Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[OH-].[Na+].[C:16](ON1C(=O)CCC1=O)([O:18][CH2:19][CH:20]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.C(OCC)(=O)C.O1CCCC1>[NH:1]([C:16]([O:18][CH2:19][CH:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27]2[C:32]1=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:17])[C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Reaction time: 8 h
Yield: 89.4 %

Procedure:
L-Tyrosine (9.06 g, 50 mmol) was dissolved in 100 ml of water and 150 ml of tetrahydrofuran (THF) with 50 ml of 1 N NaOH. To this solution was added Fmoc-OSu (16.87 g, 50 mmol); with rapid stirring. The suspension was adjusted to pH 7 with 1N NaOH and then stirred overnight, after which a small amount of solid tyrosine still remained. Solid citric acid (15 g) was added with stirring followed by 300 ml of ethyl acetate (EtOAc). The EtOAc layer was collected washed with 3×50 ml of 10% citric acid, 4×50 ml of saturated NaCl, and dried over MgSO4. Evaporation of the EtOAc solution gave a light tan syrup which was crystallized from 200 ml of dichloromethane (DCM) to give 18.04 g (89.4% yield) of product (mp 126°-130°).
Reaction SMILES: [O:1]1[CH2:20][CH:2]1[CH2:3][C:4]1([OH:19])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]1=2.[CH3:21][NH:22][CH3:23]>CCO>[CH3:21][N:22]([CH3:23])[CH2:20][CH:2]([OH:1])[CH2:3][C:4]1([OH:19])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]1=2
Reactant: CNC
Reactant: OC1(CC2CO2)c2ccccc2CCc2ccccc21
Solvent: CCO
Product: CN(C)CC(O)CC1(O)c2ccccc2CCc2ccccc21
Yield: 36.7 %

Procedure:
A mixture of 3.7 g (14 mmol) of the epoxide 11, 26.8 g (0.59 mol) of anhydrous dimethylamine, and 50 ml of EtOH was heated at 100° C. in a stainless steel autoclave for 12 hrs. When cool the contents were removed and concentrated under reduced pressure. Recrystallization of the solid residue from aqueous EtOH afforded 1.6 g (37% yield) of the crystalline amino-diol 12, m.p. 144°-146° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:7][CH2:8][CH3:9])[CH:3]1[NH:6][C:4]1=[O:5].C(=O)([O-])O.[Na+].[CH2:15]([O:22][C:23](Cl)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1.O>[CH2:15]([O:22][C:23]([NH:1][C@@H:2]([CH2:7][CH2:8][CH3:9])[CH:3]1[NH:6][C:4]1=[O:5])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCC[C@H](N)C1NC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCC[C@H](NC(=O)OCc1ccccc1)C1NC1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution obtained by dissolving 3(S)-amino-2-caprolactam (5.00 g, 39.01 mmol) in THF (20 ml) and water (40 ml), sodium hydrogen carbonate (4.92 g, 58.56 mol) and benzyloxycarbonyl chloride (5.57 ml, 39.01 mmol) were added under ice cooling, and the mixture was stirred at room temperature for 18 hours.
Reaction SMILES: C1(O[C:8](=[O:29])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[CH:22]=[C:21]([F:23])[C:20]([CH3:24])=[CH:19][C:18]=3[F:25])[C:11]=2[C:26](=[O:28])[NH2:27])C=CC=CC=1.[CH3:30][N:31]([CH3:39])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][NH2:38]>>[F:25][C:18]1[CH:19]=[C:20]([CH3:24])[C:21]([F:23])=[CH:22][C:17]=1[CH2:16][O:15][C:12]1[C:11]([C:26]([NH2:27])=[O:28])=[C:10]([NH:9][C:8]([NH:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][N:31]([CH3:39])[CH3:30])=[O:29])[S:14][N:13]=1
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)cc1F
Reactant: CN(C)CCCCCCN
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCCCCCN(C)C)c2C(N)=O)cc1F

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,5-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and N1,N1-Dimethyl-hexane-1,6-diamine by the procedure analogous to Example 6. HPLC ret. time: 3.4 minutes. 1H NMR (400 MHz, CD3OD) δ 7.18 (dd, 1H, J=6.0, 9.2 Hz), 7.03 (dd, 1H, J=6.4, 10 Hz), 5.45 (s, 2H), 3.19 (t, 2H, J=7.2 Hz), 2.28 (m, 2H), 2.24 (s, 3H), 2.22 (s, 6H), 1.55-1.45 (m, 4H), 1.35-1.33 (m, 4H) ppm; MS (APCl, m/z): 470 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([NH2:9])[CH:5]=[CH:4][N:3]=1.[Cl:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:12]=1[C:13](Cl)=[O:14].C(N(CC)CC)C>O1CCOCC1>[Cl:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:12]=1[C:13]([NH:9][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[C:7]=1[F:8])=[O:14]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: Nc1ccnc(Cl)c1F
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccnc(Cl)c1F)c1c(Cl)cccc1Cl
Temperature: 25 °C
Yield: 81.4 %

Procedure:
A mixture of 2-chloro-3-fluoropyridin-4-ylamine (660 mg, 4.5 mmol), 2,6-dichlorobenzoyl chloride (1.43 mL, 2.10 g, 10.0 mmol) and triethylamine (1.53 mL, 1.11 g, 11.0 mmol) in dioxane (12 mL) was heated under reflux for 18 hours then cooled to ambient temperature. The resultant mixture was partitioned between EtOAc (50 mL) and water (50 mL). The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was triturated with diethyl ether, filtered, dried and further purified by silica gel flash chromatography (0-25% EtOAc in pentane) to afford the title compound as a pink solid (1.17 g, 81% yield). 1H NMR (300 MHz, CDCl3): δ 8.50 (t, J=5.3 Hz, 1H), 8.22 (d, J=5.5 Hz, 1H), 7.83 (br s, 1H), 7.40-7.39 (m, 3H).
Reaction SMILES: Br[C:2]1[C:10]2[NH:9][C:8]3[CH2:11][CH2:12][N:13]([C:15]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:14][C:7]=3[C:6]=2[C:5]([Br:34])=[CH:4][CH:3]=1.C([Li])(C)(C)C.CCCCC.C[Si]([N:49]=[C:50]=[O:51])(C)C>C1COCC1.O>[Br:34][C:5]1[CH:4]=[CH:3][C:2]([C:50]([NH2:49])=[O:51])=[C:10]2[C:6]=1[C:7]1[CH2:14][N:13]([C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:12][CH2:11][C:8]=1[NH:9]2
Reactant: Brc1ccc(Br)c2c3c([nH]c12)CCN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C3
Reactant: C[Si](C)(C)N=C=O
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)c1ccc(Br)c2c3c([nH]c12)CCN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C3
Temperature: -78 °C
Reaction time: 0.12 h
Yield: 54.9 %

Procedure:
A solution of 6,9-dibromo-2-trityl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (purity about 75%, 650 mg, 0.852 mmol) in THF (10 mL) was stirred at −78° C. and treated with tert-butyllithium, 1.7 M in pentane (2.505 mL, 4.26 mmol) over 2-3 min. After stirring for about 5-10 min at −78° C., the red-orange solution was stirred on an ice-water bath for 2 h. The solution was then cooled again to −78° C. and treated with trimethylsilyl isocyanate (0.922 mL, 6.81 mmol). Stirring was continued while allowing the cooling bath to warm slowly to room temperature. After 19 h, the mixture was treated with water (5 mL) and extracted twice with EtOAc. The combined organic phases were dried and concentrated. The residue was subjected to column chromatography on silica gel (80 g), eluting with EtOAc-hexane (gradient from 20:80 to 100:0) to provide the desired product as an off-white solid (251 mg, 55% yield). LCMS (M+H-trityl)+ m/z 294, 296.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:25]=[CH:24][C:12]([CH2:13][NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N+:21]([O-])=O)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>O=[Pt]=O.C(O)C>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:25]=[CH:24][C:12]([CH2:13][NH:14][C:15]3[C:16]([NH2:21])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccccc1NCc1ccc(OCCN2CCCC2)cc1
Agent: O=[Pt]=O
Solvent: CCO
Product: Nc1ccccc1NCc1ccc(OCCN2CCCC2)cc1
Yield: 99.6 %

Procedure:
Adam's catalyst (50 mg, 20% wt.), was added to a degassed solution of N-[4-[2-(1-pyrrolidinyl)ethoxy]benzyl]-2-nitroaniline (240 mg, 0.703 mmol) in absolute ethanol (5 mL). The atmosphere was replaced with hydrogen then the reaction was stirred vigorously at ambient temperature until all of the nitro compound had been consumed as determined by tic (9:1 CHCl3:MeOH, 1% TEA). The reaction mixture was filtered through a bed of diatomaceous earth, then the solvent was removed under reduced pressure to give the desired product as a brown yellow oil (218 mg, 100%).
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31].Cl.Cl.[CH3:34][N:35]([CH3:40])[CH:36]1[CH2:39][NH:38][CH2:37]1.CN1CCCC1>C(O)C>[CH3:34][N:35]([CH3:40])[CH:36]1[CH2:39][N:38]([C:20]2[C:21]([Cl:23])=[C:22]3[C:17]([C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14][N:13]3[C:11]3[C:10]([F:30])=[CH:9][C:8]([F:31])=[C:7]([NH2:6])[N:12]=3)=[CH:18][C:19]=2[F:25])[CH2:37]1
Reactant: CN(C)C1CNC1
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Agent: CN1CCCC1
Agent: Cl
Solvent: CCO
Solvent: CN(C)C=O
Product: CN(C)C1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4nc(N)c(F)cc4F)c3c2Cl)C1
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 72.1 %

Procedure:
To 310 mg of N,N-dimethylformamide were added 100 mg of 1-(6-amino-3,5-difluoropyridine-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 100 mg of 3-(dimethylamino)azetidine dihydrochloride, and 150 mg of N-methylpyrrolidine, and the mixture was stirred at 90° C. for 15 minutes. After adding 1 ml of ethanol, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 87 mg of the title compound as a colorless powder.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[C@:12]2([CH3:13])[C@H:7]([C:8]([CH3:15])([CH3:14])[CH2:9][CH2:10][CH2:11]2)[CH2:6][CH2:5][C@@:4]1([CH3:17])[OH:16].C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>CN(C=O)C>[CH3:25][S:26]([O:1][CH2:2][C@@H:3]1[C@:12]2([CH3:13])[C@H:7]([C:8]([CH3:15])([CH3:14])[CH2:9][CH2:10][CH2:11]2)[CH2:6][CH2:5][C@:4]1([OH:16])[CH3:17])(=[O:28])=[O:27]
Reactant: CC1(C)CCC[C@]2(C)[C@@H](CO)[C@](C)(O)CC[C@@H]12
Reactant: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1(C)CCC[C@]2(C)[C@@H](COS(C)(=O)=O)[C@](C)(O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.2 %

Procedure:
A solution of (1S,2R,4aS,8aS)-1-(hydroxymethyl)-2,5,5,8a-tetramethyl-decahydronaphthalen-2-ol (3) (12 g, 50 mmol) in anhydrous DMF (100 mL) was cooled with an ice bath under N2. To this mixture, triethylamine (15 mL, 110 mmol) and methanesulfonyl chloride (5.0 mL, 60 mmol) was added. The ice bath was removed and the mixture stirred at room temperature for 3 h. The reaction was diluted with diethyl ether and washed with 1 M HCl, saturated aqueous sodium bicarbonate and brine. The organic layer was concentrated to dryness to yield [(1S,2R,4aS,8aS)-2-hydroxy-2,5,5,8a-tetramethyl-decahydronaphthalen-1-yl]-methyl methanesulfonate (12) (15 g, 97% yield) as an orange solid.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]([OH:15])=O)[CH:3]=1.CN(C)C=O.C(Cl)(=O)C(Cl)=O.[NH2:27][C:28]1[CH:33]=[CH:32][C:31]([S:34][C:35]2[CH:36]=[CH:37][C:38]3[N:39]([CH:41]=[C:42]([NH:44][C:45]([CH:47]4[CH2:49][CH2:48]4)=[O:46])[N:43]=3)[N:40]=2)=[CH:30][CH:29]=1>CN(C)C(=O)C.O1CCCC1>[CH:47]1([C:45]([NH:44][C:42]2[N:43]=[C:38]3[CH:37]=[CH:36][C:35]([S:34][C:31]4[CH:30]=[CH:29][C:28]([NH:27][C:13]([C:4]5[CH:3]=[C:2]([CH3:1])[N:6]([C:7]6[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=6)[N:5]=5)=[O:15])=[CH:33][CH:32]=4)=[N:40][N:39]3[CH:41]=2)=[O:46])[CH2:48][CH2:49]1
Reactant: Nc1ccc(Sc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1
Reactant: Cc1cc(C(=O)O)nn1-c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2ccc(Sc3ccc4nc(NC(=O)C5CC5)cn4n3)cc2)nn1-c1ccccc1
Yield: 63.6 %

Procedure:
Using 5-methyl-1-phenyl-1H-pyrazole-3-carboxylic acid (186 mg, 0.92 mmol), tetrahydrofuran (3.0 mL), N,N-dimethylformamide (20 μL, 0.26 mmol), oxalyl chloride (80 μL, 0.92 mmol), N-{6-[(4-aminophenyl)thio]imidazo[1,2-b]pyridazin-2-yl}cyclopropanecarboxamide (200 mg, 0.62 mmol) and N,N-dimethylacetamide (4.0 mL), and in the same manner as in Example 249, the title compound (201 mg, 64%) was obtained as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C@H:6]2[CH2:19][CH:18]=[C:17](C=O)[C@@H:7]2[C@H:8](OC(OCC)C)[O:9][CH:10]=1)=[O:4].C(Br)CCCC.[Mg].[Cl-].[NH4+]>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[CH:6]2[CH2:19][CH:18]=[CH:17][CH:7]2[CH2:8][O:9][CH:10]=1)=[O:4]
Reactant: CCOC(C)O[C@@H]1OC=C(C(=O)OC)[C@H]2CC=C(C=O)[C@H]12
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCCCCBr
Solvent: C1CCOC1
Product: COC(=O)C1=COCC2C=CCC12
Temperature: -78 °C
Yield: 154.9 %

Procedure:
1.55 g of (1S,4aS,7aR)-1-[1-(ethoxy) ethoxy]-7-formyl-1,4a,5,7a-tetrahydrocyclopenta [c] pyrane-4-carboxylic acid methylester were dissolved in anhydrous tetrahydrofuran, followed by dropping 20 ml of magnesium pentylbromide (0.3 M tetrahydrofuran solution) while stirring and cooling at −78° C., and then stirring for 4 hours at the same temperature. After addition of saturated aqueous ammonium chloride solution to the reaction mixture, it was extracted with ethyl acetate. After washing the organic phase with brine, it was dried over magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel chromatography to obtain a colorless oil from the hexane-ether eluate in the form of (1S,4aS,7aR)-1-[1-(ethoxy) ethoxy]-7-(2-hydroxy)-n-hexyl]-1,4a,5,7a-tetrahydrocyclopenta [c] pyrane-4-carboxylic acid methylester (1.46 g, yield: 76%). The physicochemical properties of this compound are described below.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Br[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)COc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
A mixture of 3 g (21.56 mmol) of 3-nitrophenol, 4.3 g (22 mmol) of tert-butyl bromoacetate, 3.2 g of anhydrous potassium carbonate and 50 ml of acetone is stirred overnight at room temperature. The mixture is filtered and washed with acetone and both the filtrate and the washing product are evaporated to give a yellow oil. The oil is purified on a silica gel chromatography column using an EtOAc/cyclohexane mixture (50/50) as the eluent to give 5 g (92%) of tert-butyl 3-nitrophenoxyacetate (colourless oil). 2 g of Pd/C (10%) are added to a solution of 4.8 g (18.95 mmol) of tert-butyl 3-nitrophenoxyacetate in 20 ml of ethanol and the mixture is hydrogenated overnight at one atmosphere. The catalyst is filtered off. The solvent is evaporated off to give 3.38 g (80%) of tert-butyl 3-amidophenoxyacetate, which is chromatographed on a silica gel column using an EtOAc/cyclohexane mixture (50/50) as the eluent. A mixture of the resulting amine (0.5 g, 2.24 mmol) and 1,2-epoxy-3-phenoxypropane is heated at 70° C. overnight. After cooling, the product is washed with ethanol and the precipitate is filtered off to give 0.6 g of the tert-butyl ester. 0.6 g of this ester and 15 ml of 6 N HCl are mixed overnight at 80° C. The solvent is evaporated off and the residue is washed with an EtOH/CH3CN mixture and then recrystallized from CH3CN to give 0.36 g of a salt with the following characteristics: melting point 138-139° C.; 1H NMR (DMSO-d6) δ 3.82 (m, 2H), 3.96 (m, 4H), 4.06 (m, 1H), 4.72 (s, 2H), 6.88-7.00 (n, 5H Ar), 7.24-7.45 (m, 4H Ar).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl:12][C:13]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16]>>[Cl:12][C:13]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:14]=1[C:15]([C:9]1[CH:10]=[CH:11][C:6]([F:5])=[CH:7][CH:8]=1)=[O:16]
Reactant: Fc1ccccc1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(c1ccc(F)cc1)c1ccc(Cl)cc1Cl

Procedure:
To a stirred mixture of 20 parts of aluminium chloride and 100 parts of fluorobenzene are added dropwise 20.5 parts of 2,4-dichlorobenzoyl chloride. Upon completion, the mixture is heated to reflux and stirred at reflux temperature for 5 minutes. The reaction mixture is poured onto crushed ice and the product is extracted with 1,1'-oxybisethane. The extract is dried and evaporated, yielding 30 parts of (2,4-dichlorophenyl)(4-fluorophenyl) methanone as an oily residue.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[O:11]=[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:21])[N:13]1[CH2:22][CH2:23][C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([C:33](O)=[O:34])[CH:31]=2)[NH:26][CH:25]=1.O>CN(C)C=O>[O:11]=[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:21])[N:13]1[CH2:22][CH2:23][C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([C:33]([O:10][C:7]3[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)=[O:34])[CH:31]=2)[NH:26][CH:25]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: O=C(O)c1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)c1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1
Temperature: 80 °C
Reaction time: 24 h
Yield: 61.2 %

Procedure:
Polyphosphoric acid ethyl ester (40 ml) and 4-nitrophenol (6.3 g) were added to a solution of 3-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-1H-indole-5-carboxylic acid (15 g) in dimethylformamide (70 ml) and the mixture was stirred at 80° C. for 24 hours. More polyphosphoric acid ethyl ester (20 ml) was added and the mixture stirred at 80° C. for 3 hours. The mixture was cooled, poured into ice and water (900 ml) and stirred for 1 hour with ice cooling. The resulting solid was filtered off and washed with boiling ethanol (1500 ml) and hot water (600 ml) to give the title compound (12.5 g) as pale yellow crystals m.p. 248°-251° C. T.L.C. Silica, ethyl acetate:2-propanol:water:ammonia (25:15:8:2) Rf 0.9.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][CH2:19][NH:20][CH:21]3[CH2:26][CH2:25][N:24](CC4C=CC=CC=4)[CH2:23][CH2:22]3)[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].C(O)(=O)C.[H][H]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][CH2:19][NH:20][CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)c1oc2cccc(OCCCNC3CCN(Cc4ccccc4)CC3)c2c1C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)c1oc2cccc(OCCCNC3CCNCC3)c2c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(3-(1-benzyl-piperidin-4-ylamino)-propoxy)-3-methyl-benzofuran-2-carboxylic acid ethyl ester (the compound in Example 100, 100 mg) and acetic acid (2 ml) in ethyl acetate (6 ml) was added 10% Pd on charcoal catalyst (20 mg) under N2. The nitrogen atmosphere was replaced by hydrogen (1 atom) and the resulting mixture was stirred overnight at room temperature. The reaction mixture was filtered through a pad of celite and the pad of celite was rinsed with methanol and dichloromethane. The filtrate combined was concentrated in vacuo. The residue was purified by silica gel column chromatography (dichloromethane-MeOH) to give 3-methyl-4-[3-(piperidin-4-ylamino)-propoxy]-benzofuran-2-carboxylic acid ethyl ester (48 mg) as a colorless oil. FAB-MS: m/z 361 (MH+); 1H-NMR (CDCl3): δ 1.36 (2H, m), 1.43 (3H, t, J=7 Hz), 1.97 (2H, m), 2.07 (2H, quintet, J=6.5 Hz), 2.68 (3H, m), 2.74 (3H, s), 2.89 (2H, t, J=7 Hz), 3.17 (2H, br d, J=12.5 Hz), 4.16 (2H, t, J=6 Hz), 4.44 (2H, q, J=7 Hz), 6.62 (1H, d, J=8 Hz), 7.11 (1H, d, J=8 Hz), 7.30 (1H, t, J=8 Hz).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])[C:8]([C:17]([N:19]([CH2:45][CH:46]([CH3:48])[CH3:47])[C@H:20]2[CH2:25][C@@H:24]([C:26]([N:28]3[CH2:37][CH2:36][C:31]4([O:35][CH2:34][CH2:33][O:32]4)[CH2:30][CH2:29]3)=[O:27])[CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]2)=[O:18])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])[C:8]([C:17]([N:19]([C@H:20]2[CH2:25][C@@H:24]([C:26]([N:28]3[CH2:37][CH2:36][C:31]4([O:35][CH2:34][CH2:33][O:32]4)[CH2:30][CH2:29]3)=[O:27])[CH2:23][NH:22][CH2:21]2)[CH2:45][CH:46]([CH3:48])[CH3:47])=[O:18])=[CH:7][N:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: COCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)N2CCC3(CC2)OCCO3)CN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: COCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@@H]1CNC[C@H](C(=O)N2CCC3(CC2)OCCO3)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.3 %

Procedure:
tert-Butyl (3S,5R)-3-[({2-tert-butyl-4-[(3-methoxypropyl)amino]pyrimidin-5-yl}carbonyl)(2-methylpropyl)amino]-5-(1,4-dioxa-8-azaspiro[4.5]dec-8-ylcarbonyl)piperidine-1-carboxylate (72 mg) was dissolved in acetonitrile (8 ml), TFA (2 ml) was added and the mixture was stirred at room temperature for 3 hr. The reaction mixture was poured into 25% aqueous potassium carbonate solution at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to reversed-phase preparative HPLC, and fractions eluted with water-acetonitrile (9:1) to acetonitrile were collected. The mixture was basified (pH 10) with saturated aqueous potassium carbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the object compound (29 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:8][C:9]=1[CH:10]=[CH2:11])=[O:4].C12BC(CCC1)CCC2.[OH:28]O.[OH-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)=[CH:8][C:9]=1[CH2:10][CH2:11][OH:28])=[O:4]
Reactant: OO
Reactant: C=Cc1cc(-c2ccc(Cl)cc2)sc1C(=O)OC
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1CCO
Temperature: 0 °C
Reaction time: 16 h
Yield: 100.1 %

Procedure:
Dissolve 5-(4-chloro-phenyl)-3-vinyl-thiophene-2-carboxylic acid methyl ester (5.35 g, 19.19 mmol) in tetrahydrofuran (220 mL) and cool to 0° C. Slowly add 9-borabicyclo[3.3.1]nonane (112 mL, 0.5 M, 56 mmol), warm the reaction to room temperature with stirring for 16 h. Cool the mixture to 0° C. and slowly add hydrogen peroxide (74 mL, 721 mmol) followed by 5 N sodium hydroxide (74 mL, 370 mmol). Add water (14 mL) and extract with ethyl acetate (3×150 mL). Dry the solution over Na2SO4, filter and evaporate. Purify by chromatography eluting with 50% ethyl acetate/hexane to afford 5.70 g (100%) of the title compound. LC-MS/ES m/z (35Cl) 296.7.0 [M+H]+.