Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].CO[C:7]1[CH:8]=[C:9]([C@H:16](NC2C=CC(C(N)=N)=CC=2)[C:17]2[NH:21][C:20](=O)[N:19](C3N=CC=CN=3)[N:18]=2)C=C(COC)C=1.C[O:40][C:41](=O)[N:42]=[C:43](SC)[C:44]([C:58]1[CH:63]=[C:62]([O:64][CH3:65])[CH:61]=[C:60]([O:66][CH3:67])[CH:59]=1)=[N:45][C:46]1[CH:51]=[CH:50][C:49]([C:52]2[N:56]=C(C)O[N:53]=2)=[CH:48][CH:47]=1.CC1N=C(NN)C=CC=1.COC(=O)N=C(SC)C(C1C=C(COC)C=C(OC)C=1)=NC1C=CC(C2N=C(C)ON=2)=CC=1.N(C1N=CC=CN=1)N>>[C:1]([OH:4])(=[O:3])[CH3:2].[CH3:65][O:64][C:62]1[CH:63]=[C:58]([C@H:44]([NH:45][C:46]2[CH:51]=[CH:50][C:49]([C:52]([NH2:56])=[NH:53])=[CH:48][CH:47]=2)[C:43]2[NH:42][C:41](=[O:40])[N:19]([C:20]3[C:8]([CH3:7])=[CH:9][CH:16]=[CH:17][N:21]=3)[N:18]=2)[CH:59]=[C:60]([O:66][CH3:67])[CH:61]=1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)cc(OC)c1
Reactant: COCc1cc(OC)cc([C@H](Nc2ccc(C(=N)N)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Agent: COCc1cc(OC)cc(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)c1
Agent: Cc1cccc(NN)n1
Agent: NNc1ncccn1
Solvent: CC(=O)O
Product: COc1cc(OC)cc([C@H](Nc2ccc(C(=N)N)cc2)c2nn(-c3ncccc3C)c(=O)[nH]2)c1

Procedure:
The same procedure was carried out as in Examples (10d) to (10e), except that {2-(3,5-dimethoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester and (6-methylpyridin-2-yl)hydrazine [CAS No. 5315-24-2] were used instead of respectively {2-(3-methoxy-5-methoxymethylphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester and 2-hydrazinopyrimidine in Example (10d), to give the first eluting enantiomer of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:12][CH3:13])[C:10]=1[OH:11])[C:5](O)=O.[NH2:14][NH:15][C:16]([NH2:18])=[S:17].O=P(Cl)(Cl)Cl.[NH4+].[OH-]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[S:17][C:16]([NH:18][CH:2]3[CH2:3][CH2:4][CH2:8][CH2:9][CH2:10]3)=[N:15][N:14]=2)[CH:8]=[C:9]([O:12][CH3:13])[C:10]=1[OH:11]
Reactant: NNC(N)=S
Reactant: COc1cc(C(=O)O)cc(Cl)c1O
Agent: [NH4+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: COc1cc(-c2nnc(NC3CCCCC3)s2)cc(Cl)c1O
Temperature: 95 °C
Yield: 161 %

Procedure:
To a mixture of 3-chloro-4-hydroxy-5-methoxybenzoic acid (2.468 mmol, 500 g), thiosemicarbazide (5b) (2.468 mmol, 427 mg) in dioxane (10 mL) at 65° C., POCl3 (3.2 mmol, 300 μL) was added, and the mixture was warmed at 95° C. for 3 hours 30 minutes. The solvent was removed by distillation under reduced pressure to give a crude material which was basified with a solution of diluted NH4OH. The precipitate obtained was collected by filtration, washed with water before drying under vacuum over P2O5 to give 675 mg of the desired product. Yield: 80%.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]2)[CH:5]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[CH2:4][NH:3]1.[Li+].[CH3:27][Si]([N-][Si](C)(C)C)(C)C.IC.[Cl-].[NH4+]>C1COCC1>[CH3:27][N:3]1[CH2:4][CH:5]([C:19]2[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=2)[C:6]2([CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]2)[C:2]1=[O:1]
Reactant: Cc1ccc(C2CNC(=O)C23CCCN(C(=O)OC(C)(C)C)C3)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: Cc1ccc(C2CN(C)C(=O)C23CCCN(C(=O)OC(C)(C)C)C3)cc1
Temperature: -60 °C
Reaction time: 1 h

Procedure:
To a stirred solution of tert-butyl 1-oxo-4-p-tolyl-2,7-diazaspiro[4.5]decane-7-carboxylate (333 mg, 0.967 mmol) in dry THF (6 ml) at −60° C. under nitrogen was added LiHMDS 1M in THF (1.26 ml, 1.257 mmol) dropwise and the mixture was left to stir at −60° C. for 1 hr. After this time a solution of iodomethane (79 ul, 1.257 mmol) in dry THF (1 ml) was added dropwise at −60° C. and the reaction mixture was allowed to warm from −60° C. to room temperature over 1 hr. After a further 3 hrs at room temperature the reaction mixture was added to sat. ammonium chloride (25 ml), extracted with EtOAc (3×25 ml) and the combined organics were washed with brine (25 ml), dried (MgSO4) and concentrated under reduced pressure to give the crude product as an orange oil. The crude material was purified via silica chromatography eluting with 20-80% iso-hexane/EtOAc. The appropriate fractions were combined and concentrated to give the product as a yellow solid (270 mg).
Reaction SMILES: [H-].[Na+].C1COCC1.[C:8]([CH2:10]P(=O)(OCC)OCC)#[N:9].[F:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=1[C:28]1[C:29]([CH:44]=O)=[CH:30][C:31]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)=[CH:32][CH:33]=1>O>[F:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=1[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]2[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=2)=[CH:30][C:29]=1[CH:44]=[CH:10][C:8]#[N:9]
Reactant: COc1ccc(COc2ccc(-c3cc(OC)ccc3F)c(C=O)c2)cc1
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(COc2ccc(-c3cc(OC)ccc3F)c(C=CC#N)c2)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Under a nitrogen atmosphere, to a mixture of sodium hydride (60%, 133 mg) and THF (20 mL) was added diethyl cyanomethylphosphonate (0.54 mL) at 0° C., and the mixture was stirred at 0° C. for 10 min. To the reaction mixture was added 2′-fluoro-5′-methoxy-4-((4-methoxybenzyl)oxy)biphenyl-2-carbaldehyde (1.03 g) obtained in Example 93, step 2, and the mixture was stirred at 50° C. for 30 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give a crude product of the title compound as a colorless oil. This compound was used for the next step without further purification.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][N:14]=[CH:13][C:12]2=O)=[O:8]>CN(C)C=O.C1(C)C=CC=CC=1>[CH3:5][O:6][C:7]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[N:14][CH:13]=[C:12]2[Cl:3])=[O:8]
Reactant: COC(=O)c1ccc2[nH]ncc(=O)c2c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2nncc(Cl)c2c1
Reaction time: 1.15 h
Yield: 1.3 %

Procedure:
Thionyl chloride (5 mL, 68.5 mmol) and N,N-dimethylformamide (3 drops) were added to 4-oxo-1,4-dihydro-cinnoline-6-carboxylic acid methyl ester (212 mg, 1.04 mol), and the solution was stirred for 1.15 hours under reflux. Toluene was added to the reaction mixture, which was then evaporated in vacuo. Ethyl acetate was added to the residue the organic layer was washed with an ice water, dried over anhydrous magnesium sulfate, then, evaporated in vacuo, and the title compound (192 mg, 0.862 mmol, 82.9%) was obtained. This was used in the next reaction without purification.
Reaction SMILES: [CH:1]1([NH:7][S:8]([C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14](O)=[O:15])(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B.C1COCC1.CO.Cl>C1COCC1>[CH:1]1([NH:7][S:8]([C:11]2[CH:19]=[CH:18][CH:17]=[C:13]([CH2:14][OH:15])[CH:12]=2)(=[O:9])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1cccc(S(=O)(=O)NC2CCCCC2)c1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: O=S(=O)(NC1CCCCC1)c1cccc(CO)c1
Reaction time: 0.5 h
Yield: 90.9 %

Procedure:
A solution of 3-[(cyclohexylamino)sulfonyl]benzoic acid (2.25 g) in THF (100 ml) under nitrogen at 0° was treated dropwise with 1M borane-THF solution (23.82 ml). The mixture was stirred at 0° for 0.5 h and then at 20° for 72 h. The mixture was cooled to 0° and MeOH (20 ml) was added dropwise. The mixture was stirred for 15 min and then 2N hydrochloric acid (50 ml) was added and the mixture was allowed to warm to 20°. The bulk of the organic solvents were removed by evaporation in vacuo and the residual aqueous phase was extracted with EtOAc (2×40 ml). The combined extracts were dried (Na2SO4) and the solvent evaporated in vacuo. The residue was purified by SPE on alumina (10 g, activated, neutral, Brockmann 1). Elution with MeOH-dichloromethane (1:20) gave the title compound (1.944 g). LCMS RT=2.95 min, ES+ve 270 (MH)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=O.N1C=CC=CC=1C1C=C[C:24]([CH:25]=[O:26])=CC=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9](/[CH:10]=[CH:24]/[CH:25]=[O:26])[CH:12]=[CH:13][CH:14]=1
Reactant: O=Cc1ccc(-c2ccccn2)cc1
Reactant: O=Cc1cccc(-c2ccccn2)c1
Product: O=C/C=C/c1cccc(-c2ccccn2)c1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 31 by substituting 3-(2-pyridinyl)benzaldehyde (prepared as described in Reference Example 23) for the 4-(2-pyridinyl)-benzaldehyde of Reference Example 31. MS 210 (M+H)+.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].BrC1C=CC(S([O:17][C@@H:18]2[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:20]([C:30]([O:32][CH3:33])=[O:31])[CH2:19]2)(=O)=O)=CC=1.[Br:34][C:35]1[C:44](O)=[CH:43][C:42]2[C:37](=[CH:38][CH:39]=[C:40]([O:46][CH3:47])[CH:41]=2)[N:36]=1>CN1C(=O)CCC1.CCOC(C)=O>[Br:34][C:35]1[C:44]([O:17][C@H:18]2[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[C@H:20]([C:30]([O:32][CH3:33])=[O:31])[CH2:19]2)=[CH:43][C:42]2[C:37](=[CH:38][CH:39]=[C:40]([O:46][CH3:47])[CH:41]=2)[N:36]=1
Reactant: COC(=O)[C@@H]1C[C@H](OS(=O)(=O)c2ccc(Br)cc2)CN1C(=O)OC(C)(C)C
Reactant: COc1ccc2nc(Br)c(O)cc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COC(=O)[C@@H]1C[C@@H](Oc2cc3cc(OC)ccc3nc2Br)CN1C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 3 h
Yield: 70.2 %

Procedure:
Cs2CO3 (10.7 g, 32.9 mmol) was added to a stirred mixture of 1-tert-butyl 2-methyl (2S,4S)-4-{[(4-bromophenyl)sulfonyl]oxy}pyrrolidine-1,2-dicarboxylate (8.78 g, 18.9 mmol) and 2-bromo-6-methoxyquinolin-3-ol (4.18 g, 16.45 mmol) in NMP (46 mL). The resulting mixture was stirred at 50° C. for 3 h, then cooled and diluted with EtOAc. The organics were washed with saturated aqueous NaHCO3, water and brine then dried over Na2SO4. Filtration and removal of the volatiles gave a residue, which was purified by column chromatography on silica gel (gradient elution: 1 to 100% EtOAc in petroleum ether) to give the title compound (5.56 g, 70.2%). LCMS (ES+) m/z 481, 483 (M+H)+.
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.C(N(CC)CC)C.Br.Br.Br[CH2:24][C:25]1[C:26]([NH2:32])=[N:27][C:28]([NH2:31])=[N:29][CH:30]=1>CN(C)C=O>[C:1]1([CH3:13])[CH:2]=[CH:3][C:4]([N:7]2[CH2:8][CH2:9][N:10]([CH2:24][C:25]3[C:26]([NH2:32])=[N:27][C:28]([NH2:31])=[N:29][CH:30]=3)[CH2:11][CH2:12]2)=[CH:5][CH:6]=1
Reactant: Cc1ccc(N2CCNCC2)cc1
Reactant: Nc1ncc(CBr)c(N)n1
Agent: Br
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(N2CCN(Cc3cnc(N)nc3N)CC2)cc1
Temperature: 25 °C
Reaction time: 110 h
Yield: 51.1 %

Procedure:
A solution of 0.87 g (0.00493 mol) of 1-p-tolyl-piperazine in 30 ml of dimethylformamide was treated with 1.37 ml (0.00986 mol) of triethylamine and 0.60 g (0.00164 mol) of 5-bromomethyl-pyrimidine-2,4-diamine dihydrobromide and the mixture was stirred at room temperature under argon for 110 hours. The mixture was completely freed from the solvents. The residue was chromatographed over silica gel with methanol as the eluent, digested in dichloromethane/water 1:1 and subsequently filtered off under suction. 0.25 g (51%) of 5-(4-p-tolyl-piperazin-1-ylmethyl)-pyrimidine-2,4-diamine was obtained as beige crystals; m.p. 248°-250°.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([OH:10])[C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[CH2:19](O)[CH3:20]>Cl>[CH2:19]([O:8][C:7](=[O:9])[C:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([C:5]1[CH:17]=[CH:18][C:2]([NH2:1])=[CH:3][CH:4]=1)[OH:10])[CH3:20]
Reactant: CCO
Reactant: Nc1ccc(C(O)(C(=O)O)c2ccccc2)cc1
Agent: Cl
Product: CCOC(=O)C(O)(c1ccccc1)c1ccc(N)cc1

Procedure:
4.8 g (19.7 mmol) of 4-aminobenzilic acid was dissolved in 200 ml of absolute ethanol (EtOH) saturated with dry HCl gas. The reaction mixture was refluxed for 24 hours then spin evaporated to dryness in vacuum. The residue was dissolved in water and neutralized with NaHCO3, extracted with 2×50 ml of AcOEt, washed with water (2×) and the AcOEt extract filtered through a siliconized filter and dried over MgSO4. The dried solution was filtered and spin evaporated in vacuum. Yellow oil, 2.8 g (52%). SGTLC in acetone Rf 0.8. HPLC Bondapak μC18MeOH/H2O (75:25) pH 4 (formic acid). Elemental Analysis Calc. for C16H17NO3. Calc. C 70.83, H 6.32, N 5.16; Found C 70.77, H 6.47, N 5.04, 5.26.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16](=[O:21])[CH2:17][CH:18]3[CH2:20][CH2:19]3)[N:14]=2)[N:11]=1.[CH3:25][N:26]1[C:30]([C:31](Cl)=[O:32])=[CH:29][C:28]([CH3:34])=[N:27]1>CN(C)C(=O)C>[CH:18]1([CH2:17][C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:3]=[C:2]([NH:1][C:31]([C:30]5[N:26]([CH3:25])[N:27]=[C:28]([CH3:34])[CH:29]=5)=[O:32])[CH:24]=[CH:23][CH:22]=4)=[N:11][N:10]3[CH:12]=2)=[O:21])[CH2:19][CH2:20]1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)CC4CC4)cn3n2)c1
Solvent: CC(=O)N(C)C
Product: Cc1cc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)CC5CC5)cn4n3)c2)n(C)n1
Yield: 61.8 %

Procedure:
Using N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]-2-cyclopropylacetamide (100 mg, 0.309 mmol), 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (64 mg, 0.404 mmol) and N,N-dimethylacetamide (5.0 mL), and by a reaction in the same manner as in Example 148, the title compound (85 mg, 62%) was obtained as colorless crystals.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].[CH3:17][Si]([N-][Si](C)(C)C)(C)C.[Li+].CI>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)Cc1ccc2ccccc2c1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Product: CCOC(=O)C(C)c1ccc2ccccc2c1
Yield: 108.7 %

Procedure:
5 g (23 mmol) of ethyl 2-naphthylacetate, 23.3 mL (1.0 M, 23 mmol) of lithium bis(trimethylsilyl)amide, and 1.5 mL (24 mmol) of methyl iodide were reacted as described in Preparation 11 to yield 5.71 g of a dark oil. Chromatography eluting with a solvent gradient of hexane to hexane/ethyl acetate 19:1 gave the title compound 2.85 g (54%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:18])[CH:11]=[C:12](C(O)=O)O[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C:20]1[CH:21]=[C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:23]=[CH:24][CH:25]=1>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:10](=[O:18])[CH:11]=[CH:12][N:19]([C:20]2[CH:21]=[C:22]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:23]=[CH:24][CH:25]=2)[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2ccccc2)c1
Reactant: O=C(O)c1cc(=O)c(OCc2ccccc2)co1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=c1ccn(-c2cccc(-c3ccccc3)c2)cc1OCc1ccccc1
Temperature: 250 °C
Reaction time: 0.17 h

Procedure:
5-(Benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid (36.9 g, 150 mmol) and 3-aminobiphenyl (25.35 g, 150 mmol) were combined in diphenyl ether (110 ml). The mixture was heated to 250° C. (pre-heated block) in an open flask. After 10 min, the mixture was cooled to room temperature. The residue was purified by silica gel chromatography to provide 3-(benzyloxy)-1-(biphenyl-3-yl)pyridin-4(1H)-one. 1H NMR δ (400 MHz, d6-DMSO): 7.55 (d, J=7.6 Hz, 1H), 7.46 (m, 4H), 7.44-7.31 (m, 5H), 7.29-7.11 (m, 4H), 6.51 (d, J=7.2 Hz, 1H), 5.17 (s, 2H).MS (M+H)+ 354.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][C:4]1=[O:13].Br[CH2:15][CH2:16][CH2:17][Cl:18].O>CN(C)C=O>[Cl:18][CH2:17][CH2:16][CH2:15][N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][C:4]1=[O:13]
Reactant: O=C1CCc2ccccc2N1
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCc2ccccc2N1CCCCl
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.4 %

Procedure:
A suspension of NaH in mineral oil (55-60%) (712 mg) was added to a solution of 3,4-dihydro-1H-quinolin-2-one (2.0 g, 13.6 mmol) in N,N-dimethylformamide (50 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 h. then 1-bromo-3-chloropropane (1.34 mL, 13.6 mmol) was added. The slurry was stirred for additional 16 h. at ambient temperature then water (50 mL) was added and the product was extracted with diethyl ether (2×50 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo. The product was purified by flash-chromatography (eluent: dichloromethane) to give 1-[3-chloropropyl]-3,4-dihydro-1H-quinolin-2-one (2.41 g, 10.8 mmol). KI (2.5 g, 15 mmol), K2CO3 (2.1 g, 15 mmol) and 4-butylpiperidine (1.8 mL, 15 mmol) were added to a solution of 1-[3-chloropropyl]-3,4-dihydro-1H-quinolin-2-one (2.41 g, 10.8 mmol) in acetonitrile (50 mL). The reaction mixture was stirred at 60° C. for 16 h. The acetonitrile was evaporated in vacuo, water (50 mL) was added and the product was extracted with ethyl acetate (2×50 mL). The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. Purification by flash-chromatography (eluent: ethyl acetate) gave the title product. Yield: 2.06 g, 58%. Oxalate-salt was prepared from oxalic acid (1.1 eq.) in acetone. HPLC-MS: M+1+=329.5 (UV/MS(%)=100/100). 1H NMR (400 MHz, CD3OD): δ=0.89 (3H, t), 1.12-1.36 (9H, m), 1.67 (2H, broad d), 1.83 (2H, quin.), 1.97 (2H, broad t), 2.41 (2H, t), 2.59 (2H, t), 2.84-2.96 (4H, m), 3.99 (2H, t), 7.02 (1H, broad t), 7.16 (1H, broad d), 7.20 (1H, broad d), 7.25 (1H, broad t). 13C NMR (CD3OD): δ 13.2, 22.8, 24.3, 25.0, 28.9, 31.6, 31.9 (2C), 35.6, 36.2, 40.1, 53.8 (2C), 55.9, 115.2, 123.2, 127.0, 127.4, 127.9, 139.1, 171.5
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:18]=[CH:17][C:10]([O:11][CH:12]([CH3:16])[C:13]([OH:15])=[O:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25]O.S(=O)(=O)(O)O.O>C(Cl)(Cl)Cl>[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25][O:14][C:13](=[O:15])[CH:12]([O:11][C:10]1[CH:17]=[CH:18][C:7]([O:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:20][CH:19]=2)=[CH:8][CH:9]=1)[CH3:16]
Reactant: CC(Oc1ccc(Oc2ccc(Cl)cc2)cc1)C(=O)O
Reactant: OCCCCCl
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(Oc1ccc(Oc2ccc(Cl)cc2)cc1)C(=O)OCCCCCl

Procedure:
24.4 g=0.08 mol of 2-[4'-(4"-chlorophenoxy)phenoxy]-propionic acid, 10.8 g=0.1 mol of 4-chlorobutanol and 2 ml concentrated sulfuric acid in 50 ml chloroform were refluxed for 6 hours with azeotropic distillation of the reaction water. After cooling, the reaction mixture was washed twice with 100 ml water, neutralized with bicarbonate solution and washed with water until it was free from salt. After drying over calcium chloride and distillation of the solvent, 27.0 g=88% of the theory of 2-[4'-(4"-chlorophenoxy)phenoxy]-propionic acid 4-chlorobut-1-yl ester were obtained having a refractive index nD24 of 1.5517. ##STR16##
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:13]2[N:14]=[C:15](S(C)(=O)=O)[N:16]=[CH:17][C:12]=2[CH:11]=[C:10]1[C:22]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)=[O:23].[NH2:31][CH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>CN1CCCC1=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:13]2[N:14]=[C:15]([NH:31][CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[N:16]=[CH:17][C:12]=2[CH:11]=[C:10]1[C:22]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)=[O:23]
Reactant: CS(=O)(=O)c1ncc2cc(C(=O)c3ccc(F)cc3)n(-c3c(F)cccc3F)c2n1
Reactant: NC1CCOCC1
Solvent: CN1CCCC1=O
Product: O=C(c1ccc(F)cc1)c1cc2cnc(NC3CCOCC3)nc2n1-c1c(F)cccc1F
Temperature: 90 °C

Procedure:
To a solution of [7-(2,6-difluoro-phenyl)-2-methanesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-(4-fluoro-phenyl)-methanone, 4, (0.50 g, 1.28 mmol) in 1-methyl-2-pyrrolidinone (4 mL) is added 4-aminotetrahydropyran (0.18 g, 1.80 mmol). The reaction mixture is heated to 90° C. for 19 hours after which the reaction is cooled to room temperature and concentrated in vacuo. The crude residue is purified over silica (40% EtOAc/hexanes) to afford 444 mg of the desired product as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 8.74 (s, 1H), 7.93 (dd, J=9.0, 5.4 Hz, 2H), 7.48-7.39 (m, 1H), 7.20 (t, J=9.0 Hz, 2H), 7.12-7.06 (m, 3H), 4.10-3.95 (m, 3H), 3.49 (t, J=7.6 Hz, 2H), 2.40 (t, J=7.6 Hz, 2H), 2.06-2.01 (m, 2H); HRMS calcd for C24H19F3N4O2 (M+H)+ 453.1539; found 453.1551.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:7]([OH:9])=O)=[O:4].CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.[CH3:43][O:44][CH2:45][C@@H:46]1[CH2:50][N:49](C(OC(C)(C)C)=O)[C@H:48]([C:58]2[NH:59][C:60]([C:63]3[CH:68]=[C:67]4[CH2:69][O:70][C:71]5[CH:88]=[C:87]6[C:74]([CH:75]=[CH:76][C:77]7[N:81]=[C:80]([C@@H:82]8[CH2:86][CH2:85][CH2:84][NH:83]8)[NH:79][C:78]=76)=[CH:73][C:72]=5[C:66]4=[CH:65][CH:64]=3)=[CH:61][N:62]=2)[CH2:47]1>CCN(C(C)C)C(C)C.CN(C=O)C>[CH3:43][O:44][CH2:45][C@@H:46]1[CH2:50][NH:49][C@H:48]([C:58]2[NH:59][C:60]([C:63]3[CH:68]=[C:67]4[CH2:69][O:70][C:71]5[CH:88]=[C:87]6[C:74]([CH:75]=[CH:76][C:77]7[N:81]=[C:80]([C@@H:82]8[CH2:86][CH2:85][CH2:84][N:83]8[C:7](=[O:9])[C@H:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[C:10]8[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=8)[NH:79][C:78]=76)=[CH:73][C:72]=5[C:66]4=[CH:65][CH:64]=3)=[CH:61][N:62]=2)[CH2:47]1
Reactant: COC[C@H]1C[C@@H](c2ncc(-c3ccc4c(c3)COc3cc5c(ccc6nc([C@@H]7CCCN7)[nH]c65)cc3-4)[nH]2)N(C(=O)OC(C)(C)C)C1
Reactant: COC(=O)N[C@@H](C(=O)O)c1ccccc1
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[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: COC[C@@H]1CN[C@H](c2ncc(-c3ccc4c(c3)COc3cc5c(ccc6nc([C@@H]7CCCN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]c65)cc3-4)[nH]2)C1
Reaction time: 1.5 h

Procedure:
A mixture of (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (22 mg, 0.105 mmol), COMU (45 mg, 0.069 mmol), and tert-butyl (2S,4S)-4-(methoxymethyl)-2-(5-{2-[(2S)-pyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (65 mg, 0.105 mmol) in 1.5 mL 10% DIPEA in DMF was stirred for 1.5 h. The reaction mixture was partitioned between ethyl acetate and saturated sodium bicarbonate. The organic phase was dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude intermediate was treated with 8 mL 1.25N HCl in ethanol at 50° C. for 4 h. Added saturated sodium bicarbonate and extracted the free base into dichloromethane. (106 mg).
Reaction SMILES: CS(Cl)(=O)=O.O[CH:7]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13].C(N(CC)CC)C.[NH:35]1[CH:39]=[CH:38][N:37]=[CH:36]1>ClCCl>[N:35]1([CH:7]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:39]=[CH:38][N:37]=[CH:36]1
Reactant: CCCCCCCCCCCCC(O)CCCCC(=O)OC
Reactant: c1c[nH]cn1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCC(CCCCC(=O)OC)n1ccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.6 %

Procedure:
Methanesulfonyl chloride (0.39 ml, 4.99 mmol) was added dropwise to a stirred solution of methyl 6-hydroxyoctadecanoate (1.55 g, 4.94 mmol) and triethylamine (0.89 ml, 6.42 mmol) in dry dichloromethane (30 ml) at 0° C. The reaction mixture was warmed to room temperature after the addition, and stirred for 2 h. The reaction mixture was quenched with water, diluted with 50 ml of dichloromethane, and the organic layer was washed with water and brine solution, dried on anhydrous MgSO4, concentrated and evaporated under vacuum. This crude compound was combined with imidazole (0.67 g, 9.88 mmol) and heated at 80° C. for 16 h. Crude compound was purified on silica gel (2% methanol in dichloromethane) to obtain a light brown liquid (605 mg, 33.7%).