Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]1[OH:13].[C:20]1([CH:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:27][CH2:28][NH2:29])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C>[C:30]1([CH:26]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:27][CH2:28][NH:29][C:2]2[C:3]3[N:4]=[CH:5][N:6]([C:7]=3[N:8]=[CH:9][N:10]=2)[C@@H:11]2[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]2[OH:13])[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: NCCC(c1ccccc1)c1ccccc1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Solvent: CCO
Product: OC[C@H]1O[C@@H](n2cnc3c(NCCC(c4ccccc4)c4ccccc4)ncnc32)[C@H](O)[C@@H]1O
Temperature: 5 °C

Procedure:
A solution of 6-chloro-9-β-D-ribofuranosylpurine (2.87 g, 0.010 mol) and 3,3-diphenylpropylamine (5.28 g, 0.025 mol, 250 mol %) in absolute ethanol (75 ml) is heated at reflux for six days, during which time the starting material is mostly consumed according to TLC analysis (5/1 CHCl3 /MeOH). The solution is cooled to 5° C. and the resulting first and second crops of white crystals are combined to give N6 -(3,3-diphenylpropyl)adenosine, mp 103°-118° C. (from absolute ethanol).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]([CH3:17])=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[Cl:18])(=O)=O.[CH2:21]([Sn](CCCC)(CCCC)C=C)[CH2:22]CC.[Cl-].[Li+]>C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:18][C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[C:16]([CH3:17])[C:7]=1[CH:21]=[CH2:22]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1cc2ccccc2c(Cl)c1OS(=O)(=O)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Product: C=Cc1c(C)cc2ccccc2c1Cl
Temperature: 50 °C

Procedure:
To a solution of 1-chloro-3-methylnaphthalen-2-yl trifluoromethanesulfonate (4C) (14.75 g, 45.43 mmol), tributyl(vinyl)tin (14.59 mL, 49.97 mmol) and lithium chloride (5.78 g, 136.29 mmol) was added bis(triphenylphosphine)palladium(II) dichloride under Ar. The reaction mixture was heated at 50° C. for 20 h, then heated at 90° C. for 8 h. The reaction mixture was than cooled to room temperature, diluted with ethyl acetate, washed with 5% lithium chloride solution (3×), brine and dried (MgSO4), filtered and then concentrated and purified by flash column chromatography (silica gel, 0 to 10% ethyl acetate/hexanes) to give 4D contaminated by organotin. The residue was dissolved in dichloromethane and stirred with 10% KF solution overnight. The resulting white mixture was filtered through a pad of Celite and extracted with dichloromethane (2×). The organic layer was concentrated and purified by flash column chromatography (silica gel, 0 to 10% ethyl acetate/hexanes) to give 4D as a pale yellow oil (10.1 g).
Reaction SMILES: C[O:2][C:3](=[O:26])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9](=[O:25])[C@H:10]([CH:22]([CH3:24])[CH3:23])[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].[Li+].[OH-].Cl>C1COCC1>[C:12]([NH:11][C@H:10]([C:9]([N:5]1[CH2:6][CH2:7][CH2:8][C@H:4]1[C:3]([OH:26])=[O:2])=[O:25])[CH:22]([CH3:24])[CH3:23])([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13]
Reactant: COC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 8 h

Procedure:
To a solution of N-Cbz-valylproline methyl ester (Cbz-NH-[VP]-CO2CH3) (3.62 g, 10 mmol) in THF (10 mL) is added a 1M aqueous solution of LiOH (11 mL, 11 mmol) and the solution is stirred overnight. The resulting solution is acidified to pH about 7 with 1M HCl and the contents of the flask partitioned between water (20 mL) and ethyl acetate (20 mL). The organic phase is extracted with brine, dried over Na2SO4 then concentrated in vacuo to afford the desired compound.
Reaction SMILES: C[Si](C)(C)[NH:3][C:4]1[C:5](=[CH:10][CH:11]=[CH:12][C:13]=1[CH3:14])[C:6]([O:8][CH3:9])=[O:7].CC#N.Cl[S:21]([C:24]1[N:34]=[C:27]2[N:28]=[C:29]([CH3:33])[CH:30]=[C:31]([CH3:32])[N:26]2[N:25]=1)(=[O:23])=[O:22]>N1C=CC=CC=1>[CH3:9][O:8][C:6]([C:5]1[CH:10]=[CH:11][CH:12]=[C:13]([CH3:14])[C:4]=1[NH:3][S:21]([C:24]1[N:34]=[C:27]2[N:28]=[C:29]([CH3:33])[CH:30]=[C:31]([CH3:32])[N:26]2[N:25]=1)(=[O:22])=[O:23])=[O:7]
Reactant: Cc1cc(C)n2nc(S(=O)(=O)Cl)nc2n1
Reactant: COC(=O)c1cccc(C)c1N[Si](C)(C)C
Solvent: CC#N
Solvent: c1ccncc1
Product: COC(=O)c1cccc(C)c1NS(=O)(=O)c1nc2nc(C)cc(C)n2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
A solution consisting of 145.9 mg (0.615 mmole) of methyl N-trimethylsilyl-3-methylanthranilate, 1 ml of CH3CN, and 80.4 mg (0.326 mmole) of 2-chlorosulfonyl-5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine was stirred at room temperature and the reaction monitored by reverse phase HPLC. The reaction was about 30 percent complete after 4 hours. Pyridine, 29.1 μl (0.360 mmole), was added and the solution stirred for 10 min and again analyzed. Complete reaction had occurred. The solution was allowed to stand overnight. The CH3CN was removed under a nitrogen atmosphere and the residue treated with 2 ml of 1.0N HCl and 2 ml of CH2Cl2. The CH2Cl2 phase was transferred to a column containing 50 g of silica gel and chromatographed to obtain 112.5 mg of N-(2-methoxycarbonyl-6-methylphenyl)-5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine-2-sulfonamide (0.300 mmole, 92.0 percent yield) as a white crystalline solid, m.p. 181°-182° C. The solid was dissolved in CHCl3 and the solvent again removed in vacuo affording the product as a light yellow powder, m.p. 192°-194° C.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[C:16]([Cl:23])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([O:14][CH3:15])=[C:9]([CH:13]=1)[C:10](O)=[O:11].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[CH2:47]([NH2:56])[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55]>C(Cl)Cl>[Cl:1][C:2]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[C:16]([Cl:23])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([O:14][CH3:15])=[C:9]([CH:13]=1)[C:10]([NH:56][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])=[O:11]
Reactant: COc1ccc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)cc1C(=O)O
Reactant: CCCCCCCCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCCNC(=O)c1cc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)ccc1OC
Temperature: 25 °C
Yield: 85.2 %

Procedure:
To a suspension of 5-(2,6-dichloro-4-nitro-phenoxy)-2-methoxy-benzoic acid (150 mg, 0.42 mmol) in CH2Cl2 (2 ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (84 mg, 0.44 mmol) and 1-hydroxybenzotriazole hydrate (77 mg, 0.50 mmol) with stirring at RT. To the resulting yellow solution was added nonylamine (154 μl, 0.84 mmol) at RT. The resulting mixture was stirred 2 h at RT then solvent removed under a dry nitrogen stream. The residue was purified by preparative TLC (5% Et2O, 45% hexanes, 50% CH2Cl2) to give the title compound of Step C (173 mg). MS (APCl+) Calc.: 482.1. Found: 483.2 (M+1).
Reaction SMILES: Cl.[CH3:2][C:3]([NH2:12])([CH3:11])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[N+:13]([O-])([OH:15])=[O:14]>S(=O)(=O)(O)O>[CH3:11][C:3]([NH2:12])([CH3:2])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N+:13]([O-:15])=[O:14])=[CH:7][CH:6]=1
Reactant: O=[N+]([O-])O
Reactant: CC(C)(N)Cc1ccccc1
Agent: Cl
Agent: O=S(=O)(O)O
Product: CC(C)(N)Cc1ccc([N+](=O)[O-])cc1
Temperature: -10 °C

Procedure:
α,α-Dimethylphenethylamine hydrochloride (20 g, 108 mmol) was dissolved in concentrated sulfuric acid (40 mL). The solution was cooled to −10° C. Nitric acid (31 mL, 90%) was added dropwise over a 30 min period while maintaining a reaction tempurature below −5° C. The solution was stirred an addition 45 min then poured over ice and allowed to warm to room temperature over night. The product was collected via filtration (13.7 g). Aqueous sodium hydroxide(1 N) was added to the filtrate and the title compound was isolated as a clear oil.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH2:3][O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[C:7]#N.C(O)=[O:16]>[Ni]>[F:1][C:2]([F:14])([F:13])[CH2:3][O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[O:16]
Reactant: N#Cc1ccccc1OCC(F)(F)F
Reactant: O=CO
Agent: [Ni]
Product: O=Cc1ccccc1OCC(F)(F)F

Procedure:
Under a nitrogen atmosphere in a round-bottom flask equipped with a reflux condenser were placed 0.2 g (1 mmol) of 2-(2,2,2-trifluoroethoxy)benzonitrile (J. Org. Chem., 377 (1983)) and 5 mL of formic acid. To this solution was added ca. 0.2 g of Raney nickel, and the mixture was heated at reflux for 90 minutes. The mixture was filtered through diatomaceous earth, and the filter cake was rinsed with water and chloroform (CHCl3). The layers were separated, and the aqueous phase was extracted with three portions of chloroform. The combined organic fractions were washed with saturated aqueous sodium bicarbonate and water, dried over sodium sulfate (Na2SO4) and concentrated (rotary evaporator) to obtain 176 mg of the title compound as a yellow solid, m.p. 33°-34° C.
Reaction SMILES: [CH:1]([N:3]([CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14]CC2C=CC=CC=2)[CH:9]=1)[OH:4])=[O:2]>CO.[Pd]>[CH:1]([N:3]([CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[CH:9]=1)[OH:4])=[O:2]
Reactant: O=CN(O)CCOc1cccc(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CO
Product: O=CN(O)CCOc1cccc(O)c1

Procedure:
A heterogeneous solution of N-formyl-N-hydroxy-2-(3-benzyloxyphenoxy)ethylamine (300 mg) and Pd/C (100 mg) in methanol (7 mL) was stirred under an H2 balloon for 3 h. The reaction mixture was then filtered through Celite, washing with CH2Cl2. The filtrate was concentrated to a yellow oil which was purified by reverse-phase HPLC to provide N-formyl-N-hydroxy-2-(3-hydroxyphenoxy)ethylamine as a white solid.
Reaction SMILES: [C:1]1([C:7]2[C:16]([CH3:17])=[CH:15][C:14]3[C:9](=[C:10]([C@@H:18]([N:28]4[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]4[CH3:34])[CH2:19][O:20][Si](C(C)(C)C)(C)C)[CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1.O.C(=O)([O-])O.[Na+]>C(O)(=O)C.C(OCC)C>[C:1]1([C:7]2[C:16]([CH3:17])=[CH:15][C:14]3[C:9](=[C:10]([C@@H:18]([N:28]4[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]4[CH3:34])[CH2:19][OH:20])[CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cc2cccc([C@H](CO[Si](C)(C)C(C)(C)C)N3CCCC[C@H]3C)c2nc1-c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CC(=O)O
Product: Cc1cc2cccc([C@H](CO)N3CCCC[C@H]3C)c2nc1-c1ccccc1
Temperature: 70 °C
Yield: 79.3 %

Procedure:
A solution of 0.5 g (1.05 mmol) of 2-phenyl-3-methyl-8-(1-(R)-[2-(R)-methylpiperidino]-2-[tert-butyldimethylsilyloxy]ethyl)quinoline in a mixture of 15 ml of acetic acid, 5 ml of tetrahydrofuran and 5 ml of distilled water is heated at 70° C. for 40 hours and is then poured onto an ice-cold mixture of 150 ml of ethyl ether and of 150 ml of a saturated sodium hydrogencarbonate solution. The addition of sodium hydrogencarbonate is continued until a pH of approximately 9 is obtained. The mixture is then extracted with 3×200 ml of ethyl ether. The organic phases are combined, dried over magnesium sulfate, filtered and evaporated under vacuum. The residue is purified by silica gel chromatography (eluent: dichloromethane/methanol 9/1) to provide 0.3 g of (+)-2-phenyl-3-methyl-8-(1-(R)-[2-(R)-methylpiperidino]-2-hydroxyethyl)quinoline in the form of a colorless wax. (Yield: 75%)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([C:10]3[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH2:17][CH2:18][N:19]4[C:23]([CH3:25])([CH3:24])[C:22](=[O:26])[NH:21][C:20]4=[O:27])[N:11]=3)=[CH:7][C:6]=2[CH:28]=1.[CH:29](=O)[C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C.C(=O)(O)[O-].[Na+]>[CH3:24][C:23]1([CH3:25])[N:19]([CH2:18][CH2:17][NH:16][C:12]2[N:11]=[C:10]([C:8]3[S:9][C:5]4[CH:4]=[CH:3][C:2]([NH:1][CH2:29][C:30]5[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=5)=[CH:28][C:6]=4[CH:7]=3)[CH:15]=[CH:14][N:13]=2)[C:20](=[O:27])[NH:21][C:22]1=[O:26]
Reactant: CC1(C)C(=O)NC(=O)N1CCNc1nccc(-c2cc3cc(N)ccc3s2)n1
Reactant: O=Cc1ccncc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC1(C)C(=O)NC(=O)N1CCNc1nccc(-c2cc3cc(NCc4ccncc4)ccc3s2)n1
Temperature: 60 °C
Yield: 27.1 %

Procedure:
1-(2-(4-(5-aminobenzothiophen-2-yl)pyrimidin-2-ylamino)ethyl)-5,5-dimethyl imidazo-lidin-2,4-dione (300 mg, 0.758 mmol) was suspended in dichloromethane (10 mL). Isonicotinaldehyde (97.4 mg, 0.910 mmol), acetic acid (4-5 drops), and sodium triacetoxy-borohydride (321 mg, 1.516 mmol) were added, and the mixture was heated to 60° C. for 16 h. The reaction was cooled to room temperature, diluted with a saturated aqueous solution of sodium bicarbonate (15 mL), and extracted with dichloromethane (4×15 mL). The organic layers were combined and then washed in turn with a saturated aqueous solution of sodium bicarbonate (10 mL), deionized water (15 mL), and a saturated aqueous solution of sodium chloride (15 mL). The organic layer was separated, dried over sodium sulfate (200 mg), filtered through a coarse frit (to remove the sodium sulfate), and concentrated in vacuo to give a white solid (100 mg). The crude material was purified by flash chromatography (MeOH/DCM) to yield the title compound as a white powder (20 mg). MS (M+H)+ 488.
Reaction SMILES: [CH3:1][CH:2]([CH:5]([CH3:11])[CH2:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:3]=O.[CH:12](=[O:15])[CH2:13][CH3:14]>>[CH3:14][CH:13]([CH2:3][CH:2]([CH3:1])[CH:5]([CH3:11])[CH2:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:12]=[O:15]
Reactant: CC(C=O)C(C)CC(C)(C)C
Reactant: CCC=O
Product: CC(C=O)CC(C)C(C)CC(C)(C)C

Procedure:
2,4,5,7,7-Pentamethyloctanal was prepared from 2,3,5,5-tetramethylhexanal (aldehyde of TMH from Dragoco, Holzminden) and propionaldehyde similarly to Examples 1 and 2; the compound was obtained in the form of a diastereomeric mixture.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([CH:11]2[C:19]3[C:14](=[C:15]([F:20])[CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]2=[O:21])[N:4]=1.[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)=O>O>[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([O:21][C:12]2[NH:13][C:14]3[C:19]([C:11]=2[C:5]2[N:4]=[C:3]([O:2][CH3:1])[N:8]=[C:7]([O:9][CH3:10])[N:6]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: COc1nc(OC)nc(C2C(=O)Nc3c(F)cccc32)n1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COc1nc(OC)nc(-c2c(OS(=O)(=O)c3ccc(C)cc3)[nH]c3c(F)cccc23)n1
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 23.3 %

Procedure:
3-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-7-fluoro-1,3-dihydro-2H-indol-2-one (1.15 g), 4-methylbenzenesulfonyl chloride (1.06 g) and sodium carbonate (0.41 g) are introduced as initial charge in 5.5 ml of water and 11 ml of acetone and, with stirring, heated to 80° C. in a preheated oil bath. After 45 minutes, the hot solution is filtered, and the solid is washed with 20 ml of water/acetone (1:1) and methanol and dried in vacuo. This gives 0.76 g of product in an HPLC purity of 97% (42% of theory). Structure elucidation by NMR verifies that it is the O-sulfonylated product. A further 0.41 g of product in an HPLC purity of 89% can be isolated from the filtrate (21% of theory).
Reaction SMILES: [C:1]([Si:5]([CH3:22])([CH3:21])[O:6][C@@H:7]([CH2:14]/[CH:15]=[C:16](/[CH3:20])\[CH2:17][CH:18]=[CH2:19])[C:8](N(OC)C)=[O:9])([CH3:4])([CH3:3])[CH3:2].[CH3:23][Mg]Cl>C1COCC1>[C:1]([Si:5]([CH3:22])([CH3:21])[O:6][C@@H:7]([CH2:14]/[CH:15]=[C:16](/[CH3:20])\[CH2:17][CH:18]=[CH2:19])[C:8](=[O:9])[CH3:23])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC/C(C)=C\C[C@H](O[Si](C)(C)C(C)(C)C)C(=O)N(C)OC
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: C=CC/C(C)=C\C[C@H](O[Si](C)(C)C(C)(C)C)C(C)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.2 %

Procedure:
To a THF (300 mL) solution of the starting material 5 (152.6 g, 465 mmol) was slowly added methylmagnesium chloride (200 mL, 3.0 M in THF, 600 mmol) in 30 min at 0° C. The reaction was stirred over 30 min at 0° C., and was carefully quenched with saturated ammonium chloride water solution (300 mL). Its pH was then adjusted to 7 with 1N hydrochloric acid. Volatiles were removed via a rotavap. The residue was extracted with diethyl ether (1 L). Ethereal extracts were washed with water and brine, dried over magnesium sulfate. Flash chromatography on silica gel (0-3% ethyl acetate in hexanes) afforded the desired product 6 as pale yellow oil (125 g, 95%).
Reaction SMILES: [C:1]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:27]=[CH:26][C:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:24][C:20]=3[C:21](O)=[O:22])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.Cl.[NH2:40][C@@H:41]1[CH2:45][CH2:44][C@H:43]([C:46]([O:48][CH3:49])=[O:47])[CH2:42]1>>[C:1]1([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:2]=[CH:3][C:4]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:27]=[CH:26][C:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:24][C:20]=3[C:21]([NH:40][C@@H:41]3[CH2:45][CH2:44][C@H:43]([C:46]([O:48][CH3:49])=[O:47])[CH2:42]3)=[O:22])=[CH:13][CH:14]=2)=[CH:5][CH:6]=1
Reactant: COC(=O)[C@H]1CC[C@@H](N)C1
Reactant: CCOC(=O)c1ccc(OCCCc2ccc(OCc3ccc(-c4ccccc4)cc3)cc2)c(C(=O)O)c1
Agent: Cl
Product: CCOC(=O)c1ccc(OCCCc2ccc(OCc3ccc(-c4ccccc4)cc3)cc2)c(C(=O)N[C@@H]2CC[C@H](C(=O)OC)C2)c1

Procedure:
Preparation takes place in analogy to Example 5 from 2-{3-[4-(1,1′-biphenyl-4-yl-methoxy)phenyl]propoxy}-5-(ethoxycarbonyl)benzoic acid and methyl (1S,3R)-3-aminocyclopentanecarboxylate hydrochloride.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][Cl:7].C(=O)([O-])[O-].[Cs+].[Cs+].[OH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1/[CH:21]=[CH:22]/[CH:23]([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]([O:45][CH3:46])=[O:44])=[CH:39][CH:38]=1)[CH2:24][CH2:25][C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=1>C1(C)C=CC=CC=1>[Cl:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1/[CH:21]=[CH:22]/[CH:23]([CH2:36][C:37]1[CH:38]=[CH:39][C:40]([C:43]([O:45][CH3:46])=[O:44])=[CH:41][CH:42]=1)[CH2:24][CH2:25][C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=1
Reactant: ClCCCCCBr
Reactant: COC(=O)c1ccc(CCC(/C=C/c2ccccc2O)Cc2ccc(C(=O)OC)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCCCCCCl)Cc2ccc(C(=O)OC)cc2)cc1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
1.84 g (9.9 mmol) of 1-bromo-5-chloropentane [CAS Reg. No. 586-78-7] and 6.45 g (19.8 mmol) of anhydrous cesium carbonate are added to a solution of 1.1 g (2.47 mmol) of methyl 4-{(4E)-5-(2-hydroxyphenyl)-3-[4-(methoxycarbonyl)benzyl]pent-4-en-1-yl}benzoate (racemate; Example 18A) in 16.5 ml of dry toluene, and the mixture is then stirred at 60° C. for 18 h. The mixture is then filtered, and the filtrate is evaporated to dryness. The crude product obtained is taken up in ethyl acetate and washed twice with saturated sodium bicarbonate solution, and the organic phase is dried over sodium sulfate and concentrated. The crude product is then purified by flash chromatography on silica gel (mobile phase: dichloromethane). This gives 1.00 g (1.82 mmol, 73.6% of theory) of a colorless oil.
Reaction SMILES: [CH3:1][CH:2]([CH3:34])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22](=O)[C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].Cl.[CH3:36][C:37]1[CH:42]=[CH:41][C:40]([NH:43]N)=[CH:39][CH:38]=1>>[CH3:1][CH:2]([CH3:34])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21]3[C:41]4[C:40](=[CH:39][CH:38]=[C:37]([CH3:36])[CH:42]=4)[NH:43][C:22]=3[C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4]
Reactant: Cc1ccc(NN)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(C(F)(F)F)cc3)CC2)c1
Agent: Cl
Product: Cc1ccc2[nH]c(-c3ccc(C(F)(F)F)cc3)c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c2c1

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-[3-(1-{5-oxo-5-[4-(trifluoromethyl)phenyl]pentyl}-4-piperidinyl)phenyl]propanamide and 4-methylphenylhydrazine hydrochloride: ESMS m/e: 562.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:26])[C:11]2[CH:16]=[C:15]([N+:17]([O-])=O)[C:14]([NH:20][CH3:21])=[CH:13][C:12]=2[O:22][CH2:23][CH2:24][F:25])[CH:5]=[CH:6][C:7]=1[F:8].C1COCC1.[Cl:32][C:33]1[C:46]([N:47]=[C:48]=S)=[C:45]([Cl:50])[CH:44]=[CH:43][C:34]=1[CH2:35][NH:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39].CC(C)N=C=NC(C)C>CC#N.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:11]2[C:12]([O:22][CH2:23][CH2:24][F:25])=[CH:13][C:14]3[N:20]([CH3:21])[C:48]([NH:47][C:46]4[C:45]([Cl:50])=[CH:44][CH:43]=[C:34]([CH2:35][NH:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])[C:33]=4[Cl:32])=[N:17][C:15]=3[CH:16]=2)=[O:26])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1Cl
Reactant: CNc1cc(OCCF)c(C(=O)Nc2ccc(F)c(Cl)c2)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: CC(C)N=C=NC(C)C
Solvent: CC#N
Solvent: C1CCOC1
Product: Cn1c(Nc2c(Cl)ccc(CNC(=O)C(C)(C)C)c2Cl)nc2cc(C(=O)Nc3ccc(F)c(Cl)c3)c(OCCF)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N-(3-chloro-4-fluorophenyl)-2-(2-fluoroethoxy)-4-methylamino-5-nitro-benzamide (67.9 mg, 0.176 mmol), Pd/C (15 mg) and 10 mL THF is stirred under a H2-atmosphere (3 bar) for 8 h. The crude mixture is filtered into a flask charged with N-(2,4-dichloro-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamide (59 mg, 0.185 mmol) and concentrated to ˜5 mL. The mixture is stirred for 2 h at rt and concentrated i. vac. The mixture is diluted with MeCN (2.0 mL), DIC (29 μl, 0.186 mmol) is added and it is stirred overnight at rt and 2 h at 60° C. The mixture is cooled to rt and the resulting precipitate is filtered off, washed with MeCN, redissolved in dioxane/MeCN and a few drops of HCOOH and lyophilized.
Reaction SMILES: FC1C=CC(C(C)CC(Cl)=O)=CC=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([CH2:26][CH2:27][CH3:28])[CH2:22][C:23](Cl)=[O:24])=[CH:17][CH:16]=1>>[F:14][C:15]1[CH:20]=[C:19]2[C:18]([CH:21]([CH2:26][CH2:27][CH3:28])[CH2:22][C:23]2=[O:24])=[CH:17][CH:16]=1
Reactant: CCCC(CC(=O)Cl)c1ccc(F)cc1
Agent: CC(CC(=O)Cl)c1ccc(F)cc1
Product: CCCC1CC(=O)c2cc(F)ccc21
Yield: 98.5 %

Procedure:
This compound was prepared in an analogous manner to Example 18e with the replace of 3-(4-fluorophenyl)butyryl chloride with 3-(4-fluorophenyl) hexanoyl chloride (49.95 g, 0.218 mol). The dichloromethane extractions were combined, washed with deionized water (250 ml) and concentrated by spin evaporation in vacuo. The residue was coevaporated with dichloromethane (100 ml) to give 41.26 g (98%) of 6-fluoro-3-propyl-1-indanone as a golden yellow syrup: