10])[CH:5]=[CH:6][CH:7]=1.[Na+].P(Cl)(Cl)([Cl:16])=O>S1(CCCC1)(=O)=O.C(#N)C>[I:1][C:2]1[CH:3]=[C:4]([CH2:8][S:9]([Cl:16])(=[O:12])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)([O-])Cc1cccc(I)c1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Solvent: CC#N
Solvent: O=S1(=O)CCCC1
Product: O=S(=O)(Cl)Cc1cccc(I)c1
Temperature: 0 °C

Procedure:
A stirred mixture of sodium (3-iodophenyl)methanesulfonate (3.6 g) and phosphoryl chloride (10 ml) in sulpholane (20 ml) and acetonitrile (30 ml) was heated at 70° for 2 h. The mixture was poured onto crushed ice (200 ml) and the precipitated product was collected and dried to give the title product (2.8 g) LCMS RT=3.47 min.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([Br:13])[CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.[C-:14]#[N:15].[K+]>CN(C=O)C.O>[Br:13][C:11]1[CH:12]=[C:3]([CH2:2][C:14]#[N:15])[CH:4]=[C:5]2[C:10]=1[N:9]=[CH:8][CH:7]=[CH:6]2
Reactant: [C-]#N
Reactant: BrCc1cc(Br)c2ncccc2c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCc1cc(Br)c2ncccc2c1
Temperature: 100 °C

Procedure:
To a solution 6-bromomethyl-8-bromoquinoline (described in International Patent Publication WO 94/22852) (1.0 eq) in DMF:H2O (2:1, 0.66M) was added potassium cyanide (2.5 eq). After heating at 100° C. for 1 h, the resulting mixture was quenched with H2O and extracted with EtOAc (2 x). The combined organic extracts were washed with water (3×), brine, dried over MgSO4, filtered and concentrated. Flash chromatography (Hex:EtOAc, 3:1) yielded the desired compound as a white solid.
Reaction SMILES: [C:1]1([C:7]2[NH:16][C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][O:19]C1C=CC=CC=1C=O>>[CH3:18][O:19][C:6]1[CH:5]=[CH:4][CH:3]=[CH:2][C:1]=1[C:7]1[NH:16][C:15](=[O:17])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1
Reactant: COc1ccccc1C=O
Reactant: O=c1[nH]c(-c2ccccc2)nc2ccccc12
Product: COc1ccccc1-c1nc2ccccc2c(=O)[nH]1
Yield: 89.1 %

Procedure:
According to the preparation of 41, 2-methoxybenzaldehyde (33) (1.0 g, 7.3 mmol) was used to afford 42 (1.6 g, 89.1%) as pale yellow needles.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([CH:25]2[CH2:27][CH2:26]2)[OH:24])=[CH:4][CH:3]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>N1C=CC=CC=1>[C:28]([O:24][CH:23]([C:5]1[C:6]2[N:7]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[C:8]3=[N:9][C:10]=2[C:2]([Cl:1])=[CH:3][CH:4]=1)[CH:25]1[CH2:27][CH2:26]1)(=[O:30])[CH3:29]
Reactant: OC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C1CC1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C1CC1
Temperature: 25 °C
Reaction time: 7 h
Yield: 72 %

Procedure:
To a solution of [9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl](cyclopropyl)methanol (120.0 mg, 0.284 mmol) in pyridine (0.5 mL) was added acetic anhydride (0.3 mL) at 0° C. The reaction mixture was stirred at room temperature for 7 hrs. The mixture was concentrated. The residue was neutralized with aqueous saturated sodium hydrogen carbonate and extracted with ethyl acetate (×3). The combined organic layer was washed with brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified, by silica gel column chromatography eluting with a 0-40% ethyl acetate/n-hexane gradient mixture. The residue was recrystallized from diisopropyl ether/n-hexane to give the title compound as a colorless powder (94.5 mg, 0.203 mmol, 72%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:5]=2[N:6]=1.[C:12]([O:15][CH2:16][C:17](Cl)=[O:18])(=[O:14])[CH3:13]>N1C=CC=CC=1>[C:12]([O:15][CH2:16][C:17]([NH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:5]=2[N:6]=1)=[O:18])(=[O:14])[CH3:13]
Reactant: CC(=O)OCC(=O)Cl
Reactant: Nc1nc2c(Cl)cccc2s1
Solvent: c1ccncc1
Product: CC(=O)OCC(=O)Nc1nc2c(Cl)cccc2s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Amino-4-chlorobenzothiazole (4.6 g) is dissolved in pyridine (80 ml) and thereto is added dropwise acetoxyacetyl chloride (3.0 ml) at room temperature. After the mixture is stirred at room temperature for 2 hours, the solvent is distilled off. The resulting solids are washed with water, then with diethyl ether, dried and recrystallized from ethanol to give the title compound (4.6 g) having the following physical properties.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1([C:17]([OH:19])=[O:18])[CH2:16][CH2:15][C:10]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:9][CH2:8]1.[C:20]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[CH3:20][O:18][C:17]([C:7]1([C:2]2[N:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:8][CH2:9][C:10]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:15][CH2:16]1)=[O:19]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)C1(c2ncccn2)CCC2(CC1)OCCO2
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)C1(c2ncccn2)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 15 h
Yield: 74 %

Procedure:
To a solution of crude 8-pyrimidin-2-yl-1,4-dioxa-spiro[4,5]decane-8-carboxylic acid and K2CO3 (227 mg, 1.64 mmol) in DMF (5 mL) was added MeI (76.7 μl, 1.23 mmol) at 25° C. After being stirred at 25° C. for 15 h, DMF was removed under reduced pressure and the residue was diluted (H2O), extracted (2×EtOAc), and washed (2× brine). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. Purification of the residue by flash chromatography (SiO2, 40-50% EtOAc/Hexanes, gradient elution) gave 8-pyrimidin-2-yl-1,4-dioxa-spiro[4,5]decane-8-carboxylic acid methyl ester (170 mg, 0.611 mmol, 74%) as a colorless liquid.
Reaction SMILES: C([O:4][C:5](=[O:7])[CH3:6])(=O)C.[CH:8]12[CH2:17][CH:14]([CH2:15][CH2:16]1)[C:12](=[CH2:13])[C:9]2([CH3:11])[CH3:10].C(OOC(C)(C)C)(C)(C)C.[OH-].[Na+]>>[CH3:10][C:9]1([CH3:11])[CH:8]2[CH2:17][CH:14]([CH2:15][CH2:16]2)[CH:12]1[CH2:13][CH2:6][C:5]([OH:4])=[O:7]
Reactant: CC(=O)OC(C)=O
Reactant: C=C1C2CCC(C2)C1(C)C
Agent: CC(C)(C)OOC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Product: CC1(C)C2CCC(C2)C1CCC(=O)O

Procedure:
To refluxing acetic anhydride (1050 g., 10 moles), there is added dropwise over six hours a solution of camphene (136 g., 1 mole) and di-tert-butyl peroxide (0.1 mole, 14.6 g.). After complete addition, the mixture is heated at reflux for five hours. The cooled reaction mixture is concentrated under reduced pressure to leave a yellow-orange residual oil; 750 ml. of 2.5N NaOH is added to the residue which is then heated on the steam bath for one hour. The cooled solution is extracted once with ether, made acidic with concentrated HCl, and extracted thoroughly with ether. The dried (Na2SO4) ether extracts are concentrated under reduced pressure and the residue distilled under vacuum to give a colorless product, b.p. 141° C.-144° C./0.5 mm.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([N:14]1[C:22]2[C:21](=[O:23])[NH:20][C:19](=[O:24])[N:18]([CH3:25])[C:17]=2[N:16]=[CH:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:26]([O:30][CH2:31]Cl)[CH:27]([CH3:29])[CH3:28].O>CN1CCCC1=O>[CH2:7]([N:14]1[C:22]2[C:21](=[O:23])[N:20]([CH2:31][O:30][CH2:26][CH:27]([CH3:29])[CH3:28])[C:19](=[O:24])[N:18]([CH3:25])[C:17]=2[N:16]=[CH:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Reactant: CC(C)COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)COCn1c(=O)c2c(ncn2Cc2ccccc2)n(C)c1=O
Reaction time: 1 h

Procedure:
1.9 g (14.08 mmol) of potassium carbonate were added at 60° C. to a suspension of 2.25 g (8.8 mmol) of 7-benzyl-3-methylxanthine (prepared according to Example 1 a) in 50 ml of N-methylpyrrolidone and the mixture was stirred at this temperature for one hour. 1.4 g (11.44 mmol) of isobutoxymethyl chloride were then added dropwise and the mixture was stirred at 80° C. for 3 hours. A further 0.5 g (4.4 mmol) of isobutoxymethyl chloride was then added and the mixture was stirred again for 2 hours. 50 ml of water were then added and the mixture was extracted three times using 60 ml of methyl tert-butyl ether each time. The combined organic phases were washed twice with 30 ml of water each time, dried using magnesium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography on a silica gel column, dichloromethane/methanol (19/0.2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[C:33]([Cl:35])[CH:34]=1)[CH2:5][N:6]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)[C:7]([C:9]1[CH:10]=[C:11]([CH:21]=[CH:22][CH:23]=1)[CH2:12][NH:13]C(=O)OC(C)(C)C)=[O:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:13][CH2:12][C:11]1[CH:10]=[C:9]([CH:23]=[CH:22][CH:21]=1)[C:7]([N:6]([CH2:5][C:4]1[CH:32]=[C:33]([Cl:35])[CH:34]=[C:2]([Cl:1])[CH:3]=1)[CH2:24][C:25]1[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=1)=[O:8]
Reactant: CC(C)(C)OC(=O)NCc1cccc(C(=O)N(Cc2ccc(F)cc2)Cc2cc(Cl)cc(Cl)c2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCc1cccc(C(=O)N(Cc2ccc(F)cc2)Cc2cc(Cl)cc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.3 %

Procedure:
To a solution of tert-butyl 3-((3,5-dichlorobenzyl)(4-fluorobenzyl)carbamoyl)benzylcarbamate (0.8 g, 1.55 mmol) in CH2Cl2 (8 mL) was added TFA (1.19 mL, 15.5 mmol). The reaction mixture was stirred at rt. for 4 h, concentrated and the residue was diluted with ethyl acetate and saturated aq NaHCO3 solution. The organic layer was separated, washed with brine, dried over MgSO4, and concentrated to give the product as a white solid (0.61 g, 95%). 1H NMR (DMSO-(d6): δ 7.52-7.06 (m, 11H), 4.65-4.40 (m, 4H), 3.72 (s, 2H); MS (ESI): [M+H]+=416.9.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[C:16][C:17]2[C:22]([Br:23])=[CH:21][C:20]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)=[CH:19][N:18]=2)=[CH:11][CH:10]=1)(=O)=O.[CH3:31][CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.BrCl>>[Br:23][C:22]1[C:17]([C:16]#[C:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][N:35]3[CH2:36][CH2:37][CH:32]([CH3:31])[CH2:33][CH2:34]3)=[CH:10][CH:11]=2)=[N:18][CH:19]=[C:20]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[CH:21]=1
Reactant: CS(=O)(=O)OCCOc1ccc(C#Cc2ncc(-c3ccc(Cl)cc3)cc2Br)cc1
Reactant: CC1CCNCC1
Agent: ClBr
Product: CC1CCN(CCOc2ccc(C#Cc3ncc(-c4ccc(Cl)cc4)cc3Br)cc2)CC1

Procedure:
The product was obtained analogously to Example 7.1g starting from 2-{4-[3-bromo-5-(4-chlorophenyl)pyridin-2-ylethynyl]phenoxy}ethyl methanesulfonate and 4-methylpiperidine. Yield: 0.15 g (88% of theoretical); C27H26BrClN2O (M=509.865); calc.: molpeak (M+H)+: 509/511/513 (BrCl); found: molpeak (M+H)+: 509/511/513 (BrCl); HPLC-MS: 6.11 minutes (method A).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([Sn:13](Cl)(Cl)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O>CCOCC>[C:14]1([SnH2:13][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cl[Sn](Cl)(c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: c1ccc([SnH2]c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice-cooled suspension of 0.76 g of lithium aluminum hydride in 15 ml of dry ether, was added 6.88 g of diphenyltin dichloride dissolved in 20 ml of dry ether. After stirring for 30 minutes, 20 ml of water was added to the resulted reaction mixture, and the ether layer was washed with icy water and dried over calcium chloride. The subsequent concentration under reduced pressure gave diphenyltin hydride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH:10]=[C:11]([C:13]([OH:15])=O)[N:12]=1.N=C=N.[F:26][C:27]([F:39])([F:38])[C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH2:37])(=[O:36])=[O:35])=[CH:30][CH:29]=1>CN(C1C=CN=CC=1)C.ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH:10]=[C:11]([C:13]([NH:37][S:34]([C:31]2[CH:30]=[CH:29][C:28]([C:27]([F:26])([F:39])[F:38])=[CH:33][CH:32]=2)(=[O:35])=[O:36])=[O:15])[N:12]=1
Reactant: NS(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: O=C(O)c1cn(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)n1
Agent: CN(C)c1ccncc1
Agent: N=C=N
Solvent: ClCCl
Product: O=C(NS(=O)(=O)c1ccc(C(F)(F)F)cc1)c1cn(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.7 %

Procedure:
In a 20-mL screw-cap vial, 250 mg (0.75 mmol) 2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazole-4-carboxylic acid, 18.3 mg DMAP (0.15 mmol), 1.25 g PS-Carbodimide (1.5 mmol) (polystyrene-supported cyclohexylcarbodiimide, Argonaut Technologies Inc., San Carlos, Calif.), 169 mg α,α,α-trifluoro-p-toluenesulfonamide (0.75 mmol), and 12 mL dichloromethane were added, and the reaction mixture was mixed by orbital shaking at rt overnight. The reaction mixture was filtered through a filter tube (polypropylene frit), and the filtrate was evaporated under reduced pressure. The crude product was redissolved in 2 mL MeOH and purified by preparative HPLC to give 39.3 mg of N-{[2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazol-4-yl]carbonyl}-4-(trifluoromethyl)benzenesulfonamide (beige solid, 10% yield). 1H NMR (400 MHz, CD3COCD3) δ 8.25 (d, 2 H), 7.85 (s, 1 H), 7.75 (s, 2H), 7.20-7.40 (m, 6 H), 6.95 (t, 2 H); LC-MS m/z 540 (MH+), retention time 3.36 min (method 2).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[C:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:10][C:11]([NH2:15])=[C:12]([NH2:14])[CH:13]=1.[CH3:22][O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1.ClCCl>N1C=CC=CC=1>[NH2:15][C:11]1[N:10]=[C:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[C:8]([C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[F:1])=[CH:13][C:12]=1[NH:14][C:28](=[O:29])[C:27]1[CH:31]=[CH:32][C:24]([O:23][CH3:22])=[CH:25][CH:26]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Nc1cc(-c2ccncc2F)c(-c2cccnc2)nc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2cc(-c3ccncc3F)c(-c3cccnc3)nc2N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 115 %

Procedure:
To a solution of 3″-fluoro-3,2′:3′,4″-terpyridine-5′,6′-diamine (Intermediate 1, 0.1 g, 0.36 mmol) in pyridine (2 mL), 4-methoxybenzoyl chloride (0.066 g, 0.39 mmol) was added. The mixture was stirred at room temperature overnight and the solvent was evaporated. Dichloromethane (1.6 mL) and tris-(2-aminoethyl)amine polystyrene (0.180 g, 0.72 mmol) were added and the mixture was stirred at room temperature for 1 h. The resin was filtrated and washed twice with dichloromethane. The filtrates were combined and the solvent was evaporated to give the title compound (0.172 g) which was used in the next step without further purification.