Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]2[C:12]([CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[C:13]3[C:20]4[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:19]=4[CH2:18][N:17]([CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])[C:16](=[O:31])[CH2:15][N:14]3[C:32]=2[CH:33]=1)=[O:7])(C)(C)C>C(O)(C(F)(F)F)=O.O.[SiH](CC)(CC)CC>[Cl:25][C:23]1[CH:22]=[CH:21][C:20]2[C:13]3=[C:12]([CH:34]4[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]4)[C:11]4[CH:10]=[CH:9][C:8]([C:6]([OH:7])=[O:5])=[CH:33][C:32]=4[N:14]3[CH2:15][C:16](=[O:31])[N:17]([CH2:26][CH2:27][N:28]([CH3:29])[CH3:30])[CH2:18][C:19]=2[CH:24]=1
Reactant: CN(C)CCN1Cc2cc(Cl)ccc2-c2c(C3CCCCC3)c3ccc(C(=O)OC(C)(C)C)cc3n2CC1=O
Agent: CC[SiH](CC)CC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CCN1Cc2cc(Cl)ccc2-c2c(C3CCCCC3)c3ccc(C(=O)O)cc3n2CC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of tert-butyl-3-chloro-14-cyclohexyl-6-[2-(dimethylamino)ethyl]-7-oxo-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocine-11-carboxylate (from Step 9, 1 eq) in a mixture of TFA:H2O:Et3SiH (95:3:2) (0.03 M) was stirred at RT for 1 h. Volatiles were removed in vacuo and the residue purified by RP-HPLC to afford the title compound; MS (ES+) m/z 494 (M+H)+.
Reaction SMILES: I[C:2]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]([CH3:11])[N:3]=1.C([Mg]Cl)(C)C.[CH2:17]([Sn:21]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:23][CH2:24][CH2:25][CH3:26])Cl)[CH2:18][CH2:19][CH3:20]>C1COCC1>[CH3:11][N:4]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:2]([Sn:21]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:17][CH2:18][CH2:19][CH3:20])=[N:3]1
Reactant: Cn1nc(I)c2c1CCCC2
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2c1CCCC2
Temperature: -16 °C
Reaction time: 0.33 h

Procedure:
3-Iodo-1-methyl-4,5,6,7-tetrahydro-1H-indazole (300 mg, 1.14 mmol) was dissolved in THF (3.00 mL). The colorless solution was cooled to −16° C. (NaCl/ice bath). isopropylmagnesium chloride 2 M in THF (641 μL, 1.28 mmol.12) was added dropwise at −16° C. The reaction mixture was stirred at −16° C. for 20 min. Then, tributylchlorostannane (428 mg, 357 μL, 1.32 mmol. 15) was added slowly. The reaction mixture was warmed to 25° C. and stirred for 1.5 h. The reaction mixture was quenched with saturated ammonium chloride solution, extracted with dichloromethane (3×30 mL), organics dried over MgSO4 and concentrated to a yellow oil. The residue was dried under high vacuum yielding 1-methyl-3-(tributylstannyl)-4,5,6,7-tetrahydro-1H-indazole assumed quantitative and taken into next step without further treatment.
Reaction SMILES: Cl.[O:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH2:4][CH:3]1[CH2:12][NH2:13].[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[C:19]2[CH2:25][CH2:26][CH2:27]Br.C(N(C(C)C)CC)(C)C>CN(C=O)C>[O:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH2:4][CH:3]1[CH2:12][NH:13][CH2:27][CH2:26][CH2:25][C:19]1[C:18]2[C:22](=[CH:23][CH:24]=[C:16]([O:15][CH3:14])[CH:17]=2)[NH:21][CH:20]=1
Reactant: NCC1COc2ccccc2O1
Reactant: COc1ccc2[nH]cc(CCCBr)c2c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2[nH]cc(CCCNCC3COc4ccccc4O3)c2c1
Temperature: 80 °C
Yield: 33.6 %

Procedure:
2,3-Dihydro-1,4-benzodioxin-2-methanamine hydrochloride (2.3 g, 11.0 mmole) in DMF (100 ml) was slowly added to a mixture of 5-methoxy-3-(3-bromopropyl)indole (3.0 g, 11.0 mmole) and diisopropylethylamine (9.7 ml, 55 mmole) in 100 ml of DMF with stirring and the mixture was heated at 80° C. for 24 hours. Most of DMF was removed in vacuum and the residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The dichloromethane solution was dried over anhydrous sodium sulfate, filtered, concentrated in vacuum and chromatographed on silica gel using ethyl acetate as the eluant. The combined fractions of free base of the expected product (1.3 g, 3.7 mmole, 34%) were concentrated, treated with 0.25M of fumaric acid in ethanol (8.1 ml, 2.0 mmole) and diluted first with 50 ml of ethanol-diethyl ether (1:1) and then with a minimum amount of hexane to precipitate the title compound as a white solid, (2:1) fumarate salt, m.p. 135°-136° C.
Reaction SMILES: [F:1][C:2]([F:52])([F:51])[C:3]1[CH:4]=[C:5]([CH:48]=[CH:49][CH:50]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])[CH:19]=[CH:18][C:17]=2[NH:28][C:29]([C:31]2[CH:32]=[C:33]([CH:45]=[CH:46][CH:47]=2)[CH2:34][S:35][CH2:36][CH2:37][C:38]([O:40]C(C)(C)C)=[O:39])=[O:30])[CH:11]=1)=[O:9].FC(F)(F)C(O)=O>ClCCl>[F:52][C:2]([F:1])([F:51])[C:3]1[CH:4]=[C:5]([CH:48]=[CH:49][CH:50]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([O:22][CH2:23][C:24]([F:26])([F:25])[F:27])[CH:19]=[CH:18][C:17]=2[NH:28][C:29]([C:31]2[CH:32]=[C:33]([CH:45]=[CH:46][CH:47]=2)[CH2:34][S:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:30])[CH:11]=1)=[O:9]
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(OCC(F)(F)F)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(OCC(F)(F)F)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.4 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of tert-butyl 3-(3-((2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(2,2,2-trifluoro ethoxy)phenyl)-carbamoyl)benzylthio)propanoate (200 mg, 0.27 mmol, 1.00 equiv) in dichloromethane (5 mL), and trifluoroacetic acid (2 mL). The resulting solution was stirred overnight at room temperature. The reaction progress was monitored by LCMS. The resulting mixture was concentrated under vacuum. The crude product (200 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 68 mg (37%) of a light yellow solid. 1H-NMR (300 MHz, DMSO-d6, ppm): δ 12.61 (s, 1H), 9.57-9.54 (m, 1H), 8.99-8.98 (m, 1H), 8.49-8.41 (m, 2H), 7.89-7.79 (m, 10H), 7.30-7.26 (m, 1H), 4.92-4.84 (dd, J=18 Hz, 9 Hz, 2H), 4.65-4.63 (d, J=5.4 Hz, 2H), 3.89 (s, 2H), 2.63-2.59 (m, 4H). MS (ES, m/z): 692 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]([CH2:32][CH2:33]C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)[C:29]([OH:31])=[O:30])[C:7]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)([CH3:12])[CH2:8][S:9]2)=[CH:4][CH:3]=1.[F:47][C:48]([F:75])([C:65]([F:74])([F:73])[C:66]([F:72])([F:71])[C:67]([F:70])([F:69])[F:68])[CH2:49]CCC(CCCCCC=C)C(OCC)=O>>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]([CH2:32][CH2:33][CH2:49][C:48]([F:47])([F:75])[C:65]([F:73])([F:74])[C:66]([F:71])([F:72])[C:67]([F:70])([F:69])[F:68])[C:29]([OH:31])=[O:30])[C:7]([C:13]3[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=3)([CH3:12])[CH2:8][S:9]2)=[CH:4][CH:3]=1
Reactant: C=CCCCCCC(CCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)OCC
Reactant: CC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCCCCCCC(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)O
Product: CC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCCCCCCC(CCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)O

Procedure:
Starting with the allyl compound prepared in Example 8 and the ethyl 2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)-8-nonenoate prepared in Example 4, a procedure analogous to that as shown in Example 8 was repeated to give 10-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)decanoic acid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:26])=[C:8]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[NH:9][C:10]=1[CH2:11][CH2:12][CH2:13]OS(C)(=O)=O)=[O:5])[CH3:2].[CH3:27][N:28]([CH3:32])[CH2:29][CH2:30][NH2:31].C(OCC)(=O)C>[Cl-].[Na+].O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:26])=[C:8]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[NH:9][C:10]=1[CH2:11][CH2:12][CH2:13][NH:31][CH2:30][CH2:29][N:28]([CH3:32])[CH3:27])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(CCCOS(C)(=O)=O)[nH]c(C(=O)OC(C)(C)C)c1C
Reactant: CN(C)CCN
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1c(CCCNCCN(C)C)[nH]c(C(=O)OC(C)(C)C)c1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 59.7 %

Procedure:
5-(3-Methanesulfonyloxy-propyl)-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 1 g (11.964 g, 25.7 mmol) obtained from step 6 of Example 1 was dissolved in N,N-dimethylethylenediamine (12 ml, 97 mmol), the resulting solution was stirred for 5 hours at room temperature. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was added with ethyl acetate (80 ml) and saturated brine (80 ml), stirred for 5 minutes, and separated into layers. The organic phase was washed with saturated brine (80 ml×4) to remove N,N-dimethylethylenediamine, dried over anhydrous magnesium sulfate, filtered to remove the drying agent and concentrated under reduced pressure to obtain brown oil. The residue was purified by silica gel column chromatography to obtain the title compound 5-[3-(2-dimethylamino-ethylamino)-propyl]-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 23a (5.85 g, yield 45.9%) as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([NH:6][C:7]([CH3:13])([CH3:12])[C:8]([O:10][CH3:11])=[O:9])=[O:5].C([O-])([O-])=O.[K+].[K+].Cl[CH2:25][CH:26]1[CH2:28][O:27]1>C(#N)C.CCOC(C)=O>[CH3:13][C:7]([NH:6][C:4](=[O:5])[C:3]1[CH:14]=[CH:15][CH:16]=[CH:17][C:2]=1[O:1][CH2:25][CH:26]1[CH2:28][O:27]1)([CH3:12])[C:8]([O:10][CH3:11])=[O:9]
Reactant: ClCC1CO1
Reactant: COC(=O)C(C)(C)NC(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)C(C)(C)NC(=O)c1ccccc1OCC1CO1
Yield: 5 %

Procedure:
A solution of methyl 2-[(2-hydroxybenzoyl)amino]-2-methylpropanoate, K2CO3 (20 mmol, 2.68 g) and 2-(chloromethyl)oxirane (22 mmol, 2.03 g) in acetonitrile (60 ml) was stirred at reflux temperature overnight. The reaction mixture was diluted with EtOAc and washed with 1.8% HCl/aq (250 ml) and sat. NaCl/aq (250 ml). The organic phase was dried over Na2SO4 and concentrated at reduced pressure. The residue was purified on C18-column (H2O:CH3CN, 0.1M NH4OAc buffer, gradient 10% to 95% CH3CN) to give the subtitle compound (244 mg, 5% yield, two steps).
Reaction SMILES: [H-].[Na+].[CH:3]([C:6]1[C:14]([CH:15]([OH:19])[CH:16]([CH3:18])[CH3:17])=[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][N:8]2[N:7]=1)([CH3:5])[CH3:4].[CH3:20]I.[Cl-].[NH4+]>O1CCCC1>[CH:3]([C:6]1[C:14]([CH:15]([O:19][CH3:20])[CH:16]([CH3:18])[CH3:17])=[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][N:8]2[N:7]=1)([CH3:5])[CH3:4]
Reactant: CC(C)c1nn2ccccc2c1C(O)C(C)C
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(c1c(C(C)C)nn2ccccc12)C(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 88 %

Procedure:
To a suspension of 1.24 g of sodium hydride (55% oil suspension) in 20 ml of tetrahydrofuran was slowly added a solution of 3 g of 2-isopropyl-3-(1-hydroxy-2-methylpropyl)pyrazolo[1,5-a]pyridine in 5 ml of dry tetrahydrofuran under stirring and cooling. After the addition was completed, the stirring was continued for 5 minutes at room temperature, then reflux temperature for 15 minutes. The mixture was cooled with ice-water, to which 5.5 g of methyl iodide were added, and stirred for an hour at room temperature. After treating with aqueous 20% ammonium chloride solution, the mixture was extracted with ether. The ether layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to dryness. The residue was applied to silica gel column chromatography, eluted with ethyl acetate-benzene (1:4) to give 2.8 g (88%) of the desired product as pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:15][CH2:14][C@H:13]3[C@@H:8]([CH2:9][CH2:10][C:11](=O)[NH:12]3)[C:7]=2[CH:17]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:15][CH2:14][C@H:13]3[C@@H:8]([CH2:9][CH2:10][CH2:11][NH:12]3)[C:7]=2[CH:17]=1
Reactant: COc1ccc2c(c1)[C@@H]1CCC(=O)N[C@H]1CC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(c1)[C@@H]1CCCN[C@H]1CC2

Procedure:
A solution of 8.3 g of the compound obtained in Step B in 83 ml of tetrahydrofuran is added dropwise to a suspension of 6.2 g of lithium aluminium hydride. After 18 hours' reflux, the mixture is hydrolysed in succession by 4.1 ml of water, 3.3 ml of 20% sodium hydroxide solution and 15.4 ml of water. After filtering off the mineral salts, then concentrating the filtrate using a rotary evaporator, 4.5 g of the expected product are obtained.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][N:15]=1.[C:20]([C:22]1[CH:36]=[CH:35][C:25]([O:26][C:27]([CH3:34])([CH3:33])[C:28](OCC)=[O:29])=[CH:24][CH:23]=1)#[N:21]>CCCCCC.O1CCCC1>[OH:29][C:28](=[CH:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][N:15]=1)[C:27]([CH3:34])([CH3:33])[O:26][C:25]1[CH:35]=[CH:36][C:22]([C:20]#[N:21])=[CH:23][CH:24]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(C#N)cc1
Reactant: Cc1ccncn1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(Oc1ccc(C#N)cc1)C(O)=Cc1ccncn1
Temperature: -78 °C

Procedure:
10 ml of a 1.2M solution of butyllithium in n-hexane were added to a solution of 1.68 ml of diisopropylamine in 50 ml of tetrahydrofuran while stirring at -78° C. under a nitrogen atmosphere. The solution was stirred for a further 15 minutes and a solution of 4-methylpyrimidine in 20 ml of tetrahydrofuran was then added. The solution was allowed to warm to 20° C. and was stirred for 2 hours. The solution was then cooled to -78° C., 2.33 g of ethyl 2-(4-cyanophenoxy)-2-methylpropionate in 30 ml of tetrahydrofuran were added to and the mixture was allowed to warm to 20° C. and was stirred for 16 hours. The mixture was then partitioned between ethyl acetate and water. The organic phase was washed with sodium chloride solution and evaporated. The residue was chromatographed on silica gel using ethyl acetate for the elution to give 0.69 g of 4-[2-hydroxy-1,1-dimethyl-3-(4-pyrimidinyl)-2-propenyloxy]benzonitrile in the form of a yellow solid of melting point 115°-117° C. (from ethyl acetate/n-hexane).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.[CH3:12][C:13]([C:15]1[CH:20]=[CH:19][C:18](F)=[CH:17][CH:16]=1)=[O:14].O>CN(C)C=O.C(OCC)(=O)C>[N:6]1([CH2:5][CH2:4][O:3][C:18]2[CH:19]=[CH:20][C:15]([C:13](=[O:14])[CH3:12])=[CH:16][CH:17]=2)[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1
Reactant: OCCN1CCOCC1
Reactant: CC(=O)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1ccc(OCCN2CCOCC2)cc1
Temperature: 0 °C

Procedure:
Sodium hydride (3.18 g; 0.0795 mol of a powder dispersed at 60%) is added at 23° C. to a solution containing 4-(2-hydroxyethyl)morpholine (9.40 g, 0.072 mol) in dimethylformamide (60 ml). Stirring is maintained for 30 minutes then the compound 4-fluoroacetophenone (5 g, 0.0362 mol) is added. The reaction medium is stirred for one hour at 23° C. then cooled down to 0° C. and water is added. After the addition of ethyl acetate then extraction, the organic phase is washed with a saturated sodium chloride solution, dried over sodium sulphate then the solvent is evaporated off. The residue obtained is adsorbed on silica then purified by chromatography on a Biotage-type silica column (eluent: ethyl acetate-heptane: 6-1). An orange-coloured oil is obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[CH2:9][C@@H:10]3[CH2:14][C@@H:11]3[C:12]=2[CH:13]=1)=[O:5])C.[OH-].[Li+]>>[CH2:14]1[C@H:10]2[CH2:9][C:8]3[NH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:13][C:12]=3[C@@H:11]12
Reactant: CCOC(=O)c1cc2c([nH]1)C[C@@H]1C[C@H]21
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)c1cc2c([nH]1)C[C@@H]1C[C@H]21

Procedure:
The title compound was synthesized from ±(1aS,5aS)-1a,4,5,5a-tetrahydro-1H-4-aza-cyclopropa[α]pentalene-3-carboxylic acid ethyl ester (65 mg, 0.34 mmol) and lithium hydroxide (143 mg, 3.40 mmol in 5 mL water), according to General Procedure 7. The resulting product was purified by crystallization from Et2O. 35 mg. 1H NMR (METHANOL-d4) δ: 6.61 (s, 1H), 2.90 (dd, J=16.7, 6.3 Hz, 1H), 2.69 (d, J=16.7 Hz, 1H), 1.88-2.02 (m, 2H), 0.95-1.04 (m, 1H), 0.07 (q, J=4.0 Hz, 1H). LCMS m/e 164 (M+H). Purity ˜100% (HPLC).
Reaction SMILES: [CH3:1][C@H:2]([CH2:6][CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:3][CH2:4][OH:5].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.N1C=CC=CC=1>C(Cl)(Cl)Cl>[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18]([O:5][CH2:4][CH2:3][C@H:2]([CH3:1])[CH2:6][CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: CC(C)CCC[C@@H](C)CCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)OCC[C@H](C)CCCC(C)C)cc1
Temperature: 0 °C
Reaction time: 20 h
Yield: 89 %

Procedure:
A solution of 6.5 g (41 mmol) of (R)-3,7-dimethyl-1-octanol and 7.8 g (41 mmol) of p-toluenesulphonyl chloride in 50 ml of absolute chloroform is treated at 0° with 7.9 g (0.1 mol) of absolute pyridine. The mixture is subsequently stirred at 4° for 20 hours. For the working-up the mixture is poured on to 500 g of ice and extracted three times with chloroform. The combined organic phases are washed first with cold 1-N hydrochloric acid, then with saturated aqueous sodium bicarbonate solution and subsequently with saturated aqueous common salt solution. After drying over potassium carbonate and removal of the solvent under reduced pressure, the crude product is chromatographed on 300 g of silicagel with benzene. There are obtained 11.4 g (89%) of (R)-3,7-dimethyl-1-octanol p-toluenesulphonate; [α]D20 =+2.0 (c=4.0, benzene).
Reaction SMILES: [N:1]1([C:8]([NH:10][C@@H:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([OH:14])=O)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.[CH2:26]([O:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][C@H:41]([NH2:48])[CH2:42][N:43]([CH2:46][CH3:47])[CH2:44][CH3:45])=[CH:36][CH:35]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(OCC)C>CN(C=O)C>[CH2:26]([O:33][C:34]1[CH:35]=[CH:36][C:37]([CH2:40][C@H:41]([NH:48][C:12]([C@@H:11]([NH:10][C:8]([N:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]2)=[O:9])[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:14])[CH2:42][N:43]([CH2:46][CH3:47])[CH2:44][CH3:45])=[CH:38][CH:39]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)O
Reactant: CCN(CC)C[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CN1CCOCC1
Product: CCN(CC)C[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)[C@H](CC(C)C)NC(=O)N1CCCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.2 %

Procedure:
A solution of 53 mg (0.20 mmol) of (S)-2-[(azepane-1-carbonyl)-amino]-4-methyl-pentanoic acid (Example 1, Step B) and 0.079 mL (7.2 mmol) 4-methylmorpholine in 4 mL DMF was stirred at 25° C. for 0.5 hour, and 82 mg (0.21 mmol) 0-benzotriazol-1-yl-N,N,N′,N′-bis(tetramethylene)uronium hexafluorophosphate was added. The resulting solution was cooled in an ice-bath and stirred 30 minutes, after which 64 mg (0.20 mmol) of (S)-3-(4-benzyloxy-phenyl)-N1,N1-diethyl-propane-1,2-diamine in 2 mL DMF was added. The resulting solution was warmed to 25° C. and stirred for 30 minutes. The mixture was then poured into 30 mL diethyl ether, and washed with 25 mL each of 5% HCl solution, brine, saturated aqueous sodium bicarbonate solution, and finally twice with brine. The mixture was dried over anhydrous sodium sulfate and concentrated at reduced pressure to give a clear, colorless oil that was purified by preparative thin-layer chromatography on a 500 μm silica gel plate using 50:50:1 ethyl acetate:hexane:methanol as eluant to give 21.2 mg (19%) of the title compound as a clear, colorless oil.
Reaction SMILES: [CH:1](=[O:10])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[H-].[H-].[H-].[H-].[Li+].[Al+3].C(OCC)(=O)C>CCOCC>[CH2:1]([OH:10])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCC/C=C/C=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCCCCC/C=C/CO

Procedure:
Trans-2-nonenal (7.0 g, 0.05 mole) is dissolved in 50 ml of ether and added to a solution of LiAlH4 (0.54 g, 0.014 mole) in 50 ml of ether at such a rate to maintain gentle refluxing. When the addition is complete, the solution is refluxed for one hour. Ethyl acetate (2 ml) is added to destroy excess LiAlH4. The mixture is acidified with 5M HCl. The ether layer is separated, washed 2X with water, and dried over sodium sulfate. The ether solution is concentrated and the residue vacuum distilled to yield trans-2-nonenol.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[C:13](Cl)(Cl)=[S:14]>O>[N:1]([C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1)=[C:13]=[S:14]
Reactant: Nc1ccc2c(c1)NC(=O)CC2
Reactant: S=C(Cl)Cl
Solvent: O
Product: O=C1CCc2ccc(N=C=S)cc2N1
Reaction time: 0.75 h

Procedure:
To a suspension containing 5,4 g of 7-amino-3,4-dihydro-2(1H)quinolone in 70 ml of water was added while stirring and cooling (0° C.) 4.0 ml of thiophosgene. Stirring was continued for 45 min at room temperature and product filtered and washed with water. Yield 5.8 g (87%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:15])=O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([Cl:15])=[O:12])=[CH:4][CH:3]=1
Reactant: O=C(O)CCc1ccc(Cl)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Cl)CCc1ccc(Cl)cc1
Temperature: 25 °C
Yield: 87.6 %

Procedure:
To a solution of 3-(4-chloro-phenyl)-propionic acid (1.5 g, 8.15 mmol) in benzene (50 mL) is added thionyl chloride (1.18 mL, 16.3 mmol). The resulting solution is heated to reflux for twenty-four hours and then cooled to room temperature. The solvents are removed under reduced pressure to afford 1.45 g (88% yield) of the desired compound as a colorless oil. The crude product is used without further purification. 1H NMR (CDCl3 300 MHz) δ 3.01 (t, J=7.2 Hz, 2H), 3.22 (t, J=6.9 Hz, 2H), 7.12–7.20 (m, 2H), 7.26–7.35 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[C:4]([CH3:12])[C:3]=1[CH:13]1[CH2:15][O:14]1.C([Sn](CCCC)(CCCC)C(OCC)=C)CCC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[C:13]([C:3]1[C:4]([CH3:12])=[CH:5][C:6]2[C:7](=[O:11])[O:8][CH2:9][C:10]=2[C:2]=1[CH3:1])(=[O:14])[CH3:15]
Reactant: Cc1cc2c(c(C)c1C1CO1)COC2=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC(=O)c1c(C)cc2c(c1C)COC2=O
Temperature: 110 °C
Reaction time: 1 h

Procedure:
To a 20 mL microwave tube containing a stir bar were added 4,6-dimethyl-5-oxiran-2-yl-2-benzofuran-1(3H)-one (from the synthesis of INTERMEDIATE 9, 1.0 g, 4.2 mmol), tetrakis(triphenylphosphine)palladium (0) (0.240 g, 0.207 mmol), and tributyl(1-ethoxy-vinyl)tin (2.20 g, 6.22 mmol); to the mixture was added anahydrous toluene (18 mL) and the tube was capped, degassed and purged with N2. The tube was then placed in an oil bath and heated at 110° C. for 12 h; LC indicated some product formation. The tube was taken out of the oil bath and cooled to room temperature. The solution was concentrated to dryness under reduced pressure and the resulting residue was then treated with 4M HCl (10 mL); the resulting solution was stirred at room temperature for 1 h; LC analysis indicated completion of the reaction. The solution was concentrated to dryness and the residue was re-dissolved in DCM, was absorbed in silica gel and was then loaded into silica column for separation with the solvent systems of Hexanes/EtOAc (1/1); this yielded 5-acetyl-4,6-dimethyl-2-benzofuran-1(3H)-one.