Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][CH2:10][CH2:11][Cl:12])=[CH:4][CH:3]=1.[H][H]>[Pd].C(O)(C)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:9][CH2:10][CH2:11][Cl:12])=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: Fc1ccc(C=CCCCl)cc1
Agent: [Pd]
Solvent: CC(C)O
Product: Fc1ccc(C(CCCCl)c2ccc(F)cc2)cc1
Yield: 92.8 %

Procedure:
A suspension of 150 g of 4,4-bis-(4-fluorophenyl-3-butenylchloride, 1 l isopropyl alcohol, and 10 g of 10% palladium-on-charcoal was shaken at room temperature under 40 psi of hydrogen. The uptake of hydrogen ceased after about 5 hrs. The mixture was filtered and the solvent was evaporated to provide an oil. Distillation provided 140.2 g (92.8%) of 4,4-bis-(4-fluorophenyl)butylchloride, bp 155°-158° (1.3 mm).
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([O:28][CH3:29])[CH:22]=2)([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([O:17][CH3:18])[CH:11]=2)[O:5][C:4](=[O:30])[CH:3]=1.[C:31]([C:35]1[CH:40]=[C:39]([O:41][CH2:42][CH2:43][O:44][Si](C(C)(C)C)(C)C)[C:38]([CH3:52])=[CH:37][C:36]=1[S:53]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:34])([CH3:33])[CH3:32].Cl>CN(C=O)C>[C:31]([C:35]1[CH:40]=[C:39]([O:41][CH2:42][CH2:43][OH:44])[C:38]([CH3:52])=[CH:37][C:36]=1[S:53][C:3]1[C:4](=[O:30])[O:5][C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([O:17][CH3:18])[CH:11]=2)([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([O:28][CH3:29])[CH:22]=2)[CH2:7][C:2]=1[OH:1])([CH3:34])([CH3:33])[CH3:32]
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(OCCO[Si](C)(C)C(C)(C)C)cc2C(C)(C)C)cc1
Reactant: COc1cc(CCC2(CCc3ccc(O)c(OC)c3)CC(O)=CC(=O)O2)ccc1O
Agent: Cl
Solvent: CN(C)C=O
Product: COc1cc(CCC2(CCc3ccc(O)c(OC)c3)CC(O)=C(Sc3cc(C)c(OCCO)cc3C(C)(C)C)C(=O)O2)ccc1O
Reaction time: 0.17 h

Procedure:
The compound was prepared using General Method 9 and the following quantities: 100 mg (0.24 mmol) of 4-hydroxy-6,6-bis-[2-(4-hydroxy-3-methoxy-phenyl)-ethyl]-5,6-dihydro-pyran-2-one (prepared in Example QQ), 123 mg (0.24 mol) of toluene-4-thiosulfonic acid S-{2-tert-butyl-4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-methyl-phenyl} ester (prepared in Example PPP), 133 mg (0.96 mmol) of K2 CO3, and 10 mL of DMF. The reaction was worked up by addition of 10 mL 1.0N HCl and stirring for 10 minutes, followed by extraction with EtOAc. The organic layer was dried (Na2SO4), concentrated, and chromatographed on silica gel, eluting with (1:1 CH2Cl2 :EtOAc+2% MeOH), to give the title compound, m.p. 76°-82° C. 1H NMR (DMSO-d6) δ 1.5 (s, 9 H), 1.75 (s, 3 H), 2.05 (m, 4 H), 2.6 (m, 4 H), 2.95 (s, 2 H), 3.7 (m, 8 H), 3.95 (t, 2 H), 4.8 (br s, 1 H), 6.65 (m, 7 H), 7.0 (s, 1 H), 8.75 (s, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.Br[CH:18]([CH3:22])[C:19]([NH2:21])=[O:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH:18]([CH3:22])[C:19]([NH2:21])=[O:20])=[CH:9][CH:10]=1
Reactant: Oc1ccc(Cc2ccc(Cl)cc2Cl)cc1
Reactant: CC(Br)C(N)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(Oc1ccc(Cc2ccc(Cl)cc2Cl)cc1)C(N)=O

Procedure:
A solution of 25.3 g of 4-(2,4-dichlorobenzyl)-phenol and 15.2 g of α-bromopropionic acid amide in 100 ml of dimethyl formamide was stirred for 2 hours at 100° C together with 16 g of potassium carbonate. After cooling, the reaction mixture was poured into 1 liter of water. A viscous oil precipitated which was absorbed in methylene chloride and washed with water. After drying over sodium sulfate, the solvent was distilled off under reduced pressure. The remaining colorless crystals were recrystallized from methanol. Yield: 25.8 g; melting point 148° - 149° C. ##STR5##
Reaction SMILES: [CH3:1][O:2][CH:3]([O:11][CH3:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[CH:5]=1.CC(C)([O-])C.[K+].Cl[C:20]1[CH:25]=[N:24][CH:23]=[CH:22][N:21]=1.O>CN(C)C=O>[CH3:1][O:2][CH:3]([O:11][CH3:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:20]2[CH:25]=[N:24][CH:23]=[CH:22][N:21]=2)[CH:5]=1
Reactant: COC(OC)c1cccc(O)c1
Reactant: Clc1cnccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(OC)c1cccc(Oc2cnccn2)c1
Temperature: 60 °C

Procedure:
A solution of 168 mg of 3-hydroxybenzaldehyde dimethyl acetal in 10 ml of anyhydrous dimethylformamide was stirred under nitrogen and 220 mg of potassium tert-butoxide were added. The mixture was heated at 60° C. for 1 hour, then cooled to room temperature and 115 mg of 2-chloropyrazine were added in portions. The mixture was then heated at 160° C. for 18 hours. After cooling 15 ml of water were added and the product was extracted with 50 ml of ethyl acetate. The extract was washed with 25 ml of 1M sodium hydroxide solution and 25 ml of brine and then dried over anhydrous magnesium sulphate. After filtration and evaporation of the filtrate the residual yellow oil was purified by column chromatography on silica gel using ethyl acetate/hexane (1:1) for the elution to give 3-(2-pyrazinyloxy)-benzaldehyde dimethyl acetal as a yellow oil.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[NH:7][S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9].C(N(CC)CC)C.O>C(Cl)Cl>[CH3:13][CH:11]([S:8]([NH:7][CH:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[O:1])(=[O:10])=[O:9])[CH3:12]
Reactant: CC(C)S(=O)(=O)NC1CCCC1O
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)S(=O)(=O)NC1CCCC1=O
Temperature: -55 °C
Reaction time: 0.03 h
Yield: 72.7 %

Procedure:
Scheme IA, step C: Into a flame dried 500 mL 3 neck flask fitted with a thermometer and magnetic stirrer, DMSO (6.16 mL) in methylene chloride (20 mL) was added dropwise to oxalyl chloride (3.80 mL) in methylene chloride (100 mL) while stirring at −55° C. under a nitrogen atmosphere. After 2 minutes, (2-hydroxycyclopentyl)[(methylethyl)sulfonyl]amine (8.00 g, 38.6 mmol) in methylene chloride (45 mL) was added dropwise at this temperature and the reaction was stirred for an additional 15 minutes. Triethylamine (25.5 mL) was then added dropwise and the reaction was allowed to warm to room temperature. 180 mL of water was added at room temperature and the layers were separated. The organic layer was washed once with water, dried over potassium carbonate, filtered, and concentrated under reduced vacuum to yield 7.83 g as a dark oil. This material was purified via silica gel chromatography employing the Water's Prep. 2000 and eluting with a solvent of methylene chloride/ethyl acetate 9:1 to provide the intermediate title compound (5.76 g, 73%) as a yellow oil. Ion Spray M.S. 204.1 (M*−1). Calculated for C8H15NO3S: Theory: C, 46.81; H, 7.37; N, 6.82. Found: C, 46.56; H, 7.32; N, 6.77.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6].[C:11]([C:16]1[CH:17]=[N:18][C:19]2[C:24]([C:25]=1Cl)=[CH:23][CH:22]=[CH:21][C:20]=2[O:27][CH3:28])(=[O:15])[CH2:12][CH2:13][CH3:14]>O1CCOCC1>[C:11]([C:16]1[CH:17]=[N:18][C:19]2[C:24]([C:25]=1[NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=1[CH2:3][O:2][CH3:1])=[CH:23][CH:22]=[CH:21][C:20]=2[O:27][CH3:28])(=[O:15])[CH2:12][CH2:13][CH3:14]
Reactant: CCCC(=O)c1cnc2c(OC)cccc2c1Cl
Reactant: COCc1ccccc1N
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2c(OC)cccc2c1Nc1ccccc1COC

Procedure:
2-Methoxymethylaniline (1.0 g, 7.2 mmol) and 3-butyryl-4-chloro-8-methoxyquinoline (1.9 g, 7.2 mmol) were heated together under reflux in 1,4-dioxan (50 ml) for 2 hours. The solvent was evaporated and the residue dissolved in dichloromethane, washed with water, sodium hydrogen carbonate solution and brine, dried and evaporated. Recrystallisation from ethanol-water afforded 3-butyryl-4-(2-methoxymethyl-phenylamino)-8-methoxyquinoline, m.p. 128°-30°.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:3]=1.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[C:23]1([C:2]2[CH:7]=[C:6]([S:8]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)(=[O:10])=[O:9])[CH:5]=[C:4]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:3]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: OB(O)c1ccccc1
Reactant: Nc1ccc(S(=O)(=O)c2cc(Br)nc(N3CCCC3)c2)cc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Nc1ccc(S(=O)(=O)c2cc(-c3ccccc3)nc(N3CCCC3)c2)cc1
Yield: 68.5 %

Procedure:
A mixture of 191 mg (0.5 mmole) 4-(2-bromo-6-pyrrolidine-1-yl-pyridine-4-sulfonyl)-phenylamine, 60.9 mg (0.5 mmole) benzene-boronic acid, 55 mg sodium carbonate and 18 mg bis(triphenylphosphine)-palladium(II)-chloride is refluxed for 18 hours in 5 ml 1,2-dimethoxyethane and 0.25 ml water. The solvent is removed and the residue is diluted with dichloromethane. The dichloromethane solution is washed twice with water, dried over magnesiumsulfate and concentrated in vacuo. Flash chromatography (silicagel, ethyl acetate/hexane 1/1) of the residue yields 130 mg (68%) pure 4-(2-phenyl-6-pyrrolidine-1-yl-pyridine-4-sulfonyl)-phenylamine as a pale yellow soild mp.: 255-258° C.
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]([CH2:12][CH3:13])[N:10]=[C:9]([CH3:14])[C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1.C([N:17]([CH2:20][CH3:21])[CH2:18]C)C.CC1CN1>C(Cl)Cl>[CH2:12]([N:11]1[C:3]2[C:2]([N:17]3[CH2:18][CH:20]3[CH3:21])=[N:7][C:6]([CH3:8])=[N:5][C:4]=2[C:9]([CH3:14])=[N:10]1)[CH3:13]
Reactant: CCn1nc(C)c2nc(C)nc(Cl)c21
Reactant: CCN(CC)CC
Agent: CC1CN1
Solvent: ClCCl
Product: CCn1nc(C)c2nc(C)nc(N3CC3C)c21
Reaction time: 20 h

Procedure:
A solution of 4.2 g (0.02 mol) of 7-chloro-3,5-dimethyl-1-ethyl-1H-pyrazolo[4,3-d]pyrimidine (Ex. 16), 3 ml of triethylamine and 5 ml of 2-methylaziridine in 100 ml of methylene dichloride is allowed to stand at room temperature 20 hours. The solution is washed with saturated sodium bicarbonate solution, dried (MgSO4), and evaporated in vacuo to give 4 g of 1-ethyl-3,5-dimethyl-7-(2-methylaziridinyl)pyrazolo[4,3-d]pyrimidine as an oil, characterized by IR and NMR. The aziridine (4 g, 0.017 mol) in 40 ml of acetone is refluxed 1.5 hours with 3 g (0.02 mol) of sodium iodide. The solution is evaporated in vacuo. The residue is partitioned in 100 ml of methylene dichloride and 30 ml of 20% sodium carbonate solution. The organic layer is separated, dried over magnesium sulfate, and the solvent is evaporated in vacuo to give 2.8 g (71%) of the title compound, mp 145°-147° C. from ethyl acetate-pet ether.
Reaction SMILES: O[CH2:2][CH2:3][S:4]([C:7]1[CH:8]=[C:9]([C@H:19]2[S:23][C@H:22]([C:24]3[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=3)[CH2:21][S:20]2)[CH:10]=[C:11]([O:17][CH3:18])[C:12]=1[O:13][CH2:14][CH2:15][CH3:16])(=[O:6])=[O:5].[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>C(O)C>[O:39]1[CH2:40][CH2:41][N:36]([CH2:2][CH2:3][S:4]([C:7]2[CH:8]=[C:9]([C@H:19]3[S:23][C@H:22]([C:24]4[CH:25]=[C:26]([O:34][CH3:35])[C:27]([O:32][CH3:33])=[C:28]([O:30][CH3:31])[CH:29]=4)[CH2:21][S:20]3)[CH:10]=[C:11]([O:17][CH3:18])[C:12]=2[O:13][CH2:14][CH2:15][CH3:16])(=[O:6])=[O:5])[CH2:37][CH2:38]1
Reactant: C1COCCN1
Reactant: CCCOc1c(OC)cc([C@@H]2SC[C@@H](c3cc(OC)c(OC)c(OC)c3)S2)cc1S(=O)(=O)CCO
Solvent: CCO
Product: CCCOc1c(OC)cc([C@@H]2SC[C@@H](c3cc(OC)c(OC)c(OC)c3)S2)cc1S(=O)(=O)CCN1CCOCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-(3-(vinylsufonyl)-5-methoxy-4-propoxyphenyl)-4-(3,4,5-methoxyphenyl)-1,3-dithiolane (22) (FIG. 25) (0.040 g,0.076 mmole) was dissolved in absolute ethanol (10 ml) and morpholine (13 ml) was into the reaction which was stirred at room temperature for 4 hours. The solvent and excess amine were removed in vacuo, and the remaining oil purified by flash column chromatography with 1:1 hex/ethyl acetate as eluent. The product mixture (oil) contains a 1.0/1.0 cis/trans ratio (0.022.5 g, 49%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]=[CH:13][N:12]=[C:11]3[NH2:18])[CH:5]=[CH:6][CH:7]=1.[N:19]([CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)=[C:20]=[O:21]>CN(C)C=O>[NH2:18][C:11]1[C:10]2[C:15](=[CH:16][CH:17]=[C:8]([C:4]3[CH:3]=[C:2]([NH:1][C:20]([NH:19][CH:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)=[O:21])[CH:7]=[CH:6][CH:5]=3)[CH:9]=2)[N:14]=[CH:13][N:12]=1
Reactant: O=C=NC1CCCC1
Reactant: Nc1cccc(-c2ccc3ncnc(N)c3c2)c1
Solvent: CN(C)C=O
Product: Nc1ncnc2ccc(-c3cccc(NC(=O)NC4CCCC4)c3)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.5 %

Procedure:
To a 4 mL screw-cap vial was added 6-(3-aminophenyl)quinazolin-4-amine (35 mg; 0.15 mmol) followed by dimethylformamide (0.5 mL) and isocyanatocyclopentane (1.1 equiv., 0.16 mmol, 18 mg). The reaction was stirred at room temperature overnight. The following morning the crude reaction mix was directly purified by reverse phase HPLC, yielding 19 mg of desired product. 1H NMR (400 MHz, DMSO) δ 8.51-8.45 (d, J=1.8 Hz, 1H), 8.45-8.40 (s, 1H), 8.40-8.37 (s, 1H), 8.03-7.95 (dd, J=8.7, 1.9 Hz, 1H), 7.95-7.76 (s, 2H), 7.76-7.70 (d, J=8.7 Hz, 1H), 7.43-7.28 (m, 3H), 6.33-6.20 (d, J=7.2 Hz, 1H), 4.04-3.90 (dd, J=13.4, 6.7 Hz, 1H), 1.93-1.80 (m, 2H), 1.74-1.46 (m, 4H), 1.46-1.32 (m, 2H). LCMS M/Z (M+H)=348.
Reaction SMILES: [S:1]1[C:5]([C:6]2[CH:7]=[C:8]([CH2:12][OH:13])[CH:9]=[CH:10][CH:11]=2)=[CH:4][N:3]=[CH:2]1>C(Cl)Cl.O=[Mn]=O>[S:1]1[C:5]([C:6]2[CH:7]=[C:8]([CH:9]=[CH:10][CH:11]=2)[CH:12]=[O:13])=[CH:4][N:3]=[CH:2]1
Reactant: OCc1cccc(-c2cncs2)c1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: O=Cc1cccc(-c2cncs2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of (3-(thiazol-5-yl)phenyl)methanol (162 mg; 0.84 mmol) in anh. DCM (6 ml) was treated with MnO2 (1.104 g; 12.70 mmol), and the resulting mixture was stirred at rt, under nitrogen, for 3 h. The resulting reaction mixture was then filtered over celite, and the separated solids were washed with DCM. The filtrate was concentrated to dryness under reduced pressure giving 3-(thiazol-5-yl)benzaldehyde as an orange solid. LC-MS (conditions A): tR=0.58 min.; [M+H]+: 190.02 g/mol.
Reaction SMILES: [Na].[C:2]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])(=[O:7])[CH2:3][C:4]([O-:6])=[O:5].[CH:13]12[CH2:20][CH2:19][CH:16]([CH:17]=[CH:18]1)[CH2:15][CH:14]2[C:21](Cl)=[O:22]>>[C:4]([O:6][C:21]([CH:14]1[CH2:15][CH:16]2[CH2:19][CH2:20][CH:13]1[CH:18]=[CH:17]2)=[O:22])(=[O:5])[CH2:3][C:2]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: CC(C)(C)OC(=O)CC(=O)[O-]
Reactant: O=C(Cl)C1CC2C=CC1CC2
Agent: [Na]
Product: CC(C)(C)OC(=O)CC(=O)OC(=O)C1CC2C=CC1CC2
Yield: 84.8 %

Procedure:
To a solution of sodium salt of mono-tert-butyl malonate (20.4 g) prepared according to the same procedure as in Example 4, bicyclo[2,2,2]oct-5-ene-2-carbonyl chloride (17.1 g) obtained in Preparation Example 2 is slowly added, and the reaction mixture is reacted at −20° C. in a nitrogen atmosphere for 1 hour, and further reacted at 40° C. for 6 hours. Then, the mixture is worked up as in the procedure of Example 1, to obtain 25 g of the pure title compound (purity: 99%, yield: 84%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([OH:16])[C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.C([Li])(C)(C)C.CN(C)[CH:24]=[O:25].Cl>C1COCC1>[OH:16][C:4]1[C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=[C:2]([CH:24]=[O:25])[CH:3]=1
Reactant: CC1(C)CCC(C)(C)c2c(O)cc(Br)cc21
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2c(O)cc(C=O)cc21
Temperature: -78 °C
Yield: 67 %

Procedure:
30 g (106 mmol) of 3-bromo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-1-ol are dissolved in 500 mL of anhydrous THF. The medium is cooled to −78° C. and 156 mL (265 mmol) of tert-butyllithium are then added dropwise. After 45 minutes at this temperature, 12.3 mL (159 mmol) of dimethylformamide are added. The mixture is warmed to room temperature and then treated with 1N hydrochloric acid solution and extracted with ethyl acetate. The residue obtained is then purified by chromatography (eluent: 9/1 heptane/ethyl acetate). A white solid is obtained (m=16.5 g; yield=67%; m.p.=144° C.).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[Cl:10].CS(C)=O.[Na+].[CH3:16][S:17]([O-:19])=[O:18]>O>[Cl:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[S:17]([CH3:16])(=[O:19])=[O:18])[CH:6]=[O:7]
Reactant: CS(=O)[O-]
Reactant: O=Cc1ccc(F)c(Cl)c1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(C=O)cc1Cl
Temperature: 90 °C

Procedure:
To a solution containing 1.0 g 4-fluoro-3-chlorobenzaldehyde and 45 ml DMSO, was added 1.93 g methanesulfinic acid sodium salt with stirring at 90° C. The solution was stirred 6 hours at 90° C. and poured into water. Sodiumhydrogencarbonate was added and the product was extracted with ethyl acetate. The extract was evaporated to dryness in vacuo. The residue was triturated with 2-propanol, yield 1.06 g. 1H-NMR (DMSO-d6, 400 MHz): 3.45 (s, 3H, CH3), 8.09-8.27 (m, 3 H, Ar), 10.01 (d, 1 H, CHO).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[N:16]=2)[CH2:10][CH:9]1[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:23][C:24]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27].C(N(CC)CC)C.O1CCOCC1>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][C:31]([F:33])=[CH:32][C:24]=3[Cl:23])[N:16]=2)[CH2:10][CH:9]1[CH3:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1CC(Oc2cccc(N)n2)CCN1C(=O)OC(C)(C)C
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: CO
Product: CC1CC(Oc2cccc(NC(=O)c3ccc(F)cc3Cl)n2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Combine 4-(6-amino-pyridin-2-yloxy)-2-methyl-piperidine-1-carboxylic acid tert-butyl ester cis isomer 1 (preparation 63, 0.025 g, 0.08 mmol), 2-chloro-4-fluoro-benzoyl chloride (0.10 g, 0.52 mmol), triethylamine (0.10 mL, 0.69 mmol) and 1,4-dioxane (10 mL), stir and heat to reflux. After 3 hr., cool to ambient temperature, dilute with methanol (10 mL) and load on an SCX column (10 g). Wash with methanol (2×25 mL). Elute product with 2M ammonia/methanol (2×25 mL). Eluent concentrated to give crude title compound. Mass spectrum (electrospray): m/z=364.1 (M+1-100) loss of t-BOC from parent. Use without further characterization in next step.
Reaction SMILES: Cl[C:2]1[C:3]2[C:11]([CH3:12])=[CH:10][N:9]([C:13]3[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[CH3:21])[C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1.[CH2:22]([NH:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH3:23].O>CS(C)=O.Cl>[CH2:25]([N:24]([CH2:22][CH3:23])[C:2]1[C:3]2[C:11]([CH3:12])=[CH:10][N:9]([C:13]3[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[CH3:21])[C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1)[CH2:26][CH2:27][CH3:28]
Reactant: Cc1cc(C)c(-n2cc(C)c3c(Cl)nc(C)nc32)c(C)c1
Reactant: CCCCNCC
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Product: CCCCN(CC)c1nc(C)nc2c1c(C)cn2-c1c(C)cc(C)cc1C
Yield: 81.2 %

Procedure:
A mixture of 4-chloro-2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine (1.000 g, 3.36 mmol) and N-ethylbutylamine (3.400 g, 33.60 mmol) in 5 ml of dimethylsulfoxide was heated to reflux for 1.5 hours. The mixture was cooled and treated with water and a few drops of 2 N HCl to pH 6.5 and extracted with ethyl acetate. The organic layer was separated, washed with dilute sodium bicarbonate, brine, and dried over sodium sulfate anhydrous and concentrated to dryness. The residue was purified through silica gel column chromatography to give 995 mg (81% yield) of the title compound as an oil. 1H NMR (CDCl3) δ 6 0.90 (t, 3H), 1.23(t, 3H), 1.35(m, 2H), 1.60-1.70(m, 2H), 1.92(s, 6H), 2.30(s, 3H), 2.40(s, 3H), 2.46(s, 3H), 3.58(t, 2H), 3.66(q, 2H), 6.55(s, 1H), 6.95(s, 2H) ppm. The corresponding hydrogen chloride salt was prepared as a white crystals after recrystallization from ethyl acetate. 1H NMR (D2O) δ 0.90(t, 3H), 1.34(m, 5H), 1.75(m, 2H), 1.90(s, 6H), 2.37(s, 3H), 2.48(s, 3H), 2.55(s, 3H), 3.80-3.94(m, 4H), 7.09(s, 2H) ppm.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)=[CH:6][NH:5][C:4](=[S:17])[NH:3]1.C([O-])([O-])=O.[K+].[K+].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][C:35]([CH2:38]Cl)=[CH:34][CH:33]=2)=[CH:27][C:26]=1[C:40]([F:43])([F:42])[F:41]>CC(C)=O>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:33]=[CH:34][C:35]([CH2:38][S:17][C:4]3[NH:5][CH:6]=[C:7]([CH2:8][C:9]4[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=4)[C:2](=[O:1])[N:3]=3)=[CH:36][CH:37]=2)=[CH:27][C:26]=1[C:40]([F:41])([F:42])[F:43]
Reactant: FC(F)(F)c1cc(Oc2ccc(CCl)cc2)ccc1Cl
Reactant: N#Cc1ccc(Cc2c[nH]c(=S)[nH]c2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1ccc(Cc2c[nH]c(SCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)cc3)nc2=O)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 31.6 %

Procedure:
To a suspension of 4-[(4-oxo-2-thioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)methyl]benzonitrile (70 mg, 0.288 mmol) and K2CO3 (41.3 mg, 0.299 mmol) in acetone (6 mL), which was stirred at room temperature for 5 min was added 1-chloro-4-{[4-(chloromethyl)phenyl]oxy}-2-(trifluoromethyl)benzene (60 mg, 0.187 mmol) under argon. The mixture was heated at 60° C. for 3 h. Purification via MDAP then afforded the title compound (31 mg, 0.059 mmol, 31.4% yield). LCMS: rt=3.98 min, [M+H+]=528