Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[N:5][CH:6]=[C:7]3[CH2:12][CH2:11][C:10](=[CH:13][C:14]#[N:15])[C:8]3=2)[O:3][CH2:2]1.N.C(O)C>CO.[Co]>[CH2:1]1[C:9]2[C:4](=[N:5][CH:6]=[C:7]3[CH2:12][CH2:11][C:10](=[CH:13][CH2:14][NH2:15])[C:8]3=2)[O:3][CH2:2]1
Reactant: N#CC=C1CCc2cnc3c(c21)CCO3
Agent: [Co]
Agent: N
Solvent: CCO
Solvent: CO
Product: NCC=C1CCc2cnc3c(c21)CCO3
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 1,2,6,7-tetrahydro-8H-cyclopenta[d]furo[2,3-b]pyridine-8-ylideneacetonitrile (84.9 mg, 0.428 mmol) in methanol (3 mL) were added Raney cobalt (400 mg) and 2M ammonia/ethanol solution (1.5 mL), and the mixture was stirred at room temperature for 4 hr under a hydrogen atmosphere. The catalyst was filtered through celite, and the filtrate was concentrated under reduced pressure to give the title compound. The obtained title compound was used for the reaction in Example 19 without purification.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:10]([CH3:11])=[C:9]([CH:12]=O)[NH:8][C:7]=1[CH3:14])([OH:3])=[O:2].[CH3:15][O:16][C:17]1[CH:25]=[C:24]2[C:20]([CH2:21][C:22](=[O:26])[NH:23]2)=[CH:19][CH:18]=1>N1CCCCC1.C(O)C>[CH3:15][O:16][C:17]1[CH:25]=[C:24]2[C:20]([C:21](=[CH:12][C:9]3[NH:8][C:7]([CH3:14])=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:10]=3[CH3:11])[C:22](=[O:26])[NH:23]2)=[CH:19][CH:18]=1
Reactant: COc1ccc2c(c1)NC(=O)C2
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)O
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1ccc2c(c1)NC(=O)C2=Cc1[nH]c(C)c(CCC(=O)O)c1C
Yield: 76.5 %

Procedure:
3-(2-carboxyethyl)-2,4-dimethyl-5-formylpyrrole (97.5 mg), 82 mg 6-methoxy-2-oxindole and 2 drops piperidine in 2 mL of ethanol were heated at 95° C. for overnight. The reaction mixture was cooled and concentrated. The residue was suspended in 2 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven overnight to give 130 mg (76%) of the title compound as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[NH:13][C:12](=[O:14])[NH:11][C:10]([CH3:15])=[C:9]2[C:16]#[N:17])[CH:5]=[CH:6][CH:7]=1.[N:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:16]([C:9]1[CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:21]3[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=3)[CH:3]=2)[NH:13][C:12](=[O:14])[NH:11][C:10]=1[CH3:15])#[N:17]
Reactant: OB(O)c1ccncc1
Reactant: CC1=C(C#N)C(c2cccc(Br)c2)NC(=O)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1=C(C#N)C(c2cccc(-c3ccncc3)c2)NC(=O)N1
Temperature: 95 °C
Reaction time: 0.17 h

Procedure:
A mixture of 6-(3-bromophenyl)-5-cyano-3,6-dihydro-4-methyl-2-oxo-(2H)-pyrimidine (1.62 g, 5.5 mmol), pyridine-4-boronic acid (0.75 g, 6.1 mmol), potassium carbonate (2.28 g, 16.5 mmol) and DMF (10 mL) was flushed with nitrogen gas several times before [1,1′-bis(diphenylphsophino)ferrocene]dichloropalladium (50 mg) was introduced. The reaction mixture was heated at 95° C. under nitrogen for 64 h, cooled to room temperature and filtered through Celite. The filtrate was diluted with MeOH and stirred with AG 50W-X2 Resin for 10 min. The resin was collected by vacuum filtration, washed with MeOH and then eluted with 2 M NH3 in MeOH. This NH3-MeOH solution was concentrated in vacuo to give 5-cyano-3,6-dihydro-4-methyl-2-oxo-6-(3-(4-pyridyl)phenyl)-(2H)-pyrimidine as a brown solid (1.6 1 g; 32%): 1H NMR (DMSO-d6, 400 MHz) δ 9.58 (s, 1H), 8.66 (d, 2H, J=2.2 Hz), 7.88 (s, 1H), 7.77 (d, 1H, J=7.9 Hz), 7.69 (m, 3H), 7.57 (m, 1H), 7.41 (d, 1H, J=7.9 Hz), 5.22 (s, 1H), 2.03 (d, 3H, J=2.2 Hz).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([C:7](Cl)=[O:8])=[CH:3][CH:2]=1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:28]=[CH:29][C:30]=1[Cl:31])[CH2:15][N:16]1[CH2:21][CH2:20][N:19]([CH2:22][C@@H:23]([NH2:27])[CH:24]([CH3:26])[CH3:25])[CH2:18][CH2:17]1.C(N(CC)CC)C>C(Cl)Cl>[Cl:11][C:12]1[CH:13]=[C:14]([CH:28]=[CH:29][C:30]=1[Cl:31])[CH2:15][N:16]1[CH2:21][CH2:20][N:19]([CH2:22][C@@H:23]([NH:27][C:7](=[O:8])[C:4]2[CH:5]=[CH:6][C:1]([CH3:10])=[CH:2][CH:3]=2)[CH:24]([CH3:26])[CH3:25])[CH2:18][CH2:17]1
Reactant: CC(C)[C@H](N)CN1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C(=O)N[C@H](CN2CCN(Cc3ccc(Cl)c(Cl)c3)CC2)C(C)C)cc1
Reaction time: 1 h
Yield: 89.2 %

Procedure:
p-Toluoyl chloride (0.48 ml, 3.63 mmol) was added to a solution of 1(S)-[4-(3,4-dichlorobenzyl)piperazin-1-ylmethyl]-2-methylpropylamine (1 g, 3.0 mmol) and triethylamine (0.633 ml, 4.54 mmol) in methylene chloride under nitrogen atmosphere. After 1 h, the product was extracted into ethyl acetate and the organic layer was washed with sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated in vacuo. Column chromatography with hexanes/ethyl acetate (1:2) gave N-{1(S)-[4-(3,4-dichlorobenzyl)-piperazin-1-ylmethyl]-2-methylpropyl}-4-methylbenzamide (1.2 g) as an oil. The free amine was dissolved in ether and 3.5 equivalents of 1N ethereal HCl solution (10.7 ml) was added. Filtration of the resulting solid provided N-{1(S)-[4-(3,4-dichlorobenzyl)piperazin-1-ylmethyl]-2-methylpropyl}-4-methylbenzamide (1.2 g) as the bis hydrochloride salt, mp 227.8-228.9° C.
Reaction SMILES: [Cl:1][C:2]1[C@@H:6]([OH:7])[C:5]([Cl:9])([Cl:8])[C@:4]([OH:13])(C(O)=O)[CH:3]=1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].O>C(O)(=O)C>[Cl:1][C:2]1[C@@H:6]([OH:7])[C:5]([Cl:9])([Cl:8])[C:4](=[O:13])[CH:3]=1
Reactant: O=C(O)[C@]1(O)C=C(Cl)[C@@H](O)C1(Cl)Cl
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: CC(=O)O
Solvent: O
Product: O=C1C=C(Cl)[C@@H](O)C1(Cl)Cl
Reaction time: 0.08 h
Yield: 99.3 %

Procedure:
The (1R,4R)-acid (4) (200 mg, 0.8 mmol) was added portionwise over 10 min to lead tetraacetate (500 mg, 1.13 mmol) in acetic acid (5 ml) containing water (0.05 ml) at 80°. After a further 5 min, water (25 ml) was added and the cooled mixture extracted with ether (3×25 ml). The combined ether solutions were extracted with 5% aqueous sodium bicarbonate until the washings were alkaline (pH 7.5-8), then washed with water (10 ml), dried (MgSO4), and evaporated under reduced pressure. Short path distillation (bath temp. 60°/0.1 mmHg) gave the (4R)-enone (6) (160 mg, 98%) as a colourless oil, [α]35725 +1547° (c 5.66×10-2, EtOH), [α]25225 -11,280° (c 2.26×10-3, EtOH), [θ]33325 +8407° (c 5.66×10-2, EtOH), [θ]24025 -45,025° (c 2.26×10-3, EtOH) (Found: C, 29.8; H, 1.65; Cl, 51.3; C5H3Cl3O2 requires C, 29.8; H, 1.5; Cl, 52.8%).
Reaction SMILES: [CH3:1][N:2]1[CH2:8][C:6](=O)[NH:5][C:3]1=[O:4].[C:9](#[N:12])[CH:10]=[CH2:11].[OH-:13].[Na+]>Cl>[CH3:1][N:2]1[C:8](=[O:13])[CH2:6][N:5]([CH2:11][CH2:10][C:9]#[N:12])[C:3]1=[O:4]
Reactant: [OH-]
Reactant: C=CC#N
Reactant: CN1CC(=O)NC1=O
Agent: Cl
Agent: [Na+]
Product: CN1C(=O)CN(CCC#N)C1=O
Reaction time: 0.8 h
Yield: 74.3 %

Procedure:
87.0 g (0.762 mol) of 1-methylhydantoin and 48.55 g (0.915 mol) of acrylonitrile are introduced into an apparatus at an internal temperature of 67° C., and 8 ml of 1 molar sodium hydroxide solution are added dropwise over the course of 12 minutes, during which an exothermic reaction occurs and the temperature rises to 75° C. The reaction mixture is then stirred for 1 hour and 48 minutes at 75° C.-103° C. and then neutralized with 0.92 g of 32% hydrochloric acid. The reaction product is purified by vacuum distillation, giving 94.7 g (74.3% of theory) of crystalline 3-(3-methyl-2,4-dioxoimidazolidin-1-yl)propionitrile, whose melting point is 53° C.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:19][CH2:20]OC)[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1)=[O:5])C.[CH:23]1([C:26]2[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=2)[CH2:25][CH2:24]1.[Cl-].C[Al+]C.Cl>C1(C)C=CC=CC=1>[CH:23]1([C:26]2[CH:32]=[CH:31][C:29]([N:30]3[CH2:20][CH2:19][C:6]4([CH2:7][CH2:8][NH:9][CH2:10][CH2:11]4)[C:4]3=[O:5])=[CH:28][CH:27]=2)[CH2:25][CH2:24]1
Reactant: Nc1ccc(C2CC2)cc1
Reactant: CCOC(=O)C1(CCOC)CCN(C(=O)OC(C)(C)C)CC1
Agent: C[Al+]C
Agent: Cl
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: O=C1N(c2ccc(C3CC3)cc2)CCC12CCNCC2
Temperature: 115 °C
Reaction time: 15 h

Procedure:
A mixture of 1.3 g (4.1 mmol) 4-(2-Methoxy-ethyl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester, 0.604 g (4.5 mmol) 4-cyclopropylaniline and 8.24 mL (8.24 mmol) dimethylaluminum chloride (1N in hexane) in 100 mL toluene was stirred at 115° C. for 15 h. After cooling to room temperature the mixture was poured into ice, the mixture was acidified with HCl aq. to pH=2 and extracted with ethyl acetate. The aqueous layer was basified with NaOH pellets to pH=8 and extracted with DCM. The combined organic layers were dried with MgSO4 and evaporated to dryness. The residue was purified by column chromatography on silica (amine) with a gradient formed from ethyl acetate and methanol to yield after evaporation of the product containing fractions 0.468 g (42%) of the title compound as light yellow solid. MS m/e: 270.0 [M+H]+.
Reaction SMILES: C([Li])CCC.Br[C:7]1[N:14]=[CH:13][CH:12]=[CH:11][C:8]=1[C:9]#[N:10].[Br:15][C:16]1[CH:17]=[C:18]2[C:29](=[CH:30][CH:31]=1)[O:28][C:21]1[C:22]([F:27])=[N:23][C:24]([Cl:26])=[CH:25][C:20]=1[C:19]2=[N:32]S(C(C)(C)C)=O.[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[Br:15][C:16]1[CH:17]=[C:18]2[C:19]3([C:7]4=[N:14][CH:13]=[CH:12][CH:11]=[C:8]4[C:9]([NH2:10])=[N:32]3)[C:20]3[CH:25]=[C:24]([Cl:26])[N:23]=[C:22]([F:27])[C:21]=3[O:28][C:29]2=[CH:30][CH:31]=1
Reactant: N#Cc1cccnc1Br
Reactant: CC(C)(C)S(=O)N=c1c2cc(Br)ccc2oc2c(F)nc(Cl)cc12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NC1=NC2(c3cc(Br)ccc3Oc3c2cc(Cl)nc3F)c2ncccc21
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
A solution of n-butyllithium (102 μL, 0.164 mmol, Aldrich) was added dropwise to a solution of 2-bromonicotinonitrile (30 mg, 0.164 mmol, Aldrich) in THF (2 mL) at −95° C. under N2 atmosphere. After 1 min a solution of N-(7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-ylidene)-2-methylpropane-2-sulfinamide (55 mg, 0.127 mmol, example 1b) in THF (1 mL) was added. After 2 min aqueous, saturated NH4Cl solution was added and the reaction mixture was allowed to warm to RT. EtOAc was added and the organic phase was separated. The organic phase was dried over MgSO4 and the solvent was removed under reduced pressure. The remaining residue was purified by reversed-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C18, 110 Å, 100×50 mm, 0.1% TFA in CH3CN/H2O, gradient 10% to 100% over 20 min to obtain the title compound as a light-yellow solid. MS m/z=432.8 [M+H]+. Calculated for C18H9BrClFN4O: 431.65
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)=[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[S:6][C:7]=1S(C)(=O)=O)#[N:2].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>C1COCC1>[C:1]([C:3]1[C:4]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)=[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[S:6][C:7]=1[N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)#[N:2]
Reactant: CCOC(=O)c1sc(S(C)(=O)=O)c(C#N)c1-c1ccc(Cl)c(Cl)c1
Reactant: C1COCCN1
Solvent: C1CCOC1
Product: CCOC(=O)c1sc(N2CCOCC2)c(C#N)c1-c1ccc(Cl)c(Cl)c1
Yield: 63.3 %

Procedure:
A solution of ethyl 4-cyano-3-(3,4-dichlorophenyl)-5-(methylsulfonyl)thiophene-2-carboxylate (1.77 g, 4.38 mmol) and morpholine (1.91 mL, 21.9 mmol) in THF (40 mL) was stirred at rt under an atmosphere of argon for 3 days. A precipitate had formed and was filtered to give ethyl 4-cyano-3-(3,4-dichlorophenyl)-5-morpholin-4-ylthiophene-2-carboxylate (1.14 g, 63%). 1H NMR (400 MHz, d6-DMSO) δ: 7.67-7.74 (m, 2H), 7.37 (dd, 1H), 4.06 (q, 2H), 3.74-3.78 (m, 4H), 3.59-3.63 (m, 4H) and 1.06 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:28][Si:29]([C:32]#[CH:33])([CH3:31])[CH3:30]>C1COCC1.C(N(CC)CC)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]([C:33]#[C:32][Si:29]([CH3:31])([CH3:30])[CH3:28])[CH:5]=[CH:4][N:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: Clc1cc(I)ccn1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Chloro-4-iodo-pyridine (10.0 g, 41.8 mmol) was dissolved in 200 mL dry THF and 17.5 mL triethyl amine. This mixture was evacuated and backfilled with argon several times to remove oxygen from the solution. Triphenylphosphine (329 mg, 1.25 mmol) and bis(triphenylphosphine)palladium(II)chloride (1.47 g, 2.09 mmol) were added and the reaction mixture was stirred at room temperature for 1 h. Copper(I)iodide (239 mg, 1.25 mmol) and trimethylsilylacetylen (6.28 g, 6.39 mmol) were added. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated. The residue was taken up in 500 mL water and extracted three times with ethyl acetate (500 mL each). The combined organic extracts were dried with magnesium sulfate, filtered and evaporated. The crude product was purified by chromatography on silica gel (cyclohexane/ethyl acetate 80:20). The desired product was obtained as a light brown semi solid (10 g, >100%). This material was used without any further purification for the next step.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:10]=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.N1C=CC=CC=1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>ClCCl.C(OCC)(=O)C>[C:18]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:10]=[O:11])[CH:8]=2)[CH:3]=[CH:2]1)(=[O:20])[CH3:19]
Reactant: O=Cc1ccc2cc[nH]c2c1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)n1ccc2ccc(C=O)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.9 %

Procedure:
To a solution of 1H-indole-6-carboxaldehyde (300 mg, 2.07 mmol) in 6.2 mL of dry dichloromethane were added pyridine (0.34 mL, 4.2 mmol), acetic anhydride (1.77 mL, 18.7 mmol), and N,N-dimethylaminopyridine (60 mg, 0.49 mmol) at room temperature, successively. After being stirred at room temperature overnight, the reaction mixture was diluted with ethyl acetate. The solution was washed with 1N HCl, saturated NaHCO3 aqueous solution, brine, dried over MgSO4, filtered, and concentrated in vacuo. The resulting solid was rinsed with diethyl ether/hexane to obtain the title compound as a pale orange powder (267 mg, 69%).
Reaction SMILES: [C:1]([O:5][CH:6]1[CH2:11][CH2:10][CH:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:8][CH2:7]1)(=[O:4])[CH:2]=[CH2:3].C1CC=CC=1.[C:22]1([CH3:28])[CH:27]=CC=[CH:24][CH:23]=1>>[CH:3]12[CH2:28][CH:22]([CH:23]=[CH:24]1)[CH2:27][CH:2]2[C:1]([O:5][CH:6]1[CH2:11][CH2:10][CH:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:8][CH2:7]1)=[O:4]
Reactant: Cc1ccccc1
Reactant: C=CC(=O)OC1CCC(NS(C)(=O)=O)CC1
Agent: C1=CCC=C1
Product: CS(=O)(=O)NC1CCC(OC(=O)C2CC3C=CC2C3)CC1
Temperature: 40 °C
Reaction time: 24 h
Yield: 96.7 %

Procedure:
To a mixture of 26.1 g of 4-[(methylsulfonyl)amino]-cyclohexyl acrylate (synthesized by the procedure of Example 4) and 50 g of toluene was added 8.0 g of cyclopentadiene. The mixture was stirred at 40° C. for 24 hours. The reaction solution was purified directly by silica gel column chromatography, obtaining 32.0 g of 4-[(methylsulfonyl)-amino]cyclohexyl 5-norbornene-2-carboxylate (yield 98%).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[O:6][CH:5]([CH2:7][CH2:8][CH2:9][CH2:10]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:4][O:3]1.CN(C)C=O.[Br-:28].[Li+]>O>[Br:28][CH2:10][CH2:9][CH2:8][CH2:7][CH:5]1[CH2:4][O:3][C:2]([CH3:22])([CH3:1])[O:6]1
Reactant: Cc1ccc(S(=O)(=O)OCCCCC2COC(C)(C)O2)cc1
Reactant: [Br-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OCC(CCCCBr)O1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a stirred solution of 220 g. of 2,2-dimethyl-4-(4-p-toluenesulfonyloxybutyl)-1,3-dioxolane in 800 ml. of dimethylformamide at 0° C. is added 115 g. of anhydrous lithium bromide in portions during 5 minutes. The resulting mixture is stirred at ambient temperature for 22 hours, diluted with water, and extracted with ether. The extract is washed with sodium bicarbonate solution, water, and brine; dried over magnesium sulfate; and concentrated. The residue is distilled to give a colorless liquid, b.p. 71°-74° C. (0.2 mm.).
Reaction SMILES: CC(C[AlH]CC(C)C)C.CO[C:12](=O)[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=1.[NH2:34][CH2:35][CH2:36][NH:37][S:38]([C:41]1[C:42]2[CH:43]=[CH:44][N:45]=[CH:46][C:47]=2[CH:48]=[CH:49][CH:50]=1)(=[O:40])=[O:39]>>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][CH2:12][NH:34][CH2:35][CH2:36][NH:37][S:38]([C:41]2[C:42]3[CH:43]=[CH:44][N:45]=[CH:46][C:47]=3[CH:48]=[CH:49][CH:50]=2)(=[O:40])=[O:39])=[C:16]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[CH:17]=1
Reactant: COC(=O)COc1ccc(Cl)cc1Cc1cccc(C(F)(F)F)c1
Reactant: NCCNS(=O)(=O)c1cccc2cnccc12
Agent: CC(C)C[AlH]CC(C)C
Product: O=S(=O)(NCCNCCOc1ccc(Cl)cc1Cc1cccc(C(F)(F)F)c1)c1cccc2cnccc12

Procedure:
By following a similar procedure as described in Example 1, DIBAL-H reduction of [4-chloro-2-(3-trifluoromethyl-benzyl)-phenyloxy]-acetic acid methyl ester, and subsequent reductive amination with isoquinoline-5-sulfonic acid (2-amino-ethyl)-amide gives the free amine of the title compound as a clear gum. ESIMS: m/z 564 [(M+H)+, 35Cl], 566 [(M+H)+, 37Cl].
Reaction SMILES: [CH2:1]([N:3]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22])[C:4](=[O:14])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].Br[CH2:24][C:25]1[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=1[C:27]([O:29][CH3:30])=[O:28].C(=O)([O-])[O-].[K+].[K+].C(O)C(N)(CO)CO>C(#N)C>[CH2:1]([N:3]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22])[C:4](=[O:14])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:24][C:25]2[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([O:29][CH3:30])=[O:28])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCN(Cc1ccccc1F)C(=O)CCc1ccc(O)cc1
Reactant: COC(=O)c1ccccc1CBr
Agent: NC(CO)(CO)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN(Cc1ccccc1F)C(=O)CCc1ccc(OCc2ccccc2C(=O)OC)cc1
Temperature: 65 °C
Reaction time: 3 h
Yield: 76.1 %

Procedure:
N-Ethyl-N-(2-fluorobenzyl)-3-(4-hydroxyphenyl)propanamide (0.400 g, 1.327 mmol) and methyl 2-(bromomethyl)benzoate (0.334 g, 1.460 mmol) were dissolved in acetonitrile (10 ml) and potassium carbonate (0.367 g, 2.654 mmol) was added. The mixture was stirred at 65° C. for three hours. When N-ethyl-N-(2-fluorobenzyl)-2-(4-hydroxyphenyl)acetamide was consumed, PS-trisamine (0.3 eqv) was added and the solution was stirred overnight at room temperature. The polymer was filtered off and acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two portions of water, dried (MgSO4) and the solvent was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two portions on water, dried (MgSO4) and the solvent was removed by evaporation. The crude was purified by preparative HPLC (starting with isocratic acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min). The product-containing fractions were pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4). The solvent was removed by evaporation. to give 0.454 g of methyl 2-[(4-{3-[ethyl(2-fluorobenzyl)amino]-3-oxopropyl}phenoxy)methyl]-benzoate (yield 76.1%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:5]=1[NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13].[H-].[Na+].[CH:26]1[CH:31]=[C:30]([CH2:32]Br)[C:29]([CH2:34]Br)=[CH:28][CH:27]=1>CN(C=O)C.CCOCC>[CH3:1][O:2][C:3]([C:4]1[C:5]2[N:11]([S:12]([C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)(=[O:13])=[O:14])[CH2:32][C:30]3[CH:31]=[CH:26][CH:27]=[CH:28][C:29]=3[CH2:34][O:10][C:6]=2[CH:7]=[CH:8][CH:9]=1)=[O:23]
Reactant: COC(=O)c1cccc(O)c1NS(=O)(=O)c1ccc(OC)cc1
Reactant: BrCc1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)c1cccc2c1N(S(=O)(=O)c1ccc(OC)cc1)Cc1ccccc1CO2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78.4 %

Procedure:
To a solution of 0.350 g (1.039 mmol) of the product of Example 31 in 35 mL of DMF was added 0.104 g (2.596 mmol) of 60% sodium hydride and the solution was stirred at room temperature for 15 minutes. To the resulting mixture was then added 0.384 g (1.454 mmol) of a,a'-dibromo-o-xylene and the reaction mixture was then heated to 80° C. for 18 h, cooled to room temperature, diluted with ether and washed with water. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was chromatographed on silica gel eluting with EtOAc/hexanes (1:3) to provide 0.358 g (79%) of the desired product as a white solid. Electrospray Mass Spec: 440 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Cl:22])=[CH:11][CH:10]=2)=[O:5])[CH3:2].[F:24][C:25]([F:30])([F:29])[CH:26]([OH:28])[CH3:27]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:28][CH:26]([CH3:27])[C:25]([F:30])([F:29])[F:24])=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Cl:22])=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: CC(O)C(F)(F)F
Reactant: CCOC(=O)c1c(Cl)nc2ccc(Cl)cc2c1-c1ccccc1
Product: CCOC(=O)c1c(OC(C)C(F)(F)F)nc2ccc(Cl)cc2c1-c1ccccc1

Procedure:
The title compound was prepared in analogy to example 37 step A from 2,6-dichloro-4-phenyl-quinoline-3-carboxylic acid ethyl ester (prepared as described in example 11 step B, 100 mg, 0.29 mmol) and 1,1,1-trifluoro-propan-2-ol (40 mg, 0.35 mmol). Pale yellow solid (76 mg, 62%). LC-MS: 424 (M+H)+.