Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([F:15])[CH:12]=3)[NH:7][C:6]=2[C:5]([O:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])=[C:4]2[NH:22][C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][C:28]=3[C:3]=12.[CH3:30][N:31](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[CH3:20][N:19]([CH3:21])[CH2:18][CH2:17][O:16][C:5]1[C:6]2[NH:7][C:8]3[C:13](=[CH:12][C:11]([F:15])=[CH:10][CH:9]=3)[C:14]=2[C:2]([C:30]#[N:31])=[C:3]2[C:28]3[CH:27]=[C:26]([F:29])[CH:25]=[CH:24][C:23]=3[NH:22][C:4]=12
Reactant: CN(C)C=O
Reactant: CN(C)CCOc1c2[nH]c3ccc(F)cc3c2c(Br)c2c1[nH]c1ccc(F)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CN(C)CCOc1c2[nH]c3ccc(F)cc3c2c(C#N)c2c1[nH]c1ccc(F)cc12
Temperature: 160 °C
Yield: 46 %

Procedure:
A mixture of 2-(12-bromo-2,10-difluoro-5,7-dihydroindolo[2,3-b]carbazol-6-yloxy)-N,N-dimethylethanamine (97.8 mg, 0.1991 mmol), zinc cyanide (233.7 mg, 1.9910 mmol) and tetrakis(triphenylphosphine)palladium (0) (23.0 mg, 0.01991 mmol) in anhydrous DMF was purged with high-purity Ar for five minutes, sealed with Teflon cap and heated to 160° C. for 12 hours. The reaction mixture was cooled down and filtered. The solvent was removed via vacuum pump. The residue was purified via flash chromatography to provide the title compound (37.3 mg, 46%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 11.90 (s, 2 H), 8.39 (dd, J=10.2, 2.8 Hz, 2 H), 7.55 (dd, 8.8, 4.4 Hz, 2 H), 7.31 (td, J=8.8, 2.4 Hz, 2 H), 4.33 (t, J=4.2 Hz, 2 H), 2.74 (t, J=4.2 Hz, 2 H), 2.35 (s, 6 H); MS (ESI) m/z 403.1 (M−H)−; MS (ESI) m/z 405.0 (M+H)+
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:4]([C:5](F)=[O:6])[C:3]=1[C:14](F)=[O:15].FC1(F)C2C(=C(F)C(F)=C(F)C=2F)C(=O)[O:19]1>FC(F)(F)C(O)=O>[F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:4]2[C:5](=[O:19])[O:6][C:14](=[O:15])[C:3]=12
Reactant: O=C1OC(F)(F)c2c(F)c(F)c(F)c(F)c21
Reactant: O=C(F)c1c(F)c(F)c(F)c(F)c1C(=O)F
Solvent: O=C(O)C(F)(F)F
Product: O=C1OC(=O)c2c(F)c(F)c(F)c(F)c21
Yield: 65 %

Procedure:
Into a 200 ml glass reactor equipped with a reflux condenser and a stirrer, 50 g (0.207 mol) of the mixture (1:1) of the 3,4,5,6-tetrafluorophthaloyldifluoride and the 3,3,4,5,6,7-hexafluoro-1-[3H]-isobenzofuranone of Example 2, and 50 ml of trifluoroacetic acid were charged, and the mixture was refluxed for 72 hours with vigorous stirring. Then, the reaction mixture was separated by distillation to obtain 29.6 g of tetrafluorophthalic anhydride. The yield was 65%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[F:12][C:13]([F:25])([F:24])[O:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1>>[N:8]1[C:9]2[C:4](=[CH:3][C:2]([NH:1][C:22]([NH:21][C:18]3[CH:19]=[CH:20][C:15]([O:14][C:13]([F:12])([F:24])[F:25])=[CH:16][CH:17]=3)=[O:23])=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Reactant: Nc1ccc2ncccc2c1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)Nc1ccc2ncccc2c1

Procedure:
Prepared from 6-aminoquinoline and 4-(trifluoromethoxy)phenyl isocyanate. m/z (ES+) 348 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH:9]=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N+:15]=3[O-:20])[C:7]=2[CH:21]=1)#[N:2].C1(C)C=CC=CC=1.O=O>ClCCl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH2:9][C@@H:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N+:15]=3[O-:20])[C:7]=2[CH:21]=1)#[N:2]
Reactant: CC1(C)C=C(c2cccc[n+]2[O-])c2cc(C#N)ccc2O1
Agent: O=O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC1(C)C[C@@H](c2cccc[n+]2[O-])c2cc(C#N)ccc2O1
Reaction time: 20 h

Procedure:
100 mg (359 mmol) of 2-(6-cyano-2,2-dimethyl-2H-1-benzopyran-4-yl)pyridine 1-oxide, 9 ml of toluene, 1 ml of dichloromethane, 5.8 mg (14.4 mmol) of [Rh(COD)2 ]BF4 and 6.1 mg (14,4 mmol) of (R)-BIPHAS were placed in a 30 ml autoclave in a glove box (O2 content <1 ppm). The autoclave was sealed and the hydrogenation was carried out at 40° while stirring and a pressure of 40 bar. The hydrogenation was interrupted after 20 h. In order to determine the e.e. value and the conversion, a sample of the hydrogenation solution was evaporated and analyzed by HPLC on a chiral phase (Chiralcel OD-H). (R)-2-(6-Cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4yl)-pyridine 1-oxide was obtained in quantitative yield: e.e.=85%; chem. purity >99%.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:17]=[CH:16][N:15]([C:18]4[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=4)[C:14]3=[O:25])=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:26][CH2:27][CH2:28]Br>>[Br:26][CH2:27][CH2:28][O:24][C:21]1[CH:20]=[CH:19][C:18]([N:15]2[CH:16]=[CH:17][N:13]([C:10]3[CH:9]=[CH:8][C:7]([O:6][CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)=[CH:12][CH:11]=3)[C:14]2=[O:25])=[CH:23][CH:22]=1
Reactant: O=c1n(-c2ccc(O)cc2)ccn1-c1ccc(OC2CCCC2)cc1
Reactant: BrCCBr
Product: O=c1n(-c2ccc(OCCBr)cc2)ccn1-c1ccc(OC2CCCC2)cc1

Procedure:
1-(4-Cyclopentyloxyphenyl)-3-(4-hydroxyphenyl)-1,3-dihydroimidazol-2-one was reacted with 1,2-dibromoethane as described in example 5. The product with the molecular weight of 443.34 (C22H23BrN2O3); MS (ESI): 443 ([M+H]+) was obtained in this way.
Reaction SMILES: [CH2:1]([C:3]1([CH2:21][CH3:22])[CH:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:19])[CH2:15][CH2:16][C:17]#[N:18])=[CH:10][CH:9]=2)[NH:5][C:4]1=[O:20])[CH3:2].[CH2:23]([C@@H:26]([N:34]=[C:35]=[O:36])[C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=1)[CH:24]=[CH2:25].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:21]([C:3]1([CH2:1][CH3:2])[C@H:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:19])[CH2:15][CH2:16][C:17]#[N:18])=[CH:10][CH:9]=2)[N:5]([C:35]([NH:34][C@H:26]([CH2:23][CH:24]=[CH2:25])[C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)=[O:36])[C:4]1=[O:20])[CH3:22]
Reactant: C=CC[C@@H](N=C=O)c1ccc(C)cc1
Reactant: CCC1(CC)C(=O)NC1Oc1ccc(C(=O)CCC#N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CC[C@@H](NC(=O)N1C(=O)C(CC)(CC)[C@@H]1Oc1ccc(C(=O)CCC#N)cc1)c1ccc(C)cc1

Procedure:
According to the procedure of Example 21, Step B, 1.29 gm (4.3 mmol) of 3,3-diethyl-4-(RS)-[4-(1-oxo-3-cyanopropyl)phenoxy]azetidin-2-one, 0.965 gm (5.15 mmol) of (R)-α-allyl-4-methylbenzyl isocyanate, 59 mg (0.43 mmol) of potassium carbonate in 20 mL of DMF gave, after EPLC purification on 1 kg of silica eluting with 8 L of 72:28 hexanes: ethyl acetate 1.0 gm of the product as an oil.
Reaction SMILES: N#N.[F:3][C:4]([F:17])([F:16])[C:5]1[CH:15]=[CH:14][C:8](/[CH:9]=[CH:10]/[C:11](O)=[O:12])=[CH:7][CH:6]=1.CN(C=O)C.C(Cl)(=O)C([Cl:26])=O>C1(C)C=CC=CC=1>[F:3][C:4]([F:17])([F:16])[C:5]1[CH:15]=[CH:14][C:8]([CH:9]=[CH:10][C:11]([Cl:26])=[O:12])=[CH:7][CH:6]=1
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)cc1
Reactant: O=C(Cl)C(=O)Cl
Agent: N#N
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)C=Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a suspension of trans-4-(trifluoromethyl)cinnamic acid (20 mg, 0.10 mmol) in toluene (1.0 mL) was treated with a drop of DMF followed by oxalyl chloride (0.02 mL, 0.23 mmol) and the resulting yellow solution was stirred at rt for 30 min. The solvent was then removed under reduced pressure (coevaporation with toluene) to give 3-(4-trifluoromethyl-phenyl)-acryloyl chloride.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11]C(=O)C2C=CC=CC=2)[O:8][C@@H:7]([N:20]2[CH:27]=[CH:26][C:24](=[O:25])[NH:23][C:21]2=[O:22])[C@H:6]1[F:28])(=O)C.C([O-])(=O)C.[Na+].[Br:34]Br>C(O)(=O)C>[F:28][C@H:6]1[C@H:5]([OH:4])[C@@H:9]([CH2:10][OH:11])[O:8][C@H:7]1[N:20]1[CH:27]=[C:26]([Br:34])[C:24](=[O:25])[NH:23][C:21]1=[O:22]
Reactant: CC(=O)O[C@H]1[C@H](F)[C@H](n2ccc(=O)[nH]c2=O)O[C@@H]1COC(=O)c1ccccc1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=c1[nH]c(=O)n([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2F)cc1Br
Reaction time: 0.5 h
Yield: 78.4 %

Procedure:
To a solution of 1-(3-O-acetyl-5-O-benzoyl-2-deoxy-2-fluoro-β-D-arabinofuranosyl)uracil (500 mg) and sodium acetate (100 mg) in 5 ml of glacial acetic acid is added a solution of bromine (240 mg) in 1 ml of glacial acetic acid. After 30 minutes at room temperature, the solvent is removed by evaporation in vacuo. Traces of acetic acid is removed by several co-evaporation with toluene. The residue is dissolved in saturated methanolic ammonia (50 ml) and the mixture is kept standing at room temperature for 2 days. The solvent is removed by evaporation in vacuo and the residue is crystallized from water to give 1-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-5-bromouracil (325 mg), m.p. 214°-216°.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:18]=[CH:17][C:16]2[S:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[S:19]([CH3:22])(=[O:21])=[O:20])[N:8]([CH2:23][CH2:24][CH2:25]Cl)[C:7]=2[CH:6]=1)([CH3:3])[CH3:2].[OH:27][CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH:1]([O:4][C:5]1[CH:18]=[CH:17][C:16]2[S:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[S:19]([CH3:22])(=[O:21])=[O:20])[N:8]([CH2:23][CH2:24][CH2:25][N:33]3[CH2:34][CH2:35][CH:30]([CH2:29][CH2:28][OH:27])[CH2:31][CH2:32]3)[C:7]=2[CH:6]=1)([CH3:3])[CH3:2]
Reactant: OCCC1CCNCC1
Reactant: CC(C)Oc1ccc2c(c1)N(CCCCl)c1cccc(S(C)(=O)=O)c1S2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc2c(c1)N(CCCN1CCC(CCO)CC1)c1cccc(S(C)(=O)=O)c1S2
Temperature: 150 °C
Yield: 36.7 %

Procedure:
A mixture of 2-isopropoxy-6-methylsulphonyl-10-(3-chloropropyl)phenothiazine (20 g.), 4-hydroxyethylpiperidine (6.4 g.) and sodium bicarbonate (16.5 g.) in dimethylformamide (170 cc.) is heated at 150°C. for 7 hours 30 minutes with stirring. The reaction mixture is then treated under the conditions mentioned in Example 1. 2-Isopropoxy-6-methylsulphonyl-10-[3-(4-hydroxyethylpiperidino)propyl]phenothiazine (9.0 g.), melting at about 50°C., is thus obtained.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C(O)C.[F:18][C:19]1[CH:20]=[C:21]([O:25][CH2:26][C:27]2[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=2[C:29]([OH:31])=O)[CH:22]=[CH:23][CH:24]=1>O>[F:18][C:19]1[CH:24]=[CH:23][C:22]2[C:29](=[O:31])[C:28]3[CH:32]=[CH:33][CH:34]=[CH:35][C:27]=3[CH2:26][O:25][C:21]=2[CH:20]=1
Reactant: O=C(O)c1ccccc1COc1cccc(F)c1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Solvent: CCO
Product: O=C1c2ccccc2COc2cc(F)ccc21
Temperature: 100 °C
Yield: 79.6 %

Procedure:
To 250 g of phosphorus pentoxide is slowly added 160 ml of ethanol at room temperature. The mixture is further stirred with heating at 100° C. for 1 hour. Thereto 42 g of 2-[(3-fluorophenyloxy)methyl]benzoic acid is added and the mixture is stirred with heating at 100° C. for 1 hour. After cooling to room temperature, 500 ml of water is added. After extraction with toluene, washing successively with saturated sodium hydrogen carbonate, water and a saturated saline solution and drying over magnesium sulfate, the solvent is distilled off under reduced pressure to give 31 g of 3-fluoro-6,11-dihydrodibenz[b,e]oxepin-11-one (oil). Mass spectrum m/z: 228(M+).
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][N:2]([CH3:10])[C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:9][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][Br:11]
Reactant: BrCCCCCCBr
Reactant: CN(C)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CN(C)c1cccc(OCCCCCCBr)c1

Procedure:
A mixture of 27.5 g. (0.2 mole) of m-dimethylaminophenol, 94 g. (0.39 mole) of 1,6-dibromohexane, 53.8 g. of powdered anhydrous potassium carbonate and 350 ml. of acetone was heated at reflux under nitrogen for two days. The reaction mixture was concentrated in vacuo and the residue partitioned between water and methylene dichloride. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was distilled to remove unreacted 1,6-dibromohexane (b.p. 63° C., 0.2 mm.). The remaining material was dissolved in 5% sulfuric acid by warming on a steam bath, then filtered, cooled and made basic with sodium hydroxide. The product was extracted with chloroform, washed with water, dried over magnesium sulfate and concentrated to a reddish brown oil, 52.4 g.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:11])[CH:3]=1.[CH3:12][CH2:13][CH:14]([NH2:17])[CH2:15][CH3:16]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:17][CH:14]([CH2:15][CH3:16])[CH2:13][CH3:12])=[O:8])=[C:4]([F:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1F
Reactant: CCC(N)CC
Product: CCC(CC)NC(=O)c1ccc(Br)cc1F

Procedure:
The sub-title compound was prepared by the method of example 18 step a) using 4-bromo-2-fluorobenzoic acid and 3-pentanamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].[H-].[Na+].Cl[C:13]1[C:22]2[C:17](=[C:18]([C:25]#[C:26][CH2:27][CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:19]([O:23][CH3:24])=[CH:20][CH:21]=2)[CH:16]=[N:15][N:14]=1.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH2:8][C:13]1[C:22]2[C:17](=[C:18]([C:25]#[C:26][CH2:27][CH2:28][CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:19]([O:23][CH3:24])=[CH:20][CH:21]=2)[CH:16]=[N:15][N:14]=1
Reactant: COc1ccc2c(Cl)nncc2c1C#CCCCc1ccccc1
Reactant: Cc1c(Cl)cncc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nncc2c1C#CCCCc1ccccc1
Reaction time: 1 h
Yield: 51.5 %

Procedure:
A solution under N2 of 3,5-dichloro-4-methyl-pyridine (1.28 g, 7.9 mmoles) in dry DMF (15 ml) was added under stirring at room temperature with 60% NaH (316 mg, 7.9 mmoles). The mixture was stirred for 1 hour, then dropwise added with 1-chloro6-methoxy-5-(5-phenyl-pent-1-ynyl)-phthalazine (1.33 g, 3.95 mmoles), prepared as described in example 65, in dry DMF (20 ml). After 3 hours the mixture was poured into water, extracted with ethyl acetate, washed with water, anhydrified over Na2SO4 and brought to dryness. The residue was flash chromatographed (eluent: petrolatum/ethyl acetate 1:1). The separated product was taken up in ethanol (10 ml) and crystallised. The resultant product was filtered and dried under vacuum at 40° C. to give 940 mg of the title compound (yield: 51%). m.p.: 130-132° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)=[O:6].C([O:27][C:28]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)=[O:29])C.COCCOC.C(=O)([O-])[O-].[Cs+].[Cs+]>O>[CH3:24][O:23][C:22]1[CH:21]=[CH:20][C:4]([C:5](=[O:6])[NH:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[CH:10][CH:9]=2)=[CH:3][C:2]=1[C:33]1[CH:34]=[CH:35][C:30]([C:28]([OH:29])=[O:27])=[CH:31][CH:32]=1
Reactant: COc1ccc(C(=O)Nc2ccc(N3CCOCC3)cc2)cc1Br
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(C(=O)Nc2ccc(N3CCOCC3)cc2)cc1-c1ccc(C(=O)O)cc1

Procedure:
A mixture of 3-Bromo-4-methoxy-N-(4-morpholin-4-yl-phenyl)-benzamide (788 mg) and 4-(ethoxycarbonyl)-phenyl boronic acid (564 mg) in 2:1 DME:water (15 ml) containing cesium carbonate (1.31 g) and tetrakis(triphenylphosphine)palladium0 (232 mg) was heated to reflux for 18 h.
Reaction SMILES: [NH3:1].[CH3:2][O:3][C:4]([C:6]1[CH:7]=[C:8]([CH3:28])[C:9]2[O:15][C:14]3[C:16]([Cl:24])=[CH:17][C:18]([NH:20][CH2:21][CH2:22]Cl)=[CH:19][C:13]=3[CH2:12][S:11](=[O:26])(=[O:25])[C:10]=2[CH:27]=1)=[O:5]>CO>[CH3:2][O:3][C:4]([C:6]1[CH:7]=[C:8]([CH3:28])[C:9]2[O:15][C:14]3[C:16]([Cl:24])=[CH:17][C:18]([NH:20][CH2:21][CH2:22][NH2:1])=[CH:19][C:13]=3[CH2:12][S:11](=[O:25])(=[O:26])[C:10]=2[CH:27]=1)=[O:5]
Reactant: N
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCCl)cc(Cl)c1O2
Solvent: CO
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCN)cc(Cl)c1O2
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Aqueous ammonia solution (2.5 mL, 30%) was added to a solution of Example 56k (0.4 g, 0.93 mmol) in methanol (1 mL). The reaction mixture was sealed under argon in a reactor vessel and kept in an oven at 120° C. for 2 h. It was concentrated and the solid obtained was washed thoroughly with methanol to remove excess ammonia and dried under vacuo. It was treated with a methanolic HCl solution and stirred at 70° C. for 3 h. The reaction mixture was concentrated, treated with 10% aqueous sodium bicarbonate solution and extracted with ethylacetate. The organic layer was washed with water, brine, dried, and purified using flash chromatography (silica gel, 10% methanol/chloroform) to obtain the title compound as a white solid. Yield: 0.340 g, (89.23%); 1H NMR (DMSO-d6): δ 2.70 (s, 3H, CH3), 3.00 (t, 2H, CH2), 3.35 (t, 2H, CH2), 3.90 (s, 3H, OCH3), 5.20 (s, 2H, CH2), 6.40 (t, 1H, NH), 6.80 (s, 2H, Ar), 7.80 (t, 2H, NH2), 8.15 (s, 1H, Ar) and 8.30 (s, 1H, Ar). MS: m/e (CI+) 411 (M+).
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:7][C:6]=2[CH:5]=[C:4]([OH:17])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>C(C(C)=O)C>[OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:7][C:6]=2[CH:5]=[C:4]([O:17][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:3]=1
Reactant: O=c1c2ccccc2oc2cc(O)cc(O)c12
Reactant: CCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCCOc1cc(O)c2c(=O)c3ccccc3oc2c1

Procedure:
22.8 g of 1,3-dihydroxyxanthone (prepared according to Grover, J. Chem. Soc. 1955, 3982) together with 15.2 g of K2CO3 and 21.2 g of 1-bromooctane are refluxed for 15 hours in 250 ml of methyl ethyl ketone. The salt is isolated by filtration from the cooled reaction mixture and the methyl ethyl ketone solution is concentrated by evaporation under vacuum. Recrystallisation of the residue from heptane gives 1-hydroxy-3-octoxyxanthone with a melting point of 98° C.
Reaction SMILES: CN(C)C=O.CS([O:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([CH3:19])=[C:16]([F:18])[F:17])(=O)=O.[CH3:20][C:21]1[N:22]=[C:23]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[S:24][C:25]=1[C:26](O)=[O:27].C(=O)([O-])O.[Na+]>O>[CH3:20][C:21]1[N:22]=[C:23]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[S:24][C:25]=1[C:26]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([CH3:19])=[C:16]([F:17])[F:18])=[O:27]
Reactant: CC(CCCCOS(C)(=O)=O)=C(F)F
Reactant: Cc1nc(-c2ccccc2)sc1C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(CCCCOC(=O)c1sc(-c2ccccc2)nc1C)=C(F)F
Temperature: 100 °C
Reaction time: 6 h
Yield: 73.7 %

Procedure:
To 10 ml of N,N-dimethylformamide were dissolved 0.50 g (2.2 mmol) of 6,6-difluoro-5-methyl-5-hexenyl methanesulfonate and 0.53 g (2.4 mmol) of 4-methyl-2-phenylthiazole-5-carboxylic acid, followed by the addition of 0.37 g (4.4 mmol) of sodium hydrogencarbonate and stirring at 100° C. for 6 hours. The reaction liquid was then poured in water and extracted with ethyl acetate. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate:hexane=1:19) to obtain 0.57 g (yield: 74%) of 6,6-difluoro-5-methyl-5-hexenyl 4-methyl-2-phenylthiazole-5-carboxylate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].I[C:34]1[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:34]3[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=3)[CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: FC(F)(F)c1ccc(I)cc1
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCNC2)c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCN(c3ccc(C(F)(F)F)cc3)C2)c1
Yield: 35.9 %

Procedure:
To a solution of compound 33b, 4-Methyl-2-(5-piperidin-3-yl-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (35 mg, 0.08 mmol) in toluene (1.0 ml), 1-Iodo-4-trifluoromethyl-benzene (11.4 μl, 0.08 mmol), racemic-2-Ditbutylphosphino-1-1′binapthyl (14 mg, 0.035 mmol), and sodium t-butoxide ((10.0 mg, 0.01 mmol) were added and the reaction was bubbled with nitrogen for 20 minutes. The reaction was degassed with nitrogen and Pd (II) OAc) 8.0 mg, 0.01 mmol) was added. The reaction was microwaved at 120° C. for 30 minutes. The reaction was concentrated in vacuo, and purified by silica gel chromatography to give the product as a yellow oil (17 mg, 22%). Calcd for C33H35F6NO2 (M+H) 591.63, Found 592.3
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][OH:13])[N:6]=[CH:5]2.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[CH:23][C:24]([C:27]#[CH:28])=[N:25][CH:26]=2)=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:22]=[CH:23][C:24]([C:27]#[C:28][C:2]3[CH:3]=[C:4]4[C:8](=[CH:9][CH:10]=3)[N:7]([CH2:11][CH2:12][OH:13])[N:6]=[CH:5]4)=[N:25][CH:26]=2)=[CH:19][CH:20]=1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: OCCn1ncc2cc(I)ccc21
Product: OCCn1ncc2cc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)ccc21

Procedure:
The product was prepared analogously to Example 7.1e starting from 2-(5-iodoindazol-1-yl)ethanol and 5-(4-chlorophenyl)-2-ethynylpyridine. Yield: 1.60 g (73% of theoretical); C22H16ClN3O (M=373.835); calc.: molpeak (M+H)+: 374/376 (Cl); found: molpeak (M+H)+: 374/376 (Cl).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[O-:11][CH2:12][CH3:13].[Na+].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:11][CH2:12][CH3:13])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1
Reactant: CC[O-]
Reactant: CSc1nc(Cl)cc(Cl)n1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(Cl)nc(SC)n1
Temperature: 70 °C
Reaction time: 8 h
Yield: 100.2 %

Procedure:
To a solution of 4,6-dichloro-2-methylsulfanylpyrimidine (500 mg, 2.56 mmol) in anhydrous DMF (6 mL) was added sodium ethoxide (174 mg, 2.56 mmol). The reaction mixture was stirred at 70° C. for overnight. The resulting mixture was poured into 30 mL of water and was extracted with diethyl ether (20 mL×3) three times. The ether layer was separated and dried with anhydrous MgSO4 and concentrated in vacuo to give crude product 4-chloro-6-ethoxy-2-methylsulfanylpyrimidine (525 mg). 1H-NMR (CDCl3): δ 6.39 (s, 1 H), 4.43 (q, J=7.1 Hz, 2 H), 2.54 (s, 3 H), 1.38 (t, J=7.1 H, 3 H).