Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][O:9][CH2:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)(O)[CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)=O.CCOCC.C(=O)([O-])[O-].[Na+].[Na+]>N1C=CC=CC=1>[C:1]1([CH2:7][CH2:8][O:9][CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1cccc(C(C)(O)COCCc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOCC
Product: COc1cccc(C(C)COCCc2ccccc2)c1
Temperature: 20 °C
Reaction time: 1.5 h

Procedure:
To a 0° C. solution of 2-(3-methoxyphenyl)-2-hydroxypropyl 2-phenylethyl ether (498 mg. 1.74 mmole) in pyridine (2 ml.) is added dropwise phosphorous oxychloride (477 μl., 5.22 mmole). The reaction is allowed to warm to 20° C. over a 1.5 hour period. It is then stirred for 1.5 hours at 20° C. and then added to ether (150 ml.) and 15% sodium carbonate (100 ml.). The organic phase is separated and washed with 15% sodium carbonate (3×50 ml.), dried over magnesium sulfate and evaporated to an oil. The oil is dissolved in absolute ethanol (15 ml.), 10% palladium-on-carbon (100 mg.) added and the mixture stirred under one atmosphere of hydrogen gas. When hydrogen uptake ceases the reaction is filtered through diatomaceous earth and the filtrate evaporated to an oil. The oil is purified via preparative layer chromatography on silica gel plates, eluted twice with 6:1 pentane:ether to yield the title compound.
Reaction SMILES: C1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[CH:26]=[C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[CH:28]=[CH:29][CH:30]=4)[CH2:21][CH2:20]3)=[C:8]2C2C=CC=CC=2)C=CC=CC=1.[O:43]1CCO[CH:44]1CCCCN1CCC(C2C=C(NC(=O)C(C)C)C=CC=2)CC1.Cl.COC1C=CC(NN)=CC=1>>[CH3:44][O:43][C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][CH:13]=1)[NH:7][CH:8]=[C:9]2[CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:26]=[C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:34])[CH3:35])[CH:28]=[CH:29][CH:30]=2)[CH2:21][CH2:20]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccccc4)n(-c4ccccc4)c4ccccc34)CC2)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC3OCCO3)CC2)c1
Agent: COc1ccc(NN)cc1
Agent: Cl
Product: COc1ccc2[nH]cc(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c2c1
Yield: 42 %

Procedure:
According to the procedure used for the synthesis of N-(3-{1-[3-(1,2-diphenyl-1H-indol-3-yl)propyl]-4-piperidinyl}phenyl)-2-methylpropanamide, N-(3-{1-[4-(1,3-dioxolan-2-yl)butyl]-4-piperidinyl}phenyl)-2-methylpropanamide (23.5 mg, 0.0628 mmol) and 1-(4-methoxyphenyl)hydrazine hydrochloride (13.2 mg, 0.0774 mmol) provided N-(3-{1-[3-(5-methoxy-1H-indol-3-yl)propyl]-4-piperidinyl}phenyl)-2-methylpropanamide (11 mg, 42%). 1H NMR (400 MHz, CDCl3) δ 7.86 (s, 1H), 7.45 (s, 1H), 7.32 (d, 1H, J=8.4 Hz), 7.28-7.21 (m, 2H), 7.10 (s, 1H), 7.05 (d, 1H, J=2.3 Hz), 7.00-6.91 (m, 2H), 6.85 (dd, 1H, J=2.7, 9.0 Hz), 3.87 (s, 3H), 3.06 (d, 2H, J=11.6 Hz), 2.75 (t, 2H, J=7.2 Hz), 2.55-2.42 (m, 4H), 2.08-1.90 (m, 4H), 1.88-1.74 (m, 4H), 1.25 (d, 6H, J=6.9 Hz); ESMS m/e: 434.2 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9](=[O:14])[CH2:10][CH:11]([CH3:13])[CH3:12])[CH2:4]1.[H-].[Na+].[NH2:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22](F)[C:19]=1[C:20]#[N:21]>C1COCC1>[NH2:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([O:1][CH2:2][C@@H:3]2[CH2:8][CH2:7][CH2:6][N:5]([C:9](=[O:14])[CH2:10][CH:11]([CH3:12])[CH3:13])[CH2:4]2)[C:19]=1[C:20]#[N:21]
Reactant: CC(C)CC(=O)N1CCC[C@@H](CO)C1
Reactant: N#Cc1c(N)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)CC(=O)N1CCC[C@@H](COc2cccc(N)c2C#N)C1
Temperature: 25 °C
Yield: 41.7 %

Procedure:
To a solution of (R)-1-(3-(hydroxymethyl)piperidin-1-yl)-3-methylbutan-1-one (Example 34c) (145 mg, 0.73 mmol) in THF (15 mL) was added NaH (44 mg, 1.09 mmol, 60% dispersion in mineral oil) at 0° C. The reaction was warmed to room temperature and stirred for 15 minutes, at which time 2-amino-6-fluorobenzonitrile (109 mg, 0.80 mmol) was added. The mixture was heated at 80° C. overnight, quenched with water, concentrated under reduced pressure to remove THF and extracted with EtOAc (3×). The combined extracts were dried over Na2SO4, filtered, concentrated under reduced pressure and purified by flash chromatography on silica gel (EtOAc/hexanes). The residue was further purified by chiral HPLC (normal phase, ethanol/isopropanol/methanol/hexanes) to give the title compound as a white solid (96 mg, 41%). MS 316 (MH+).
Reaction SMILES: [OH:1][C:2]1[C:6]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][N:4]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[N:3]=1.[H-].[Na+].[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30]Cl)[CH:25]=1.O>CN(C)C=O>[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][O:1][C:2]2[C:6]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][N:4]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([O:21][CH2:30][C:26]4[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=4)=[CH:19][CH:20]=3)[N:3]=2)[CH:25]=1
Reactant: ClCc1cccnc1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)nc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3cccnc3)cc2)nc1OCc1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
To a solution of ethyl 3-[3-hydroxy-1-(4-hydroxybenzyl)-1H-pyrazol-4-yl]propionate (435 mg) in N,N-dimethylformamide (10 ml), sodium hydride (60%, oily, 120 mg) was added at 0° C., and then the solution was stirred at room temperature for 30 minutes. 3-Picolyl chloride (574 mg) was added to the reaction mixture, which was stirred at room temperature for one hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, then, with saturated aqueous sodium chloride solution, and dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[3-(3-pyridylmethoxy)-1-[4-(3-pyridylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (533 mg, yield: 75%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][OH:12])=[CH:6][CH:5]=1.FC(F)(F)C(O)=O.[CH2:20]([C:22]1[S:23][CH:24]=[C:25]([C:27]([N:29]2[CH2:34][C:33]3([CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)[O:32][CH2:31][CH2:30]2)=[O:28])[N:26]=1)[CH3:21].C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1.O>[CH2:20]([C:22]1[S:23][CH:24]=[C:25]([C:27]([N:29]2[CH2:34][C:33]3([CH2:39][CH2:38][N:37]([CH2:2][CH2:3][C:4]4[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][OH:12])=[CH:6][CH:5]=4)[CH2:36][CH2:35]3)[O:32][CH2:31][CH2:30]2)=[O:28])[N:26]=1)[CH3:21]
Reactant: OCCc1ccc(CCBr)cc1
Reactant: CCc1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN1CCCC1=O
Solvent: O
Product: CCc1nc(C(=O)N2CCOC3(CCN(CCc4ccc(CCO)cc4)CC3)C2)cs1
Temperature: 75 °C
Reaction time: 4 h

Procedure:
A solution of 2-(4-(2-bromoethyl)phenyl)ethanol [Organometallics 2002, 21(20), 4217] (1.71 g) in NMP (5 mL) was added to a suspension of (2-ethylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate [Example 3, step b] (3.0 g) and cesium carbonate (5.60 g) in NMP (10 mL) and the mixture stirred at 75° C. under nitrogen for 4 hours. More 2-(4-(2-bromoethyl)phenyl)ethanol (0.65 g) was added and the mixture stirred at 75° C. for 18 hours. The mixture was cooled, diluted with water and extracted into ethyl acetate (×3). The combined extracts were washed with 10% brine, 30% brine and saturated brine, dried over magnesium sulfate, filtered and the solvent removed. The crude product was purified by flash silica chromatography, successively eluted with 50% ethyl acetate in isohexane with 5% triethylamine, then 100% ethyl acetate with 5% triethylamine, then 10% methanol in ethyl acetate with 5% triethylamine. Fractions containing the product were evaporated to dryness to afford the subtitled compound as a yellow oil. Yield 1.90 g.
Reaction SMILES: C(O)C.[C:4]1([C:10](=O)[C:11](=O)[CH3:12])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:15]([NH2:18])[CH2:16][NH2:17].[OH-].[K+].[CH3:21][C:22]([CH3:24])=O>O>[CH:22]([C:16]1[N:17]=[C:11]([CH3:12])[C:10]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[N:18][CH:15]=1)([CH3:24])[CH3:21]
Reactant: CC(=O)C(=O)c1ccccc1
Reactant: CC(C)=O
Reactant: NCCN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1nc(C(C)C)cnc1-c1ccccc1
Yield: 35 %

Procedure:
20 mL of dehydrated ethanol, 2.22 g of 1-phenyl-1,2-propanedione and 0.90 g of anhydrous ethylenediamine were put in an eggplant flask with a reflux pipe, and the inside air of the flask was substituted by argon. Then, it was irradiated with microwave (2.45 GHz, 1 to 100 W) for 10 minutes and reacted. Then, into this reacted solution, 2.20 mL of acetone and 1.01 g of potassium hydroxide were added, and irradiated with microwave (2.45 GHz, 1 to 100 W) for 20 minutes. Water was added into this mixture and an organic layer was extracted with ethyl acetate. The obtained organic layer was washed with water and dried with magnesium sulfate. The solution after drying was filtrated and a solvent of the filtrate was distilled off. The obtained residue was purified by silicagel column chromatography using dichloromethane as a developing solvent, thereby obtaining an objective pyrazine derivative Hmppr-iPr (orange liquid, yield: 35%). For the irradiation of microwave, a microwave synthesis system (Discovery, manufactured by CEM Corporation) was used. A synthesis scheme of Step 1 is shown by the following (a-3).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[CH2:10][CH:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=2)[C:12]1=[O:23])(=[O:3])[CH3:2].[F:24][C:25]([F:35])([F:34])[C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][Br:30]>>[Br-:30].[C:1]([C:4]1[CH:5]=[N+:6]([CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[C:26]([C:25]([F:24])([F:34])[F:35])[CH:27]=2)[CH:7]=[CH:8][C:9]=1[CH2:10][CH:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=2)[C:12]1=[O:23])(=[O:3])[CH3:2]
Reactant: COc1ccc2c(c1)CCC(Cc1ccncc1C(C)=O)C2=O
Reactant: FC(F)(F)c1cccc(CBr)c1
Product: COc1ccc2c(c1)CCC(Cc1cc[n+](Cc3cccc(C(F)(F)F)c3)cc1C(C)=O)C2=O
Product: [Br-]

Procedure:
The title compound 124 is prepared according to the procedure reported in Example 38.1 with compound 103 (62 mg, 0.2 mmol) and 3-trifluoromethylbenzyl bromide (52 μL, 0.34 mmol) as reactants. White solid. (Yield 89.9 mg, 82%).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:20]=[CH:19][C:12]([O:13][CH2:14][CH:15]([OH:18])[CH2:16][OH:17])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[C:23]1[CH:42]=[CH:41][CH:40]=[CH:39][C:24]=1[C:25](Cl)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[O:43]1CCC[CH2:44]1>N1C=CC=CC=1>[CH3:44][O:43][C:29]1[CH:30]=[CH:31][C:26]([C:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:24]2[CH:23]=[CH:42][CH:41]=[CH:40][CH:39]=2)[O:17][CH2:16][CH:15]([OH:18])[CH2:14][O:13][C:12]2[CH:19]=[CH:20][C:9]([O:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:10][CH:11]=2)=[CH:27][CH:28]=1
Reactant: OCC(O)COc1ccc(OCc2ccccc2)cc1
Reactant: COc1ccccc1C(Cl)(c1ccccc1)c1ccccc1
Reactant: C1CCOC1
Solvent: c1ccncc1
Product: COc1ccc(C(OCC(O)COc2ccc(OCc3ccccc3)cc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 24 h

Procedure:
To a solution of 18.9 g of 3-[4-(phenylmethoxy)-phenoxy]-1,2-propanediol in 50 ml of pyridine and 24 ml of tetrahydrofuran was added 25.57 g of methoxy trityl chloride in several portions. This mixture was stirred for 24 hours and the solvents removed under reduced pressure. The residue was dissolved in chloroform, washed with aqueous sodium bicarbonate, then water, dried and evaporated, giving 30 g of the desired compound.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C(O)(C)C.[C:13](=[O:15])=O.[CH3:16][C:17]1([CH3:37])[CH:26]=C[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([S:27]([C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[CH:23]=2)[O:18]1.CS(C)=O>O>[O:18]1[CH2:17][CH:16]=[C:13]([OH:15])[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]1=2.[Br:1][CH:26]1[C:17]([CH3:37])([CH3:16])[O:18][C:19]2[CH:24]=[CH:23][C:22]([S:27]([C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)(=[O:29])=[O:28])=[CH:21][C:20]=2[CH:13]1[OH:15]
Reactant: O=C=O
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(S(=O)(=O)c2ccc3c(c2)C=CC(C)(C)O3)cc1
Solvent: CC(C)O
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)c2ccc3c(c2)C(O)C(Br)C(C)(C)O3)cc1
Product: OC1=CCOc2ccccc21
Temperature: 20 °C
Reaction time: 1 h

Procedure:
14.2 g (0.08 mol) of freshly recrystallized N-bromosuccinimide are introduced with cooling (isopropanol/dry ice) at about 15° C. into 12.6 g (0.04 mol) of 2,2-dimethyl-6-(4'-methylphenylsulfonyl)-chromene in a solution of 70 ml of dimethyl sulfoxide and 1.4 ml of water. The temperature rises temporarily to 27° C. The mixture is cooled to 20° C. and, after stirring for 1 hour, introduced into ice/ethyl acetate. The ethyl acetate phase is washed several times with water and dried over Na2SO4. On concentrating, the bromohydrin derivative crystallizes. Crystals of melting point: 141-142° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH2:7][OH:8])=[N:2]1.C(=O)([O-])[O-].[Na+].[Na+].I[CH:16]([CH3:18])[CH3:17]>CN(C)C=O>[CH:16]([N:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH2:7][OH:8])=[N:2]1)([CH3:18])[CH3:17]
Reactant: CC(C)I
Reactant: OCCc1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1ccc(CCO)n1
Temperature: 100 °C
Yield: 25.9 %

Procedure:
To a solution of 1.0 gm (9.0 mMol) 2-(3-pyrazolyl)-1-ethanol in 36 mL dimethylformamide were added 2.38 gm (22.5 mMol) sodium carbonate followed by the dropwise addition of a solution of 0.89 mL (9.0 mMol) 2-iodopropane in 8 mL dimethylformamide. The reaction mixture was heated to 100° C. for 18 hours. The reaction mixture was then cooled to ambient and then concentrated under reduced pressure. The residue was partitioned between water and dichloromethane. The organic phase was then washed with water followed by saturated aqueous sodium chloride and was then dried over sodium sulfate. The remaining organics were concentrated under reduced pressure to give 0.36 gm (26.0%) of the title compound as a brown oil. 1H-NMR (DMSO-d6): δ7.50 (s, 1H); 7.25 (s, 1H); 4.60 (t, 1H); 4.40 (m, 1H); 3.50 (m, 2H); 2.55 (t, 2H); 1.35(d, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:17][CH2:18][CH:19]([CH2:25][CH2:26][CH2:27][OH:28])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:36]1([CH3:46])[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[CH:38][CH:37]=1>ClCCl>[CH2:23]([O:22][C:20](=[O:21])[CH:19]([CH2:25][CH2:26][CH2:27][O:28][S:42]([C:39]1[CH:40]=[CH:41][C:36]([CH3:46])=[CH:37][CH:38]=1)(=[O:44])=[O:43])[CH2:18][CH2:17][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])[CH3:24]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)C(CCCO)CC[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(CCCOS(=O)(=O)c1ccc(C)cc1)CC[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 3 h

Procedure:
190 mg (0.47 mmol) of 1-tert-Butyl 6-ethyl (2S)-2-[(tert-butoxycarbonyl)amino]-5-(3-hydroxypropyl)hexanedioate (5b) were dissolved in 10 mL dichloromethane at 0° C. Then, 284 mg (391 microL, 2.8 mmol) triethylamine and 179 mg (0.94 mmol) p-toluene sulfonyl chloride were added at 0° C. and the mixture was stirred at this temperature for 3 h. After stirring for 18 h at r.t. the solution was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (hexane/ethyl acetate gradient) to give (S)-2-tert-Butoxycarbonylamino-5-[3-(toluene-4-sulfonyloxy)-propyl]-hexanedioic acid 1-tert-butyl ester 6-ethyl ester as a colourless oil.
Reaction SMILES: C1(COC([NH:11][CH:12]([CH3:63])[C:13]([O:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([CH:22]2[CH2:31][CH2:30][C:29]3[C:24](=[C:25]([CH2:60][CH2:61][CH3:62])[C:26]([O:32][CH2:33][CH2:34][CH2:35][O:36][C:37]4[CH:42]=[C:41]([O:43]CC5C=CC=CC=5)[C:40]([C:51]5[CH:56]=[CH:55][C:54]([F:57])=[CH:53][CH:52]=5)=[CH:39][C:38]=4[CH2:58][CH3:59])=[CH:27][CH:28]=3)[O:23]2)=[O:21])=[O:14])=O)C=CC=CC=1>CO.C(Cl)(Cl)Cl.[Pd]>[NH2:11][CH:12]([CH3:63])[C:13]([O:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([CH:22]1[CH2:31][CH2:30][C:29]2[C:24](=[C:25]([CH2:60][CH2:61][CH3:62])[C:26]([O:32][CH2:33][CH2:34][CH2:35][O:36][C:37]3[C:38]([CH2:58][CH3:59])=[CH:39][C:40]([C:51]4[CH:56]=[CH:55][C:54]([F:57])=[CH:53][CH:52]=4)=[C:41]([OH:43])[CH:42]=3)=[CH:27][CH:28]=2)[O:23]1)=[O:21])=[O:14]
Reactant: CCCc1c(OCCCOc2cc(OCc3ccccc3)c(-c3ccc(F)cc3)cc2CC)ccc2c1OC(C(=O)NCCCOC(=O)C(C)NC(=O)OCc1ccccc1)CC2
Agent: [Pd]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCc1c(OCCCOc2cc(O)c(-c3ccc(F)cc3)cc2CC)ccc2c1OC(C(=O)NCCCOC(=O)C(C)N)CC2
Yield: 95.2 %

Procedure:
3-((7-(3-(2-ethyl-4-(4-fluorophenyl)-5-(phenylmethyloxy)phenoxy)propoxy)-8-propylchroman-2-yl)carbonylamino)propyl 2-((phenylmethoxy)carbonylamino)propanoate (125 mg) is dissolved in methanol/chloroform (2:1, 7 mL) with 50 mg 10% Pd/C catalyst. Hydrogen gas is bubbled in for 3 hours, when the mixture is filtered through Celite® and concentrated to yield 88 mg of product as a white crunchy foam. Mass Spec (EI) m/z=637.5 (M+H)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.C(N(C(C)C)C(C)C)C.C(Cl)(Cl)Cl.[CH3:24][O:25][CH2:26]Cl>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][CH2:24][O:25][CH3:26])=[CH:4][CH:3]=1
Reactant: OCCc1ccc(Br)cc1
Reactant: COCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: COCOCCc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 103.2 %

Procedure:
To a mixture of 4-bromophenylethyl alcohol (12 g, 59.7 mmol), ethyldiisopropylamine (11.5 g, 89.5 mmol) and chloroform (200 mL), chloromethyl methyl ether (7.2 g, 89.5 mmol) was slowly added at 0° C. The reaction mixture was stirred at 0° C. for 1 hour and at room temperature for 2.5 hours, and then poured into water. After the mixture was extracted twice with chloroform, the combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give bromo-4-(2-methoxymethoxyethyl)benzene (15.1 g).
Reaction SMILES: CN(C)[CH:3]=[O:4].S(Cl)(Cl)=O.[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][C:18](O)=[O:19].CO>ClCCl>[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][C:18]([O:4][CH3:3])=[O:19]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: COC(=O)Cc1ccccc1Br
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Add dimethylformamide (2.1 mL, 27.3 mmol) followed by thionyl chloride (52.3 mL, 717.8 mmol) over 7 minutes to a solution of 2-bromophenylacetic acid (150.0 g, 683.6 mmol) in dichloromethane (1.50 L) cooled with an ambient temperature water bath. Stir mixture for 5 hours, add methanol (41.5 mL, 1.0 mol) over 5 minutes. Bubble nitrogen through solution overnight. Concentrate to obtain the title compound as a colorless oil in quantitative yield (166.0 g, 724.7 mmol). 1H NMR (300 MHz, CDCl3): 7.57 (d, J=7.9 Hz, 1H), 7.30-7.26 (m, 2H), 7.19-7.12 (m, 1H), 3.80 (s, 2H), 3.72 (s, 3H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][C:19]=2[O:20][CH3:21])[C:16]([C:22](=[O:32])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH2:30][CH3:31])[CH:24]=2)=[N:15][CH:14]=[C:13]3[CH:33]=[O:34])[CH2:5][CH2:4][CH2:3][CH2:2]1.O.P([O-])(O)(O)=[O:37].[Na+].CC(=CC)C.[Cl:47]([O-])=O.[Na+]>C(O)(C)(C)C.O>[ClH:47].[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][C:19]=2[O:20][CH3:21])[C:16]([C:22](=[O:32])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH2:30][CH3:31])[CH:24]=2)=[N:15][CH:14]=[C:13]3[C:33]([OH:37])=[O:34])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOc1cccc(C(=O)c2ncc(C=O)c3cc(OCCCN4CCCC4)c(OC)cc23)c1
Reactant: [O-][Cl+][O-]
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: CCOc1cccc(C(=O)c2ncc(C(=O)O)c3cc(OCCCN4CCCC4)c(OC)cc23)c1
Product: Cl
Temperature: 25 °C
Reaction time: 14 h
Yield: 29.9 %

Procedure:
To a stirred solution of 6-(3-pyrrolidin-1-yl-propoxy)-7-methoxy-1-(3-ethoxy-benzoyl)-isoquinoline-4-carbaldehyde (63 mg, 0.13 mmol) in t-butanol (0.5 mL) and water (0.5 mL) solution was added sodium dihydrogenphosphate monohydrate (73 mg, 0.53 mmol), 2-methyl-2-butene (0.089 mL, 0.80 mmol) and sodium chlorite (71.2 mg, 0.80 mmol) at room temperature. The reaction suspension was then stirred at room temperature for 14 hrs. The resulting two-phase mixture was partitioned between dichloromethane and water and acidified to pH=3 by addition of 1N hydrochloric acid. The aqueous phase was then extracted with dichloromethane (3×20 mL). The combined extracts were washed with saturated sodium chloride solution (30 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford a brown semi-solid oil. The crude product was recrystallized in ethyl acetate to afford 6-(3-pyrrolidin-1-yl-propoxy)-1-(3-ethoxy-benzoyl)-7-methoxy-isoquinoline-4-carboxylic acid hydrochloride (20 mg, 32% yield) as a light brown solid. HR-MS m/e calcd for C27H30N2O6 (M−H+) 479.2177, found 479.2182; 1H NMR (300 MHz) compatible.
Reaction SMILES: C([O:3][C:4]([CH:6]1[C@H:13]2[CH2:14][CH:8]([CH2:9][CH2:10][CH2:11][CH2:12]2)[N:7]1[S:15]([C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1)(=[O:17])=[O:16])=[O:5])C.[OH-].[Li+]>O1CCCC1.O>[CH:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:26]=[CH:27][C:18]=1[S:15]([N:7]1[CH:6]([C:4]([OH:5])=[O:3])[C@H:13]2[CH2:14][CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12]2)(=[O:17])=[O:16]
Reactant: CCOC(=O)C1[C@@H]2CCCCC(C2)N1S(=O)(=O)c1ccc2ccccc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1[C@@H]2CCCCC(C2)N1S(=O)(=O)c1ccc2ccccc2c1
Temperature: 80 °C
Yield: 98 %

Procedure:
To a solution of (R)-7-(naphthalene-2-sulfonyl)-7-aza-bicyclo[4.2.1]nonane-8-carboxylic acid ethyl ester (0.55 g, 1.42 mmol) in tetrahydrofuran (15 mL) is added a solution of lithium hydroxide (1.2 g, 28.6 mmol) in water (15 mL). The reaction is heated to 80° C. for 16 h, and the solvent is removed in vacuo. The residue is dissolved in water and washed with diethyl ether. The aqueous layer is then acidified with 6 N hydrochloric acid to pH less than 4 and extracted three times with ethyl acetate. The combined organic extracts are washed with brine, dried over magnesium sulfate, and concentrated to afford the title compound as a yellow solid (0.50 g, 98% yield). LCMS (m/z): 360.07 (M+1), 358.12 (M−1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:27][OH:28].C(=O)([O-])O.[Na+]>>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[N:27][OH:28])=[CH:4][CH:3]=1
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(O)cc2)c2ccccc2C)ccn1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(C(C[C@H](c2ccc(O)cc2)c2ccccc2C)=NO)ccn1

Procedure:
In analogy to example 132, step 6, from (R)-3-(4-hydroxy-phenyl)-1-(2-methyl-pyridin-4-yl)-3-o-tolyl-propan-1-one and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a white solid, MS (ESI+): m/z=347.2 ([M+H]+).