Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8](I)=[CH:9][N:10]=[C:4]2[CH:3]=1.CC1(C)C(C)(C)OB([C:20]2[CH:21]=[C:22]([NH:26][C:27]([NH:29][CH2:30][C:31]([F:34])([F:33])[F:32])=[O:28])[CH:23]=[CH:24][CH:25]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:24]3[CH:23]=[C:22]([NH:26][C:27]([NH:29][CH2:30][C:31]([F:32])([F:33])[F:34])=[O:28])[CH:21]=[CH:20][CH:25]=3)=[CH:9][N:10]=[C:4]2[CH:3]=1
Reactant: Clc1ccn2c(I)cnc2c1
Reactant: CC1(C)OB(c2cccc(NC(=O)NCC(F)(F)F)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(Cl)ccn23)c1
Temperature: 80 °C
Yield: 65.7 %

Procedure:
To a solution of 7-Chloro-3-iodo-imidazo[1,2-a]pyridine (15.17 g, 54.5 mmol) in 1,4-dioxane (260 ml) was added 1-[3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea (22.5 g, 65.4 mmol) and aqueous K3PO4 (23.1 g in 65 ml H2O, 109 mmol) [reaction degassed by bubbling N2 through] followed by 1,1′-bis(diphenylphosphino)ferrocene palladium (II) chloride (1.99 g, 2.72 mmol). The mixture was heated at 80° C. overnight, then diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was triturated with DCM (100 ml), filtered and the filtercake washed with 1:1 DCM:Petroleum ether to give the product (13.2 g) as a beige solid. MS: [M+H]+=369.
Reaction SMILES: [CH3:1][C:2]([N+:15]([O-:17])=[O:16])([CH3:14])[CH2:3][C:4]1[N:8]2[CH:9]=[CH:10][CH:11]=[C:12]([OH:13])[C:7]2=[N:6][CH:5]=1.Cl[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(=O)CC>[CH3:14][C:2]([N+:15]([O-:17])=[O:16])([CH3:1])[CH2:3][C:4]1[N:8]2[CH:9]=[CH:10][CH:11]=[C:12]([O:13][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:7]2=[N:6][CH:5]=1
Reactant: CC(C)(Cc1cnc2c(O)cccn12)[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)(C)OC(=O)COc1cccn2c(CC(C)(C)[N+](=O)[O-])cnc12
Yield: 80.8 %

Procedure:
3-(2-Methyl-2-nitropropyl)imidazo[1,2-a]pyridin-8-ol (1.0 g, 4.25 mmol), tert-butyl chloroacetate (964 mg, 6.4 mmol), potassium carbonate (590 mg, 4.27 mmol), and a small amount of potassium iodide in 2-butanone (30 ml) are reacted as described in Amine 9. The crude product residue is chromatographed on silica gel with dichloromethane/ethanol 9:1 to give 1.2 g of tert-butyl [3-(2-methyl-2-nitropropyl)imidazo[1,2-a]pyridin-8-yloxy]-acetate (81%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:26][CH2:27][CH2:28][CH2:29]I>CCOC(C)=O.CCCCCC>[Cl:26][CH2:27][CH2:28][CH2:29][CH:10]([C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:14])([F:15])[F:1])=[CH:9][CH:8]=1)[C:11]([OH:13])=[O:12]
Reactant: O=C(O)Cc1ccc(OC(F)(F)F)cc1
Reactant: ClCCCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C(O)C(CCCCl)c1ccc(OC(F)(F)F)cc1
Yield: 10.1 %

Procedure:
Step AAK (1): 2-(4-(Trifluoromethoxy)phenyl)acetic acid (3.54 g, 16.1 mmol) was deprotonated with NaHMDS (2.0 M in THF, 18.1 mL, 36.2 mmol) and reacted with 1-chloro-3-iodopropane (3.62 g, 17.7 mmol) using a procedure analogous to Step AC (1) to afford after purification by silica gel column chromatography (25-50% EtOAc/hexane), 5-chloro-2-(4-(trifluoromethoxy)phenyl)pentanoic acid (0.48 g, 1.62 mmol, 10% yield) as a pale-yellow oil. LC-MS (M−H)− 295.2.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH3:4].CCN(C(C)C)C(C)C.[N:14]([C:17]([CH3:23])([CH3:22])[CH2:18][C:19](Cl)=[O:20])=[N+:15]=[N-:16]>C(Cl)Cl>[N:14]([C:17]([CH3:23])([CH3:22])[CH2:18][C:19]([N:2]([CH2:3][CH3:4])[CH3:1])=[O:20])=[N+:15]=[N-:16]
Reactant: CCNC
Reactant: CC(C)(CC(=O)Cl)N=[N+]=[N-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCN(C)C(=O)CC(C)(C)N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 3 h
Yield: 89.4 %

Procedure:
To a stirred ice cold solution of N-methylethanamine (2.65 mL, 1 equiv, 30.9 mmol) and DIEA (7.0 mL, 1.3 equiv, 40.2 mmol) in anhydrous DCM (150 mL) was added 3-azido-3-methylbutanoyl chloride (5.0 g, 30.9 mmol) in small portions. The ice bath was removed and the reaction was stirred and left at room temperature for 3 h. The contents of the reaction were poured into a separatory funnel. The organic layer was washed with 1 M HCl (3×100 mL) and saturated NaHCO3 (2×100 mL). It was dried over anhydrous MgSO4, filtered, concentrated and dried under high vacuum to give a crude oil (7.14 g, 96.1%). This material was purified on an ISCO flash chromatography system with ethyl acetate and hexanes as eluent. The desired fractions were collected and concentrated to give a pale yellow oil (5.09 g, 89.4%). 1H NMR (CDCl3, 400 MHz): δ 1.42 (s, 6H), 2.40 (s, 2H), (dq, J=2.4 & 8.8, 2H). LRMS (ESI+) for C8H16N4O (184.1); Found: 185 (MH+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.BrCC1CCCCO1.[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]2([C:36]3[C:32]4=[N:33][O:34][N:35]=[C:31]4[CH:30]=[CH:29][C:28]=3[O:27][CH2:26]2)[C:18]1=[O:37]>>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]2([C:36]3[C:32]4=[N:33][O:34][N:35]=[C:31]4[CH:30]=[CH:29][C:28]=3[O:27][CH2:26]2)[C:18]1=[O:37]
Reactant: O=C1Nc2ccccc2C12COc1ccc3nonc3c12
Reactant: BrCc1ccccn1
Agent: BrCC1CCCCO1
Product: O=C1N(Cc2ccccn2)c2ccccc2C12COc1ccc3nonc3c12

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-(bromomethyl)pyridine to replace 2-(bromomethyl)tetrahydro-2H-pyran, and spiro[furo[3,2-e][2,1,3]benzoxadiazole-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 1′-(pyridin-2-ylmethyl)spiro[furo[3,2-e][2,1,3]benzoxadiazole-8,3′-indol]-2′(1′H)-one was obtained (81%) as a colorless solid: mp 180-182° C.; 1H NMR (300 MHz, CDCl3) δ8.63-8.59 (m, 1H), 7.84 (d, J=9.6 Hz, 1H), 7.77-7.70 (m, 1H), 7.57 (d, J=7.8 Hz, 1H), 7.32 (d, J=9.6 Hz, 1H), 7.28-7.16 (m, 3H), 7.04 (ddd, J=7.5, 7.5, 0.9 Hz, 1H), 6.88 (d, J=7.8 Hz, 1H), 5.45 (d, J=16.2 Hz, 1H), 5.28 (d, J=9.6 Hz, 1H), 5.01 (d, J=9.6 Hz, 1H), 4.92 (d, J=16.2 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ176.1, 163.0, 155.1, 149.4, 148.3, 144.9, 142.2, 137.3, 129.8, 129.7, 123.7, 123.67, 122.8, 121.9, 121.6, 119.4, 110.1, 107.0, 82.0, 57.4, 46.5; MS (ES+) m/z 371.0 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N:8]([CH3:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[N:3]=1.C([Li])CCC.[C:33](=[O:35])=[O:34].Cl>C(OCC)C.C(OCC)(=O)C.O>[CH3:16][N:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:6]1[CH:5]=[C:4]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[N:3]=[C:2]([C:33]([OH:35])=[O:34])[CH:7]=1
Reactant: O=C=O
Reactant: CN(Cc1ccccc1)c1cc(Br)nc(Oc2cccc(C(F)(F)F)c2)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: O
Product: CN(Cc1ccccc1)c1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)O)c1
Reaction time: 0.17 h

Procedure:
2-bromo-4-[methyl(phenylmethyl)amino]-6-[3-(trifluoromethyl)phenoxy] pyridine (6.38 g, 0.0146 mol) was dissolved in about 300 ml of diethyl ether. While cooling in a dry ice-acetone bath in an argon atmosphere, the obtained solution was mixed with n-butyl lithium [10 ml (ca. 1.63 M in hexane solution), 0.0146×1.1 mol] and then stirred for about 10 minutes. After the interior of the reactor was replaced with a carbon dioxide gas, the solution was removed from the bath and stirred at room temperature for about one hour. The obtained reaction solution was mixed with about 30 ml of a 1 N aqueous hydrochloric acid solution, distributed in ethyl acetate-water, and then washed with saturated brine. The organic phase separated from the solution was dried with anhydrous sodium sulfate, concentrated, and then purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]2([CH2:21][CH2:20][CH2:19]2)[CH2:16][C:15]2[N:14]=[C:13]([CH:22]([CH3:24])[CH3:23])[C:12]([C@@H:25]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:29][CH:28]=3)[OH:26])=[C:11](I)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[O:38]1[CH2:43][CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH2:40][CH2:39]1>>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]2([CH2:21][CH2:20][CH2:19]2)[CH2:16][C:15]2[N:14]=[C:13]([CH:22]([CH3:24])[CH3:23])[C:12]([C@@H:25]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:29][CH:28]=3)[OH:26])=[C:11]([C:41]3[CH2:42][CH2:43][O:38][CH2:39][CH:40]=3)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)c1nc2c(c(I)c1[C@H](O)c1ccc(C(C)(C)C)cc1)[C@@H](O[Si](C)(C)C(C)(C)C)CC1(CCC1)C2
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Product: CC(C)c1nc2c(c(C3=CCOCC3)c1[C@H](O)c1ccc(C(C)(C)C)cc1)[C@@H](O[Si](C)(C)C(C)(C)C)CC1(CCC1)C2

Procedure:
Obtained by starting from (R)—((S)-5′-(tert-butyldimethylsilyloxy)-4′-iodo-2′-isopropyl-6′,8′-dihydro-5′H-spiro[cyclobutane-1,7′-quinoline]-3′-yl)(4-tert-butylphenyl)methanol and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH:8][S:21]([CH3:20])(=[O:23])=[O:22])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: NCCc1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)NCCc1ccc(Cl)cc1
Temperature: -5 °C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
A solution of 4-chlorophenethylamine (5.0 g, 32 mmol) and DIEA (6.0 ml, 35 mmol) in anhydrous DCM (100 ml) was cooled at −5° C. and methanesulfonyl chloride (2.75 ml, 35 mmol) was added dropwise. The resulting mixture was stirred at −5° C. for 1 hour. Then the reaction mixture was washed with a 1N aqueous solution of HCl (2×100 ml) and a saturated aqueous solution of NaHCO3 (100 ml). The aqueous layers were extracted with DCM (100 ml). The organic layers were combined, dried (MgSO4) and the solvent was removed under reduced pressure to give 7.4 g (98%) of the title compound as a pale yellow powder. HPLC, Rt: 2.6 min (purity: 95.1%). LC/MS, M+(ESI): 234.1, M−(ESI): 232.1.
Reaction SMILES: [OH-].[Li+].C([O:5][C:6](=[O:33])[C@H:7]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)[CH:17]=1)[NH:8]C(=O)C(F)(F)F)C.Cl>O1CCCC1>[CH:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:31]=[CH:32][C:23]=1[O:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[CH2:15][C@@H:7]([C:6]([OH:33])=[O:5])[NH2:8]
Reactant: CCOC(=O)[C@H](Cc1cccc(Oc2ccc3ccccc3c2)c1)NC(=O)C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: N[C@@H](Cc1cccc(Oc2ccc3ccccc3c2)c1)C(=O)O
Yield: 84.7 %

Procedure:
0.5 N Lithium hydroxide (1.6 ml, 0.8 mmol) was added to a solution of N-trifluoroacetyl-3-(2-naphthyloxy)-L-phenylalanine ethyl ester (94 mg, 0.219 mmol) in tetrahydrofuran (2 ml) at 5° C. and the mixture was reacted at 5° C. for 69 hrs. The reaction mixture was adjusted to pH 3-4 with 1N hydrochloric acid and the precipitates were collected by filtration. The resultant solid was washed with water and ethanol in turn and then dried to give 3-(2-naphthyloxy)-L-phenylalanine (57 mg, 78%) as a colorless solid.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([OH:8])([C:6]#[CH:7])[CH3:5].[CH3:9][O:10][C:11](=[O:15])[CH:12](Br)[CH3:13]>O1CCCC1>[CH3:9][O:10][C:11](=[O:15])[CH:12]([O:8][C:4]([CH3:5])([CH3:3])[C:6]#[CH:7])[CH3:13]
Reactant: C#CC(C)(C)O
Reactant: COC(=O)C(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CC(C)(C)OC(C)C(=O)OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 88.9 %

Procedure:
To a mixture of sodium hydride (23.8 g, 0.595 mol) in tetrahydrofuran (400 ml) cooled to 0° C., is added a solution of 2-methyl-3-butyne-2-ol (50 g, 0.595 mol) in tetrahydrofuran (50 ml). The reaction mixture is stirred at 0° C. for 1 hour. A solution of methyl-2-bromo-propionate (99.36 g, 0.595 mol) in tetrahydrofuran (100 ml) is added to the reaction mixture slowly at 0° C. The reaction mixture is stirred at 0° C. for 2 hours and allowed to come to ambient temperature and stirred for 1 hour. The reaction mixture is cooled to 10° C. and quenched with ice cold water. The mixture is extracted with diethyl ether (3×200 ml), the organic phases are combined, washed with water, and dried over anhydrous sodium sulfate. The mixture is filtered and the filtrate is evaporated under reduced pressure to give 2-(1,1-dimethylprop-2-ynyloxy)propionic acid methyl ester (90 g) as a colorless oil, used without further purification in the next step.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.Cl.[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[NH:19]N.CS(O)(=O)=O>C(O)C>[CH3:1][NH:2][CH:3]1[CH2:8][C:7]2[C:14]3[C:13](=[C:12]([F:11])[CH:17]=[C:16]([F:18])[CH:15]=3)[NH:19][C:6]=2[CH2:5][CH2:4]1
Reactant: CNC1CCC(=O)CC1
Reactant: NNc1ccc(F)cc1F
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CCO
Product: CNC1CCc2[nH]c3c(F)cc(F)cc3c2C1

Procedure:
A solution of 3.5 g. of 4-methylaminocyclohexanone, 5.1 g. of 2,4-difluorophenylhydrazine hydrochloride, and 4 g. of methanesulfonic acid in 50 ml. of absolute ethyl alcohol was heated under reflux for four hours, cooled, and filtered. The resulting solids were washed with isopropanol and treated in chloroform with 10% potassium hydroxide solution. The chloroform extract was evaporated to dryness to give 3-(methylamino)-6,8-difluoro-1,2,3,4-tetrahydrocarbazole, m.p. 135°-138° C., which was converted to the hydrochloride salt, m.p. >280° C.
Reaction SMILES: [B].C[C@H]1CC(=[O:8])[C@H](C(C)C)CC1.C(N[C@H:22]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C@H:23](O)[C:24]([O:26][C:27](C)(C)[CH3:28])=[S:25])(=O)C1C=CC=CC=1.CO[C@](C1C=CC=CC=1)(C(F)(F)F)C(O)=O.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.CN(C)C1C=CN=CC=1>[C:27]([O:26][C:24](=[S:25])[CH2:23][CH2:22][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[O:8])[CH3:28]
Reactant: CC(C)(C)OC(=S)[C@@H](O)[C@H](NC(=O)c1ccccc1)c1ccccc1
Reactant: CC(C)[C@@H]1CC[C@@H](C)CC1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: CO[C@](C(=O)O)(c1ccccc1)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)OC(=S)CCc1ccccc1

Procedure:
A pure sample of tertbutyl 3(R)-benzoylamino-2(S)-hydroxy-3-phenylthiopropionate was obtained via the same reaction sequence, but using the boron reagent di{[(1S,2S,5R)-2-isopropyl-5-methylcyclohex-1-yl]-methyl}boron bromide, derived from (-)menthone. Compound tertbutyl 3(R)-benzoylamino-2(S)-hydroxy-3-phenylthiopropionate was treated with excess (S)-(-)-α-methoxy-α-(trifluoromethyl) phenylacetic acid in dichloromethane in the presence of 1,3-dicyclohexylcarbodiimide (DCC) and catalytic 4-dimethylaminopyridine (DMAP). The Mosher derivative tertbutyl 3(R)-benzoylamino-2(S)-O-[(S)-α-methoxy-α-trifluoromethyl)phenyl]acetyl-3-phenylthiopropionate was obtained:
Reaction SMILES: CO[C:3](=[O:26])[CH:4]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH:8]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH2:7]1.[CH3:27][NH:28][C:29]([NH2:31])=[O:30].C[O-].[Mg+2].C[O-].CO>>[Cl:25][C:20]1[CH:19]=[C:18]([CH:4]([CH2:5][CH:6]2[CH2:10][CH2:9][CH:8]([O:11][CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[CH2:7]2)[C:3]([NH:31][C:29]([NH:28][CH3:27])=[O:30])=[O:26])[CH:23]=[CH:22][C:21]=1[Cl:24]
Reactant: COC(=O)C(CC1CCC(OC2CCCCO2)C1)c1ccc(Cl)c(Cl)c1
Reactant: CNC(N)=O
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: CNC(=O)NC(=O)C(CC1CCC(OC2CCCCO2)C1)c1ccc(Cl)c(Cl)c1
Temperature: 100 °C
Yield: 9.1 %

Procedure:
2-(3,4-Dichloro-phenyl)-3-[3-(tetrahydro-pyran-2-yloxy)-cyclopentyl]-propionic acid methyl ester (1.60 mg, 3.98 mmol) and methylurea (443 mg, 5.98 mmol) in a solution of magnesium methoxide in methanol (7.4 wt. % , 11.4 mL, 7.97 mmol) was heated under reflux at 100° C. for 18 h. The reaction mixture was then concentrated in vacuo and filtered through a plug of celite (100% ethyl acetate as eluent). Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 1-{2-(3,4-dichloro-phenyl)-3-[3-(tetrahydro-pyran-2-yloxy)-cyclopentyl]-propionyl}-3-methyl-urea (160.6 mg, 9.1%) as a white solid: mp 62-65° C.; FAB-HRMS m/e calcd for C21H28Cl2N2O4 (M+Na)+ 465.1324. found 465.1324.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Br[CH2:11][CH2:12][CH2:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[Na+]>CN(C)C=O.O>[CH2:15]([O:14][CH2:13][CH2:12][CH2:11][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: BrCCCOCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCCOCc2ccccc2)cc1
Yield: 99.8 %

Procedure:
A mixture of 4-hydroxybenzaldehyde (1 g), benzyl 3-bromopropyl ether (1.88 g), cesium carbonate (3.2 g) and a catalytic amount of sodium iodide in N,N-dimethylformamide (15 mL) was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 4-(3-benzyloxypropoxy)-benzaldehyde (2.21 g). To a suspension of methyltriphenyl-phosphoniumbromide (2.92 g) in tetrahydrofuran (30 mL) was added n-butyl lithium (2.71 mol/L n-hexane solution, 3.02 mL) under ice-cooling, and the mixture was stirred for 5 minutes. To the reaction mixture was added a solution of 4-(3-benzyloxy-propoxy)benzaldehyde (2.21 g) in tetrahydrofuran (10 mL), and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=5/1) to give the title compound (1.4 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[S:11][C:10]3[N:12]=[CH:13][CH:14]=[N:15][C:9]=3[N:8]([CH2:16][O:17][CH3:18])[C:7]=2[CH:19]=1.[Cl-].[NH4+].[C:22](OCC)(=[O:24])C>C(OCC)=O>[CH3:18][O:17][CH2:16][N:8]1[C:7]2[CH:19]=[C:3]([CH2:2][NH:1][CH:22]=[O:24])[CH:4]=[CH:5][C:6]=2[S:11][C:10]2[N:12]=[CH:13][CH:14]=[N:15][C:9]1=2
Reactant: COCN1c2cc(CN)ccc2Sc2nccnc21
Reactant: CCOC(C)=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC=O
Product: COCN1c2cc(CNC=O)ccc2Sc2nccnc21

Procedure:
250 mg of 8-aminomethyl-10-methoxymethyl-10H-pyrazino-[2,3-b][1,4]benzothiazine was heated under reflux in 10 ml of ethyl formate for 3 hours. Then the reaction mixture was brought back to room temperature and distributed into an aqueous solution of ammonium chloride and ethyl acetate. The organic layer was extracted, washed with water and then dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the crystals thus precipitated were filtered after adding diisopropyl ether. Thus 230 mg of the title compound was obtained as yellow crystals.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[CH:9][C:10]([N+:14]([O-])=O)=[C:11]([CH:13]=2)[NH2:12])[CH2:3][CH2:2]1>[Pd].C(OCC)(=O)C.CO>[NH2:12][C:11]1[CH:13]=[C:7]([N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)[CH:8]=[CH:9][C:10]=1[NH2:14]
Reactant: Nc1cc(N2CCOCC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccc(N2CCOCC2)cc1N
Reaction time: 8 h

Procedure:
To a solution of 5-morpholino-2-nitroaniline (0.50 g, 2.2 mmol) in 4:1 ethyl acetate/methanol (25 ml) was added 5% palladium on carbon (0.11 g) and the reaction mixture stirred under an atmosphere of hydrogen overnight. The reaction mixture was then filtered through celite, the filtered solid washed with methanol, and the combined filtrate and washings concentrated in vacuo to give the crude 2-amino-4-morpholinoaniline which was used immediately for the next step.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]([S:7]([NH:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([C:17]([O:19]C)=[O:18])[CH2:13][CH2:12]1)(=[O:9])=[O:8])([CH3:6])[CH3:5]>CO>[CH3:6][C:4]([S:7]([NH:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([C:17]([OH:19])=[O:18])[CH2:13][CH2:12]1)(=[O:8])=[O:9])([CH3:3])[CH3:5]
Reactant: COC(=O)[C@H]1CC[C@H](NS(=O)(=O)C(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)S(=O)(=O)N[C@H]1CC[C@H](C(=O)O)CC1
Temperature: 24 °C

Procedure:
An aqueous solution (4.4 L) of sodium hydroxide (441 g, 2.5 eq) was added dropwise to a solution of methyl trans-4-(2-methylpropane-2-sulfonylamino)cyclohexane carboxylate (12) (1222 g, 4,407 mol) in methanol (2.45 L) over 30 minutes at 4 to 12° C. The mixture was stirred for an hour at 12 to 36° C. and methanol was removed under reduced pressure. The pH value of the residue was adjusted to 9.7 with hydrochloric acid and the mixture was washed with ethyl acetate (4.5 L). The organic layer was extracted with water (1 L). Aqueous layers were combined, acidified with hydrochloric acid, and extracted with ethyl acetate (5 L, 4 L). Each of organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The appeared crystals were collected by filtration and washed with IPE to obtain (13) (1012 g, 87.2%).
Reaction SMILES: [CH3:1][CH:2]([C:6]1([CH:13]=[O:14])[CH2:11][CH2:10][C:9]([CH3:12])=[CH:8][CH2:7]1)[CH:3]([CH3:5])[CH3:4].[BH4-].[Na+]>CO>[CH3:1][CH:2]([C:6]1([CH2:13][OH:14])[CH2:11][CH2:10][C:9]([CH3:12])=[CH:8][CH2:7]1)[CH:3]([CH3:4])[CH3:5]
Reactant: CC1=CCC(C=O)(C(C)C(C)C)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC1=CCC(CO)(C(C)C(C)C)CC1
Reaction time: 2 h
Yield: 87.3 %

Procedure:
1-(1,2-Dimethyl-propyl)-4-methyl-cyclohex-3-enecarbaldehyde (415 g) and methanol (300 mL) were charged into a reaction flask. Sodium borohydride (15 g) was added slowly and the temperature was kept at 35° C. with an ice bath. The reaction mixture was aged for 2 hours and quenched onto HCl (42 g) and ice and extracted with toluene. The reaction mixture was washed until neutral. The rushed over material provided the recovery of [1-(1,2-dimethyl-propyl)-4-methyl-cyclohex-3-enyl]methanol (366 g).
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:21](O)([CH2:24][CH3:25])([CH3:23])[CH3:22]>O>[C:1]([O:20][C:21]([CH2:24][CH3:25])([CH3:23])[CH3:22])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCC(C)(C)O
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Solvent: O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OC(C)(C)CC
Temperature: 60 °C

Procedure:
Oleic acid (purity greater than 99%; 828 mg) was mixed with t-amyl alcohol (purity greater than 99%; 258 mg) together with 23 mg of distilled water. To this was added 62.5 mg of immobilised Candida antarctica liplase A (code SP433, ex Novo Industri, Denmark) as in Example I. The temperature of the reaction mixture was raised to 60° C. After 22 hours the amount of t-amyl oleate formed in the reaction was determined by GC analysis of the sample. 70.4 mg was removed and the mixture eluted down an alumina column (basic activity 2) to remove free fatty acid, using 60-80 petroleum ether as the eluant. 2.5 mg of eicosane was used as an internal standard for GC analysis. A final product yield of 14.8% based on oleic acid was achieved. Confirmation of the product identity was by GCMS.