Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B.CSC.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH:13]=O)=[CH:8][C:7]=1[C:15]1([CH3:37])[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([Cl:24])[CH:22]=2)[N:17]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=2[O:34][CH3:35])[C:16]1=[O:36].Cl.CO>O1CCCC1>[Cl:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=1[O:34][CH3:35])[C:16](=[O:36])[C:15]2([C:7]1[CH:8]=[C:9]([NH:12][CH3:13])[CH:10]=[CH:11][C:6]=1[Cl:5])[CH3:37]
Reactant: COc1ccc(CN2C(=O)C(C)(c3cc(NC=O)ccc3Cl)c3cc(Cl)ccc32)c(OC)c1
Agent: B
Agent: Cl
Solvent: CSC
Solvent: C1CCOC1
Solvent: CO
Product: CNc1ccc(Cl)c(C2(C)C(=O)N(Cc3ccc(OC)cc3OC)c3ccc(Cl)cc32)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
0.56 ml of a 2M solution of borane-dimethyl sulphide in tetrahydrofuran is added to a solution, cooled to 0° C., of 0.4 g of the compound of Example 67 in 1 ml of tetrahydrofuran. After 1 hour at 58° C. and then cooling to 0° C., 0.2 ml of 10N hydrochloric acid and 1 ml of methanol are added to the reaction mixture. The mixture is heated at 60° C. for 1 hour and cooled, and the solvents are evaporated under reduced pressure. The solid residue is treated with 1 ml of a saturated potassium carbonate solution and extraction is carried out several times with ethyl acetate. The organic phases are dried over anhydrous sodium sulphate and the solvents are evaporated under reduced pressure. Purification is carried out by chromatography on a column of silica gel, elution being carried out with an 85/15 (v/v) cyclohexane/ethyl acetate mixture. The expected product is isolated in the form of the hydrochloride by treating the residue obtained with diethyl ether comprising hydrogen chloride and then filtration is carried out; M.p.=121° C. (0.5H2O.1HCl).
Reaction SMILES: I[CH:2]([CH2:12][C:13]([F:25])([F:24])[C:14]([F:23])([F:22])[C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17])[CH2:3][C:4]([F:11])([F:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6].C([SnH](CCCC)CCCC)CCC>CCOCC>[F:10][C:4]([F:11])([CH2:3][CH2:2][CH2:12][C:13]([F:24])([F:25])[C:14]([F:22])([F:23])[C:15]([F:20])([F:21])[C:16]([F:19])([F:17])[F:18])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(F)(F)CC(I)CC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: CCCC[SnH](CCCC)CCCC
Solvent: CCOCC
Product: CCOC(=O)C(F)(F)CCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Yield: 90.1 %

Procedure:
Ethyl 2,2,6,6,7,7,8,8,9,9,9-undecafluorononanoate (17.3 g, 90% yield) was prepared from ethyl 4-iodo-2,2,6,6,7,7,8,8,9,9,9-undecafluorononanoate (25.5 g, 50 mmol), tributyltin hydride (16.0 g, 55 mmol) and anhydrous ether (100 mL) according to the procedure of Example 6. Boiling point was 53°-55° C. at 0.7 mmHg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)([CH2:13][CH2:14]S(C)(=O)=O)[CH2:9]1)=[O:7].C(N(C(C)C)CC)(C)C.[F:43][C:44]1[CH:67]=[CH:66][C:47]([CH2:48][N:49]2[C:53]3[CH:54]=[CH:55][CH:56]=[CH:57][C:52]=3[N:51]=[C:50]2[C:58]([CH:60]2[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]2)=[O:59])=[CH:46][CH:45]=1.C(#N)C>CO.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:63]2[CH2:64][CH2:65][CH:60]([C:58]([C:50]3[N:49]([CH2:48][C:47]4[CH:46]=[CH:45][C:44]([F:43])=[CH:67][CH:66]=4)[C:53]4[CH:54]=[CH:55][CH:56]=[CH:57][C:52]=4[N:51]=3)=[O:59])[CH2:61][CH2:62]2)([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[CH2:9]1)=[O:7]
Reactant: O=C(c1nc2ccccc2n1Cc1ccc(F)cc1)C1CCNCC1
Reactant: COc1cc(C(=O)N2CCC(CCS(C)(=O)=O)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)c4nc5ccccc5n4Cc4ccc(F)cc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reaction time: 18 h

Procedure:
Combine 1-(3,4,5-trimethoxy-benzoyl)-3-(3,4-dichloro-phenyl)-3-(2-methanesulfonyl-ethyl)-pyrrolidine (0.48 g, 1.41 mmol), diisopropylethylamine (0.24 g, 1.9 mmol), 4-[1-(4-fluoro-benzyl)-1 H-benzoimidazole-2-carbonyl]-piperidine (0.50 g, 0.94 mmol), and acetonitrile (15 mL). Heat to reflux. After 18 hours, cool and partition the reaction mixture between ethyl acetate and water. Extract the organic layer with a saturated sodium bicarbonate solution and a saturated sodium chloride solution. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with 12% methanol/ethyl acetate containing 0.1% concentrated aqueous ammonia solution to give the title compound: Rf=0.35 (silica gel, 12% methanol/ethyl acetate containing 0.1% concentrated aqueous ammonia solution).
Reaction SMILES: [CH3:1][CH2:2][C:3]([CH2:5][CH2:6]/[CH:7]=[C:8](/[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])\[CH3:9])=[CH2:4].[S:16](=[O:18])=[O:17]>>[CH3:9][C:8]([CH2:10][CH2:11][CH:12]=[C:13]([CH3:14])[CH3:15])=[CH:7][CH2:6][CH2:5][C:3]1[CH2:4][S:16]([CH2:1][CH:2]=1)(=[O:18])=[O:17]
Reactant: O=S=O
Reactant: C=C(CC)CC/C=C(\C)CCC=C(C)C
Product: CC(C)=CCCC(C)=CCCC1=CCS(=O)(=O)C1
Reaction time: 18 h
Yield: 58 %

Procedure:
The (E)-β-farnesene containing product of Example 1 (17 g) and liquid sulphur dioxide are sealed in a glass ampoule and stored at ambient temperature for 18 hours. The ampoule is opened after cooling and the excess SO2 is allowed to evaporate. The residue is then chromatographed on Florisil using sequentially hexane, an ether/hexane mixture of increasing concentration in ether, and finally ether, the effluent being monitored by n.m.r. Removal of the solvent under vacuum from the appropriate fractions gives 3-(4,8-dimethyl-3,7-nonadienyl) sulpholene (II) as a straw coloured liquid (9 g, 58%); nD20 1.5080; M+ (m/z as % of base peak): 268 (0.02); δ(CCl4) 1.70 (m, 9H), 2.08 (m, 8H), 3.70 (m, 4H), 5.16 (m, 2H), 5.78 (br, t, 1H). Note: On heating at 180° C. under a vacuum of 1τ the sulpholene regenerates an (E)- and (Z)-β-farnesene mixture in high yield.
Reaction SMILES: C([O:8][C:9]([C:11]1[C:19]([CH3:20])=[C:18]2[C:14]([C:15]3[CH2:24][CH2:23][O:22][C:21]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])([CH2:25][CH2:26][CH3:27])[C:16]=3[NH:17]2)=[C:13]([C:34]#[N:35])[CH:12]=1)=[O:10])C1C=CC=CC=1>[OH-].[OH-].[Pd+2].CO.CCOC(C)=O>[C:34]([C:13]1[CH:12]=[C:11]([C:9]([OH:10])=[O:8])[C:19]([CH3:20])=[C:18]2[C:14]=1[C:15]1[CH2:24][CH2:23][O:22][C:21]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])([CH2:25][CH2:26][CH3:27])[C:16]=1[NH:17]2)#[N:35]
Reactant: CCCC1(CC(=O)OCC)OCCc2c1[nH]c1c(C)c(C(=O)OCc3ccccc3)cc(C#N)c21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCC1(CC(=O)OCC)OCCc2c1[nH]c1c(C)c(C(=O)O)cc(C#N)c21
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
A 500 mL Parr flask was charged with 5-cyano-1-ethoxycarbonylmethyl-8-methyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indole-7-carboxylic acid benzyl ester (14.24 g, 0.030 mol), 1:1 MeOH/EtOAc (180 mL), and Pd(OH)2 (20% on C, 3.02 g). The flask was shaken on a Parr shaker at 5 psi above ambient pressure for 30 minutes. The reaction mixture was filtered through a pad of Celite, washed with methanol and concentrated. Trituration with hexanes yielded 11.11 g (96.4%) of an off-white powder. 1H NMR (CDCl3) δ 10.21 (br s, 1H), 8.22 (s, 1H), 4.22 (m, 2H), 4.00 (m, 2H), 3.09 (m, 4H), 2.89 (s, 3H), 2.00 (m, 2H), 1.30 (m, 5H), 0.90 (t, J=7.6 Hz, 3H).
Reaction SMILES: [BH4-].[Na+].[Cl-].[Ca+2].[Cl-].C([O:8][C:9](=O)[CH2:10][O:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:14][CH2:13]1)C.[Cl-].[NH4+]>C1COCC1.C(O)C>[OH:8][CH2:9][CH2:10][O:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[CH2:14][CH2:13]1
Reactant: CCOC(=O)COC1CCN(C(=O)OCc2ccccc2)CC1
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(OCc1ccccc1)N1CCC(OCCO)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.2 %

Procedure:
A mixture of sodium borohydride (10.1 g), calcium chloride (13.3 g), ethanol (100 mL) and THF (50 mL) was stirred at 0° C. for 30 min. After stirring, a mixture of benzyl 4-(2-ethoxy-2-oxoethoxy)piperidine-1-carboxylate (9.68 g) and THF (50 mL) was added dropwise at 0° C., and the obtained mixture was stirred at room temperature for 2 days. Saturated aqueous ammonium chloride solution was added thereto, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure. The residue was extracted with ethyl acetate, and the extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (6.33 g).
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.Cl[CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.[OH-].[Na+]>C(O)C>[C:1]1([O:11][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: ClCCN1CCOCC1
Reactant: Oc1cccc2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: c1ccc2c(OCCN3CCOCC3)cccc2c1
Reaction time: 3 h

Procedure:
441 g of 1-naphthol and 648 g of N-(2-chloroethyl)morpholine hydrochloride are initially charged in 2680 ml of ethanol at 50° C. 554 g of 50% aqueous sodium hydroxide are added dropwise within 3 h. Stirring is then continued at 50° C. for 3 h and then for 1 h under reflux.
Reaction SMILES: O[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:4][N:3]=1.P(Cl)(Cl)([Cl:17])=O.[Na].C(=O)([O-])O>>[Cl:17][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:4][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)Cc1cnc(O)c([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na]
Product: CC(C)Cc1cnc(Cl)c([N+](=O)[O-])c1
Temperature: 120 °C

Procedure:
A mixture of 1.7 g of 2-hydroxy-3-nitro-5-(2-methylpropyl)pyridine (starting material D4) and 15 ml of phosphorous oxychloride is heated under reflux to 120° C. for two hours. After cooling the mixture is carefully added to ice/water, then neutralized with sodium-hydrogencarbonate and extracted three times with ethylacetate. The combined organic phases are evaporated to dryness and the residue is chromatographed on a silica gel column (ethylacetate/petroleum ether 1:15). Concentration of the chromatographically pure fractions gives 1.17 g of the title compound as an orange oil.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:5]=1[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[CH:10]=1)=[O:7].[CH:28]1([C:31](Cl)=[O:32])[CH2:30][CH2:29]1>O1CCOCC1>[ClH:3].[Cl:3][C:4]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:5]=1[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N:15]([C:31]([CH:28]2[CH2:30][CH2:29]2)=[O:32])[CH:16]2[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]2)[CH:10]=1)=[O:7]
Reactant: CN1CCC(Nc2cccc(NC(=O)c3ccc(F)cc3Cl)c2)CC1
Reactant: O=C(Cl)C1CC1
Agent: Cl
Solvent: C1COCCO1
Product: CN1CCC(N(C(=O)C2CC2)c2cccc(NC(=O)c3ccc(F)cc3Cl)c2)CC1
Temperature: 106 °C
Yield: 172.8 %

Procedure:
Combine 2-chloro-4-fluoro-N-(3-(1-methylpiperidin-4-ylamino)phenyl)benzamide dihydrochloride (Example 1, 48 mg, 0.134 mmol), dioxane (1 mL) and cyclopropylcarbonyl chloride (0.013 mL, 0.148 mmol). Shake and heat (106° C.) in a J-Kem® Reaction Block for 2 hr. Load onto a SCX column (Varian) and elute with 2 M ammonia methanol to give the free base of the title compound (54 mg, 93%). Following a salt formation method similar to that described in Example 1 gives the title compound as a white solid (47 mg): mp 133–6° C.; mass spectrum (freebase, ion spray): m/z=430.1 (M+1), 1H NMR (freebase, CDCl3): 8.31 (bs, N—H), 7.76 (dd, J=6.0 Hz, 8.6 Hz, 1H), 7.61–7.56 (m, 2H), 7.38 (t, J=8.0 Hz, 1H), 7.19 (dd, J=2.4 Hz, 8.3 Hz, 1H), 7.09 (td, J=2.4 Hz, 8.2 Hz, 1H), 6.96 (d, J=8.2 Hz, 1H), 4.62–4.53 (m, 1H), 2.80 (bd, J=11.5 Hz, 2H), 2.20 (s, 3H), 2.05 (td, J=2.2 Hz, 12.1 Hz, 2H), 1.83–1.69 (bm, 2H), 1.59–1.37 (bm, 2H), 1.21–1.13 (m, 1H), 0.99–0.89 (bm, 2H), 0.56 (bd, J=7.4 Hz, 2H). Analysis calc'd for C23H26Cl2FN3O2.0.8H2O: C, 57.46; H, 5.79; N, 8.74. Found: C, 57.16; H, 5.73; N, 8.70.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1Cl)[C:7]([O:9][CH3:10])=[O:8])([O-:3])=[O:2].[CH3:15][O-:16].[Na+]>CO>[N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[O:16][CH3:15])[C:7]([O:9][CH3:10])=[O:8])([O-:3])=[O:2]
Reactant: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(OC)c([N+](=O)[O-])c1

Procedure:
Methyl 3-nitro-4-chlorobenzoate (COMPOUND XIII) (see above for synthesis of 4-chloro-anti-CG) (1 equivalent) is treated with sodium methoxide (1.1 equivalent) in methanol with heating to produce the methyl 3-nitro-4-methoxybenzoate (COMPOUND XIV) which is purified by column chromatography and/or crystallization.
Reaction SMILES: [OH:1][C@@H:2]([CH2:30][OH:31])[C:3]([C@H]1CCN(C2C=CC(N3C[C@H](CNC4C=CON=4)OC3=O)=CC=2F)C1)=[O:4].Cl.[NH:33]1[CH2:38][CH2:37][C:36]([C:39]2[C:44]([F:45])=[CH:43][C:42]([N:46]3[CH2:50][C@H:49]([CH2:51][N:52]([C:60]4[CH:64]=[N:63][S:62][N:61]=4)C(OC(C)(C)C)=O)[O:48][C:47]3=[O:65])=[CH:41][C:40]=2[F:66])=[CH:35][CH2:34]1>>[OH:1][C@@H:2]([CH2:30][OH:31])[C:3]([N:33]1[CH2:38][CH2:37][C:36]([C:39]2[C:40]([F:66])=[CH:41][C:42]([N:46]3[CH2:50][C@H:49]([CH2:51][NH:52][C:60]4[CH:64]=[N:63][S:62][N:61]=4)[O:48][C:47]3=[O:65])=[CH:43][C:44]=2[F:45])=[CH:35][CH2:34]1)=[O:4]
Reactant: O=C([C@H]1CCN(c2ccc(N3C[C@H](CNc4ccon4)OC3=O)cc2F)C1)[C@@H](O)CO
Reactant: CC(C)(C)OC(=O)N(C[C@H]1CN(c2cc(F)c(C3=CCNCC3)c(F)c2)C(=O)O1)c1cnsn1
Agent: Cl
Product: O=C([C@@H](O)CO)N1CC=C(c2c(F)cc(N3C[C@H](CNc4cnsn4)OC3=O)cc2F)CC1
Yield: 71 %

Procedure:
Using the method described for the appropriate intermediate of Example 17, apart from routine changes in the eluant used for chromatography, and starting from 3-(4-(1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)-5(R)-(N-(t-butoxycarbonyl)-1,2,5-thiadiazol-3-ylaminomethyl)oxazolidin-2-one hydrochloride (800 mg, 1.51 mM, see Example 25), gave the title product (669 mg, 71%). NMR (DMSO-d6) δ: 1.29 (s, 3H); 1.32 (s, 3H); 1.52 (s, 9H); 2.30 (m, 1H); 2.40 (m, 1H); 3.68 (m, 2H); 3.90 (dd, 1H); 4.04-4.28 (m, 4H); 4.37 (m, 1H); 4.90 (m, 1H); 5.06 (m, 1H); 5.72 (m, 2H); 5.88 (m, 1H); 7.31 (d, 2H); 8.96 (s, 1H). MS (ESP): 622 (MH+) for C28H33F2N5O7S
Reaction SMILES: O.[OH-].[Li+].[CH2:4]([O:6][CH2:7][CH2:8][N:9]([C:23]1[CH:32]=[CH:31][C:30]2[C:29]([CH3:34])([CH3:33])[CH2:28][CH2:27][C:26]([CH3:36])([CH3:35])[C:25]=2[CH:24]=1)[C:10](=[O:22])[NH:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=1)[CH3:5].CO.Cl>C1COCC1.O>[CH2:4]([O:6][CH2:7][CH2:8][N:9]([C:23]1[CH:32]=[CH:31][C:30]2[C:29]([CH3:34])([CH3:33])[CH2:28][CH2:27][C:26]([CH3:35])([CH3:36])[C:25]=2[CH:24]=1)[C:10](=[O:22])[NH:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1)[CH3:5]
Reactant: CCOCCN(C(=O)Nc1ccc(C(=O)OC)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCOCCN(C(=O)Nc1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Yield: 79.4 %

Procedure:
Lithium hydroxide hydrate (0.5 g) was added to a solution of methyl 4-[3-(2-ethoxy-ethyl)-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-ureido]-benzoate (39) (520 mg) dissolved in 20 mL THF, 5 mL methanol and 5 mL and the reaction mixture was stirred at room temperature for two hours. The reaction mixture was diluted with 20 mL water, the pH was adjusted to 2 with concentrated HCl and extracted with three 25 mL portions of ethyl acetate. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to give 400 mg of 4-[3-(2-ethoxy-ethyl)-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-ureido]-benzoic acid (33) as a colorless oil, which crystallized upon addition of hexanes. M.P.: 82-85° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]([CH3:29])([O:6][C:7]1[CH:8]=[C:9]([C:13]2[C:22]([CH3:24])([CH3:23])[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:25]([O:27][CH3:28])=[O:26])[CH:19]=3)[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH3:5]>CO.O1CCCC1.[Pd]>[CH3:1][O:2][C:3](=[O:30])[C:4]([CH3:29])([O:6][C:7]1[CH:8]=[C:9]([CH:13]2[C:22]([CH3:24])([CH3:23])[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:25]([O:27][CH3:28])=[O:26])[CH:19]=3)[NH:14]2)[CH:10]=[CH:11][CH:12]=1)[CH3:5]
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(OC(C)(C)C(=O)OC)c1)=N2
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(OC(C)(C)C(=O)OC)c1)N2
Reaction time: 13 h
Yield: 93.7 %

Procedure:
To a solution of methyl 2-(3-(1-methoxy-2-methyl-1-oxopropan-2-yloxy)phenyl)-3,3-dimethyl-3,4-dihydroquinoline-6-carboxylate (230 mg, 0.56 mmol) in methanol (5 mL) and tetrahydrofuran (5 mL) was added 10% Pd/C (100 mg). The mixture was hydrogenated by H2 balloon for 13 h. Pd/C was removed by filtration. The filtrate was concentrated to afford 216 mg of methyl 2-(3-(1-methoxy-2-methyl-1-oxopropan-2-yloxy)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate as syrup. (Yield: 93%).
Reaction SMILES: [N:1]1([C:6]2[N:11]=[CH:10][C:9]3[CH:12]([C:15]([OH:17])=O)[CH2:13][CH2:14][C:8]=3[CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.Cl.[CH3:19][C:20]1[C:28]2[CH2:27][O:26][C:25](=[O:29])[C:24]=2[CH:23]=[CH:22][C:21]=1[CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[CH3:19][C:20]1[C:28]2[CH2:27][O:26][C:25](=[O:29])[C:24]=2[CH:23]=[CH:22][C:21]=1[CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][N:35]([C:15]([CH:12]2[C:9]3[CH:10]=[N:11][C:6]([N:1]4[CH:5]=[N:4][N:3]=[N:2]4)=[CH:7][C:8]=3[CH2:14][CH2:13]2)=[O:17])[CH2:34][CH2:33]1
Reactant: O=C(O)C1CCc2cc(-n3cnnn3)ncc21
Reactant: Cc1c(CCN2CCNCC2)ccc2c1COC2=O
Agent: Cl
Product: Cc1c(CCN2CCN(C(=O)C3CCc4cc(-n5cnnn5)ncc43)CC2)ccc2c1COC2=O

Procedure:
4-Methyl-5-[2-(4-{[3-(1H-tetrazol-1-yl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl]carbonyl}piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one was prepared starting from 3-(1H-tetrazol-1-yl)-6,7-dihydro-5H-cyclopenta[c]pyridine-7-carboxylic acid and 4-methyl-5-(2-piperazin-1-ylethyl)-2-benzofuran-1(3H)-one hydrochloride in an analogous fashion to that described by GENERAL METHOD B. The resulting mixture of two enantiomers was separated by preparative chiral SFC HPLC using a ChiralPak AD-H 250×30 mm I.D. column and eluting with A: SF CO2 and B: ethanol/acetonitrile (2:1) (0.1% DEA) with flow rate of 50 mL/min. The single title isomers were obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:2].[CH2:18](Br)/[CH:19]=[C:20](/[CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])\[CH3:21].C1OCCOCCOCCOCCOCCOC1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)(=[O:7])=[O:8])[CH2:18][CH:19]=[C:20]([CH3:21])[CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[CH3:2]
Reactant: CC(C)=CCC/C(C)=C/CBr
Reactant: CCOC(=O)CS(=O)(=O)c1ccc(OC)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(CC=C(C)CCC=C(C)C)S(=O)(=O)c1ccc(OC)cc1

Procedure:
To a stirred solution of (4-methoxy-benzenesulfonyl)-acetic acid ethyl ester (5.16 g, 20 mmol), geranyl bromide (4.2 g, 20 mmol) and 18-Crown-6 (500 mg) in acetone (250 ml) was added K2CO3 (10 gms, excess) and the mixture refluxed foe 24 hours. At the end, the reaction mixture was filtered and the acetone layer was concentrated. The residue obtained was extracted with chloroform, washed well with water, dried over anhydrous MgSO4, filtered and concentrated. The product obtained was purified by silica-gel column chromatography, eluting with 30% ethy acetate: hexane. The product 2-(4-methoxy-benzenesulfonyl)-5,9-dimethyl-deca-4,8-dienoic acid ethyl ester was isolated as a colourless oil. Yield: 7.0 g, 89%.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[C:24](=[O:29])N(OC)C)=[O:17])([CH3:14])([CH3:13])[CH3:12]>>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[C:24]([C:3]1[O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:2]=1[CH3:1])=[O:29])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CON(C)C(=O)C1CCCCN1C(=O)OC(C)(C)C
Reactant: Cc1coc2ccccc12
Product: Cc1c(C(=O)C2CCCCN2C(=O)OC(C)(C)C)oc2ccccc12

Procedure:
The title compound (300 mg) was prepared from 3-methyl-benzofuran (390 mg) and (RS)-1-(tert-butyloxycarbonyl)-2-(N-methoxy-N-methylcarbamoyl)-piperidine, D1 (820 mg) according to a procedure similar to that for Description 2.
Reaction SMILES: [CH:1]1([O:4][CH2:5][CH2:6][OH:7])[CH2:3][CH2:2]1.[S:8](Cl)([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)(=[O:10])=[O:9].CCN(CC)CC.Cl>>[CH3:15][C:14]1[CH:16]=[CH:17][C:11]([S:8]([O:7][CH2:6][CH2:5][O:4][CH:1]2[CH2:3][CH2:2]2)(=[O:10])=[O:9])=[CH:12][CH:13]=1
Reactant: OCCOC1CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCOC2CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-cyclopropoxyethanol (400 mg, 3.92 mmol) DCM (10 mL) were added TsCl (821 mg, 4.31 mmol) and Et3N (0.6 mL, 4.31 mmol). The reaction was stirred at room temperature overnight. Then, 1N HCl was added, and the reaction was extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give a yellow oil. The oil was purified by preparative TLC to obtain intermediate BP (50 mg) as a yellow oil.
Reaction SMILES: C(O[C:4](=[O:24])[CH2:5][C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])C.[C:25]([CH2:27][C:28]([NH2:30])=[O:29])#[N:26].N1CCCCC1>CO>[C:25]([C:27]1[C:28]([OH:29])=[N:30][C:4]([OH:24])=[CH:5][C:6]=1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])#[N:26]
Reactant: N#CCC(N)=O
Reactant: CCCCCCCCCCCCCCCCC(=O)CC(=O)OCC
Solvent: CO
Solvent: C1CCNCC1
Product: CCCCCCCCCCCCCCCCc1cc(O)nc(O)c1C#N
Yield: 40 %

Procedure:
3-Oxo-nonadecanoic acid ethyl ester (11.3 mmol), cyanoacetamide (0.95 g, 11.3 mmol) and piperidine (0.95 g, 11.3 mmol) in MeOH (3 mL) were heated under reflux for 24 h. The solvent was evaporated, and the residue was dissolved in hot water. The product was precipitated by addition of concentrated HCl, filtered, washed with ice water and CHCl3 and dried in vaccum to give 3-cyano-2,6-dihydroxy-4-hexadecyl-pyridine as a white powder. Yield: 40%. Anal. C22H36N2O2: Calcd: C, 73.29; H, 10.06; N, 7.77; O, 8.88. Found: C, 73.35; H, 10.12; N, 7.85; O, 8.97. MS (ESIMS): m/z: 360.3.