Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1([CH3:20])[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[C:5]1=[O:19].C([O-])(=O)C.[Cs+].Br[C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][N:28]=1.CS(C)=O>C(OCC)(=O)C.[OH-].[NH4+].[Cu]>[CH3:3][C:4]1([CH3:20])[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH:13]2[CH2:18][CH2:17][N:16]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][N:28]=3)[CH2:15][CH2:14]2)[C:5]1=[O:19]
Reactant: Cc1ccc(Br)nc1
Reactant: CC1(C)C(=O)N(C2CCNCC2)c2ncccc21
Agent: [Cu]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1ccc(N2CCC(N3C(=O)C(C)(C)c4cccnc43)CC2)nc1
Temperature: 100 °C
Reaction time: 14 h
Yield: 24.7 %

Procedure:
A mixture of 3,3-dimethyl-1-(piperidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-2(3H)-one dihydrochloride (intermediate 57, 0.2000 g, 0.628 mmol), cesium acetate (0.869 g, 4.52 mmol), 2-bromo-5-methylpyridine (0.119 g, 0.691 mmol), and dry dimethylsulfoxide (1.0 mL) was heated at 100° C. for 14 hours. Additional 2-bromo-5-methylpyridine (0.119 g, 0.691 mmol) and copper (7.99 mg, 0.126 mmol) were added to the mixture and the reaction was continued for an additional 14 hours. The mixture was diluted with ethyl acetate and ammonium hydroxide and the phases separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by silica gel chromatography (0-100% ethyl acetate in hexane gradient) to give 3,3-dimethyl-1-(1-(5-methylpyridin-2-yl)piperidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-2(3H)-one (0.052 g, 0.155 mmol, 24.6% yield). M+1: 337.0. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.37 (s, 6 H) 1.72-1.84 (m, 2 H) 2.20 (s, 3 H) 2.72-3.01 (m, 4 H) 4.40 (d, J=12.52 Hz, 2 H) 4.54 (tt, J=11.93, 3.91 Hz, 1 H) 6.66 (d, J=8.61 Hz, 1 H) 6.92 (dd, J=7.24, 5.28 Hz, 1 H) 7.31 (dd, J=8.61, 1.76 Hz, 1 H) 7.41 (dd, J=7.24, 1.37 Hz, 1 H) 8.02 (s, 1 H) 8.12 (dd, J=5.18, 1.27 Hz, 1 H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].[C:12]([C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)#[N:13].[F-].[Cs+]>COCCOC.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[C:12]([C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[CH3:11])=[CH:16][CH:15]=1)#[N:13]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: Cc1cc([N+](=O)[O-])ccc1Br
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: Cc1cc([N+](=O)[O-])ccc1-c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 125.7 %

Procedure:
A mixture of 2-bromo-5-nitrotoluene (7.05 gm, 32.67 mmol), 4-cyanophenylboronic acid (Tet. Lett., 1993, 34, 8237)(6.0 gm, 40.83 mmol), caesium fluoride (11.02 gm, 72.53 mmol) and tri-(2-methylphenyl)phosphine (1.0 gm, 3.27 mmol) in 1,2-dimethoxyethane (240 mL) were stirred under an atmosphere of nitrogen at room temperature for 40 mins. Tris(dibenzylideneacetone)dipalladiumn (1.50 gm, 1.63 mmol) was added and stirred for 10 mins at room temperature, then heated at 80° C. for 4 h. After being cooled, the mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was separated, washed with water, then dried (Na2SO4) and concentrated under reduced pressure to give crude 1-(4-cyanophenyl)-2-methyl-4-nitrobenzene (9.78 gm) which was used without further purification.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[OH:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: OCCCCCCBr
Reactant: c1ccc2c(c1)CCCN2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: OCCCCCCN1CCCc2ccccc21
Temperature: 25 °C

Procedure:
A stirred solution of 133.2 g (1 mole) of 1,2,3,4-tetrahydroquinoline, 181.1 g (1 mole) of 6-bromohexanol, and 138.2 g (1 mole) of potassium carbonate in toluene is heated at 80° C. for 3 hours. The solution is cooled to room temperature, and the solids are removed by filtration. The solvent is removed in vacuo, and the N-hydroxyhexyltetrahydroquinoline is purified by chromatography (silica gel, hexane:ethyl acetate).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.[CH:29]1([CH2:32][C:33]2[NH:34][C:35]3[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=3[N:37]=2)[CH2:31][CH2:30]1>>[CH:29]1([CH2:32][C:33]2[N:34]([C:2]3[N:10]=[C:9]4[C:5]([N:6]=[C:7]([CH2:12][N:13]5[CH2:14][CH2:15][CH:16]([C:19]([OH:22])([CH3:20])[CH3:21])[CH2:17][CH2:18]5)[N:8]4[CH3:11])=[C:4]([N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)[N:3]=3)[C:35]3[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=3[N:37]=2)[CH2:30][CH2:31]1
Reactant: c1ccc2[nH]c(CC3CC3)nc2c1
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Product: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-n3c(CC4CC4)nc4ccccc43)nc21

Procedure:
Following General Procedure I for Buchwald coupling, 2-(1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol and 2-(cyclopropylmethyl)-benzimidazole were reacted to give 308. LCMS m/z: 545.3 (MH+)
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:9])[NH:4][N:5]=[CH:6][C:7]=1[NH2:8].[CH3:10][O:11][C:12]1[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:13]=1[C:14](O)=O>>[CH3:10][O:11][C:12]1[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:13]=1[C:14]1[N:1]=[C:2]2[C:3](=[O:9])[NH:4][NH:5][CH:6]=[C:7]2[N:8]=1
Reactant: COc1cc(N)ccc1C(=O)O
Reactant: Nc1cn[nH]c(=O)c1N
Product: COc1cc(N)ccc1-c1nc2c[nH][nH]c(=O)c-2n1

Procedure:
Prepared analogously to Example 1 from 4,5-diamino-2H-pyridazin-3-one and 2-methoxy-4-amino-benzoic acid.
Reaction SMILES: [O:1]([CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([CH2:17]O)[C:12]=1[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[OH-].[Na+].[SH:26][C:27]1[NH:28][C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=1>C(O)C.ClCCl>[O:1]([CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([CH2:17][S:26][C:27]2[NH:31][C:30]3[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=3[N:28]=2)[C:12]=1[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(OCCOc2ccccc2)ccnc1CO
Reactant: Sc1nc2ccccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCO
Product: Cc1c(OCCOc2ccccc2)ccnc1CSc1nc2ccccc2[nH]1
Temperature: 70 °C
Reaction time: 1 h
Yield: 79.5 %

Procedure:
A mixture comprising 1.0 g of [4-(2-phenoxyethoxy)-3-methylpyridine-2-yl]methanol, 0.60 ml of thionyl chloride and 12 ml of dichloromethane was kept at 40° C. for 60 minutes to carry out the reaction. The reaction mixture was distilled to remove the solvent. Thus, a brown syrupy residue was obtained. 50 ml of ethanol, 0.70 g of sodium hydroxide and 1.2 g of 2-mercaptobenzimidazole were added to the residue. The obtained mixture was heated at 70° C. for two hours and distilled to remove the ethanol. The obtained residue was chromatographed over a silica gel column and eluted with 30% ethyl acetate in hexane and then with ethyl acetate to obtain 1.2 g of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][CH2:9][C:10](O)=[O:11])=O)=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].O.[NH2:19][NH2:20]>C(O)(=O)C>[NH2:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]2[CH2:8][CH2:9][C:10](=[O:11])[NH:19][N:20]=2)=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16]
Reactant: NN
Reactant: Nc1ccc(C(=O)CCC(=O)O)cc1[N+](=O)[O-]
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccc(C2=NNC(=O)CC2)cc1[N+](=O)[O-]

Procedure:
18.1 gm of 3-(4-amino-3-nitro-benzoyl)-propionic acid were reacted, as in Example 1a, with 18.1 gm of hydrazine hydrate in 200 ml of glacial acetic acid, yielding the desired compound which had a melting point above 330° C.
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:8]=[C:9]([OH:17])[CH:10]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:12]=1)([CH3:6])([CH3:5])[CH3:4].[Br:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1Br>[Cu].CC(N(C)C)=O>[C:13]([C:11]1[CH:10]=[C:9]([CH:8]=[C:7]([C:3]([CH3:6])([CH3:5])[CH3:4])[CH:12]=1)[O:17][C:22]1[CH:23]=[CH:24][C:19]([Br:18])=[CH:20][CH:21]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: Brc1ccccc1Br
Reactant: CC(C)(C)c1cc(O)cc(C(C)(C)C)c1
Agent: [Cu]
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)c1cc(Oc2ccc(Br)cc2)cc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 8.8 g. of 50% sodium hydride (mineral oil dispersion) in 320 ml. of dry dimethylacetamide is added, in portions over 15 minutes with vigorous stirring, 32 g. of 3,5-di-tertiary butylphenol, during which the reaction mixture is cooled with an icebath to moderate the internal temperature. The reaction mixture is then stirred at room temperature for 1 hour, after which is added 75.2 g. of dibromobenzene and 800 mg. of copper powder. The resultant mixture is refluxed for 8 hours, after which time it is cooled and the dimethylacetamide is removed in vacuo. The resultant residue is extracted several times with methylene chloride and the insoluble copper filtered off. The combined methylene chloride extracts are washed two times with water, dried over sodium sulfate, filtered, evaporated in vacuo to dryness and the residue recrystallized from ethanol to obtain 1-(3,5-di-tertiary butylphenoxy)-4-bromobenzene, m.p. 98°-100° C.
Reaction SMILES: C(O[CH:6]([OH:14])[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH3:13])=[O:8])CCC.[C:15]([NH2:20])(=[O:19])[C:16]([CH3:18])=[CH2:17].COC.C1(C=CC(O)=CC=1)O.C(OC(NC(=O)C=CC)C(OCCCC)=O)CCC>>[C:15]([NH:20][CH:6]([OH:14])[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH3:13])=[O:8])(=[O:19])[C:16]([CH3:18])=[CH2:17]
Reactant: C=C(C)C(N)=O
Reactant: CCCCOC(=O)C(O)OCCCC
Agent: CC=CC(=O)NC(OCCCC)C(=O)OCCCC
Agent: COC
Agent: Oc1ccc(O)cc1
Product: C=C(C)C(=O)NC(O)C(=O)OCCCC
Reaction time: 1.5 h

Procedure:
The procedure of example VI was again followed using the following change: butyl glyoxylate butyl hemiacetal 273 parts; methacrylamide 110 parts; methyl ether of hydroquinone 0.27 parts. The reaction was run at 70° to 75° C. for 1.5 hours. The material was not isolated, instead it was used directly to make butyl methylacrylamidoglycolate butyl ether.
Reaction SMILES: [CH3:1][N:2]([CH:16]1[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]1)[C:3]([N:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[N:7]=[CH:6]1)=[O:4].[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32]>>[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32].[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32].[CH3:1][N:2]([CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[C:3]([N:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[N:7]=[CH:6]1)=[O:4]
Reactant: CN(C(=O)n1cnc(-c2cccnc2)c1)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)n1cnc(-c2cccnc2)c1)C1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
To tert-butyl 4-(N-methyl-4-(pyridin-3-yl)-1H-imidazole-1-carboxamido)piperidine-1-carboxylate (500 mg, 1.297 mmol) was added trifluoroacetic acid (4 mL, 51.9 mmol) to give a turbid solution. The mixture was allowed to stir at room temperature for 1 h, whereupon the solvent was removed by evaporation. The oily residue was triturated with ether, and the resulting white solid was filtered off to give a white solid (653.2 mg, 88% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[O:6][C@H:5]2[C@H:7]([NH:12][C:13]3[N:18]4[N:19]=[C:20]([C:22]5[CH:27]=[CH:26][CH:25]=[C:24]([C:28]#[C:29][Si](C)(C)C)[CH:23]=5)[CH:21]=[C:17]4[N:16]=[CH:15][CH:14]=3)[CH2:8][C@H:9]([CH2:10][OH:11])[C@H:4]2[O:3]1.C1(C#C[Si](C)(C)C)C=CC=CC=1.CO.C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>>[C:28]([C:24]1[CH:23]=[C:22]([C:20]2[CH:21]=[C:17]3[N:16]=[CH:15][CH:14]=[C:13]([NH:12][C@H:7]4[C@@H:5]5[O:6][C:2]([CH3:34])([CH3:1])[O:3][C@@H:4]5[C@@H:9]([CH2:10][OH:11])[CH2:8]4)[N:18]3[N:19]=2)[CH:27]=[CH:26][CH:25]=1)#[CH:29]
Reactant: CC1(C)O[C@@H]2[C@@H](CO)C[C@@H](Nc3ccnc4cc(-c5cccc(C#C[Si](C)(C)C)c5)nn34)[C@@H]2O1
Agent: C[Si](C)(C)C#Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CO
Product: C#Cc1cccc(-c2cc3nccc(N[C@@H]4C[C@H](CO)[C@H]5OC(C)(C)O[C@H]54)n3n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
(rac)-rel-{(3aR,4R,6R,6aS)-2,2-dimethyl-6-[(2-{3-[(trimethylsilyl)ethynyl]phenyl}pyrazolo[1,5-a]pyrimidin-7-yl)amino]tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl}methanol (0.067 g, 0.00014 mol; synthesized following Step 1 in Method A except using 4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylethynyl-trimethylsilane instead of 1-naphthaleneboronic acid) is dissolved in methanol (0.03 mL, 0.0007 mol). Potassium carbonate (21 mg, 0.00015 mol) is added and the solution is stirred at room temperature overnight. The reaction mixture is neutralized with saturated ammonium chloride solution and extracted with dichlormethane. The organic layer is concentrated in vacuo and purified by column chromatography (0-15% MeOH/CH2Cl2) to provide (rac)-rel-[(3aR,4R,6R,6aS)-6-{[2-(3-ethynylphenyl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]methanol (0.046 g, yield 81%). LCMS: (AA) M+ 405; 1H NMR (400 MHz, DMSO) δ 8.25-8.05 (m, 4H), 7.52-7.44 (m, 2H), 7.00 (s, 1H), 6.25 (d, J=5.4 Hz, 1H), 5.25-5.17 (m, 1H), 4.59-4.48 (m, 2H), 4.27 (s, 1H), 4.16-3.99 (m, 1H), 3.65-3.44 (m, 2H), 2.48-2.38 (m, 1H), 2.28-2.19 (m, 1H), 1.87-1.72 (m, 1H), 1.46 (s, 3H), 1.24 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:15]2[N:16]=[C:17]([CH3:24])[C:18]([C:19]([O:21]CC)=[O:20])=[C:14]2[CH:13]=[CH:12][C:11]=1[CH3:25].[OH-].[K+]>C(O)C.C1COCC1.O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:15]2[N:16]=[C:17]([CH3:24])[C:18]([C:19]([OH:21])=[O:20])=[C:14]2[CH:13]=[CH:12][C:11]=1[CH3:25]
Reactant: CCOC(=O)c1c(C)nn2c(-c3ccc(OC)cc3Cl)c(C)ccc12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2c(C)ccc3c(C(=O)O)c(C)nn23)c(Cl)c1
Temperature: 25 °C
Reaction time: 192 h
Yield: 78.9 %

Procedure:
A solution of ethyl 7-(2-chloro-4-methoxyphenyl)-2,6-dimethylpyrazolo[1,5-a]pyridine-3-carboxylate (0.82 g, 2.3 mmol) in ethanol (14 mL), THF (8 mL) and H2O (8 mL) was treated with KOH (3.12 g, 55.6 mmol) and stirred at room temperature for 8 days adding more KOH periodically. The reaction was concentrated in vacuo and the residue partitioned between Et2O and H2O. The aqueous layer was acidified with concentrated HCl, extracted with ethyl aceatate, washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo to give a brown solid (0.60 g, 79%) as the title compound: 1H NMR (400 MHz, CDCl3) δ 8.18 (d, J=9.0 Hz, 1H), 7.43 (d, J=9.0 Hz, 1H), 7.30 (d, J=8.5 Hz, 1H), 7.16 (d, J=2.5 Hz, 1H), 7.04 (dd, J=8.5, 2.5 Hz, 1H), 3.93 (s, 3H), 2.67 (s, 3H), 2.19 (s, 3H); HRMS (FAB) calcd for C17H15N2O3Cl+H 331.0849. found 331.0853.
Reaction SMILES: ClC1C=CC=CC=1C1C=CN=CC=1N(CCS(C)(=O)=O)[C:15](=[O:30])[C:16]1C=C(C(F)(F)F)[CH:19]=[C:18](C(F)(F)F)[CH:17]=1.[F:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2[CH:49]=[CH:48][N:47]=[CH:46][C:45]=2[NH:50][C:51](=[O:57])[O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[C:40]([O:58][CH3:59])[CH:39]=1.C(Cl)C1OCCC1>>[F:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2[CH:49]=[CH:48][N:47]=[CH:46][C:45]=2[N:50]([CH2:19][CH:18]2[CH2:17][CH2:16][CH2:15][O:30]2)[C:51](=[O:57])[O:52][C:53]([CH3:54])([CH3:55])[CH3:56])=[C:40]([O:58][CH3:59])[CH:39]=1
Reactant: COc1cc(F)ccc1-c1ccncc1NC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccccc1Cl
Agent: ClCC1CCCO1
Product: COc1cc(F)ccc1-c1ccncc1N(CC1CCCO1)C(=O)OC(C)(C)C

Procedure:
The title compound was prepared in analogy to example 85, intermediate c, from tert-butyl 4-(4-fluoro-2-methoxyphenyl)pyridin-3-ylcarbamate and tetrahydrofurfurylchloride after a reaction time of 72 hours at 70° C. The compound was purified by silica gel chromatography on a 20 g column using an MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Light yellow solid (38%). MS (ESI): m/z=403.205 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[C:6]([C:8]1[C:12]2[CH:13]=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:17]C(C)C)[C:11]=2[O:10][CH:9]=1)=[O:7].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[C:6]([C:8]1[C:12]2[CH:13]=[CH:14][C:15]([O:21][CH3:22])=[C:16]([OH:17])[C:11]=2[O:10][CH:9]=1)=[O:7]
Reactant: COc1cc(C(=O)c2coc3c(OC(C)C)c(OC)ccc23)cc(OC)c1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc(C(=O)c2coc3c(O)c(OC)ccc23)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 86.6 %

Procedure:
A solution of 3-(3,4,5-trimethoxybenzoyl)-6-methoxy-7-isopropoxybenzofuran (23 mg, 0.058 mmol, co-distilled with toluene before use) in dry dichloromethane (1 mL) was treated with solid aluminum chloride (16 mg, 0.116 mmol). The reaction mixture was stirred for 20 minutes at room temperature (monitored by tlc) then quenched with saturated ammonium chloride solution and extracted with ethyl acetate (10 mL). The organic layer was washed with water (5 mL), dried over magnesium sulfate and concentrated under vacuum. The crude product was purified by flash chromatography (silica gel, eluent=hexane/diethyl ether/ethyl acetate; 80:19:1) to afford the title compound as a creamy white crystalline solid (18 mg, 86%); 1H NMR (300 MHz, CDCl3) δ 8.04 (s, 1H, C2H), 7.63 (d, 1H, J=8.53 Hz), 7.14 (s, 2H, benzoyl Hs), 7.02 (d, 1H, J=8.38 Hz), 3.97 (s, 3H, OMe), 3.93 (s, 3H, OMe), 3.89 (s, 6H, 2×OMe); 13C NMR (75 MHz, CDCl3) δ 188.73 (CO), 152.82, 151.24, 144.54, 143.30, 141.76, 133.97, 130.87, 120.92, 120.62, 112.43, 109.16, 106.06, 60.62, 56.85, 55.97.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([NH:7][CH:8]([C:10](=O)[NH:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[CH3:9])[CH3:6])C.C(OCC)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([NH:11][CH2:10][CH:8]([NH:7][CH:5]([CH3:6])[CH2:4][OH:3])[CH3:9])=[CH:17][CH:16]=1
Reactant: CCOC(=O)C(C)NC(C)C(=O)Nc1ccc(Cl)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CC(CO)NC(C)CNc1ccc(Cl)cc1
Yield: 98.5 %

Procedure:
95 Grams of 2-[1-(p-chlorophenylcarbamyl)ethylamino]-propionic acid ethyl ester dissolved in 1200 ml. of anhydrous diethyl ether is gradually added under stirring to a suspension of 38 g. of LiAlH4 in 2000 ml. of diethyl ether cooled to 0° C. The reaction mixture is refluxed for two hours with stirring, then the reaction complex is decomposed at 0° C. with water, stirred for 30 minutes at room temperature and the inorganic solids separated by filtration. The ether solution is dried and evaporated, and the residue, distilled in a bulb, yields 76 g. of the title compound. B.p. 170° C./0.4 mm Hg. yield 98.5%. The corresponding acetate, obtained by treatment of the title compound with acetyl chloride in acetic acid, boils at 160° C./0.5 mm Hg. In the same way, the corresponding m-chlorophenyl-substituted derivative is synthesized. B.p 170° C./0.5 mm Hg. The corresponding acetate boils at 160° C./0.5 mm Hg.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6]2)#[N:2].[BH4-].[Na+]>CO.C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:8]([OH:12])[CH2:7][CH2:6]2)#[N:2]
Reactant: N#Cc1ccc2c(c1)CCC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)CCC2O
Reaction time: 3 h
Yield: 71.2 %

Procedure:
A solution of 5-cyano-1-indanone (3.40 g, 21.63 mmol, prepared according to Reich, S. H., et. al. J. Med. Chem., 2000, 43, 1670–1683) in methanol (50 mL) was treated with sodium borohydride (0.25 g, 6.48 mmol). After stirring for 3 h, the reaction was diluted with methylene chloride (50 mL) and washed with saturated aqueous sodium bicarbonate (50 mL). The aqueous layer was further extracted with methylene chloride (2 50 mL). The extracts were combined, dried over magnesium sulfate and concentrated in vacuo. Silica gel chromatography eluting with 40% ethyl acetate/hexanes gave 2.45 g (15.40 mmol, 71%) of the title compound as a white solid: 1H NMR (500 MHz, CDCl3) δ 7.48–7.54 (m, 3H), 5.25–5.29 (m, 1H), 3.03–3.10 (m, 2H), 2.81–2.89 (m, 2H), 2.52–2.59 (m, 2H), 1.94–2.01 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ 150.1, 144.2, 130.9, 128.6, 125.0, 119.1, 111.8, 75.9, 35.8, 29.5.
Reaction SMILES: [CH2:1]([CH:3]([CH:11]([OH:13])[CH3:12])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[CH3:2].C(OC=C)(=O)CCCCCCCCCCC>>[CH2:1]([CH:3]([C@@H:11]([OH:13])[CH3:12])[C:4]([O:6][C:7]([CH3:9])([CH3:8])[CH3:10])=[O:5])[CH3:2]
Reactant: CCC(C(=O)OC(C)(C)C)C(C)O
Agent: C=COC(=O)CCCCCCCCCCC
Product: CCC(C(=O)OC(C)(C)C)[C@H](C)O
Temperature: 35 °C
Reaction time: 48 h
Yield: 66 %

Procedure:
A mixture of 15.0 g of t-butyl 2-ethyl-3-hydroxybutanoate as racemate, 9.0 g of vinyl laurate and 8.0 g of Lipase P (trade name, supplied by Amano Pharmaceutical Co., Ltd.) was stirred at 35° C. for two days. After stopping the reaction, the enzyme was removed by filtration and the enzyme was washed with n-heptane on a filter paper. n-Heptane was distilled away from the filtrate and the residue was subjected to vacuum distillation to obtain 9.9 g of t-butyl (3S)-2-ethyl-3-hydroxybutanoate, b.p. 73.5°-75° C. (4.5 mm Hg), [α]D28 =+1.5°(C=1.22, CHCl3) of the following formula. ##STR75## The NMR chart is shown in FIG. 8.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:23]=[CH:22][CH:21]=[CH:20][C:7]=1[CH2:8][NH:9][CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:4])([CH3:3])[CH3:2].[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]Br.C([O-])([O-])=O.[K+].[K+]>CC#N>[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][N:9]([CH2:8][C:7]1[CH:20]=[CH:21][CH:22]=[CH:23][C:6]=1[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:17])[CH3:18]
Reactant: BrCCCCCCBr
Reactant: CC(C)(C)OC(=O)NCCNCc1ccccc1OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCN(CCCCCCBr)Cc1ccccc1OC(C)(C)C
Reaction time: 48 h
Yield: 64 %

Procedure:
Compound 14 (3.56 g, 14.6 mmol), 1,6-dibromohexane (35.3 g, 146 mmol) and K2CO3 (2 g, 14.6 mmol) were added to 50 mL CH3CN, and the solution was stirred for 48 h. The solvent was evaporated to dryness and the residue was dissolved in a minimum amount of CH2Cl2 followed by purification via silica gel chromatographed, eluting with a 2% methanolic NH3 (7 M NH3 in methanol/98% CH2Cl2 yield the desired product as a pale yellow oil (64%). 1H NMR (CDCl3) δ 7.354 (dd, 1H, Ar), 7.121 (ddd, 1H, Ar), 7.013 (d, 1H, Ar), 6.986 (t, 1H, Ar), 3.569 (s, 2H, —CH2), 3.351 (t, 2H, —CH2—), 3.145 (d, 2H, —CH2—), 2.507 (t, 2H, —CH2—), 2.399 (t, 2H, —CH2—), 1.805 (p, 2H, —CH2—),1.447 (p, 2H, —CH2—), 1.409 (s, 9H, —C(CH3)3), 1.372 (s, 9H, —C(CH3)3), 1.362 (p, 2H, —CH2—), 1.254 (p, 2H, —CH2—). Mass Spec.=485.48 (M+H)+.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13].[H-].[Na+].[CH3:18][O:19][CH2:20][CH2:21][O:22][CH2:23]Cl>O1CCCC1>[CH3:18][O:19][CH2:20][CH2:21][O:22][CH2:23][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1ccc2ccccc2c1O
Reactant: COCCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOCc1c(C(=O)OC)ccc2ccccc12
Yield: 38.4 %

Procedure:
A solution of 2.3 g (11.4 mmol) of methyl 1-hydroxy-naphthalene-2-carboxylate in 15 ml of dry tetrahydrofuran was treated with 0.51 g (17 mmol) of sodium hydride (80%) and subsequently 2.13 g of 2-methoxyethoxymethyl chloride were added dropwise while cooling with ice. After 3 hours at room temperature the solution was extracted with aqueous sodium hydrogen carbonate solution and the organic phase was separated, dried over sodium sulphate and evaporated under reduced pressure. For purification, the crude product was chromatographed on silica gel using a 9:1 mixture of methylene chloride and ether as the eluent. In addition to 1.55 g of starting material there were obtained 1.2 g of methyl 1-(2-methoxy-ethoxymethyl)-naphthalene-2-carboxylate; MS: 290 (M)+.