Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]([CH2:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][CH:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=3)[CH2:26][CH2:25]2)[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(N(CC)CC)C.[C:45](Cl)(=[O:47])[CH3:46].[OH-].[Na+]>O1CCCC1>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]([CH2:21][CH2:22][CH2:23][N:24]2[CH2:25][CH2:26][CH:27]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([NH:37][C:45](=[O:47])[CH3:46])=[CH:35][CH:36]=3)[CH2:28][CH2:29]2)[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC(=O)N1CCC(C(=O)N(CCCN2CCC(Cc3ccc(N)cc3)CC2)c2ccc(Cl)c(Cl)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(CC2CCN(CCCN(C(=O)C3CCN(C(C)=O)CC3)c3ccc(Cl)c(Cl)c3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.1 %

Procedure:
1-Acetyl-N-{3-[4-(4-aminobenzyl)-1-piperidinyl]propyl}-N-(3,4-dichlorophenyl}-4-piperidinecarboxamide (Example 303) (18 mg, 6.033 mmol) was dissolved in tetrahydrofuran (0.3 mL). To the solution were added triethylamine (5.0 mg, 0.050 mmol) and acetyl chloride (3.4 mg, 0.043 mmol), and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added aqueous solution of 1N-sodium hydroxide (5 mL), and the mixture was extracted with ethyl acetate (5 mL×2). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The concentrate was subjected to alumina column chromatography (alumina 2 g, ethyl acetate), and the desired fraction was concentrated under reduced pressure to give the titled compound (18 mg, 0.031 mmol, Yield 93%) as a colorless oily substance.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CC1C=CC(S(O[CH2:16][C:17]2([OH:34])[C:21](=[O:22])[O:20][C@H:19]3[C:23]4[C@@:28]([CH3:31])([CH2:29][CH2:30][C:18]23[OH:33])[CH2:27][CH2:26][CH2:25][C:24]=4[CH3:32])(=O)=O)=CC=1>CN(C)C=O>[N:1]([CH2:16][C:17]1([OH:34])[C:21](=[O:22])[O:20][C@H:19]2[C:23]3[C@@:28]([CH3:31])([CH2:29][CH2:30][C:18]12[OH:33])[CH2:27][CH2:26][CH2:25][C:24]=3[CH3:32])=[N+:2]=[N-:3]
Reactant: CC1=C2[C@@H]3OC(=O)C(O)(COS(=O)(=O)c4ccc(C)cc4)C3(O)CC[C@@]2(C)CCC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1=C2[C@@H]3OC(=O)C(O)(CN=[N+]=[N-])C3(O)CC[C@@]2(C)CCC1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
Sodium azide (32.5 mg, 0.5 mmol) was added to the solution of compound of example 5 (218 mg, 0.5 mmol) in dimethylformamide (DMF) (2 mL) and stirred at 50° C. under nitrogen atmosphere for 24 hours. The reaction mixture was concentrated, dried and was dissolved in water (25 mL) and was extracted with ethyl acetate (3×50 mL). The ethyl acetate layer was washed with water and brine and was dried over sodium sulfate. Solvent was removed and crude product was washed with petroleum ether, to obtain the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH:16]2[CH2:17][CH2:18][C:13]([C:19]([OH:21])=O)([CH:14]=[CH:15]2)[O:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[N:23]1C2N=CC=CC=2N=N1.C(=O)([O-])O.[NH4+]>CN(C=O)C.O>[CH2:1]([O:8][C:9]([N:11]1[CH:16]2[CH2:17][CH2:18][C:13]([C:19](=[O:21])[NH2:23])([CH:14]=[CH:15]2)[O:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: On1nnc2cccnc21
Reactant: O=C(OCc1ccccc1)N1OC2(C(=O)O)C=CC1CC2
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)C12C=CC(CC1)N(C(=O)OCc1ccccc1)O2
Reaction time: 8 h
Yield: 82.7 %

Procedure:
The benzyl ester (d) (12.0 g, 41.5 mmol) and 1-hydroxy-7-azabenzotriazole (6.26 g, 46 mmol) were dissolved in DMF (100 ml) then I-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (8.79 g, 46 mmol) added. After stirring for 5 minutes ammonium hydrogen carbonate (8.22 g, 104 mmol) was added. Four further small portions of ammonium hydrogen carbonate were added over the next 7 hours. The mixture was then stirred overnight, diluted with water and extracted with ethyl acetate (×4). The combined organic extracts were washed with 5% aqueous citric acid then brine, dried and evaporated to give an off-white solid (9.9 g, 83%).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[H][H].Cl[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][N:18]=1>O1CCCC1>[N+:23]([C:20]1[CH:21]=[CH:22][C:17]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])=[N:18][CH:19]=1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: [H][H]
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)c1ccc([N+](=O)[O-])cn1

Procedure:
Diethyl malonate (151 g, 0.044 mol) was added dropwise under stirring to 60% sodium hydride in mineral oil (37.8 g, 0.944 mol) in dry tetrahydrofuran (1 L). After hydrogen evolution ceased, 2-chloro-5-nitropyridine (125 g, 0.787 mol) was added. The reaction mixture was refluxed for 2 hours and then the tetrahydrofuran was evaporated in vacuo to give crude diethyl (5-nitropyridin-2-yl)malonate, which was used at the next stage without purification.
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:12]2[C:7](=[CH:8][C:9]([Cl:14])=[CH:10][C:11]=2[Cl:13])[NH:6][CH:5]([C:15]([O:17][CH3:18])=[O:16])[CH2:4]1.C(N(CC)CC)C.ON1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2N=N1.Cl.CN(C)CCCN=C=NCC.[O:48]1CC[CH2:50][CH2:49]1>>[Cl:13][C:11]1[CH:10]=[C:9]([Cl:14])[CH:8]=[C:7]2[C:12]=1[C@@H:3]([NH:2][C:49]([CH2:50][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:48])[CH2:4][C@H:5]([C:15]([O:17][CH3:18])=[O:16])[NH:6]2
Reactant: C1CCOC1
Reactant: On1nnc2ccccc21
Reactant: COC(=O)C1CC(N)c2c(Cl)cc(Cl)cc2N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1C[C@H](NC(=O)Cc2ccccc2)c2c(Cl)cc(Cl)cc2N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 4-amino-5,7-dichloro-2-methoxycarbonyl-1,2,3,4-tetrahydroquinoline hydrochloride (example 9a) (3.0 g, 9.63 mmol) in anhydrous tetrahydrofuran (300 ml) under an atmosphere of nitrogen was added dry triethylamine (2.95 ml, 21.2 mmol) and the resulting mixture was stirred at room temperature for 0.5 h. To this suspension was added phenlyacetic acid (1.44 g, 10.6 mmol), 1-hydroxybenzotriazole (1.43 g, 10.6 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.03 g, 10.6 mmol) and stirring was continued for 65 h. The reaction mixture was concentrated in vacuo and the residue obtained was partitioned between ethyl acetate (1000 ml) and 1M aqueous citric acid (300 ml). The organic layer was collected, washed successively with 1M aqueous citric acid (1×300 ml), saturated sodium bicarbonate solution (2×300 ml) and brine (200 ml) then dried (MgSO4) and evaporated. The resulting crude product was recrystallised from methanol to give the title compound as colourless needles (2 crops, 3.26 g) identical in physical properties to the material obtained in example 34 step a.
Reaction SMILES: C[C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][C:9]2[CH2:8][CH:7]([NH:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:6][CH2:5][C:4]=2[N:3]=1.[H][H].[CH3:26]CO>[Pd]>[CH3:26][N:15]([CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH:7]1[CH2:6][CH2:5][C:4]2[N:3]=[CH:2][C:11]([NH2:12])=[CH:10][C:9]=2[CH2:8]1
Reactant: CCO
Reactant: Cc1nc2c(cc1[N+](=O)[O-])CC(NCCc1ccccc1)CC2
Reactant: [H][H]
Agent: [Pd]
Product: CN(CCc1ccccc1)C1CCc2ncc(N)cc2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 100 mL flask, equipped with a magnetic stirbar, was charged with methyl-3-nitro-N-(2-phenylethyl)-5,6,7,8-tetrahydroquinolin-6-amine (0.71 g, 2.28 mmol), Pd/C (10% w/w, 0.15 g, 0.14 mmol), and EtOH (10 mL). The flask was capped with a balloon filled with hydrogen and the mixture was stirred at ambient temperature for 2 hours. The mixture was filtered over Celite (5 g) to remove the catalyst. The filtrate was concentrated to afford the title compound. The material was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:12])=[CH:8][C:9]=2[Cl:11])[NH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[CH2:18](N(CC)CC)C.[F:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](Cl)=[O:30].C(OCC)(=O)C>C(Cl)Cl>[F:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](=[O:30])[CH2:18][NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:12])=[CH:8][C:9]=2[Cl:11])[NH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCN(CC)CC
Reactant: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1N
Reactant: O=C(Cl)c1cccc(F)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1NCC(=O)c1cccc(F)c1
Yield: 78.4 %

Procedure:
Dissolve 3-amino-2-carbethoxy-4,6-dichloroindole (1.09 g, mmol) in methylene chloride (25 mL) and add triethylamine (0.578 mL, 4 mmol) followed by m-fluorobenzoyl chloride (0.488 mL, 4 mmol). Stir the reaction for 1 hour at room temperature. Add an additional amount of methylene chloride (25 mL) and stir overnight. Dilute the reaction with ethyl acetate (100 mL), wash with water (100 mL) and dry the organic phase. Concentrate in vacuo and recrystallize the residue from ethyl acetate/hexane to yield the title compound (1.28 g, 81%); mp 234°-235° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][NH:10][C:11]([O:13][CH2:14][CH2:15][Cl:16])=[O:12].[CH3:17][O:18][CH2:19][C:20](Cl)=[O:21].COCC(O)=O.S(Cl)(Cl)=O>C1(C)C(C)=CC=CC=1>[CH3:17][O:18][CH2:19][C:20]([N:9]([C:3]1[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])[NH:10][C:11]([O:13][CH2:14][CH2:15][Cl:16])=[O:12])=[O:21]
Reactant: Cc1cccc(C)c1NNC(=O)OCCCl
Reactant: COCC(=O)Cl
Agent: COCC(=O)O
Solvent: Cc1ccccc1C
Solvent: O=S(Cl)Cl
Product: COCC(=O)N(NC(=O)OCCCl)c1c(C)cccc1C

Procedure:
200 g (0.825 mol) 2-Chloroethyl 2-(2,6-dimethylphenyl)-hydrazinecarboxylate in 500 ml xylene are warmed to 80°, and added to a warm (80°) solution of 2-methoxyacetylchloride in 250 ml xylene, prepared in situ by treating 73.5 g (0.826 mol) 2-methoxyacetic acid in 250 ml xylene with 107.1 g (0.9 mol) thionyl chloride at 80° for 2 hours. The mixture is heated for 30 minutes at 80°, then worked up as described in Example 1a.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[Mg].[CH:23]1[C:36]2[C:35](=O)[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:28][C:27]=2[CH:26]=[CH:25][CH:24]=1.Cl>C(OCC)C.O1CCCC1>[CH:23]1[C:36]2[C:27](=[CH:28][C:29]3[C:34]([C:35]=2[C:15]2[C:16]4[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:12]([C:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[CH:2]=[CH:3][CH:4]=4)=[CH:13][CH:14]=2)=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:26]=[CH:25][CH:24]=1
Reactant: Brc1ccc(-c2cccc3ccccc23)c2ccccc12
Reactant: O=C1c2ccccc2Cc2ccccc21
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: c1ccc2c(-c3ccc(-c4c5ccccc5cc5ccccc45)c4ccccc34)cccc2c1

Procedure:
4-bromo-1,1′-binaphthyl and magnesium were refluxed in diethylether for one hour, which was then added to a solution of anthrone in tetrahydrofuran. The resulting mixture was heated for two hours, which was then poured into diluted hydrochloric acid. After being extracted by diethylether, organic layer was separated and dried over magnesium sulfate. It was purified according to conventional method, whereby 1-(9-anthryl)-4-(1-naphthyl)-naphthalene was obtained. This was dissolved in chloroform to which was added two equivalent amounts of N-bromosuccinimide, and they were stirred at room temperature for one day. The product was purified according to conventional method and 1-(10-bromo-9-anthryl)-4-(4-bromo-1-naphthyl)-naphthalene was obtained. With this pdoruct, diphenylamine was reacted in nitrobenzene at 180° C. for 40 hours together with potasium carbonate and copper powder. After nitrobenzene was removed by vacuum distillation, the reaction mixture was purified according to conventional method, whereby the target compound (18) was obtained.
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][C:3]=1[CH:11]=[CH:12][CH2:13][CH2:14][CH3:15].BrC1C=C(CCO)C=C[C:22]=1[O:23]C.BrC1C=C(CCO)C=CC=1C>>[O:23]([C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][C:3]=1[CH:11]=[CH:12][CH2:13][CH2:14][CH3:15])[CH3:22]
Reactant: CCCC=Cc1cc(CCO)ccc1C
Reactant: COc1ccc(CCO)cc1Br
Agent: Cc1ccc(CCO)cc1Br
Product: CCCC=Cc1cc(CCO)ccc1OC

Procedure:
By working as described for preparation 1c), but using compound 2b) from the previous step instead of compound 1b), the title compound is obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[F:17])[O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][OH:13])=[CH:8][CH:7]=1.Cl[C:19]1[CH:35]=[C:23]2[N:24](C(OC(C)(C)C)=O)[CH2:25][CH2:26][CH2:27][N:22]2[C:21](=[O:36])[N:20]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[F:17])[O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][O:13][C:19]2[CH:35]=[C:23]3[NH:24][CH2:25][CH2:26][CH2:27][N:22]3[C:21](=[O:36])[N:20]=2)=[CH:10][CH:11]=1
Reactant: OCc1ccc(Oc2ccc(F)c(F)c2)cc1
Reactant: CC(C)(C)OC(=O)N1CCCn2c1cc(Cl)nc2=O
Product: O=c1nc(OCc2ccc(Oc3ccc(F)c(F)c3)cc2)cc2n1CCCN2

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E111 starting from (4-(3,4-difluorophenoxy)phenyl)methanol and tert-butyl 8-chloro-6-oxo-2,3,4,6-tetrahydro-1H-pyrimido[1,6-a]pyrimidine-1-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[O:10][C:9]([C:11]([OH:13])=O)=[CH:8][C:6]=2[N:7]=1.[CH3:20][N:21](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[O:10][C:9]([C:11]([NH:21][CH3:20])=[O:13])=[CH:8][C:6]=2[N:7]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1cc2nc(Cl)nc(N3CCOCC3)c2o1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cc2nc(Cl)nc(N3CCOCC3)c2o1

Procedure:
A solution of 2-chloro-4-morpholinofuro[3,2-d]pyrimidine-6-carboxylic acid (1.0 eq), HATU (1.5 eq), hydrochloride salt of methylamine (1.5 eq), diisopropylethylamine (3.0 eq) in DMF was stirred for 30 minutes. Reaction mixture was quenched with saturated aq. NaHCO3 and extracted with ethyl acetate. The combined organic layers were dried (Na2SO4) and concentrated. The crude reaction mixture was purified by flash chromatography to give 2-chloro-N-methyl-4-morpholinofuro[3,2-d]pyrimidine-6-carboxamide. MS (Q1) 297 (M)+
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:22]=[CH:21][CH:20]=[CH:19][C:6]=1[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[CH:11][CH:10]=1)=[O:4].[F:23][C:24]([F:34])([F:33])[C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1.C(Cl)CCl.Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C.O>[O:18]=[C:16]([NH:30][CH2:29][C:28]1[CH:27]=[CH:26][C:25]([C:24]([F:23])([F:33])[F:34])=[CH:32][CH:31]=1)[CH2:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:7][C:6]2[CH:19]=[CH:20][CH:21]=[CH:22][C:5]=2[C:3]([O:2][CH3:1])=[O:4])=[CH:14][CH:13]=1
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1ccccc1COc1ccc(CC(=O)O)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCCl
Solvent: ClCCl
Product: COC(=O)c1ccccc1COc1ccc(CC(=O)NCc2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
(4-{[2-(Methoxycarbonyl)benzyl]oxy}phenyl)acetic acid (50 mg, 0.167 mmol) was dissolved in DCM (2 ml), 4-(Trifluoromethyl)benzylamine (35 mg, 0.2 mmol) was added, then EDC (38 mg, 0.2 mmol) was added and then DMAP (24.4 mg, 0.2 mmol) was added. The mixture was stirred at room temperature overnight. 1% hydrochloric acid (1 ml) and water (1 ml) was added into the mixture. The two phases were separated using a Whatman Filter Tube. The obtained organic solution was evaporated in vacuum and the solid product (72 mg) was left, yield 95%.
Reaction SMILES: C([CH:5]1[CH2:10][C:9]([C:27]#[N:28])([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH:22]3[CH2:26][CH2:25][CH2:24]C3)[CH:12]=2)[CH2:8][CH2:7][C:6]1=[O:29])(OC)=O.CS(C)=O.[Cl-].[Na+]>O>[C:27]([C:9]1([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:26]3[CH2:24][CH2:25]3)[CH:12]=2)[CH2:10][CH2:5][C:6](=[O:29])[CH2:7][CH2:8]1)#[N:28]
Reactant: COC(=O)C1CC(C#N)(c2ccc(OC(F)F)c(OC3CCCC3)c2)CCC1=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CC1(c2ccc(OC(F)F)c(OCC3CC3)c2)CCC(=O)CC1
Temperature: 25 °C
Yield: 51.7 %

Procedure:
A mixture of 2-carbomethoxy-4-cyano-4-(3-cyclopentyloxy-4-difluoromethoxyphenyl)cyclohexan-1-one (0.5 g, 1.27 mmole), dimethyl sulfoxide (10 mL), water (1 mL) and sodium chloride (0.5 g) under an argon atmosphere was heated at 145°-150° C. for 4.5 h. The reaction mixture was cooled to room temperature and concentrated. The residue was partitioned between ethyl acetate and water, extracted twice with ethyl acetate, the organic layer was washed twice with water and once with brine, was dried (sodium sulfate) and the solvent was removed in vacuo. The product was purified by flash chromatography, eluting with 20-25% ethyl acetate/hexanes, and the resultant solid was triturated with ether/hexane and then with cold ether to provide a solid (0.22 g, 51.6%): m.p. 85.5°-86.5° C. Analysis Calc. for C18H19F2NO3 : C 64.47, H 5.71, N 4.18; found: C 64.28, H 5.63, N 4.20.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[O:12][CH2:11][CH2:10][CH2:9]2)=[O:5])[CH3:2].[CH3:16][O:17]C(Cl)Cl>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[C:14]([CH:16]=[O:17])[CH:15]=1)[O:12][CH2:11][CH2:10][CH2:9]2)=[O:5])[CH3:2]
Reactant: COC(Cl)Cl
Reactant: CCOC(=O)c1ccc2c(c1)CCCO2
Solvent: ClCCl
Product: CCOC(=O)c1cc(C=O)c2c(c1)CCCO2

Procedure:
Compounds of the invention where the variable Y is an ethynyl-methyl (CH≡C—CH2—) group can, generally speaking, be synthesized in accordance with Reaction Scheme 12. The starting compound in accordance with this scheme is a 6-chromanoic acid ethyl ester derivative of Formula 3 which can be obtained as described above in connection with Reaction Scheme 1. The 6-chromanoic acid ethyl ester of Formula 3 is thereafter treated with α,α-dichloromethyl methyl ether in a suitable aprotic solvent such as methylene chloride to provide the 8-formyl-6-chromanoic acid ethyl ester derivative of Formula 12. The formyl compound of Formula 12 is reduced with sodium borohydride in methanol to give the corresponding hydroxymethyl compound of Formula 13. The hydroxymethyl compound of Formula 13 is then reacted with N-bromosuccinimide in the presence of triphenylphosphine in an aprotic solvent such as methylene chloride to give the 8-(bromomethyl)-6-chromanoic ester derivative of Formula 14. The 8-(bromomethyl)-6-chromanoic ester derivative of Formula 14 is reacted with trimethylsilyl acetylene in triethyl amine and dimethylformamide (DMF) under argon atmosphere in the presence of dichlorobis(triphenylphosphine)palladium(II) (Pd(PPh3)2Cl2). The trimethylsilyl group and the ethyl group of the ester moiety of the resulting 8-(trimethylsilylmethyl) 6-chromanoic acid ethyl ester are then removed by treatment with base (such as lithium hydroxide shown in the reaction scheme) to provide the 8-(ethynylmethyl)-6-chromanoic acid of Formula 15.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=4[F:32])[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[NH2:34][C:35]1[CH:44]=[CH:43][C:38]2[N:39]=[CH:40][CH2:41][O:42][C:37]=2[CH:36]=1.Cl.C([OH:49])(C)C>>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[C:24]([NH:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:9]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:34][C:35]4[CH:44]=[CH:43][C:38]5[NH:39][C:40](=[O:49])[CH2:41][O:42][C:37]=5[CH:36]=4)[N:7]=3)=[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)[CH:18]=1)=[O:33]
Reactant: CC(C)O
Reactant: Nc1ccc2c(c1)OCC=N2
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Agent: Cl
Product: O=C1COc2cc(Nc3nccc(-c4c(-c5cccc(NC(=O)c6c(F)cccc6F)c5)nn5ccccc45)n3)ccc2N1

Procedure:
A mixture of N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide (which may be prepared according to a procedure similar to Example 27, Step C) and 7-amino-2H1,4-benzoxazin-3(4H-one are heated in isopropanol with catalytic conc. HCl at approximately 85° C. to afford the product. ES-LCMS m/z 590 (M+H).
Reaction SMILES: [CH2:1]([OH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].[Cl:13][C:14]1[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:11]#[C:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:12])=[CH:16][CH:15]=1
Reactant: C=CCCCCCCCCCO
Reactant: Clc1ccc(I)cc1
Product: OCCCCCCCCCC#Cc1ccc(Cl)cc1

Procedure:
In a manner described in Example 18 above, 10-undecene-1-ol was reacted with 1-chloro-4-iodobenzene to give the title compound; NMR (CDCl3) δ1.21-1.50 (m, 10H), 1.50-1.65 (m, 4H), 2.36-2.41 (m,2H), 3.61-3.66(m,2H), 7.16-7.31 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:15]2[O:14][CH2:13][CH2:12][CH2:11][O:10][C:9]=2[C:8]([N+:16]([O-])=O)=[CH:7][CH:6]=1)=[O:4].C1COCC1.CO>C(OCC)C.[Pd]>[CH3:1][O:2][C:3]([C:5]1[C:15]2[O:14][CH2:13][CH2:12][CH2:11][O:10][C:9]=2[C:8]([NH2:16])=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c2c1OCCCO2
Agent: [Pd]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc(N)c2c1OCCCO2
Temperature: 70 °C

Procedure:
To a mixture of 9-nitro-3,4-dihydro-2H-benzo[b][1,4]dioxepine-6-carboxylic acid methyl ester (C-5; 2.53 g) and Pd/C (450 mg) suspended in 90 mL of a 1/1 mixture of THF/CH3OH was added HCO2HN4 (3.153 g) and the resulting reaciton heated to 70° C. for 30 minutes. The reaction was diluted with 900 mL of diethyl ether. The resulting solution was filtered through celite and the organic solvent removed in vacuo to yield 2.152 g of white crystalline soldid. AP+ 192 (—OCH3).
Reaction SMILES: FC(F)(F)C(O[C:6](=[O:11])[C:7](F)(F)F)=O.[Br:14][C:15]1[C:16]([Cl:23])=[CH:17]C(C)=[N+:19]([O-])[CH:20]=1.CO>C(Cl)Cl>[Br:14][C:15]1[C:16]([Cl:23])=[CH:17][C:7]([CH2:6][OH:11])=[N:19][CH:20]=1
Reactant: Cc1cc(Cl)c(Br)c[n+]1[O-]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: OCc1cc(Cl)c(Br)cn1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
3.0 mL trifluoroacetic anhydride were added dropwise at 10° C. to 2.6 g (12 mmol) 5-bromo-4-chloro-2-methylpyridine-1-oxide in 30 mL DCM. The reaction mixture was stirred for 5 days at RT. After the addition of MeOH the reaction mixture was evaporated down, the residue was combined with 15% potassium carbonate solution and extracted several times with EtOAC. The combined organic phases were dried on sodium sulphate and evaporated down.
Reaction SMILES: F.[C:2]1([OH:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9](O)(=[O:11])[CH3:10]>>[OH:8][C:2]1[CH:7]=[CH:6][C:5]([C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: Oc1ccccc1
Agent: F
Product: CC(=O)c1ccc(O)cc1
Yield: 40 %

Procedure:
Simons et al, Journal of the American Chemical Society, 61, 1795 and 1796 (1939) teach the acylation of aromatic compounds using hydrogen fluoride as a condensing agent and in Table 1 on page 1796 show the acetylation of phenol with acetic acid to produce p-hydroxyacetophenone in 40% yield.