Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1C=CC(O)=[C:6](O)[CH:5]=1.[CH2:12]1[N:17]([CH2:18][CH2:19]O)[CH2:16][CH2:15]N(CCS(O)(=O)=O)C1>C(O)[C@H]1O[C@H](O[C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O>[N:1]1[CH:2]=[C:3]([C@@H:16]2[CH2:15][CH2:19][CH2:18][N:17]2[CH3:12])[CH:4]=[CH:5][CH:6]=1
Reactant: NCCc1ccc(O)c(O)c1
Reactant: O=S(=O)(O)CCN1CCN(CCO)CC1
Agent: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Product: CN1CCC[C@H]1c1cccnc1
Reaction time: 0.17 h

Procedure:
Dopamine release was measured by preparing synaptosomes from the striatal area of rat brain obtained from Sprague-Dawley rats generally according to the procedures set forth by Nagy et al., J. Neurochem., Vol. 43, pp. 1114-1123 (1984). Striata from 4 rats were homogenized in 2 ml of 0.32M sucrose buffered with 5 mM HEPES (pH 7.5), using a glass-Teflon tissue grinder. The homogenate was diluted to 5 ml with additional homogenization solution and centrifuged at 1,000×g for 10 min. This procedure was repeated on the new pellet and the resulting supernatant was centrifuged at 12,000×g for 20 min. A 3 layer discontinuous Percoll gradient consisting of 16 percent, 10 percent and 7.5 percent Percoll in HEPES-buffered sucrose was made with the final pellet dispersed in the top layer. After centrifugation at 15,000×g for 20 min., the synaptosomes were recovered above the 16 percent layer with a Pasteur pipette, diluted with 8 ml of perfusion buffer (128 mM NaCl, 2.4 mM KCl, 3.2 mM CaCl2, 1.2 mM KH2PO4, 1.2 mM MgSO4, 25 mM HEPES pH 7.4, 10 mM dextrose, 1 mM ascorbate, 0.01 mM pargyline), and centrifuged at 15,000×g for 20 min. The new pellet was collected and re-suspended in perfusion buffer. The synaptosome suspension was incubated for 10 min. at 37° C. [3H]-Dopamine (Amersham, 40-60 Ci/mmol) was added to the suspension to give a final concentration of 0.1 uM, and the suspension was incubated for another 5 min. Using this method, 30 to 90 percent of the dopamine was taken up into the synaptosomes, as determined by scintillation counting following filtration through glass fiber filters soaked with 0.5 percent polyethyleneimine. A continuous perfusion system was used to monitor release following exposure to each ligand. Synaptosomes were loaded onto glass fiber filters (Gelman type A/E). Perfusion buffer was dripped onto the filters (0.2-0.3 ml/min.) and pulled through the filters with a peristaltic pump. Synaptosomes were washed with perfusion buffer for a minimum of 20 min. before addition of the ligand. After the addition of 0.2 ml of a solution containing various concentrations of ligand, the perfusate was collected into scintillation vials at 1 min. intervals and the dopamine released was quantified by scintillation counting. Peaks of radioactivity released above background were summed and the average basal release during that time was subtracted from the total. Release was expressed as a percentage of release obtained with an equal concentration of (S)-(-)-nicotine.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([O:19]C(=O)CCCCC)[C@H:10]([CH3:18])[CH2:11][CH2:12][C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>O1CCCC1.CO>[C:1]([O:5][C:6]([NH:8][CH:9]([OH:19])[C@H:10]([CH3:18])[CH2:11][CH2:12][C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCCC(=O)OC(NC(=O)OC(C)(C)C)[C@H](C)CCc1cccs1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](CCc1cccs1)C(O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
(2R)-t-Butoxycarbonylamino-1-n-hexanoyloxy-2-methyl-4-(thiophen-2-yl)butane (22.0 g, 57.4 mmol) obtained in Example 67(a) was dissolved in a mixture solution of tetrahydrofuran (140 ml) and methanol (280 ml), and a 1N aqueous sodium hydroxide solution (280 ml) was added in an ice bath followed by stirring 30 minutes in an ice bath and subsequently for 1 hour at room temperature. The reaction solution was concentrated in vacuo, and water was added thereto, and after the resulting solution was extracted with dichloromethane, the dichloromethane layer was washed with a saturated aqueous sodium chloride solution. The dichloromethane layer was dried over anhydrous sodium sulfate, and the solvent was evaporated in vacuo to afford the title compound (15.5 g, 95% yield) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([S:15]([C:18]2[C:19]3[CH:20]=[CH:21][N:22]=[CH:23][C:24]=3[CH:25]=[CH:26][CH:27]=2)(=[O:17])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:28]([O-:30])=[O:29].[Na+].C(OC(=O)C)(=O)C.N>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([S:15]([C:18]2[C:19]3[CH:20]=[CH:21][N:22]=[C:23]([N+:28]([O-:30])=[O:29])[C:24]=3[CH:25]=[CH:26][CH:27]=2)(=[O:17])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=N[O-]
Reactant: CC(C)(C)OC(=O)N1CCCN(S(=O)(=O)c2cccc3cnccc23)CC1
Agent: N
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCCN(S(=O)(=O)c2cccc3c([N+](=O)[O-])nccc23)CC1
Reaction time: 8 h

Procedure:
To a stirred solution of the isoquinoline from step A (1.17 g, 3.0 mmol) in anhydrous DMSO (12 mL) was added sodium nitrite (1.24 g, 18 mmol). To the mixture was added slowly over 30 min a solution of acetic anhydride (1.84 g, 18 mmol) in anhydrous DMSO (12 mL). The mixture was stirred overnight and TLC showed most starting material remained. More sodium nitrite (1.24 g, 18 mmol) and acetic anhydride (1.84 g, 18 mmol) in anhydrous DMSO (12 mL) was added and stirring was continued for about 1 h. During this period yellow solid precipitated and TLC showed a new product at Rf 0.5 (hexane/EtOAc 1:1). The mixture was poured into a saturated aqueous solution of sodium bicarbonate (100 mL) and extracted with EtOAc (100 mL×2). Chromatography on silica eluting with 20% EtOAc/Hexane gave an oil. (0.81 g, 62%). LCMS (+APCI) m/z 454 (M+H+NH3).
Reaction SMILES: Br[C:2]1[C:7]2[O:8][C:9]3([C:15]4[C:20]([C:6]=2[CH:5]=[CH:4][CH:3]=1)=[CH:19][N:18]=[C:17]([NH2:21])[N:16]=4)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]3.[CH3:22][N:23](CCN(C)C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>CN(C=O)C.O.[C-]#N.[C-]#N.[Zn+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:21][C:17]1[N:16]=[C:15]2[C:9]3([O:8][C:7]4[C:6]([C:20]2=[CH:19][N:18]=1)=[CH:5][CH:4]=[CH:3][C:2]=4[C:22]#[N:23])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]3
Reactant: Nc1ncc2c(n1)C1(CCCCC1)Oc1c(Br)cccc1-2
Reactant: CN(C)CCN(C)C
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cccc2c1OC1(CCCCC1)c1nc(N)ncc1-2
Temperature: 160 °C
Yield: 337 %

Procedure:
A solution of 7-bromospiro[chromeno[3,4-d]pyrimidine-5,1′-cyclohexan]-3-amine (44) (0.233 g, 0.673 mmol), Zn(CN)2 (0.0474 g, 0.404 mmol), and TMEDA (0.0202 ml, 0.135 mmol), in DMF (2 mL) was degassed by bubbling nitrogen through the solution for ˜1 min before adding Pd2(dba)3 (0.0462 g, 0.0505 mmol), and Xantphos (4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene, 0.0584 g, 0.101 mmol). The mixture was heated to 160° C. for 5 min with microwave irradiation. The reaction mixture was diluted in water and extracted with 10% iPrOH/DCM (3×75 ml). The organic layer was dried with MgSO4 and concentrated in vacuo. Purification on a 40 g combiflash column [(dry loaded), eluting with 50% EtOAc:Hexane to 100% EtOAc then with 4% MeOH/36% DCM/EtOAc] afforded 3-aminospiro[chromeno[3,4-d]pyrimidine-5,1′-cyclohexane]-7-carbonitrile (47) as a white solid (0.133 g, 68%). LCMS-ESI (POS), M/Z, M+1: Found 293.0.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8](Cl)[N:7]=[C:6]([NH:11][CH:12]([CH2:14][CH3:15])[CH3:13])[CH:5]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.[Na].[S:39]1(=[O:46])(=[O:45])[CH2:44][CH2:43][CH2:42][CH2:41][NH:40]1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([N:40]2[CH2:41][CH2:42][CH2:43][CH2:44][S:39]2(=[O:46])=[O:45])[N:7]=[C:6]([NH:11][CH:12]([CH2:14][CH3:15])[CH3:13])[CH:5]=1
Reactant: CCC(C)Nc1cc(C(=O)OC)cc(Cl)n1
Reactant: O=S1(=O)CCCCN1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CCC(C)Nc1cc(C(=O)OC)cc(N2CCCCS2(=O)=O)n1
Temperature: 100 °C
Reaction time: 18 h
Yield: 37.8 %

Procedure:
Add 2-sec-butylamino-6-chloro-isonicotinic acid methyl ester (1.0 g, 4.13 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.189 g, 0.207 mmol), 2-(di-tert-butylphosphino)biphenyl (0.123 g, 0.413 mmol) and the sodium salt of [1,2]thiazinane 1,1-dioxide (0.844 g, 5.37 mmol) in toluene (10 mL) to a sealed flask flushed with nitrogen. Heat and stir the sealed flask at 100° C. for 18 h. Cool to room temperature and filter through a bed of filtering agent, and wash with dichloromethane. Concentrate the filtrate and purify (silica gel chromatography, eluting with 20:80 to 30:70 ethyl acetate:hexanes) to give the title compound (0.533 g, 38%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([O:21][CH3:22])=[O:20])[CH:14]=2)[CH:10]=[CH:11][CH:12]=1)=[O:5].C(=O)([O-])[O-].[Na+].[Na+].O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[Cl:55][C:56]1[CH:57]=[C:58]([CH:64]=[CH:65][CH:66]=1)[C@@H:59]([OH:63])[C:60](O)=[O:61]>C(OCC)(=O)C>[Cl:55][C:56]1[CH:57]=[C:58]([C@H:59]([OH:63])[C:60]([NH:2][CH2:3][C:4]([NH:6][C:7]2[CH:8]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([O:21][CH3:22])=[O:20])[CH:14]=3)[CH:10]=[CH:11][CH:12]=2)=[O:5])=[O:61])[CH:64]=[CH:65][CH:66]=1
Reactant: O=C(O)[C@H](O)c1cccc(Cl)c1
Reactant: COC(=O)c1cccc(-c2cccc(NC(=O)CN)c2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cccc(-c2cccc(NC(=O)CNC(=O)[C@@H](O)c3cccc(Cl)c3)c2)c1
Temperature: 10 °C
Yield: 426.2 %

Procedure:
A suspension of methyl 3′-[(aminoacetyl)amino][1,1′-biphenyl]-3-carboxylate hydrochloride (50 g) in ethyl acetate (350 ml) is treated with 1 M aqueous sodium carbonate (250 ml) at room temperature. The lower aqueous phase is discarded, 1-hydroxybenzotriazole hydrate (10 g) and then dicyclohexylcarbodiimide (30.6 g) is added to the organic phase and the mixture is cooled to approximately 10° C. This mixture is treated with a solution of (R)-3-chloromandelic acid (5.8 g) in ethyl acetate (40 ml) over approximately 1 hour. The mixture is stirred for several hours and filtered. The filtrate is washed with 6% w/w aqueous sodium bicarbonate and water, and the organic phase is concentrated to low volume. Isopropanol is added and the organic solution is further concentrated to low volume. The organic solution is warmed to 70° C., treated with water, cooled to room temperature and the mixture is filtered to give the title product (60 g).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][CH:12]=[N:11][C:10]=2[C:14](OCC)=[O:15])=[CH:5][CH:4]=1.[H-].C([Al+]CC(C)C)C(C)C>C1COCC1>[F:20][C:2]([F:1])([F:19])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:13][CH:12]=[N:11][C:10]=2[CH:14]=[O:15])=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1ncoc1-c1ccc(C(F)(F)F)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: O=Cc1ncoc1-c1ccc(C(F)(F)F)cc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
A solution of Example 52A (2.08 g, 7.29 mmol) in THF (20 mL) was cooled to −78° C. Diisobutylaluminum hydride (1.0 M in toluene, 14.6 mL, 14.6 mmol) was added slowly via syringe, and the reaction mixture was allowed to proceed 1 hr, then warmed to −20° C. After an additional 1 hr the reaction mixture was quenched with 1 N aq HCl, and the mixture was partitioned between Et2O and saturated aq NH4Cl solution. The separated aqueous phase was extracted with EtOAc, and the combined organic layer was washed with 3 N aq HCl and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified on silica gel (Analogix® Intelliflash 280™; SF40-150 g column; 15% to 55% EtOAc/hexanes, 30 min) to give 1.26 g (72%) of the title compound as a pale yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 10.07 (s, 1H), 8.75 (s, 1H), 8.30 (d, J=8.1, 2H), 7.97 (d, J=8.2, 2H). MS (DCI+) m/z 259 (M+NH4).
Reaction SMILES: ClC1N=CC(S(NC2CCCC2)(=O)=O)=CC=1.C(Br)C=C.[Cl:21][C:22]1[N:27]=[CH:26][C:25]([S:28]([N:31]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37]C=2)[CH2:32][CH:33]=[CH2:34])(=[O:30])=[O:29])=[CH:24][CH:23]=1>>[Cl:21][C:22]1[N:27]=[CH:26][C:25]([S:28]([N:31]([CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37]2)[CH2:32][CH:33]=[CH2:34])(=[O:29])=[O:30])=[CH:24][CH:23]=1
Reactant: C=CCN(c1ccccc1)S(=O)(=O)c1ccc(Cl)nc1
Agent: O=S(=O)(NC1CCCC1)c1ccc(Cl)nc1
Solvent: C=CCBr
Product: C=CCN(C1CCCC1)S(=O)(=O)c1ccc(Cl)nc1

Procedure:
According to Process 10.2, starting with 1 g of 6-chloro-N-cyclopentylpyridine-3-sulfonamide and 0.42 mL of allyl bromide, 1.2 g of 6-chloro-N-phenyl-N-(prop-2-en-1-yl)pyridine-3-sulfonamide are obtained in the form of an orange-coloured oil.
Reaction SMILES: [H-].[Na+].O1CCCC1.[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH:17]=[O:18])[CH:15]=2)[CH:10]=[CH:9]1.[CH2:19]([S:22](Cl)(=[O:24])=[O:23])[CH2:20][CH3:21]>>[CH2:19]([S:22]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH:17]=[O:18])[CH:15]=2)[CH:10]=[CH:9]1)(=[O:24])=[O:23])[CH2:20][CH3:21]
Reactant: O=Cc1ccc2cc[nH]c2c1
Reactant: CCCS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCS(=O)(=O)n1ccc2ccc(C=O)cc21
Reaction time: 0.5 h
Yield: 0.1 %

Procedure:
To sodium hydride (0.174 g, 4.35 mmol) in tetrahydrofuran (6.8 mL, 0.084 mol), 1H-Indole-6-carbaldehyde (59, 0.486 g, 3.35 mol) was added. After 30 minutes, propane-1-sulfonyl chloride (0.565 mL, 5.02 mol) was added. After two hours, it was quenched with 1M HCl (aqueous) and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated. The desired compound was purified by silica gel column chromatography eluting with a gradient of ethyl acetate in hexane to give 516 mg of desired compound. MS (ESI) [M−H+]−=250.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH2:20][C:21]([OH:23])=O)[S:10]([C:13]1[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:12])=[O:11].[CH2:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[CH3:25]>>[CH2:24]([N:26]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[C:21](=[O:23])[CH2:20][N:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[S:10]([C:13]1[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:11])=[O:12])[CH3:25]
Reactant: CCNCc1ccccn1
Reactant: COc1ccccc1N(CC(=O)O)S(=O)(=O)c1ccccc1C
Product: CCN(Cc1ccccn1)C(=O)CN(c1ccccc1OC)S(=O)(=O)c1ccccc1C

Procedure:
prepared by reaction of [(2-methoxy-phenyl)-(toluene-2-sulfonyl)-amino]-acetic acid with ethyl-pyridin-2-ylmethyl-amine
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:7][C:6](=[O:8])[CH2:5][CH2:4]1.[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.N1C=CC=CC=1.Cl>C1COCC1.CN(C1C=CN=CC=1)C>[CH3:19][C:9]1[CH:14]=[CH:13][C:12]([S:15]([O:1][CH2:2][C@@H:3]2[CH2:4][CH2:5][C:6](=[O:8])[O:7]2)(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1CC[C@@H](CO)O1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2CCC(=O)O2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.8 %

Procedure:
To a solution of (S)-5-(hydroxymethyl)dihydrofuran-2(3H)-one (25.97 g, 223.66 mmol) in THF (125 mL) were added p-toluenesulfonyl chloride (44.8 g, 234.84 mmol), pyridine (45.2 mL, 559.14 mmol) and DMAP (30.1 g, 246.02 mmol) at 0° C., and the mixture was stirred at room temperature for 4 hr. The reaction mixture was poured into ice water (400 mL), and the pH of the mixture was adjusted to 3 with 6N hydrochloric acid. Then, the mixture was extracted with ethyl acetate (×3). The organic layer was washed with water and brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The crystals were collected by filtration, and washed with IPE/hexane to give (S)-(5-oxotetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate (51.81 g, 192 mmol, 86%) as a white powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]([C:23](OC)=[O:24])[CH:16]=[C:17]([CH:22]=1)[C:18](OC)=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[OH:24][CH2:23][C:15]1[CH:14]=[C:13]([CH:22]=[C:17]([CH2:18][OH:19])[CH:16]=1)[O:12][CH2:11][CH2:10][CH2:9][N:8]([CH2:27][CH:28]([CH3:29])[CH3:30])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1cc(OCCCN(CC(C)C)C(=O)OC(C)(C)C)cc(C(=O)OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)CN(CCCOc1cc(CO)cc(CO)c1)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 52.9 %

Procedure:
To a solution of dimethyl 5-(3-((tert-butoxycarbonyl)(isobutyl)amino)propoxy)isophthalate (0.60 g, 1.44 mmol) in THF (10 mL) was added LiAlH4 (0.30 g, 7.89 mmol). The reaction mixture was stirred for 8 h and subsequently quenched with 2N HCl (10 mL) and extracted with Et2O (2×25 mL) and EtOAc (2×25 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the desired product (0.28 g, 54%) as an oil, which was used without further purification.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:3]1.O[C@H]1CC(=O)C(CCC[CH2:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=O)=C1>>[O:33]1[CH2:34][CH2:28][CH2:29][CH2:30][CH:31]1[O:1][C@@H:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:3]1
Reactant: COC(=O)CCCCCCC1=C[C@@H](O)CC1=O
Reactant: COC(=O)CCCCCCC1=C[C@H](O)CC1=O
Product: COC(=O)CCCCCCC1=C[C@H](OC2CCCCO2)CC1=O

Procedure:
Substitution of an equivalent quantity of methyl 7-(3(R)-hydroxy-5-oxocyclopent-1-en-1-yl)heptanoate for the methyl 7-(3(S)-hydroxy-5-oxocyclopent-1-en-1-yl)heptanoate and substantial repetition of the procedure detailed above affords methyl 7-(3(R)-tetrahydropyran-2-yloxy-5-oxocyclopent-1-en-1-yl)heptanoate.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:13]=[C:12]([OH:14])[CH:11]=[CH:10][C:9]=1[CH2:15][N:16]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:31])[C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[N:17]1.Br[CH2:33][CH2:34][CH2:35][CH3:36]>CS(C)=O.CO>[CH2:33]([O:14][C:12]1[CH:11]=[CH:10][C:9]([CH2:15][N:16]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:31])[C:23]3[C:24]([F:30])=[CH:25][CH:26]=[CH:27][C:28]=3[F:29])=[N:17]2)=[C:8]([Cl:7])[CH:13]=1)[CH2:34][CH2:35][CH3:36]
Reactant: CCCCBr
Reactant: O=C(Nc1ccn(Cc2ccc(O)cc2Cl)n1)c1c(F)cccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CO
Product: CCCCOc1ccc(Cn2ccc(NC(=O)c3c(F)cccc3F)n2)c(Cl)c1
Reaction time: 0.08 h

Procedure:
Potassium t-butoxide (9.7 mg, 0.086 mmol, Aldrich) was added to a solution of N-{1-[(2-chloro-4-hydroxyphenyl)methyl]-1H-pyrazol-3-yl}-2,6-difluorobenzamide (for a preparation see Example 31)(29.4 mg, 0.081 mmol) in DMSO (0.5 ml). The reaction was stirred for 5 min before adding 1-bromobutane (10.42 μL, 0.097 mmo, Acros). The reaction was stirred for 56 h at ambient temperature. The reaction mixture was diluted with methanol (0.5 ml) and the sample purified by MDAP on Sunfire C18 column using Acetonitrile-Water with a Formic acid modifier. (Method B). The solvent was evaporated in vacuo to give the title compound as a yellow gum (14.5 mg); LCMS: (System 4) MH+=420, tRET=3.45 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](/[CH:10]=[CH:11]\[C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[NH:24]([C:30]([O:32][CH2:33][CH:34]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:40]2[C:35]1=[CH:36][CH:37]=[CH:38][CH:39]=2)=[O:31])[C@H:25]([C:27](O)=[O:28])[CH3:26].C[N:48]([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(=O)([O-])O.[Na+]>CN(C)C=O>[NH2:1][C:2]1[CH:3]=[C:4](/[CH:10]=[CH:11]\[C:12]2[CH:13]=[C:14]([O:22][CH3:23])[C:15]([O:20][CH3:21])=[C:16]([O:18][CH3:19])[CH:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:30]([NH:24][C@H:25]([C:27]([NH2:48])=[O:28])[CH3:26])([O:32][CH2:33][CH:34]1[C:35]2[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:41]2[C:46]1=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:31]
Reactant: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: COc1ccc(/C=C\c2cc(OC)c(OC)c(OC)c2)cc1N
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(N)=O
Temperature: 60 °C
Yield: 41.5 %

Procedure:
(Z)-1-(3-Amino-4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-ethene (2.2 g, 6.9 mmols), 2.7 g (8.3 mmols) of Fmoc-L-Ala and 12.1 g (27.6 mmols) of a BOP reagent were dissolved in 22 ml of N,N-dimethylformamide, and the mixture was heated at 60° C. for 4 hours. After the reaction mixture was cooled, a saturated aqueous solution of sodium hydrogencarbonate was added thereto, and the resulting mixture was extracted three times with dichloromethane. The extract was dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The product was purified through silica-gel column chromatography (mixture of ethyl acetate and hexane at a ratio of 1:2) to produce 1.79 g of the final product in a yield of 41.4%.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[N:5]([NH2:12])[CH:4]=1)[CH3:2].[F:13][C:14]1[CH:15]=[C:16]([C:20]2[N:25]=[C:24]([CH3:26])[C:23]([C:27](O)=[O:28])=[CH:22][N:21]=2)[CH:17]=[CH:18][CH:19]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[N:5]([NH:12][C:27]([C:23]2[C:24]([CH3:26])=[N:25][C:20]([C:16]3[CH:17]=[CH:18][CH:19]=[C:14]([F:13])[CH:15]=3)=[N:21][CH:22]=2)=[O:28])[CH:4]=1)[CH3:2]
Reactant: CCc1cn(N)c2cnccc12
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1cn(NC(=O)c2cnc(-c3cccc(F)c3)nc2C)c2cnccc12
Reaction time: 1 h
Yield: 39.7 %

Procedure:
A mixture of 3-ethyl-pyrrolo[2,3-c]pyridin-1-ylamine (93 mg, 0.577 mmol), 2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (134 mg, 0.757 mmol), HATU (263 mg, 0.692 mmol) and DIPEA (223 mg, 1.73 mmol) in DMF (3 mL) is heated at 1500 C. for 1 h. The reaction is quenched with water and extracted with EtOAc. The organic layer is dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel column chromatography eluting with 0-100% ethyl acetate in heptane to afford 2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (3-ethyl-pyrrolo[2,3-c]pyridin-1-yl)-amide (86 mg). MS: 376 (M+H); 1H NMR (300 MHz, CD3OD): δ 9.15 (s, 1H), 8.69 (s, 1H), 8.37 (d, 1H), 8.15-8.26 (m, 2H), 7.70 (d, 1H), 7.55 (q, 1H), 7.49 (s, 1H), 7.29 (t, 1H), 2.80-2.90 (m, 5 H), 1.38 (t, 3H). IC50=7 nM.