Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[C:4]([C:6]1[CH:19]=[CH:18][C:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])=[CH:8][CH:7]=1)=[O:5])[CH3:2].[OH-].[Na+].[CH2:24]1[O:26][CH:25]1[CH2:27][OH:28]>O1CCOCC1.O>[CH2:20]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[CH:19]=[CH:18][C:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH2:24][CH:25]([OH:26])[CH2:27][OH:28])=[CH:8][CH:7]=1)=[O:5])[CH3:21]
Reactant: CCN(CC)C(=O)c1ccc(Cc2ccccc2O)cc1
Reactant: OCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCN(CC)C(=O)c1ccc(Cc2ccccc2OCC(O)CO)cc1
Temperature: 90 °C
Reaction time: 18 h
Yield: 59 %

Procedure:
The 2-(4-diethylcarbamoylbenzyl)phenol (355 mg) obtained in Reference Example 1(d) was dissolved in a mixed solution of dioxane (3.6 ml) and water (3.6 ml), added with 1 N aqueous sodium hydroxide (63 μl) and glycidol (0.12 ml) and stirred at 90° C. for 18 hours. The reaction mixture was added with water (30 ml) and extracted twice with dichloromethane (30 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to obtain 263 mg of the title compound. Yield: 59%.
Reaction SMILES: [CH:1]([C:3]1[C:4]([O:14][CH2:15][C:16]2[CH:37]=[CH:36][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=4)[C:31]#[N:32])[O:25][C:26]=3[CH3:27])=[C:18]([O:38][CH3:39])[CH:17]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1)=O.[CH2:40](P(=O)(OCC)OCC)[P:41](=[O:48])([O:45][CH2:46][CH3:47])[O:42][CH2:43][CH3:44].CN(C)C=O.[H-].[Na+]>O>[C:31]([C:30]1[CH:29]=[C:28]([C:24]2[O:25][C:26]([CH3:27])=[C:22]([CH2:21][O:20][C:19]3[CH:36]=[CH:37][C:16]([CH2:15][O:14][C:4]4[C:3](/[CH:1]=[CH:40]/[P:41](=[O:48])([O:45][CH2:46][CH3:47])[O:42][CH2:43][CH3:44])=[CH:7][N:6]([C:8]5[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=5)[N:5]=4)=[CH:17][C:18]=3[O:38][CH3:39])[N:23]=2)[CH:35]=[CH:34][CH:33]=1)#[N:32]
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2cccc(C#N)c2)oc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3cccc(C#N)c3)oc2C)c(OC)c1)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
To a mixture of 3-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}benzonitrile (2.50 g), tetraethyl methylenediphosphonate (1.53 g) and N,N-dimethylformamide (50 mL) was added sodium hydride (60% in oil, 0.23 g) at room temperature. The mixture was stirred at room temperature for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give diethyl [(E)-2-{3-[(4-{[2-(3-cyanophenyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}ethenyl]phosphonate as colorless crystals (2.20 g, yield 70%) from a fraction eluted with ethyl acetate-hexane (4:1 to 9:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 147-148° C.
Reaction SMILES: [CH2:1]=[CH:2][CH3:3].[C:4]1([CH3:10])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>>[CH2:10]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH:2]([CH3:3])[CH3:1]
Reactant: Cc1ccccc1
Reactant: C=CC
Product: CC(C)Cc1ccccc1
Temperature: 163 °C
Reaction time: 6 h

Procedure:
In a 300 ml autoclave equipped with a magnetic stirrer, Solid Base A (4.07 g) and toluene (79.5 g) were charged under nitrogen and then liquid propylene (70 ml) was injected under pressure. The mixture was stirred at 163° C. for 6 hours to obtain isobutylbenzene (hereinafter referred to as "IBB").
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C:10]([C:14]#[C:15][C:16]2[CH:17]=[CH:18][C:19]3[O:28][CH2:27][CH2:26][N:25]4[C:21](=[N:22][C:23]([C:29](=[O:31])[NH2:30])=[CH:24]4)[C:20]=3[CH:32]=2)([OH:13])[CH2:9]1)=O)(C)(C)C.Cl.CC(=O)OCC>CO>[OH:13][C:10]1([C:14]#[C:15][C:16]2[CH:17]=[CH:18][C:19]3[O:28][CH2:27][CH2:26][N:25]4[CH:24]=[C:23]([C:29]([NH2:30])=[O:31])[N:22]=[C:21]4[C:20]=3[CH:32]=2)[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(C#Cc2ccc3c(c2)-c2nc(C(N)=O)cn2CCO3)C1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: NC(=O)c1cn2c(n1)-c1cc(C#CC3(O)CCNC3)ccc1OCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 10.3 %

Procedure:
In a solution of 3-(2-Carbamoyl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-9-ylethynyl)-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (40 mg, 0.1 mmol) in methanol (20 ml) was added HCl/EA (20 ml). The solution was stirred for 3 h at room temperature. The reaction mixture was purified by column to afford the titled compound (3.5 mg, 10%). 1HNMR (Methanol-d4, 400 MHz): δ 8.62 (d, J=2.0 Hz, 1H), 7.78 (s, 1H), 7.41 (dd, J=2.0, 8.8 Hz, 1H), 7.08 (d, J=8.4 Hz, 1H), 4.52 (s, 4H), 3.54-3.40 (m, 4H), 2.43 (t, J=5.4 Hz, 2H), LCMS: 339.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:13]=3[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH:20]1[C:25]([C:26]([OH:28])=[O:27])=[CH:24][C:23]2[C:29]([O:31][C:32](=O)[C:22]=2[CH:21]=1)=[O:30]>>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:13]=3[N:14]=2)=[CH:3][C:2]=1[N:1]1[C:29](=[O:30])[C:23]2[C:22](=[CH:21][CH:20]=[C:25]([C:26]([OH:28])=[O:27])[CH:24]=2)[C:32]1=[O:31]
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: COc1ccc(-c2nc3cc(Cl)ccc3o2)cc1N
Product: COc1ccc(-c2nc3cc(Cl)ccc3o2)cc1N1C(=O)c2ccc(C(=O)O)cc2C1=O

Procedure:
Prepared by the method of Example 1b), from 2-(3-amino-4-methoxyphenyl)-5-chlorobenzoxazole (63 mg, 0.23 mmol) and 1,2,4-benzenetricarboxylic anhydride (50 mg, 0.26 mmol) the title compound was obtained, 62 mg (60%). 1H NMR (DMSO) δ 8.45(dd, 1H), 8.33(m, 3H), 8.12(d, 1H), 7.89(d, 1H), 7.80(d, 1H), 7.47(m, 2H), 3.89(s, 3H). MS 447 m/z (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:14]=[C:15]3[CH2:21][C:20](=[O:22])[NH:19][C:16]3=[N:17][CH:18]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[C:23]([C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1)#[N:24].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:22]=[C:20]1[NH:19][C:16]2=[N:17][CH:18]=[C:13]([C:5]3[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:14]=[C:15]2[C:21]1=[CH:29][C:28]1[CH:31]=[CH:32][C:25]([C:23]#[N:24])=[CH:26][CH:27]=1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: COc1cc(-c2cnc3c(c2)CC(=O)N3)cc(OC)c1OC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc(-c2cnc3c(c2)C(=Cc2ccc(C#N)cc2)C(=O)N3)cc(OC)c1OC
Yield: 53.6 %

Procedure:
A mixture of 5-(3,4,5-trimethoxy-phenyl)-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one (Intermediate BY, 42 mg, 0.14 mmol), 4-cyanobenzaldehyde (22 mg, 0.168 mmol), triethylamine (22 μl, 0.168 mmol) and molecular sieves 4 Å (100 mg) in toluene (2 ml) was reacted at 80° C. for Id. The mixture was partitioned between DCM and water, the aqueous phase extracted with DCM, combined organic phases dried, evaporated and purified by silica gel chromatography (0-5% MeOH:DCM) to obtain 31 mg (54%) of the title compound as a mixture of (E)- and (Z)-isomers.
Reaction SMILES: [F:1][C:2]1([F:32])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:25][CH2:24][CH2:23][C@H:22]2[CH2:26][N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].[CH3:35][O:36][CH2:37][CH2:38]Br>CN(C)C=O>[F:32][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([CH2:38][CH2:37][O:36][CH3:35])[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:25][CH2:24][CH2:23][C@H:22]2[CH2:26][N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: COCCBr
Reactant: O=C(c1cc2cc(C(=O)N3CCC[C@H]3CN3CCCC3)ccc2[nH]1)N1CCC(F)(F)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCn1c(C(=O)N2CCC(F)(F)CC2)cc2cc(C(=O)N3CCC[C@H]3CN3CCCC3)ccc21
Yield: 69 %

Procedure:
The title compound was synthesized in analogy to example 51, from [2-(4,4-difluoro-piperidine-1-carbonyl)-1H-indol-5-yl]-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone (example 44), sodium hydride and 2-bromoethyl methyl ether in N,N-dimethylformamide, to give the desired product as a white foam (69%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[CH2:26][C:25](=[N:28][OH:29])[CH:24]=[CH:23][C:22]=3[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.Br[CH2:31][CH2:32][CH2:33][CH2:34][N:35]([CH2:42][CH2:43][S:44]([CH3:47])(=[O:46])=[O:45])[C:36](=[O:41])[C:37]([F:40])([F:39])[F:38].C(=O)([O-])[O-].[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[CH2:26][C:25](=[N:28][O:29][CH2:31][CH2:32][CH2:33][CH2:34][N:35]([CH2:42][CH2:43][S:44]([CH3:47])(=[O:45])=[O:46])[C:36](=[O:41])[C:37]([F:39])([F:38])[F:40])[CH:24]=[CH:23][C:22]=3[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: ON=C1C=Cc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2C1
Reactant: CS(=O)(=O)CCN(CCCCBr)C(=O)C(F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CS(=O)(=O)CCN(CCCCON=C1C=Cc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2C1)C(=O)C(F)(F)F
Temperature: 60 °C
Reaction time: 1.3 h
Yield: 29.9 %

Procedure:
In N,N-dimethylacetamide (1.5 ml) were dissolved 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(hydroxyimino)quinazoline (V-2, 84 mg) and N-(4-bromobutyl)-N-(2-methanesulfonylethyl)-2,2,2-trifluoroacetamide (71 mg), and potassium carbonate (41 mg) was added, followed by stirring at 60° C. for 1.3 hours with heating. Thereafter, the reaction mixture was poured into 0.5 M citric acid, followed by extraction with ethyl acetate. The organic layer was washed with water and aqueous sodium chloride solution, and dried over magnesium sulfate. The crude product was purified by silica gel chromatography (eluting with hexane:ethyl acetate=1:4) to obtain 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(4-(N-(2-(methanesulfonyl)ethyl)-2,2,2-trifluoroacetamido)butyloxyimino)quinazoline (V-14, 41 mg) as a pale yellow solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C@@H:8]1[CH2:25][C:24]2[CH:23]=[C:22]([OH:26])[CH:21]=[CH:20][C:19]=2[C@@H:18]2[C@@H:9]1[C@H:10]1[C@@:14]([CH2:16][C@@H:17]2[F:27])([CH3:15])[C:13](=[O:28])[CH2:12][CH2:11]1.[I-:29].[Na+].O>C(C(C)=O)C>[F:27][C@H:17]1[CH2:16][C@@:14]2([CH3:15])[C@@H:10]([CH2:11][CH2:12][C:13]2=[O:28])[C@H:9]2[C@H:18]1[C:19]1[CH:20]=[CH:21][C:22]([OH:26])=[CH:23][C:24]=1[CH2:25][C@H:8]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][I:29]
Reactant: [I-]
Reactant: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCCCl)[C@H]3[C@@H]1CCC2=O
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: O
Product: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCCI)[C@H]3[C@@H]1CCC2=O
Temperature: 90 °C
Reaction time: 8 h
Yield: 102.8 %

Procedure:
2.7 g of 7α-(6-chlorohexyl)-11β-fluoro-3-hydroxy-estra-1,3,5(10)-trien-17-one is dissolved in 40 ml of ethylmethylketone, mixed with 3.0 g of sodium iodide and stirred overnight at a bath temperature of 90° C. For working-up, the reaction mixture is cooled to room temperature, stirred into water, extracted 3 times with ethyl acetate, washed with common salt solution, dried on magnesium sulfate and concentrated by evaporation in a vacuum. 3.4 g of 11β-fluoro-3-hydroxy-7α-(6-iodohexyl)-estra-1,3,5(10)-trien-17-one is obtained as a crude product, which is used without further purification in the next stage.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)=[CH:4][CH:3]=1.C([Li])CCC.[B:26](OC)([O:29]C)[O:27]C.Cl>O1CCCC1>[CH:10]1[C:9]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([B:26]([OH:29])[OH:27])=[CH:7][CH:6]=3)[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: Brc1ccc(-n2c3ccccc3c3ccccc32)cc1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(-n2c3ccccc3c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.9 %

Procedure:
Then, 21.8 g (67.5 mmol) of 9-(4-bromophenyl)carbazole was put into a 500 mL three-necked flask, and the air in the flask was replaced with nitrogen. Then, 200 mL of tetrahydrofuran (THF) was added thereto. The temperature in the flask was set to be −78° C. and then, 48.9 mL (74.3 mmol) of n-butyllithium (1.52 mol/L, hexane solution) was dropped to the mixture and was stirred for 2 hours at the same temperature. Then, 17.4 mL (155 mmol) of trimethyl borate was added thereto. The mixture was stirred for one hour at the same temperature, then, was stirred for 24 hours while raising the temperature to room temperature. After the reaction, 200 mL of hydrochloric acid (1.0 mol/L) was added to the reaction mixture, and then stirred for one hour at room temperature. After that, the organic layer in the reaction mixture was washed with water and the product was extracted with ethyl acetate from the water which was used for the washing. The obtained extraction solution and the organic layer, which was washed with water, were mixed. The mixture was further washed with a saturated aqueous solution of sodium chloride, and then dried with magnesium sulfate. After the drying, the mixture was suction filtrated, and the filtrate was concentrated. The obtained residue was recrystallized with a mixed solvent of chloroform and hexane to give 12.8 g of a white powdered solid of 4-(carbazol-9-yl)phenylboronic acid (yield: 65.9%). A synthesis scheme (f-3) of 4-(carbazol-9-yl)phenylboronic acid is shown below.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21](O)[N:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6]([CH3:24])=[N:5]1)([CH3:3])[CH3:2].[CH2:25]1[C@@H:29]([C:30]([NH2:32])=[O:31])[NH:28][CH2:27][C@H:26]1[F:33].Cl>>[F:33][C@@H:26]1[CH2:27][N:28]([C:21]2[N:20]=[CH:19][C:16]3[C:17]4[N:11]([CH:10]=[C:9]([C:8]5[N:4]([CH:1]([CH3:2])[CH3:3])[N:5]=[C:6]([CH3:24])[N:7]=5)[N:18]=4)[CH2:12][CH2:13][O:14][C:15]=3[CH:22]=2)[C@H:29]([C:30]([NH2:32])=[O:31])[CH2:25]1
Reactant: NC(=O)[C@@H]1C[C@H](F)CN1
Reactant: Cc1nc(-c2cn3c(n2)-c2cnc(O)cc2OCC3)n(C(C)C)n1
Agent: Cl
Product: Cc1nc(-c2cn3c(n2)-c2cnc(N4C[C@@H](F)C[C@H]4C(N)=O)cc2OCC3)n(C(C)C)n1
Yield: 42 %

Procedure:
Following the procedures of Example 339, 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ol and 4-cis-fluoro-L-prolinamide hydrochloride with added TEA (2.5 eq.), were reacted and the crude product recrystallised from IMS/DCM to give 382 as a white solid (68 mg, 42%). LCMS: RT=2.58 min, [M+H]+441. 1H NMR 400 MHz (DMSO-d6) δ: 9.04 (1 H, s), 7.76 (1 H, s), 7.10 (1 H, s), 6.91 (1 H, s), 5.95 (1 H, s), 5.87-5.80 (1 H, m), 5.42 (1 H, s), 5.29 (1 H, s), 4.49-4.36 (5 H, m), 3.74-3.73 (2 H, m), 2.46-2.45 (1 H, m), 2.20 (3 H, s), 1.40 (6 H, dd, J=6.59, 3.37 Hz)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[N:35]1([C:41]([C:43]2[CH:48]=[C:47]([O:49][CH3:50])[C:46]([O:51][CH3:52])=[C:45]([O:53][CH3:54])[CH:44]=2)=[O:42])[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)=[CH:9][CH2:10][CH2:11][CH2:12][C:13]([N:38]2[CH2:39][CH2:40][N:35]([C:41](=[O:42])[C:43]3[CH:48]=[C:47]([O:49][CH3:50])[C:46]([O:51][CH3:52])=[C:45]([O:53][CH3:54])[CH:44]=3)[CH2:36][CH2:37]2)=[O:15])=[CH:4][CH:3]=1
Reactant: COc1cc(C(=O)N2CCNCC2)cc(OC)c1OC
Reactant: O=C(O)CCCC=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)N2CCN(C(=O)CCCC=C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
A solution of 6,6-bis-(4-fluoro-phenyl)-hex-5-enoic acid (2.64 g, 8.75 mmol) and CDI (1.42 g, 8.75 mmol) in dry THF (30 ml) was stirred for 1 hr at room temperature under nitrogen. A solution of piperazin-1-yl-(3,4,5,-trimethoxy-phenyl)-methanone (2.45 g, 8.75 mmol) in dry THF (30 ml) was added to above solution and resulting mixture stirred at room temperature overnight. The mixture is diluted with EtOAc (30 ml) and washed with water (2×30 ml) and dried over MgSO4. Evaporation of solvent followed by column chromatography using CH2Cl2:MeOH (15:1) gave the desired product in 49% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[C:23]([Cl:25])[CH:24]=1)[O:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[S:11][C:10]=2[CH:9]=[C:8](Cl)[CH:7]=1.[CH2:26]([C:33]#[N:34])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].Cl>C1(C)C=CC=CC=1.CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[C:23]([Cl:25])[CH:24]=1)[O:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[S:11][C:10]=2[CH:9]=[C:8]([CH:26]([C:33]#[N:34])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:7]=1
Reactant: N#CCc1ccccc1
Reactant: O=c1c2ccccc2sc2cc(Cl)cc(Oc3cc(Cl)cc(Cl)c3)c12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: N#CC(c1ccccc1)c1cc(Oc2cc(Cl)cc(Cl)c2)c2c(=O)c3ccccc3sc2c1
Yield: 30.1 %

Procedure:
2 g (4.9 mmol) of 1-(3',5'-dichlorophenoxy)-3-chlorothioxanthone, 0.86 g of benzyl cyanide, 2.03 g of potassium carbonate and 20 ml of DMSO are stirred at 80° C. for 6 hours. The mixture is discharged into 2N HCl/tetrahydronfuran/toluene, and the organic phase is separated off, dired over sodium sulfate and evaporated. Chromatography on silica gel using methylene chloride gives 0.72 g (30%) of product, melting point 145°-155° C.
Reaction SMILES: IC.[CH2:3]([O:5][C:6]([C:8]1[O:9][C:10]2[C:15]([C:16](=[O:25])[C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)=[CH:14][C:13]([CH2:26][CH3:27])=[C:12]([OH:28])[CH:11]=2)=[O:7])[CH3:4].[C:29](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:3]([O:5][C:6]([C:8]1[O:9][C:10]2[C:15]([C:16](=[O:25])[C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)=[CH:14][C:13]([CH2:26][CH3:27])=[C:12]([O:28][CH3:29])[CH:11]=2)=[O:7])[CH3:4]
Reactant: CCOC(=O)c1oc2cc(O)c(CC)cc2c(=O)c1-c1ccc(F)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CCOC(=O)c1oc2cc(OC)c(CC)cc2c(=O)c1-c1ccc(F)cc1
Yield: 86.8 %

Procedure:
Iodomethane (0.10 ml, 12 equiv.) was added to a solution of 6-Ethyl-3-(4-fluoro-phenyl)-7-hydroxy-4-oxo-4H-chromene-2-carboxylic acid ethyl ester (50 mg, 0.14 mmol) and potassium carbonate (58 mg, 3.0 equiv.) in acetone and the mixture refluxed overnight. The volatiles were then evaporated in vacuo and the residue partitioned between water (15 ml) and EtOAc (15 ml). The organic layer was washed with brine, dried over MgSO4 and evaporated to dryness in vacuo to give a white crystalline product (45 mg, 87% yield)
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[CH:25]=[C:24]([Cl:26])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:16]=1>>[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:15]1[N:16]=[C:11]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[C:12]2[CH:25]=[C:24]([Cl:26])[S:23][C:13]=2[N:14]=1
Reactant: NCc1ccc(F)cc1
Reactant: Clc1cc2c(Cl)nc(-c3ccccn3)nc2s1
Product: Fc1ccc(CNc2nc(-c3ccccn3)nc3sc(Cl)cc23)cc1

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(pyridin-2-yl)-6-chloro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(4-fluorobenzylamino)-6-chloro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:28][CH:27]=3)=[CH:22][N:21]=2)=[CH:16][CH:15]=1)[C:3]([N:5]1[CH2:8][CH:7]([C:9]([O:11][CH3:12])=[O:10])[CH2:6]1)=[O:4].[C:40]([C:44]1[S:48][C:47]([C:49](O)=[O:50])=[CH:46][CH:45]=1)([CH3:43])([CH3:42])[CH3:41].CN(C=O)C.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[C:40]([C:44]1[S:48][C:47]([C:49]([NH:1][C@@H:2]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:25]=[CH:24][C:23]([C:26]4[CH:27]=[CH:28][C:29]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:30][CH:31]=4)=[CH:22][N:21]=3)=[CH:16][CH:15]=2)[C:3]([N:5]2[CH2:6][CH:7]([C:9]([O:11][CH3:12])=[O:10])[CH2:8]2)=[O:4])=[O:50])=[CH:46][CH:45]=1)([CH3:43])([CH3:41])[CH3:42]
Reactant: CC(C)(C)c1ccc(C(=O)O)s1
Reactant: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](N)C(=O)N4CC(C(=O)OC)C4)cc3)nc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](NC(=O)c4ccc(C(C)(C)C)s4)C(=O)N4CC(C(=O)OC)C4)cc3)nc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.3 %

Procedure:
To a stirred solution of (S)-methyl 1-(2-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate (360 mg, 0.678 mmol) and 5-(tert-butyl)thiophene-2-carboxylic acid (125 mg, 0.678 mmol) in DMF (6 mL, 77 mmol) was added DIEA (0.47 mL, 2.71 mmol) and the mixture cooled to 0° C. HATU (284 mg, 0.746 mmol) was added portion-wise and the reaction stirred at room temperature for 1 h. The mixture was poured onto citric acid (70 mL of a 10% w/w aqueous solution) and extracted with EA (2×100 mL). The combined organic extracts were washed with brine (50 mL), dried over MgSO4 and solvents evaporated. Column chromatography (EA/iso-hexanes) gave 389 mg (82%) of (S)-methyl 1-(2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate as a pale yellow solid. LCMS-ESI (m/z) calculated for C40H48N4O5S: 696.3. found 697.0 [M+H]+, tR=3.60 min (Method 6).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:18])=O>>[Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[C:3]=1[C:4]([Cl:18])=[O:5]
Reactant: O=C(O)c1c(C(F)(F)F)cc(Cl)nc1Cl
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1c(C(F)(F)F)cc(Cl)nc1Cl

Procedure:
A solution of 2,6-dichloro-4-(trifluoromethyl)nicotinic acid (3.22 g, 13.2 mmol) in thionyl chloride (9 mL) was heated at reflux for 3 h. After cooling, the solution was concentrated in vacuo to give 2,6-dichloro-4-(trifluoromethyl)nicotinoyl chloride as a yellow oil which was carried on to the next step without further purification. This transformation can also be accomplished using oxalyl chloride with catalytic DMF in place of thionyl chloride.
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[NH2:16]>>[Cl:12][C:13]1[CH:14]=[C:15]([NH:16][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([I:1])[CH:3]=[CH:4][C:5]=2[OH:11])[CH:17]=[C:18]([Cl:20])[CH:19]=1
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: O=C(O)c1cc(I)ccc1O
Product: O=C(Nc1cc(Cl)cc(Cl)c1)c1cc(I)ccc1O
Yield: 65.4 %

Procedure:
Using 5-iodosalicylic acid and 3,5-dichloroaniline as the raw materials, the same operation as the example 16 gave the title compound.