Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]#[C:16][Si](C)(C)C)[CH:13]=2)[CH:8]=[N:7][CH:6]=1.C([O-])([O-])=O.[K+].[K+].C(O)(=O)C>CO>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]#[CH:16])[CH:13]=2)[CH:8]=[N:7][CH:6]=1
Reactant: COC(=O)Cc1cncc2ccc(C#C[Si](C)(C)C)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CO
Product: C#Cc1ccc2cncc(CC(=O)OC)c2c1
Reaction time: 1 h

Procedure:
To a solution of (6-trimethylsilanylethynyl-isoquinolin-4-yl)-acetic acid methyl ester, as prepared for Intermediate 32 (0.19 g, 0.64 mmol), in anhydrous methanol (7 ml) is added K2CO3 (72 mg) and the resulting mixture stirred for 1 h. Additional K2CO3 (11 mg) is then added and stirring continued for 30 min. The mixture is then neutralized with glacial acetic acid and concentrated. Purification by flash silica column chromatography (ethylacetate/hexane 1:1) gives (6-ethynyl-isoquinolin4-yl)-acetic acid methyl ester M+ 225. This intermediate (79 mg, 0.35 mmol) is dissolved in methanol under an inert atmosphere and 10% Pd on carbon (79 mg) added. The resulting suspension is stirred vigorously under an atmosphere of gaseous hydrogen. After 90 mins, filtration, washing with methanol and concentration give (6-ethyl-isoquinolin-4-yl)-acetic acid methyl ester MW 229. To a solution of this intermediate (68 mg, 0.30 mmol) in THF/methanol/water (3:1:1, 3.5 ml) is added LiOH (12.5 mg) and the mixture stirred for 20 h at room temperature. Concentration under reduced pressure gives lithium (6-ethyl-isoquinolin4-yl)-acetate M+ 221.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][CH2:24][OH:25])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O>>[OH:25][CH2:24][CH2:23][CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:26])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1
Reactant: OB(O)c1ccccn1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccccn2)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one and pyridine-2-boronic acid following procedures analogous to those described in Example 75 Step 1. LC-MS Method 2 tR=1.01 min, m/z=416.21; 1H NMR (CD3OD) 1.30 (m, 1H), 1.55 (d, 3H), 1.62 (m, 1H), 1.94 (m, 2H), 2.20 (m, 1H), 2.32 (m, 1H), 2.48 (m, 1H), 3.09 (m, 1H), 3.44 (m, 2H), 5.57 (m, 1H), 7.03 (d, 2H), 7.29-7.40 (m, 6H), 7.67 (d, 2H), 7.73 (d, 1H), 7.84 (t, 1H), 8.55 (d, 1H).
Reaction SMILES: C([N:8]1[C@@H:13]([CH3:14])[C:12](=[O:15])[N:11]2[C@@H:16]([CH2:19][CH2:20][N:21]3[CH2:28][CH2:27][C:24]4([CH2:26][CH2:25]4)[C@H:23]([OH:29])[CH2:22]3)[CH2:17][O:18][C@:10]2([CH3:30])[CH2:9]1)C1C=CC=CC=1>CCO.[Pd]>[OH:29][C@@H:23]1[CH2:22][N:21]([CH2:20][CH2:19][C@@H:16]2[N:11]3[C:12](=[O:15])[C@H:13]([CH3:14])[NH:8][CH2:9][C@@:10]3([CH3:30])[O:18][CH2:17]2)[CH2:28][CH2:27][C:24]21[CH2:26][CH2:25]2
Reactant: C[C@H]1C(=O)N2[C@@H](CCN3CCC4(CC4)[C@H](O)C3)CO[C@]2(C)CN1Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: C[C@@H]1NC[C@@]2(C)OC[C@H](CCN3CCC4(CC4)[C@H](O)C3)N2C1=O
Yield: 82.4 %

Procedure:
A solution of (3S,6S,8aR)-7-benzyl-3-[2-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-ethyl]-6,8a-dimethyl-hexahydro-oxazolo[3,2-a]pyrazin-5-one (160 mg, 0.39 mmol) in EtOH (3 mL) was stirred at 50° C. for 3 h under a hydrogen atmosphere (3 bar) in the presence of palladium (10% on activated charcoal, 63 mg), then insoluble material was removed by filtration through diatomaceous earth. The filtrate was evaporated to afford the title compound (104 mg, 83%). Off-white foam, MS: 324.5 (M+H)+.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:7]=[CH:6][N:5]=[N:4]1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]=[CH:27][C:28]2[O:29][CH:30]=[C:31]([CH2:33]Cl)[N:32]=2)=[CH:22][CH:21]=1>CN(C)C=O>[Cl:19][C:20]1[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]2[O:29][CH:30]=[C:31]([CH2:33][O:18][C:15]3[CH:14]=[CH:13][C:12]([CH2:11][O:10][CH2:9][CH2:8][N:3]4[CH:7]=[CH:6][N:5]=[N:4]4)=[CH:17][CH:16]=3)[N:32]=2)=[CH:22][CH:21]=1
Reactant: ClCc1coc(C=Cc2ccc(Cl)cc2)n1
Reactant: Oc1ccc(COCCn2ccnn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(/C=C/c2nc(COc3ccc(COCCn4ccnn4)cc3)co2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78.1 %

Procedure:
25 mg (1.0 mmol) of 95% sodium hydride were given to a solution of 219 mg (1.0 mmol) 4-(2-[1,2,3]triazol-1-yl-ethoxymethyl)-phenol in 5 ml N,N-dimethylformamide and stirred for 15 min at room temperature. Then 254 mg (1.0 mmol) 2-[2-(4-chloro-phenyl)-vinyl]-4-chloromethyl-oxazole were added and stirring continued over night. The mixture was quenched with water, stirred for 1 h and the precipitate isolated by filtration. After washing with water, little methanol, ethyl acetate/heptane 2:1 and ether, and drying at 40° C. in vacuo, 341 mg (78%) 1-[2-(4-{2-[2-(E)-(4-chloro-phenyl)-vinyl]-oxazol-4-ylmethoxy}-benzyloxy)-ethyl]-1H-[1,2,3]triazole were obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13](=O)/[CH:14]=[C:15](\[O-])/[C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].Cl.Cl.[NH2:26][NH2:27]>C(O)C>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[CH:14]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[NH:27][N:26]=2)[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: CCOC(=O)/C([O-])=C/C(=O)c1cn(Cc2ccccc2)cn1
Agent: Cl
Agent: [Li+]
Solvent: CCO
Product: CCOC(=O)c1cc(-c2cn(Cc3ccccc3)cn2)n[nH]1
Temperature: 25 °C
Yield: 90 %

Procedure:
Lithium (Z)-4-(1-benzyl-1H-imidazol-4-yl)-1-ethoxy-1,4-dioxobut-2-en-2-olate (9.80 mmol, 3.0 g) was suspended in dry ethanol (20 ml). Hydrazine dihydro-chloride (12.74 mmol, 1.337 g) was added and the resulting mixture was refluxed for 2 h. The mixture was cooled to ambient temperature and evaporated. The sticky oil was purified by trituration from ethanol. The precipitate was separated by filtration and flushed with cold ethanol. 2.614 g of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.31 (t, 3H), 4.33 (q, 2H), 5.81 (bs, 2H), 7.11-7.39 (m, 6H), 8.16 (bs, 1H), 9.31 (bs, 1H), 14.50 (bs, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:4]=1[NH2:5].C([O:14][CH:15]=[C:16]([C:22](OCC)=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])C>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[C:4]2[C:6]=1[C:15](=[O:14])[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:22][NH:5]2
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: COc1ccc(OC)c(N)c1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1c[nH]c2c(OC)ccc(OC)c2c1=O

Procedure:
Ethyl 5,8-dimethoxy-3-quinolinecarboxylate was formed as described in the literature (E. H. Erickson, C. F. Hainline, L. S. Lenon, et al. J. Med. Chem. 1979, 22, 816). 2,5-Dimethoxyaniline and diethyl ethoxymethylenemalonate condense and then cyclise at high temperature (250° ) in diphenyl ether to form ethyl 1,4-dihydro-5,8-dimethoxy-4-oxo-3-quinolinecarboxylate which is chlorinated at the 4-position with phosphorus oxychloride to give ethyl 4-chloro-5,8-dimethoxy-3-quinolinecarboxylate. The dehalogenation of this quinoline (20.34 g, 0.069 mol) in 150 ml of absolute ethanol with 1 g of 5% Pd/C and 22.53 ml of triethylamine (0.156 mol) was done with a Parr hydrogenator apparatus which gave the correct product, ethyl 5,8-dimethoxy-3-quinolinecarboxylate, as well as the 1,4-dihydro and the 1,2,3,4-tetrahydro quinoline products. This result of further reduction to the 1,4-dihydro product was indicated in the article listed above on page 817, but the formation of the 1,2,3,4-tetrahydro product had not been mentioned there. These three quinoline products were separated on a silica gel column which was eluted with hexane, followed by hexane:ethyl acetate/4:1 and 1:1, giving 0.46 g (2.6% yield) of the title compound, NMR: CDCl3 δ1.23 (tr, 3, CH2Me), 2.94 (br-m, 2, CH2), 3.2-3.6 (m, 3, CH2, CH), 3.76 (s, 6, (OMe)2), 4.21 (quartet, 2, CH2Me), 4.2 (br, 1, NH), 6.12 (d, 1, Ar), 6.57 (d, 1, Ar); 3.31 g of the 1,4-dihydro quinoline product (18.5%), NMR: CDCl3 δ 1.28 (tr, 3, CH2Me), 3.61 (s, 2, CH2), 3.73 (s, 6, (OMe)2), 4.19 (quartet, 2, CH2Me), 6.2-6.7 (br, 1, NH), 6.29 (d, 1, Ar), 6.60 (d, 1, Ar), 7.32 (d, 1, pyr-H); and 2.04 g (11%) of the ethyl 5,8-dimethoxy-3-quinolinecarboxylate.
Reaction SMILES: [CH3:1][N:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=O)[CH:8]=2)[O:4][C:3]1=[O:16].[H][H]>CO.C(Cl)(Cl)Cl.[Pd]>[NH2:13][C:9]1[CH:8]=[C:7]([C:5]2[O:4][C:3](=[O:16])[N:2]([CH3:1])[N:6]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: [H][H]
Reactant: Cn1nc(-c2cccc([N+](=O)[O-])c2)oc1=O
Agent: [Pd]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cn1nc(-c2cccc(N)c2)oc1=O
Yield: 79.6 %

Procedure:
3-Methyl-5-(3-nitrophenyl)-1,3,4-oxadiazol-2(3H)-one (2.17 g, 9.79 mmol) obtained in Step 2 was dissolved in methanol (60 mL) and chloroform (51 mL), and the mixture was stirred at room temperature for 4 hours under a stream of hydrogen after adding 10% palladium-on-carbon (217 mg, 0.102 mmol). The mixture was further stirred at room temperature for 4 hours under a stream of hydrogen after adding 10% palladium-on-carbon (217 mg, 0.102 mmol). Then, insolubles were separated by filtration through sellite, and the filtrate was concentrated under reduced pressure. The residue was triturated with diethyl ether, and the solid was filtered off and dried to give 5-(3-aminophenyl)-3-methyl-1,3,4-oxadiazol-2(3H)-one (1.49 g, 80%).
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[N:11][CH:12]=[C:13]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:14]=2[C:15]2[O:16][CH:17]=[C:18]([C:20]([O:22]C)=O)[N:19]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:30][Mg+].[Br-]>C1COCC1>[C:5]1([C:9]2[N:10]=[N:11][CH:12]=[C:13]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:14]=2[C:15]2[O:16][CH:17]=[C:18]([C:20](=[O:22])[CH3:30])[N:19]=2)[CH:6]=[CH:7][CH:8]=[CH:3][CH:4]=1
Reactant: COC(=O)c1coc(-c2c(-c3ccccc3)cnnc2-c2cccc(OC)c2)n1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(=O)c1coc(-c2c(-c3ccccc3)cnnc2-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.8 %

Procedure:
To a solution of compound 26 (50 mg, 0.14 mmol) in THF (4 mL), MeMgBr (0.7 mL, 0.70 mmol) was added at −40° C. and the reaction mixture was warmed to rt and stirred for 1 h. The reaction mixture was quenched by addition of saturated ammonium chloride solution, extracted with ethyl acetate (25 mL), washed with brine (1×10 mL) and dried over Na2SO4. Evaporation of the solvent under reduced pressure gave the crude product which was purified by column chromatography (100-200 mesh silica gel, 20% EtOAc-hexane) to furnish 1-(2-(3,5-diphenylpyridazin-4-yl)oxazol-4-yl)ethanone (20 mg, 42%) as an off white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:8]([O:10]CC)=[O:9])[N:6]=1.[OH-].[Na+].CO>O1CCCC1>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CCOC(=O)C(=NOCC(C)C)c1csc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)CON=C(C(=O)O)c1csc(N)n1
Yield: 91.6 %

Procedure:
Ethyl 2-(2-aminothiazol-4-yl)-2-iso-butoxyiminoacetate (syn isomer, 19.6 g.), 2N aqueous solution of sodium hydroxide (72.2 ml.), methanol (72.2 ml.) and tetrahydrofuran (72.2 ml.) were treated in a similar manner to that of Example F-(4) to give 2-(2-aminothiazol-4-yl)-2-isobutoxyiminoacetic acid (syn isomer, 16.1 g.), mp 180° C. (dec.).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH3:5].[O:6]1[CH2:10][CH2:9][O:8][CH2:7]1>>[CH3:1][O:2][CH2:3][O:4][CH2:5][CH2:10][O:6][CH2:7][O:8][CH3:9]
Reactant: COCOC
Reactant: C1COCO1
Product: COCOCCOCOC
Yield: 50 %

Procedure:
The reaction of 500 g dimethoxymethane (6.6 moles) with 100 g 1,3-dioxolane (1.4 moles), in the presence of an acidic catalyst, gave a mixture of unreacted dimethoxymethane, low molecular weight oligomers of 1,3-dioxolane and a product having the formula: CH3OCH2OCH2CH2OCH2OCH3 which was isolated in 50% yield. Fluorination of 80 g of the product in a 4 liter reactor containing 1.5 liters (CF2Cl)2CFOCF2OCF(CF2Cl)2 and 400 g sodium fluoride in an 18 hour reaction at 10° C., gave a 60% yield of perfluoro-2,4,7,9-tetraoxadecane (b.p. 79.0° C.).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:9].C([O-])([O-])=O.[K+].[K+].[NH:19]1[CH2:24][CH2:23][S:22][CH2:21][CH2:20]1>CN(C=O)C>[N:19]1([CH2:2][CH2:3][O:4][C:5]2[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=2)[CH:8]=[O:9])[CH2:24][CH2:23][S:22][CH2:21][CH2:20]1
Reactant: C1CSCCN1
Reactant: O=Cc1cccc(OCCBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cccc(OCCN2CCSCC2)c1
Temperature: 25 °C

Procedure:
A mixture of 3-(2-bromoethoxy)benzaldehyde (3.91 g, 17.07 mmol), K2CO3 (3.1 g), thiomorpholine (1.9 ml) and DMF (30 ml) was warmed on a steambath overnight. Additional K2CO3 (0.7 g) and thiomorpholine (1.0 ml) were added and the reaction mixture was warmed on a steam bath overnight. The reaction mixture was cooled to room temperature, filtered and the filtrate was stripped to afford an amber oil. The oil was combined with the product from a similar experimental run and purified by column chromatography on silica gel eluting with EtOAc (100%) to afford, as an oil, 3-[2-(4-thiomorpholinyl)ethoxy]benzaldehyde.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH3:30])[N:8]=[CH:9][C:10]=1[NH:11][C:12]([C:14]1[C:19]([NH:20][C:21]2[CH:22]=[N:23][CH:24]=[N:25][CH:26]=2)=[N:18][CH:17]=[C:16]([CH:27]2[CH2:29][CH2:28]2)[N:15]=1)=[O:13])=[O:5])C.[OH-].[Na+].Cl>C(O)C.O>[CH:27]1([C:16]2[N:15]=[C:14]([C:12]([NH:11][C:10]3[CH:9]=[N:8][N:7]([CH3:30])[C:6]=3[C:4]([OH:5])=[O:3])=[O:13])[C:19]([NH:20][C:21]3[CH:26]=[N:25][CH:24]=[N:23][CH:22]=3)=[N:18][CH:17]=2)[CH2:29][CH2:28]1
Reactant: CCOC(=O)c1c(NC(=O)c2nc(C3CC3)cnc2Nc2cncnc2)cnn1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cn1ncc(NC(=O)c2nc(C3CC3)cnc2Nc2cncnc2)c1C(=O)O
Temperature: 85 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
To a suspension of 4-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyrazine-2-carbonyl]-amino}-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester (1.13 g, 2.77 mmol) in ethanol (15 ml) and water (12 ml) was added 1N NaOH (3.32 ml) at r.t. under argon atmosphere. The yellow suspension was stirred at 85° C. for 1 h. After cooling down to r.t., the mixture was treated with 1M HCl (3.3 ml) and stirred for 30 min. The product was collected by filtration, washed with water and EtOH, and dried to yield a light yellow solid (1.0 g, 95%).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:15]([NH2:19])[CH:16]([CH3:18])[CH3:17].[C:20]([O:24][C:25]([N:27]1[CH2:33][CH2:32][CH2:31][C@H:28]1[CH:29]=O)=[O:26])([CH3:23])([CH3:22])[CH3:21].[OH-].[Na+]>ClCCCl.O>[CH2:15]([NH:19][CH2:29][C@@H:28]1[CH2:31][CH2:32][CH2:33][N:27]1[C:25]([O:24][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:26])[CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)CN
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: O
Product: CC(C)CNC[C@@H]1CCCN1C(=O)OC(C)(C)C
Yield: 76.1 %

Procedure:
Sodium triacetoxyborohydride (2.9 g, 14 mmol, 1.4 eq) is added to a solution of isobutylamine (0.77 g, 10 mmol, 1.05 eq) and N-(tert-butoxycarbonyl)-L-prolinal (2 g, 10 mmol, 1 eq) in 1,2-dichloroethane (35 ml). After 1 hr water (25 ml) followed by 2N aqueous sodium hydroxide (25 ml) is added. The aqueous layer is separated and extracted with dichloromethane (3×50 ml). The organic layers are combined and dried over magnesium sulphate, filtered, and concentrated in vacuo giving a residue. The residue is purified by flash chromatography, eluting with 20-70% methanol in ethyl acetate to give the tert-butyl (2S)-2-[(isobutylamino)methyl]pyrrolidine-1-carboxylate (1.95 g, 76%): 1H NMR (300 MHz, CDCl3) δH: 3.69-4.07 (1H, m), 3.19-3.50 (2H, m), 2.67-2.87 (1H, m), 2.48-2.65 (1H, m), 2.35-2.47 (2H, m), 1.62-2.01 (5H, m), 1.34-1.53 (9H, m) and 0.88 (6H, d); LCMS: Rt=2.74 (6 min method) [M+H]=257.5.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[OH-].[K+]>>[CH2:5]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6])[C:4]1[CH:7]=[CH:8][CH:9]=[CH:2][CH:3]=1
Reactant: O=Cc1ccc(O)c(O)c1
Agent: [K+]
Agent: [OH-]
Product: O=Cc1ccc(O)c(OCc2ccccc2)c1
Reaction time: 8 h
Yield: 59.8 %

Procedure:
To a mixture of 3,4-dihydroxy benzaldehyde (40.80 gms, 0.29 mol) and ethanolic potassium hydroxide (2 N, 320 mL) benzylchloride (37.54 g, 0.29 mol) was added slowly at room temperature. The reaction mixture was stirred overnight under nitrogen. The ethanol was removed on rotavapour and remaining solution treated with ice water. For removal of dibenzyl ether alkaline solution was extracted with diethyl ether (500 ml). Then the aqueous layer was acidified with concentrated hydrochloric acid and extracted thrice with ethyl acetate (800 ml). The organic layer was dried (Na2SO4), filtered and concentrated. The crude product was purified on silica gel column using EtOAc:light petroleum (1:9) as eluent to give 3-bezyloxy-4-hydroxy benzaldehyde (19.80 g, 29%). TLC: Ethyl acetate:light petroleum (1:4), Rf=0.3; m.p: 109-111° C.; 1H NMR (CDCl3, 200 MHz): δ 5.06 (s, 2H), 6.39 (s,1H), 6.95 (d, J=8.0 Hz, 1H), 7.1-7.4 (m, 7H) and 9.57 (s, 1H).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][C:15](O)=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[CH3:19][NH:20][O:21][CH3:22]>>[CH:5]1[C:13]2[CH:12]([CH2:14][C:15]([N:20]([O:21][CH3:22])[CH3:19])=[O:16])[C:11]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:1]=2[CH:2]=[CH:3][CH:4]=1
Reactant: CNOC
Reactant: O=C(O)CC1c2ccccc2-c2ccccc21
Agent: Cl
Product: CON(C)C(=O)CC1c2ccccc2-c2ccccc21

Procedure:
In analogy to example 55, step 1, from fluorene-9-acetic acid (CAS RN: [6284-80-6]) and N,O-dimethylhydroxylamine hydrochloride was prepared the title compound as an off-white oil, MS (ESI+): m/z=268.1 ([M+H]+).
Reaction SMILES: [CH3:1]/[C:2](=[CH:8]\[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21]/[CH:22]=[CH:23]\[CH2:24][CH3:25])/[C:3]([O:5]CC)=[O:4].[Li+].[OH-].Cl>CO.O>[CH3:1]/[C:2](=[CH:8]\[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21]/[CH:22]=[CH:23]\[CH2:24][CH3:25])/[C:3]([OH:5])=[O:4]
Reactant: CC/C=C\C/C=C\C/C=C\CCCCCCC/C=C(\C)C(=O)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC/C=C\C/C=C\C/C=C\CCCCCCC/C=C(\C)C(=O)O
Temperature: 50 °C

Procedure:
Ethyl (2E,11Z,14Z,17Z)-2-methyl-eicosa-2,11,14,17-tetraenoate (6) (160 mg, 0.46 mmol) was dissolved in methanol (3 ml) and added LiOH (193 mg, 4.6 mmol) in water (3 ml) and the mixture was heated at 50° C. for 2 hrs. The mixture was cooled, and diluted hydrochloric acid was added to pH 2. Extraction with diethylether, drying (MgSO4) and evaporation of solvents under reduced pressure afforded the acid 7. The acid was purified by flash chromatography on silica gel (8:2 hexane-EtOAc); δH(300 MHz) 0.95 (t, J 7.5, 3H, CH3), 1.2-1.5 (m, 10H), 1.81 (s, 3H, CH3), 2.0-2.2 (m, 6H), 2.79 (t, J 5.8, 4H), 5.2-5.4 (m, 6H), 6.90 (dt, J 7.5, J 1.3, 1H); δc(75 MHz) 11.93, 14.25, 20.53, 25.51, 25.60, 27.19, 28.40, 28.87, 29.16, 29.31, 29.58, 126.94, 127.10, 127.71, 128.24, 128.25, 130.25, 131.93, 145.41, 173.76.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=O)[NH:8][C:4]=2[CH:3]=1.P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:7]1[NH:8][C:4]2[CH:3]=[C:2]([F:1])[CH:11]=[CH:10][C:5]=2[N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c2ccc(F)cc2[nH]1
Product: Fc1ccc2nc(Cl)[nH]c2c1
Yield: 81.7 %

Procedure:
4-Fluorobenzene-1,2-diamine (2 g, 15.86 mmol) was dissolved in THF (49.4 ml) and 1,1′-Carbonyldiimidazole (2.83 g, 17.44 mmol) was added at RT. The reaction mixture was stirred overnight at RT. To this was added concentrated ammonia solution (1.5 ml) and the mixture stirred for 30 minutes and then diluted with water (100 ml). The resultant solid was collected by filtration, washed with water, followed by Et2O and then dried in vacuo to afford 5-fluoro-1H-benzo[d]imidazol-2(3H)-one (1.250 g, 52%); 1H NMR (400 MHz, DMSO-d6) 6.66-6.79 (2H, m), 6.81-6.94 (1H, m), 10.64 (1H, s), 10.76 (1H, s); m/z: (ES+) MH+, 151.19. b) A solution of 5-fluoro-1H-benzo[d]imidazol-2(3H)-one (1.25 g, 8.22 mmol) in phosphorus oxychloride (25.2 ml, 270.34 mmol) was heated for 18 hours at 100° C. The reaction mixture was cooled to RT and excess of POCl3 was evaporated in vacuo. The residue was neutralized with saturated NaHCO3 solution (10 ml) and extracted with EtOAc (3×20 ml). The organic phase was washed with brine and then dried over MgSO4, filtered and concentrated under reduced pressure to afford 2-chloro-6-fluoro-1H-benzo[d]imidazole (1.146 g, 82%); 1H NMR (400 MHz, DMSO-d6) 7.09 (1H, ddd), 7.36 (1H, dd), 7.53 (1H, dd); m/z: (ES+) MH+, 171.34. c) 2-Chloro-6-fluoro-1H-benzo[d]imidazole (1.146 g, 6.72 mmol) was charged to high pressure autoclave PV10832 (Parr 160 ml) with methylamine 40% EtOH solution (50 ml, 6.72 mmol) and sealed on its trolley and the resulting solution heated to 160° C. in high pressure blast cell 60 for 16 hours. The pressure in the autoclave reached 13 bar. The reaction mixture was evaporated and the residue dissolved in MeOH and added to an SCX column. The desired product was eluted from the column using 7M NH3/MeOH. Fractions containing product were evaporated and the residue was purified by flash chromatography on silica, eluting with a gradient of 0 to 10% MeOH in DCM. Pure fractions were evaporated to afford 6-fluoro-N-methyl-1H-benzo[d]imidazol-2-amine (0.707 g, 64%); 1H NMR (400 MHz, DMSO-d6) 2.27 (3H, d), 6.38-6.44 (2H, m), 6.67 (1H, dd), 6.79-6.84 (1H, m); m/z: (ES+) MH+, 166.31.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:18][C:17]2[C:16]([C:19](O)=[O:20])=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1COCC1>[OH:20][CH2:19][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:17]=1[CH2:18][CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:10][CH2:11]2
Reactant: CC(C)(C)OC(=O)NC1CCc2cccc(C(=O)O)c2C1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCc2cccc(CO)c2C1
Temperature: 25 °C

Procedure:
To a flask was added 7-((tert-butoxycarbonyl)amino)-5,6,7,8-tetrahydro-naphthalene-1-carboxylic acid (20-1) (2.02 g, 6.93 mmol), then anhydrous THF (20 mL). The reaction mixture was cooled to 0 C (ice water bath) while stirring under an atmosphere of nitrogen. Then a 1M solution of BORANE TETRAHYDROFURAN COMPLEX (30 mL, 30.0 mmol) was added dropwise while stirring. The reaction mixture was stirred at 0 C for 1.5 hours. Followed by LC/MS. The reaction mixture was then uncapped (always at 0 C), then quenched by dropwise addition of saturated NH4Cl (lots of bubbling/gas evolution). The reaction mixture was then warmed to room temperature, then suspended in EtOAc, separated, the organics were then washed with saturated NaHCO3, then H2O, then brine; dried over Na2SO4, filtered & concentrated. The resulting residue was purified by silica gel chromatography (0-50% EtOAc/Hex; 80 g ISCO); desired fractions concentrated to yield tert-butyl (8-(hydroxymethyl)-1,2,3,4-tetrahydronaphthalen-2-yl)carbamate (20-2).