Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[CH2:2][C@@H:3]([OH:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C-:11]#[N:12].[Na+]>CS(C)=O>[C:11]([CH2:2][CH:3]([OH:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])#[N:12]
Reactant: [C-]#N
Reactant: CCOC(=O)C[C@H](O)CI
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)CC(O)CC#N

Procedure:
The recombinant E. coli HB101 (pNTS1G) obtained in Example 10 was inoculated in 100 ml of a 2×YT medium sterilized in a 500 ml Sakaguchi flask, and cultured with agitation at 37° C. for 13 hours. Glucose, 0.5 g, 3.2 mg of NADP, and then 0.5 g of ethyl 4-iodoacetoacetate were added to 50 ml of the resultant culture. The culture was stirred at 30° C. while being adjusted at pH 6.5 with a 5 M sodium hydroxide solution to allow for reaction for 72 hours. After the reaction, the reaction solution was subjected to extraction using ethyl acetate, the solvent was removed under decompression, and the concentrate was purified by silica gel column chromatography, to obtain 900 mg of ethyl (S)-4-iodo-3-hydroxybutyrate. The optical purity of the ethyl (S)-4-iodo-3-hydroxybutyrate was analyzed as follows and found to be 91.6% e.e. That is, the sample was heated together with sodium cyanide in dimethyl sulfoxide to obtain ethyl 4-cyano-3-hydroxybutyrate, which was then changed to a benzoic ester using benzoyl chloride under the presence of pyridine. The optical purity of the benzoic ester was measured by an HPLC method. NMR(CDCl3) δ (ppm): 1.28(3H,t), 2.65(2H,d), 3.31(3H,m), 4.00(1H,m), 4.20(2H,q); Column: Chiralpak AS (0.46×25 cm) manufactured by Daicel Chemical Industries, Co., Ltd.; Column temperature: 25° C.; Eluent: n-hexane/ethanol of 95/5; Flow rate: 1 ml/min.; Detection: 254 nm; Elution time: 19.6 minutes for (S), 21.3 minutes for (R).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:28][C@H:29]4[CH2:34][CH2:33][C@H:32]([CH3:35])[CH2:31][CH2:30]4)[C:15]([N:17]4[CH2:22][C:21](=[O:23])[N:20]([CH3:24])[C@H:19]5[CH2:25][CH2:26][CH2:27][C@H:18]45)=[N:16][C:12]=3[CH:11]=[C:10]([C:36](=[N:38][OH:39])[NH2:37])[N:9]=2)[CH:5]=[N:6][CH:7]=1.[CH3:40][OH:41]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:28][C@H:29]4[CH2:34][CH2:33][C@H:32]([CH3:35])[CH2:31][CH2:30]4)[C:15]([N:17]4[CH2:22][C:21](=[O:23])[N:20]([CH3:24])[C@H:19]5[CH2:25][CH2:26][CH2:27][C@H:18]45)=[N:16][C:12]=3[CH:11]=[C:10]([C:36]3[NH:37][C:40](=[O:41])[O:39][N:38]=3)[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CN1C(=O)CN(c2nc3cc(C(N)=NO)nc(-c4cncc(Cl)c4)c3n2C[C@H]2CC[C@H](C)CC2)[C@H]2CCC[C@@H]21
Reactant: CO
Solvent: ClCCl
Product: CN1C(=O)CN(c2nc3cc(-c4noc(=O)[nH]4)nc(-c4cncc(Cl)c4)c3n2C[C@H]2CC[C@H](C)CC2)[C@H]2CCC[C@@H]21

Procedure:
(4aS,7aS)-4-[4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl]-1-methyloctahydro-2H-cyclopenta[b]pyrazin-2-one was prepared in analogy to Example 3.1, Step 3 using 4-(5-chloropyridin-3-yl)-N′-hydroxy-3-[(trans-4-methylcyclohexyl)methyl]-2-[(4aS,7aS)-4-methyl-3-oxooctahydro-1H-cyclopenta[b]pyrazin-1-yl]-3H-imidazo[4,5-c]pyridine-6-carboximidamide (197 mg, 0.357 mmol) as starting material and 0-20% methanol in DCM as eluant for chromatography. MS ESI calc'd. for C29H33ClN8O3 [M+H]+ 577. found 577. 1H NMR (500 MHz, DMSO-d6) δ 12.89 (s, 1H), 8.98 (d, J=2.0 Hz, 1H), 8.81 (d, J=2.0 Hz, 1H), 8.49 (t, J=2.0 Hz, 1H), 8.04 (s, 1H), 4.31-4.28 (m, 1H), 3.88-3.84 (m, 2H), 3.69-3.61 (m, 3H), 2.88 (s, 3H), 2.34-2.24 (m, 1H), 2.31-2.04 (m, 1H), 1.89-1.75 (m, 2H), 1.70-1.61 (m, 1H), 1.47-1.33 (m, 3H), 1.25-1.20 (m, 2H), 1.08-0.98 (m, 1H), 0.85-0.82 (m, 1H), 0.73-0.60 (m, 5H), 0.62-0.33 (m, 2H).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:8]=[CH:7][C:6]=1[CH:15]1[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][OH:22])[CH2:16]1.CC(C)=[O:25]>S(=O)(=O)(O)O.[O-2].[Cr+6].[O-2].[O-2]>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:8]=[CH:7][C:6]=1[CH:15]1[CH2:20][CH2:19][CH2:18][CH:17]([C:21]([OH:25])=[O:22])[CH2:16]1
Reactant: COCOc1ccc(C2CCCC(CO)C2)c(OCOC)c1
Reactant: CC(C)=O
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Product: COCOc1ccc(C2CCCC(C(=O)O)C2)c(OCOC)c1
Reaction time: 3 h
Yield: 29 %

Procedure:
A solution of (±)-{3-[2,4-bis(methoxymethoxy)phenyl]cyclohexyl}methanol (50 mg) in acetone (1 ml) was added to a stirred solution of chromium (VI) oxide (64 mg) in 2M sulfuric acid (0.64 ml) at 0° C. over 3 hr. After 3 hr at 0° C. and then 16 hr at room temperature, the reaction mixture was partitioned between water (10 ml) and ethyl acetate (20 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×20 ml). The combined organic extracts were washed with water (20 ml), dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate/petrol, 4:1 v/v) to give the title compound as a colourless oil (15 mg, 29%). Rf (ethyl acetate/petrol, 4:1 v/v) 0.5.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:10][C:11]([CH3:20])([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12]I>>[CH3:10][C:11]([CH3:20])([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][O:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: CCCCCCC(C)(C)CI
Reactant: O=Cc1ccccc1O
Product: CCCCCCC(C)(C)COc1ccccc1C=O

Procedure:
2-Hydroxybenzaldehyde was condensed with 2,2-dimethyl-1-iodo octane to yield 2-(2,2-dimethyl octyloxy) benzaldehyde which was reduced to 2-(2,2-dimethyl, octyloxy)benzyl alcohol and then converted to [[2-(2,2-dimethyloctyloxy)phenyl]methyl]triphenylphosphonium bromide as in Example 1. Condensation of this phosphonium bromide with 7-formyl-3-methyl-2,4,6-octatrienoic acid ethyl ester as described in Example 3 followed by hydrolysis, as in Example 5, gave the (All-E)-3,7-Dimethyl-9-[2-[2,2-dimethyl-octyl)oxy]phenyl]-2,4,5,8-atetraehoic acid mp 113-117° (from dichloromethane/hexane mixture).
Reaction SMILES: NC1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.[OH-].[K+].C(O)(=O)C>O.C(O)CO>[NH2:6][C:5]1[CH:7]=[CH:8][C:9]([O:11][C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)=[CH:10][C:4]=1[SH:3]
Reactant: Nc1nc2ccc(Oc3ccc(F)cc3)cc2s1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: OCCO
Solvent: O
Product: Nc1ccc(Oc2ccc(F)cc2)cc1S
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.5 %

Procedure:
22 g of 2-amino-6-(4-fluorophenoxy)benzothiazole (prepared as described in preparation 7) were added to a mixture of a solution of 90 g of potassium hydroxide in 100 ml of water and 28 ml of ethylene glycol, and the mixture was stirred for 2 hours on an oil bath kept at 130° C under an atmosphere of nitrogen. After the mixture had been cooled to room temperature, 90 ml of acetic acid was added dropwise to the resulting homogenous solution to deposit a precipitate: this was extracted with toluene. The toluene extract was dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure, to afford 16 g of the title compound as a pale yellow solid.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[N:30]1([C:35]([C@H:37]2[CH2:41][CH2:40][NH:39][CH2:38]2)=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:39]4[CH2:40][CH2:41][C@H:37]([C:35]([N:30]5[CH2:31][CH2:32][CH2:33][CH2:34]5)=[O:36])[CH2:38]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: O=C([C@H]1CCNC1)N1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC[C@H](C(=O)N4CCCC4)C3)n(C)c2n1
Reaction time: 18 h
Yield: 93.4 %

Procedure:
A solution of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (100 mg, 0.26 mmol) and pyrrolidin-1-yl-(S)-pyrrolidin-3-ylmethanone (51 mg, 0.30 mmol) in DCE (5 mL) was stirred at ambient temperature for 2 h. Sodium triacetoxyborohydride (96 mg, 0.45 mmol) was added and the mixture stirred for 18 h, then loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:MeOH; gradient from 100:0 to 70:30) to afford 399 as a white solid (132 mg, 86%). LCMS (Method G): RT=6.43 min, M+H+=544. 1H NMR (CDCl3, 400 MHz) δ 7.99 (m, 1 H); 7.75 (m, 1 H); 7.27 (m, 2 H); 4.35 (m, 4 H); 3.94 (s, 2 H); 3.87 (m, 7 H); 3.50-3.38 (m, 4 H); 3.35 (q, J=7.5 Hz, 2 H); 3.20-3.10 (m, 1 H); 3.01 (m, 1 H); 2.87 (m, 2 H); 2.72 (m, 1 H); 2.16-2.07 (m, 2 H); 2.01-1.90 (m, 2 H); 1.91-1.81 (m, 2 H) and 1.45 (t, J=7.5 Hz, 3 H)
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].Cl.[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([C@H:23]([NH2:25])[CH3:24])=[N:21][CH:22]=1.C(Cl)CCl.ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]([NH:25][C@@H:23]([C:20]2[CH:19]=[CH:18][C:17]([O:16][CH3:15])=[CH:22][N:21]=2)[CH3:24])=[O:13])=[CH:8][CH:9]=1)([CH3:2])[CH3:3]
Reactant: COc1ccc([C@@H](C)N)nc1
Reactant: CC(C)c1ccc(CC(=O)O)cc1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1ccc([C@@H](C)NC(=O)Cc2ccc(C(C)C)cc2)nc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a suspension of 4-isopropylphenylacetic acid (2.5 g, 14.0 mmol), (1R)-1-(5-methoxypyridin-2-yl)ethylamine hydrochloride (3.2 g, 16.8 mmol), EDC (3.24 g, 16.9 mmol), and 1-hydroxy-7-azabenzotriazole (2.3 g, 16.8 mmol) in DMF (60 mL) was added N,N-diisopropylethylamine (5.2 mL, 29.6 mmol). The reaction mixture was stirred at room temperature for 2.5 h and then concentrated to 20 mL and diluted with CH2Cl2 (100 mL). The solution was washed with water (100 mL) and the aqueous layer was extracted with CH2Cl2 (2×75 mL). The combined organic layer was washed with water (100 mL), dried over MgSO4, concentrated and purified by normal phase chromatography (10-100% EtOAc/Hexanes) to give of 2-(4-isopropylphenyl)-N-[(1R)-1-(5-methoxypyridin-2-yl)ethyl]acetamide as a pale yellow solid. 1H NMR (CDCl3, 400 MHz) δ 8.14 (d, J=2.56 Hz, 1H), 7.20 (m, 4H), 7.13 (m, 2H), 6.69 (d, J=6.78 Hz, 1H), 5.08 (quint., J=6.96 Hz, 1H), 3.84 (s, 3H), 3.55 (s, 2H), 2.90 (sept., J=6.96 Hz, 1H), 1.39 (d, J=6.77 Hz, 3H), 1.25 (d, J=6.96 Hz, 6H); MS (Electrospray): m/z 313.4 (M+H).
Reaction SMILES: [CH:1](=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br:11]Br.C([O-])([O-])=O.[K+].[K+].O>C(O)(=O)C>[Br:11][C:2](=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH:1]=[O:10]
Reactant: O=CC=Cc1ccccc1
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: O=CC(Br)=Cc1ccccc1

Procedure:
1.33 g (10 mmol) cinnamaldehyde was dissolved in 5 mL glacial acetic acid and cooled on an ice-water bath. 1.62 g bromine was added, and anhydrous K2CO3 was then added, and it was stirred until no gas was evolving. After refluxing for 30 min, the reaction mixture was poured into 100 mL cold water with stirring, extracted with 50 mL ethyl ether three times. The combined ethyl ether layers were washed with water one time, saturated aqueous NaCl solution one time, dried over MgSO4 for 2 hours, filtrated, and the filtrate was dried under vacuum, and washed with anhydrous ethyl ether: petroleum ether (1:1) to give the title compound as light yellow powder.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[CH2:6][CH2:5]2.[CH2:14]([CH:16]1[CH2:21][C:20]([OH:29])([C:22]2[CH:27]=[CH:26][CH:25]=[C:24](I)[CH:23]=2)[CH2:19][CH2:18][O:17]1)[CH3:15]>>[CH2:14]([CH:16]1[CH2:21][C:20]([OH:29])([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([S:1][C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[N:8]([CH3:12])[C:7](=[O:13])[CH2:6][CH2:5]4)[CH:23]=2)[CH2:19][CH2:18][O:17]1)[CH3:15]
Reactant: CN1C(=O)CCc2cc(S)ccc21
Reactant: CCC1CC(O)(c2cccc(I)c2)CCO1
Product: CCC1CC(O)(c2cccc(Sc3ccc4c(c3)CCC(=O)N4C)c2)CCO1
Yield: 63 %

Procedure:
Using an analogous procedure to that described in Example 6, 6-mercapto-1-methyl-1,2,3,4-tetrahydroquinolin-2-one was reacted with (2SR,4RS)-2-ethyl-4-hydroxy-4-(3-iodophenyl)tetrahydropyran to give (2SR,4RS)-2-ethyl-4-hydroxy-4-[3-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-ylthio)phenyl]tetrahydropyran in 63% yield as a gum;
Reaction SMILES: [CH2:1]([N:3]([CH2:33][CH3:34])[CH2:4][CH2:5][N:6]1[C:14]2[CH:13]=[CH:12][C:11]([NH:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][O:20]C3=O)=[C:10]3[S:24][C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=4[C:8]([C:9]=23)=[N:7]1)[CH3:2].[OH-].[K+].O>CO.C1COCC1>[CH2:33]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]1[C:14]2[CH:13]=[CH:12][C:11]([NH:15][CH2:16][CH2:17][NH:18][CH2:22][CH2:21][OH:20])=[C:10]3[S:24][C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=4[C:8]([C:9]=23)=[N:7]1)[CH3:34]
Reactant: CCN(CC)CCn1nc2c3c(c(NCCN4CCOC4=O)ccc31)Sc1ccc(OC)cc1-2
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCN(CC)CCn1nc2c3c(c(NCCNCCO)ccc31)Sc1ccc(OC)cc1-2
Yield: 82.6 %

Procedure:
A mixture of 8.0 g (0.017 mol) of 3-[2-[[2[2-(diethylamino)ethyl]-9-methoxy-2H[1]benzothiopyrano-[4,3,2-cd]indazol-5-yl]amino]ethyl]-2-oxazolidinone, 70 ml of 2N KOH in MeOH, 35 ml of THF, and 35 ml of H2O was treated and the product isolated as described in Example 56 to furnish 6.4 g of the product, mp 111°-115° C.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1.[Br:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1.Cl>C(OCC)C>[Br:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]([C:3]2[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=2)[OH:16])=[CH:13][CH:12]=1
Reactant: Cc1ccc(Br)cc1
Reactant: O=Cc1ccc(Br)cc1
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: Cc1ccc(C(O)c2ccc(Br)cc2)cc1
Reaction time: 1 h
Yield: 306.7 %

Procedure:
Magnesium turnings (0.39 g, 0.016 mol) were dried in a flask and then cooled under nitrogen. Anhydrous diethyl ether (3 mL) was added, followed by 4-bromotoluene (3.0 g, 1.8 mmol). The mixture was refluxed, and more anhydrous diethyl ether was added to keep the solution volume constant. The resultant Grignard solution was added dropwise to a solution of 4-bromobenzaldehyde (1.66 g, 9.0 mmol) in anhydrous diethyl ether(6 mL). The reaction was heated with reflux for 30 minutes, following which it was cooled. The cooled solution was poured into a solution of hydrochloric acid (HCl) (3.7 milliliters (mL) concentrated HCl in 17 grams of ice-water) and stirred for 1 hour (h). The resulting mixture was extracted with diethyl ether (3 times, 50 mL each), and the combined organic extracts were dried using magnesium sulfate (MgSO4) and concentrated in vacuo. Purification by flash chromatography on silica gel (petroleum ether/ethyl acetate, 90/10, v/v) afforded 1.53 grams of (4′-bromophenyl)-4-methylphenyl methanol, a yield of about 62% as a white solid. The melting point (mp) was 80-81° C.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=[O:6].[H-].[Na+].[CH2:17]([OH:22])[CH2:18][CH2:19][CH:20]=[CH2:21].Cl>CN(C=O)C>[CH2:17]([O:22][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=[O:6])[CH2:18][CH2:19][CH:20]=[CH2:21]
Reactant: O=C(O)c1cc(F)cc(C(F)(F)F)c1
Reactant: C=CCCCO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCCCOc1cc(C(=O)O)cc(C(F)(F)F)c1
Temperature: 60 °C
Yield: 55.1 %

Procedure:
A solution of 3-fluoro-5-trifluoromethyl-benzoic acid (400 mg, 1.92 mmol) in DMF (2 ml) was added dropwise to a suspension of sodium hydride (60% oily, 235 mg, 5.88 mmol) and pent-4-en-1-ol (506 mg, 5.88 mmol) in DMF (12 ml), and the mixture was stirred at 60° C. Further, this mixture was irradiated in a microwave apparatus (150° C., 20 min). The reaction solution was poured into 0.2 N aqueous hydrochloric acid and then extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 3-pent-4-enyloxy-5-trifluoromethyl-benzoic acid (290 mg, 55%).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][O:8][C:9]1[CH:23]=[CH:22][C:12]([CH2:13][N:14]2[CH:19]([CH3:20])[CH2:18][O:17][CH2:16][C:15]2=O)=[CH:11][CH:10]=1>O1CCCC1.O>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH:19]2[CH3:20])=[CH:22][CH:23]=1
Reactant: COc1ccc(CN2C(=O)COCC2C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CN2CCOCC2C)cc1
Temperature: 0 °C

Procedure:
Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of LiAlH4 (3.83 g, 100.79 mmol, 2.00 equiv) in tetrahydrofuran (100 mL). This was followed by the addition of a solution of 4-(4-methoxybenzyl)-5-methylmorpholin-3-one (11.9 g, 50.42 mmol, 1.00 equiv) in tetrahydrofuran (50 mL) dropwise with stirring at 0° C. The resulting solution was heated to reflux for 1 h in an oil bath and cooled to room temperature. The resulting solution was diluted with 100 mL of H2O. The resulting solution was extracted with 3×200 mL of ethyl acetate and the organic layers combined and dried over anhydrous magnesium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:30). This resulted in 7 g (58%) of 4-(4-methoxybenzyl)-3-methylmorpholine as yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[O:11][CH3:12].[Cl-].[NH4+]>CO.O.[Fe]>[CH3:12][O:11][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:2]=1[Br:1])[NH2:8]
Reactant: COc1cc([N+](=O)[O-])ccc1Br
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: COc1cc(N)ccc1Br
Yield: 92.3 %

Procedure:
2-Bromo-5-nitroanisole (31 g, 134 mmoles) in methanol (700 ml) was added to a mixture of iron powder (22.5 g, 400 mmoles), and ammonium chloride (33.5 g, 630 mmoles) in water (600 ml). The mixture was heated under reflux for 3 hrs. The mixture was allowed to cool and filtered. The filtrate was concentrated in vacuo and the residue partitioned between water and dichloromethane. The organic phase was dried (Na2SO4), filtered and evaporated to dryness to give the title compound (D1) (25 g, 93%).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3([C:26](O)=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.Cl.[NH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl>CN(C=O)C>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]3([C:26]([NH:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:19][CH:20]=2)=[CH:11][CH:10]=1
Reactant: COC(=O)CCCN
Reactant: C[C@@H]1CCCN1CCc1ccc(-c2ccc(C3(C(=O)O)CCCC3)cc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COC(=O)CCCNC(=O)C1(c2ccc(-c3ccc(CCN4CCC[C@H]4C)cc3)cc2)CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (R)-1-(4′-(2-(2-methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl)cyclopentanecarboxylic acid (15 mg, 0.040 mmol), methyl 4-aminobutanoate hydrochloride (6.71 mg, 0.044 mmol), HATU (16.62 mg, 0.044 mmol), and TEA (0.017 mL, 0.119 mmol) in DMF (0.4 mL) was stirred at room temperature overnight. The mixture was acidified with 1M HCl and purified by HPLC to give the title compound. LCMS m/z=477.5 [M+H]+.
Reaction SMILES: ClC1C=C([B:10]([OH:12])[OH:11])C=C(F)C=1O.Br[C:14]1[CH:15]=[C:16]([F:23])[C:17]([O:21][CH3:22])=[C:18]([F:20])[CH:19]=1>>[F:20][C:18]1[CH:19]=[C:14]([B:10]([OH:12])[OH:11])[CH:15]=[C:16]([F:23])[C:17]=1[O:21][CH3:22]
Reactant: OB(O)c1cc(F)c(O)c(Cl)c1
Reactant: COc1c(F)cc(Br)cc1F
Product: COc1c(F)cc(B(O)O)cc1F

Procedure:
This compound is prepared analogously to Intermediate 8 by replacing 4-Bromo-2-chloro-6-fluoro-phenol with 5-Bromo-1,3-difluoro-2-methoxy-benzene to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]([OH:14])=O)=[C:6]([CH3:15])[CH:5]=1.Cl.Cl.[CH3:19][C:20]([CH3:30])([CH3:29])[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>CN(C1C=CN=CC=1)C.ClCCl.C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]([N:26]2[CH2:27][CH2:28][N:23]([CH2:22][CH2:21][C:20]([CH3:30])([CH3:29])[CH3:19])[CH2:24][CH2:25]2)=[O:14])=[C:6]([CH3:15])[CH:5]=1
Reactant: CC(C)(C)CCN1CCNCC1
Reactant: COC(=O)c1ccc(OCC(=O)O)c(C)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(OCC(=O)N2CCN(CCC(C)(C)C)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
WSCD (5.14 g, 27.2 mmol) and DMAP (1.64 g, 13.6 mmol) were added to a solution of 4-carboxymethoxy-3-methyl-benzoic acid methyl ester from Example E41.2 (3.04 g, 13.6 mmol) in dichloromethane (100 ml) and triethylamine (5 ml). The mixture was stirred for 1 h at room temperature then 1-(3,3-dimethyl-butyl)-piperazine dihydro-chloride from Example E4 (3.67 g, 14.9 mmol) was added. The mixture was stirred for 20 h at room temperature then solvents were removed in vacuo. The residue was dissolved in EtOAc, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; EtOAc) to yield the title compound (2.8 g, 55%).
Reaction SMILES: [ClH:1].[OH:2][C:3]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH3:28])([CH3:27])[C:22]([O:24]CC)=[O:23])=[CH:17][CH:16]=2)=[O:14])[CH2:6][CH2:5]1.[OH-].[Na+].[BH4-].[Na+].Cl>O.CC(C)=O.CO>[OH2:2].[ClH:1].[OH:2][C:3]([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][CH:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH3:28])([CH3:27])[C:22]([OH:24])=[O:23])=[CH:17][CH:16]=2)[OH:14])[CH2:6][CH2:5]1
Reactant: CCOC(=O)C(C)(C)c1ccc(C(=O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: CO
Product: CC(C)(C(=O)O)c1ccc(C(O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Temperature: 73 °C
Reaction time: 2 h
Yield: 196.7 %

Procedure:
Place ethyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneacetate, hydrochloride (60.01 g, 0.106 mol) in a 1-L three necked round-bottom flask and fit the flask with a mechanical stirrer, a Claisen head, a thermometer and a reflux condenser with a nitrogen bubbler on top. Add methanol (300 mL) and turn the stirrer on. Dilute the slurry with water (60 mL) and heat to 52–54° C. over 15–20 minutes. Hold at 52° C. for 2 hours and then add 50% sodium hydroxide (42.54 g, 0.532 mol). Heat at 73° C. for approximately 1 hour, 45 minutes, cool to less than 35° C. using a water bath and then add sodium borohydride (2.02 g, 0.0534 mol). Stir overnight at 35° C., treat with acetone (15.5 mL) and stir for 2 hours at 35° C. Acidify the mixture to a pH of 1.85 with 28% hydrochloric acid (75.72 g), dilute with water (282 mL), stir for about 30 minutes and cool over about 2 hours to −15° C. Filter the solids off and wash with water (2×75 mL) and ethyl acetate (2×75 mL). Vacuum dry the solid and allow to stand for 2 days to give 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic acid hydrochloride hydrate (Form II) (57.97 g, 91.5%) as a fine powder.