Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C[Si]([C:25]#[CH:26])(C)C.CCN(CC)CC>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[C:25]([C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1)#[CH:26]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(I)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C#Cc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 95.8 %

Procedure:
A microwave vial was charged with tert-butyl 4-(4-iodophenyl)piperazine-1-carboxylate (300 mg, 0.773 mmol), trimethylsilylacetylene (0.22 mL, 1.54 mmol), NEt3 (3.0 mL), DMF (1.5 mL), CuI (15 mg, 0.080 mmol), and PdCl2(PPh3)2 (27 mg, 0.039 mmol). The vial was capped and heated in the microwave at 100° C. for 1 h. After removing the NEt3 in vacuo, the residue was extracted with EtOAc (15 mL). The organic layer was then washed with NaHCO3 (sat.) (5 mL), H2O (5 mL), brine (5 mL) and then dried over MgSO4. The solvent was removed and then the material was dissolved into MeOH (4 mL) and THF (2 mL). K2CO3 (1.0 mL of a 1M solution) was added and the reaction stirred for 3 h. The solvent was removed and the residue extracted with EtOAc (15 mL). The organic layer was washed with brine (5 mL) and then dried over MgSO4. The solvent was removed and the product dried under high vacuum to give the title compound as a brown solid (212 mg, 96%); MS ESI 287.0 [M+H]+, calcd for [C17H22N2O2+H]+ 287.18.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([C:11](Cl)=[O:12])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[NH2:14][C:15]1[N:20]([C:21]2[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=2)[CH2:19][N:18]=[C:17]2[S:28][CH:29]=[CH:30][C:16]=12>>[NH2:14][C:15]1[N:20]([C:21]2[CH:22]=[CH:23][C:24]([NH:27][C:11]([C:8]3([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[CH2:10][CH2:9]3)=[O:12])=[CH:25][CH:26]=2)[CH2:19][N:18]=[C:17]2[S:28][CH:29]=[CH:30][C:16]=12
Reactant: O=C(Cl)C1(c2cccc(Cl)c2)CC1
Reactant: NC1=c2ccsc2=NCN1c1ccc(N)cc1
Product: NC1=c2ccsc2=NCN1c1ccc(NC(=O)C2(c3cccc(Cl)c3)CC2)cc1

Procedure:
The compound was prepared following the procedure described in Example 469, using 1-(3-chloro-phenyl)-cyclopropanecarbonyl chloride as the acid chloride of choice, and 4-Amino-3-(4-aminophenyl)thieno[2,3-d]pyrimidine as the diamine of choice. MS(ES) m/e 421 [M+H]+.
Reaction SMILES: [C:1]1([NH:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:10]1[CH:12]([CH2:13][CH3:14])[CH2:11]1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[NH:9]=[C:8]1[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:11][CH:12]([CH2:13][CH3:14])[O:10]1
Reactant: N#CNc1ccccc1
Reactant: CCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCC1CN(c2ccccc2)C(=N)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a flask were combined 3.0 grams (g) (25.4 mmol) phenyl cyanamide, 1.83 g (25.4 mmol) 1,2-epoxy butane, 3.51 g (25.4 mmol) potassium carbonate and 50 milliliters (ml) methyl ethyl ketone. The mixture was stirred overnight under a nitrogen blanket at room temperature. It was then filtered and the methyl ethyl ketone removed in vacuo. The solids recovered from the filter were extracted with acetone and combined with the residue from the main portion. The combined solids were dissolved in water and extraced with 15% isopropanol in chloroform. The solvents were removed in vacuo producing 2.30 g (48% of theoretical yield) of the desired product. Spectroscopic analysis confirmed the structure of the desired product. No type II product was detected.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([CH2:25][C:26](=[N:30][OH:31])[C:27]([OH:29])=O)=[CH:17]1.ON1C(=O)CCC1=O.Cl.[NH2:41][C@H:42]([C:47]([O:49][CH3:50])=[O:48])[CH2:43][CH:44]([CH3:46])[CH3:45]>O1CCOCC1.C(OCC)(=O)C.C(N(CC)CC)C>[OH:31][N:30]=[C:26]([CH2:25][C:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[NH:16][CH:17]=1)[C:27]([NH:41][C@H:42]([C:47]([O:49][CH3:50])=[O:48])[CH2:43][CH:44]([CH3:46])[CH3:45])=[O:29]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: O=C(O)C(Cc1c[nH]c2ccccc12)=NO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CC(C)C)NC(=O)C(Cc1c[nH]c2ccccc12)=NO
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
8.68 g of dicyclohexylcarbodiimide was added to 200 ml of a solution of 8.73 g of 3-(3-indolyl)-2-hydroxyiminopropionic acid and 4.83 g of N-hydroxysuccinimide in anhydrous dioxane, with ice-cooling. The mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered to remove the insoluble materials, to obtain a brown solution. Separately, 5.6 ml of triethylamine was added to 70 ml of a suspension of 7.27 g of methyl L-leucinate hydrochloride in anhydrous dioxane. The mixture was stirred at room temperature for 2 hours. Thereto was added the above brown solution. The mixture was stirred for 16 hours. The reaction mixture was diluted with 700 ml of ethyl acetate. The resulting solution was washed with 1N hydrochloric acid, an aqueous solution saturated with sodium chloride and an aqueous solution saturated with sodium hydrogen carbonate in this order, then dried with anhydrous magnesium sulfate, and subjected to distillation to remove the solvent, to obtain 13.81 g of methyl N-[2-hydroxyimino-3-(3-indolyl)propionyl]-L-leucinate as a brown oily substance.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]3[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][C:4]=1[N+:19]([O-:21])=[O:20].[H-].[Na+].[CH2:24]([O:26][CH2:27]Cl)[CH3:25]>C1COCC1>[N+:19]([C:4]1[CH:5]=[C:6]([C:9]2[S:10][C:11]3[CH:17]=[C:16]([O:18][CH2:27][O:26][CH2:24][CH3:25])[CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:7]=[CH:8][C:3]=1[NH:2][CH3:1])([O-:21])=[O:20]
Reactant: CCOCCl
Reactant: CNc1ccc(-c2nc3ccc(O)cc3s2)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOCOc1ccc2nc(-c3ccc(NC)c([N+](=O)[O-])c3)sc2c1

Procedure:
A 3 necked 250 ml round bottom flask was dried in an oven at 80° C. overnight. A suspension of 6 (16.6 mmol, 5 g) in dry THF (180 ml) has been poured drop wise into a suspension of NaH 60% dispersion in mineral oil (33.2 mmol, 1.26 g, 2 eq) in dry THF (20 ml). Once the addition was complete neat ethoxy methyl chloride (16.6 mmol, 1.54 ml, 1 eq) was added and the reaction stirred over night. The dark brown mixture was filtrated under vacuum and the filtrate concentrated under high vacuum.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([Cl:10])=[CH:4][C:3]=1[CH:11](C(OCC)=O)[C:12]([O:14]CC)=[O:13].[OH-].[Na+]>C1COCC1.CCO>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([Cl:10])=[CH:4][C:3]=1[CH2:11][C:12]([OH:14])=[O:13]
Reactant: CCOC(=O)C(C(=O)OCC)c1cc(Cl)c(OC)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(Cl)c(CC(=O)O)cc1Cl
Temperature: 60 °C
Reaction time: 17 h
Yield: 60.7 %

Procedure:
A solution of diethyl 2-(2,5-dichloro-4-methoxyphenyl)malonate (Intermediate 4-5; 1.88 g, 5.61 mmol) in THF (55 mL) and EtOH (5 mL) was treated with 2M sodium hydroxide (11.22 mL, 22.44 mmol) in one portion and the resulting solution was stirred at 60° C. for 17 hours. The reaction mixture was evaporated and the aqueous residue was acidified with 2M HCl. The precipitate was collected by filtration, washed with water (25 mL) and dried under vacuum to afford 2-(2,5-dichloro-4-methoxyphenyl)acetic acid (0.800 g, 60.7%) as a grey solid, which was used without further purification.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)=[O:17].[F:31][C:32]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][C:33]=1[NH2:34]>>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:8][N:7]2[C:2]([NH:34][C:33]3[CH:35]=[C:36]([CH3:39])[CH:37]=[CH:38][C:32]=3[F:31])=[C:3]([C:16]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)=[O:17])[CH:4]=[N:5][C:6]=12)=[O:12])[CH3:15]
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Reactant: Cc1ccc(F)c(N)c1
Product: CCOC(=O)c1cnn2c(Nc3cc(C)ccc3F)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 99.9 %

Procedure:
In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-[4-(4-fluorophenyl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine (0.090 g, 0.21 mmol) obtained in step 2 and 2-fluoro-5-methylaniline (0.053 g, 0.42 mmol), the title compound (0.109 g, 99%) was obtained.
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C@@H:12]2[CH2:16][NH:15][C@H:14]([C:17]([N:19]3[CH2:23][CH2:22][S:21][CH2:20]3)=[O:18])[CH2:13]2)=[CH:7][CH:6]=1)([O-])=O.Cl.O1CCOCC1>C(O)C.[Pd]>[ClH:1].[NH2:2][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C@@H:12]2[CH2:16][NH:15][C@H:14]([C:17]([N:19]3[CH2:23][CH2:22][S:21][CH2:20]3)=[O:18])[CH2:13]2)=[CH:7][CH:6]=1
Reactant: O=C([C@@H]1C[C@H](Nc2ccc([N+](=O)[O-])cc2)CN1)N1CCSC1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: Nc1ccc(N[C@@H]2CN[C@H](C(=O)N3CCSC3)C2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 7.1 %

Procedure:
The title compound (200 mg) of Example 55 was dissolved in ethanol (10 mL), and 4 mol/L hydrochloric acid-1,4-dioxane (0.28 mL) and 10% palladium/carbon (100 mg) were added. The mixture was stirred under a hydrogen atomosphere (1 atm) at room temperature for 18 hr. The reaction mixture was filtrated and the filtrate was concentrated under reduced pressure, and the obtained solid was washed with ethanol to give the title compound (13 mg) as a white powder.
Reaction SMILES: CN1CCOCC1.C(Cl)(=O)C.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH:22]([C:31]2[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=2[F:38])[C:23]2N=CC(CN)=C[CH:24]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1.[Si:39]([O:46][CH2:47][CH2:48]C(C)C(C1C=C(F)C=CC=1F)S(C1C=CC(Cl)=CC=1)(=O)=O)([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40]>ClCCl.C(OCC)(=O)C.O>[Si:39]([O:46][CH:47]([CH3:48])[CH2:24][CH2:23][CH:22]([C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1[F:38])[S:19]([C:16]1[CH:15]=[CH:14][C:13]([Cl:12])=[CH:18][CH:17]=1)(=[O:21])=[O:20])([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40]
Reactant: CC(CCO[Si](C)(C)C(C)(C)C)C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Reactant: NCc1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: CC(CCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.5 %

Procedure:
Under ice cooling, N-methylmorpholine (26 μl, 0.234 mmol) and acetyl chloride (16 μl, 0.234 mmol) were added to a solution of the [6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methylamine (40 ing, 0.0978 mmol), which had been obtained in Example 351, in dichloromethane (3 ml). The resulting mixture was stirred at room temperature for 16 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed successively with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to flash chromatography on a silica gel column. A fraction obtained from the elution portion with hexane:ethyl acetate=2:3 was concentrated under reduced pressure, whereby the title compound A (low polarity compound) (15 mg, 0.0304 mmol, 40%) was obtained as a white powder and the title compound B (high polarity compound) (12 mg, 0.0266 mmol, 27%) was obtained as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([C:43]3[CH:48]=[CH:47][C:46]([N:49]4[CH2:54][CH2:53][NH:52][C:51](=[O:55])[CH2:50]4)=[CH:45][CH:44]=3)=[CH:39][CH:38]=2)[N:12]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C:23](=[O:25])[N:22](COCC[Si](C)(C)C)[S:21]3(=[O:35])=[O:34])=[CH:16][CH:15]=2)[CH:13]=1.I[CH3:57]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([C:43]3[CH:44]=[CH:45][C:46]([N:49]4[CH2:54][CH2:53][N:52]([CH3:57])[C:51](=[O:55])[CH2:50]4)=[CH:47][CH:48]=3)=[CH:39][CH:38]=2)[N:12]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C:23](=[O:25])[NH:22][S:21]3(=[O:34])=[O:35])=[CH:16][CH:15]=2)[CH:13]=1
Reactant: CI
Reactant: C[Si](C)(C)CCOCN1C(=O)CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(N5CCNC(=O)C5)cc4)cc3)cc2)S1(=O)=O
Product: CN1CCN(c2ccc(-c3ccc(Cc4nc(-c5ccc(Cl)cc5Cl)cn4-c4ccc(N5CC(=O)NS5(=O)=O)cc4)cc3)cc2)CC1=O

Procedure:
4-[4′-(4-(2,4-Dichloro-phenyl)-1-{4-[1,1,4-trioxo-5-(2-trimethylsilanyl-ethoxy methyl)-[1,2,5]thiadiazolidin-2-yl]-phenyl}-1H-imidazol-2-ylmethyl)-biphenyl-4-yl]-piperazin-2-one (17 mg, 0.02 mmol) was treated as described in general procedure L (using iodomethane) and general procedure W stepwise to give the desired compound 4-(4′-{4-(2,4-dichloro-phenyl)-1-[4-(1,1,4-trioxo-[1,2,5]thiadiazolidin-2-yl)-phenyl]-1H-imidazol-2-ylmethyl}-biphenyl-4-yl)-1-methyl-piperazin-2-one.
Reaction SMILES: [CH:1]([N:4]([CH:16]([CH3:18])[CH3:17])[C:5]([C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1)=[O:6])([CH3:3])[CH3:2].[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([C@@H:30]2[C@H:35]([NH2:36])[CH2:34][CH2:33][O:32][CH2:31]2)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH3:20].C(N(CC)CC)C>ClCCl>[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([C@@H:30]2[C@H:35]([NH:36][C:11](=[O:12])[C:10]3[CH:14]=[CH:15][C:7]([C:5]([N:4]([CH:16]([CH3:18])[CH3:17])[CH:1]([CH3:3])[CH3:2])=[O:6])=[CH:8][CH:9]=3)[CH2:34][CH2:33][O:32][CH2:31]2)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH3:20]
Reactant: CC(C)N(C(=O)c1ccc(C(=O)Cl)cc1)C(C)C
Reactant: CCOc1cc([C@H]2COCC[C@H]2N)ccc1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1cc([C@H]2COCC[C@H]2NC(=O)c2ccc(C(=O)N(C(C)C)C(C)C)cc2)ccc1OC
Reaction time: 2 h

Procedure:
A solution of 1 equivalent 4-diisopropylcarbamoyl-benzoyl chloride (prepared from N,N-diisopropyl-terephthalamic acid and thionyl chloride) in dichloromethane is added dropwise at RT in the course of 10 min. to a solution of 1 equivalent of (3R,4R)-3-(3-ethoxy-4-methoxy-phenyl)-tetrahydro-pyran-4-ylamine in dichloromethane and 1.1 equivalents of triethylamine. After stirring for about 2 h, the mixture is extracted with saturated sodium hydrogencarbonate solution, and the organic phase is washed a further two times with water and dried over sodium sulfate. The viscous residue remaining after concentration is purified by column chromatography on SiO2 (dichloromethane/ethyl acetate 85/15 vol/vol). The main product fraction concentrated in vacuo affords a brownish solid foaming residue which is used for the next reaction step without further treatment.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:21](N1C=CN=C1)([N:23]1C=CN=[CH:24]1)=O.CNC>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([N:23]([CH3:24])[CH3:21])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)Cn1c(-c2ccc(Br)cc2)nc2cccnc21
Agent: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)Cn1c(-c2ccc(Br)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.4 %

Procedure:
A suspension of 2-(4-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.5 g, 0.0166 mole), 1,1'-carbonyldiimidazole (2.7 g, 0.0166 mole), and anhydrous tetrahydrofuran (100 ml) was stirred at room temperature with a stream of nitrogen bubbling through it for 21/2 hours. The nitrogen flow was stopped and a solution of dimethylamine (0.5M in tetrahydrofuran) (66 ml) was added. The solution was stirred at room temperature, stoppered, for 16 hours. The reaction mixture was concentrated in vacuo and the residue triturated in water (100 ml) and filtered. The filter cake was recrystallized from ethanol to give 3.78 g (63%) of white needles, mp 224°-225° C.
Reaction SMILES: [CH2:1]([O:12][C:13]1[CH:14]=[N:15][C:16]([C:19]2[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[CH2:27][CH2:28][CH2:29][CH:30]([OH:32])[CH3:31])=[CH:21][CH:20]=2)=[N:17][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH3:33]I>[Ag]=O.C(Cl)(Cl)Cl>[CH2:1]([O:12][C:13]1[CH:14]=[N:15][C:16]([C:19]2[CH:20]=[CH:21][C:22](/[CH:25]=[CH:26]/[CH2:27][CH2:28][CH2:29][CH:30]([O:32][CH3:33])[CH3:31])=[CH:23][CH:24]=2)=[N:17][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CI
Reactant: CCCCCCCCCCCOc1cnc(-c2ccc(/C=C/CCCC(C)O)cc2)nc1
Agent: O=[Ag]
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCOc1cnc(-c2ccc(/C=C/CCCC(C)OC)cc2)nc1
Yield: 52 %

Procedure:
At room temperature, 4.0 g (9 mmol) of the (-)-5-undecyloxy-2-{4-(6-hydroxy-1-trans-heptenyl)-phenyl}-pyrimidine obtained in Example 14, 40 ml of methyl iodide and 6.3 g (27 mmol) of silver oxide were stirred for 40 hours. Then, the reaction mixture was washed with 1N hydrochloric acid and saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Purification of the residue by silica gel column chromatography gave 2.1 g (yield 52%) of (-)-5-undecyloxy-2-{4-(6-methoxy-1-trans-heptenyl)-phenyl}-pyrimidine, [α]D20 =-1.6 (c=1.0, CHCl3).
Reaction SMILES: O.[Cl:2][C:3]1[N:8]=[C:7]([Cl:9])[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[S:16]C)=[CH:5][N:4]=1.[C:18]([Cl:22])(Cl)([Cl:20])[Cl:19]>>[Cl:2][C:3]1[N:8]=[C:7]([Cl:9])[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[S:16][C:18]([Cl:22])([Cl:20])[Cl:19])=[CH:5][N:4]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: CSc1ccccc1-c1cnc(Cl)nc1Cl
Solvent: O
Product: Clc1ncc(-c2ccccc2SC(Cl)(Cl)Cl)c(Cl)n1
Temperature: 25 °C
Yield: 99 %

Procedure:
A 2-neck 250 mL round bottom flask was equipped with a gas inlet adapter and a gas outlet attached to two traps in series, the first trap being empty and the second trap containing water. The reaction vessel was charged with 2,4-dichloro-5-(2-(methylthio)phenyl)pyrimidine and carbon tetrachloride (49.8 ml) and heated to reflux to dissolve the 2,4-dichloro-5-(2-(methylthio)phenyl)pyrimidine, then cooled to room temperature creating a clear colorless solution. Chlorine gas was bubbled through the reaction solution while stirring vigorously creating a clear yellow solution. The reaction was monitored by direct NMR of aliquots diluted in DMSO-d6. Upon completion the reaction solution was concentrated in vacuo yielding 14.7 g (99% yield) of 2,4-dichloro-5-(2-((trichloromethyl)thio)phenyl)pyrimidine as yellow solids.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[C:20](=[O:21])[C:19]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[C:35]#[N:36])=[CH:25][CH:24]=3)=[C:18]([CH2:37][CH2:38][CH3:39])[N:17]3[N:40]=[CH:41][N:42]=[C:16]23)[CH2:11][CH2:10]1)(=O)=O.[NH:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1.[I-].[Na+]>O1CCCC1>[N:43]1([CH2:6][CH2:7][O:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([N:15]3[C:20](=[O:21])[C:19]([CH2:22][C:23]4[CH:28]=[CH:27][C:26]([C:29]5[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=5)=[CH:25][CH:24]=4)=[C:18]([CH2:37][CH2:38][CH3:39])[N:17]4[N:40]=[CH:41][N:42]=[C:16]34)[CH2:11][CH2:10]2)[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCCOS(C)(=O)=O)CC2)c2ncnn12
Reactant: C1COCCN1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCCN3CCOCC3)CC2)c2ncnn12
Temperature: 70 °C
Reaction time: 5 h

Procedure:
A mixture of 2-[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]ethyl methanesulfonate (0.3 g), morpholine (0.88 g), sodium iodide (0.015 g) and tetrahydrofuran (10 mL) was stirred at 70° C. for 5 hr. The reaction mixture was concentrated, and the obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.3 g, 100%).
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:5]2[O:6][CH:7]([CH3:11])[C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.[C:14]([C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1)([OH:16])=[O:15].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.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>[CH3:11][CH:7]1[O:6][C:5]2[CH:12]=[CH:13][C:2]([C:21]3[CH:22]=[C:17]([CH:18]=[CH:19][CH:20]=3)[C:14]([OH:16])=[O:15])=[CH:3][C:4]=2[NH:9][C:8]1=[O:10]
Reactant: O=C(O)c1cccc(B(O)O)c1
Reactant: CC1Oc2ccc(Br)cc2NC1=O
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: [Na+]
Solvent: CN(C)C=O
Product: CC1Oc2ccc(-c3cccc(C(=O)O)c3)cc2NC1=O
Temperature: 80 °C

Procedure:
To a 20 mL screw cap vial was added 6-bromo-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one 19 (100 mg, 0.5 mmol), 3-carboxy phenylboronic acid (91 mg, 0.55 mmol), Pd(PPh3)4 (17 mg, 0.015 mmol), and aqueous Na2CO3 (2M, 0.62 mL, 1.25 mmol) in DMF (4 mL). The reaction was heated at 80° C. overnight then cooled and filtered. The filtrate was purified by preparative HPLC-MS (15-60% MeCN in water). The appropriate fractions were combined and concentrated in vacuo to give a white solid: 1H NMR (DMSO-d6, 400 MHz): δ=13.11 (br. s., 1H), 10.72 (s, 1H), 8.09 (t, J=1.6 Hz, 1H), 7.91 (dt, J=7.6, 1.4 Hz, 1H), 7.80-7.85 (m, 1H), 7.54-7.62 (m, 1H), 7.27 (dd, J=8.3, 2.3 Hz, 1H), 7.20 (d, J=2.0 Hz, 1H), 7.07 (d, J=8.3 Hz, 1H), 4.69-4.77 (m, 1H), 1.45 ppm (d, J=6.8 Hz, 3H). ESI-MS: m/z 284.2 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[CH3:13][O:14][CH:15]([O:18][CH3:19])[CH2:16]Cl>CC(N(C)C)=O>[CH3:13][O:14][CH:15]([O:18][CH3:19])[CH2:16][O:1][C:2]1[C:11]2[C:6](=[C:7]([O:12][CH2:16][CH:15]([O:18][CH3:19])[O:14][CH3:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Oc1cccc2c(O)cccc12
Reactant: COC(CCl)OC
Solvent: CC(=O)N(C)C
Product: COC(COc1cccc2c(OCC(OC)OC)cccc12)OC
Temperature: 80 °C
Reaction time: 3 h
Yield: 52.9 %

Procedure:
72 g (0.45 mol) 1,5-dihydroxynaphthalene are dissolved in 400 ml DMAc while heating in a three-necked flask fitted with a dropping funnel, internal thermometer, column and distillation cap. Then, at an internal temperature of 110-130° C., 178 g (1.1 mol) of a 30% solution of sodium methanolate in methanol are added dropwise and the resulting methanol is distilled off continuously via the column. When all the methanol has been transferred, 136 g (1.1 mol) chloracetaldehyde dimethylacetal is added in one portion, and the reaction is allowed to continue for approximately 3 hours at 130° C. Following this, the reaction mixture is cooled to 80° C., filtered while still warm, and the filtrate is poured onto 1000 g iced water to which 15 g NaOH have been added. The precipitate is filtered off, washed thoroughly with water and then dried under vacuum at 60° C. A yield of 80 g (53%) 1,5-bis-(2,2′-dimethoxyethoxy)naphthalene is obtained. Melting point: 117° C.; IR (KBr): 1273 cm−1 (ether); MS: m/e=336 (M+), 304, 273, 241, 215, 197, 185, 171, 160, 115, 89, 75, 59, 43.