Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][OH:10]>ClCCl.O=[Mn]=O>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]=[O:10]
Reactant: Nc1cccc(F)c1CO
Agent: O=[Mn]=O
Solvent: ClCCl
Product: Nc1cccc(F)c1C=O
Yield: 51.1 %

Procedure:
To (2-amino-6-fluoro-phenyl)-methanol (2.49 g, 17.3 mmol) in dichloromethane (30 mL) was added MnO2 (3.01 g, 34.7 mmol, activated). The mixture was refluxed for 3 hrs and then filtered over celite. The mixture was concentrated and purified via silica gel flash chromatography (eluting with 30% ethyl acetate in hexane) to give 2-amino-6-fluoro-benzaldehyde as a yellow solid (1.23 g). tR=2.20 min. (method 1)
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:12])=[CH:4][C:3]=1[O:13][CH3:14].[CH3:15][C:16](C)([O-])[CH3:17].[K+].C(Br)C=C.O>C(O)(C)(C)C.C1C=CC=CC=1>[CH2:17]([CH:7]1[CH2:6][C:5]2[C:9](=[C:10]([Cl:11])[C:2]([Cl:1])=[C:3]([O:13][CH3:14])[CH:4]=2)[C:8]1=[O:12])[CH:16]=[CH2:15]
Reactant: CC(C)(C)[O-]
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)CC2
Agent: [K+]
Solvent: O
Solvent: C=CCBr
Solvent: c1ccccc1
Product: C=CCC1Cc2cc(OC)c(Cl)c(Cl)c2C1=O
Temperature: 20 °C

Procedure:
6,7-Dichloro-5-methoxy-2,3-dihydro-1H-inden-1-one (63.5 gm., 0.274 mole) is dissolved in a mixture of dry tert.-butyl alcohol (500 ml.) and dry benzene (1.5 liters). The solution is refluxed and potassium tert.-butoxide (46 gm., 0.301 mole) in dry tert.-butyl alcohol (1 liter) is added as rapidly as possible. The solution is refluxed for another 1/2 hour, cooled to 20° C., stirred and treated with allyl bromide (36 gm., 0.301 mole). The mixture is stirred and refluxed for 4 hours, cooled and treated with water (250 ml.). The crude 2-allyl-6,7-dichloro-5-methoxy-2,3-dihydro-1H-inden-1-one is separated by filtration, washed with water, dried and recrystallized from a mixture of benzene and hexane.
Reaction SMILES: [CH3:1][C@@:2]12[C@:10]3([C:16]([CH2:18][OH:19])=[O:17])[O:11][C:12]([CH3:15])(C)[O:13][C@@H:9]3[CH2:8][C@H:7]1[C@@H:6]1[CH2:20][CH2:21][C:22]3[C@@:28]([CH3:29])([C@H:5]1[C@@H:4]([OH:30])[CH2:3]2)[CH:27]=[CH:26][C:24](=[O:25])[CH:23]=3.[CH:31](=O)[CH2:32]CC.F>O>[CH3:31][CH2:32][CH2:15][CH:12]1[O:11][C@:10]2([C:16]([CH2:18][OH:19])=[O:17])[C@@H:9]([CH2:8][C@@H:7]3[C@:2]2([CH3:1])[CH2:3][C@H:4]([OH:30])[C@H:5]2[C@H:6]3[CH2:20][CH2:21][C:22]3[C@:28]2([CH3:29])[CH:27]=[CH:26][C:24](=[O:25])[CH:23]=3)[O:13]1
Reactant: CC1(C)O[C@@H]2C[C@H]3[C@@H]4CCC5=CC(=O)C=C[C@]5(C)[C@H]4[C@@H](O)C[C@]3(C)[C@]2(C(=O)CO)O1
Reactant: CCCC=O
Agent: F
Solvent: O
Product: CCCC1O[C@@H]2C[C@H]3[C@@H]4CCC5=CC(=O)C=C[C@]5(C)[C@H]4[C@@H](O)C[C@]3(C)[C@]2(C(=O)CO)O1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
50 Grams of desonide (16β-hydroxyprednisolone-16,17-acetonide) and immediately thereafter 12,5 ml of butyraldehyde were added to 500 ml of a 70% hydrofluoric acid solution, at -5° C. The mixture was stirred at 0° C. for one hour and then poured into 5 liters of demineralized water at 0° C. The precipitate was filtered, washed to neutrality with water and dried under vacuum to give 51 g of pure budesonide with an A/B epimer ratio of 9/91.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[O:18])[CH:15]=3)[C:10]([S:25][CH3:26])=[CH:9]2)=[N:6][CH:7]=1.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH3:26][S:25][C:10]1[C:11]2[C:16](=[CH:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])=[CH:13][CH:12]=2)[N:8]([C:5]2[N:4]=[CH:3][C:2]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:7][N:6]=2)[CH:9]=1
Reactant: OB(O)c1ccccc1
Reactant: CSc1cn(-c2ncc(Br)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Product: CSc1cn(-c2ncc(-c3ccccc3)cn2)c2cc(C(=O)N3CCOCC3)ccc12

Procedure:
Obtained according to general procedure 1 from (1-(5-bromopyrimidin-2-yl)-3-(methylthio)-1H-indol-6-yl)(morpholino)methanone (0.7 g, 1.616 mmol) and phenyl boronic acid (0.232 g, 1.939 mmol). Yield: 0.5 g (72% of theory)
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH:10]2[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][CH2:18][OH:19])[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].C(N(CC)CC)C.[C:27](Cl)(=[O:31])[C:28]([CH3:30])=[CH2:29]>ClCCl>[CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH:10]2[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][CH2:18][O:19][C:27](=[O:31])[C:28]([CH3:30])=[CH2:29])[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: C=C(C)C(=O)Cl
Reactant: CCCC1CCC(C2CCC(CCCO)CC2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCCCC1CCC(C2CCC(CCC)CC2)CC1
Reaction time: 8 h

Procedure:
3-(4′-Propyl-bicyclohexyl-4-yl)-propan-1-ol (5 g, 18.8 mmol) is dissolved in dichloromethane (50 ml) and triethylamine (3.5 ml) and a solution of methacryloyl chloride (2.2 ml, 21.8 mmol) in dichloromethane (30 ml) is added dropwise at 0° C. The reaction is stirred overnight, evaporated, filtered through silica with heptane/ethyl acetate (19:1) and the crude product is crystallised from ethanol to give 2-methyl acrylic acid 3-(4′-propyl-bicyclohexyl-4-yl)-propyl ester as colourless crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][CH:5]([CH:8]=O)[CH2:4][CH2:3]1.Cl.[NH2:12][OH:13]>>[CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][CH:5]([CH:8]=[N:12][OH:13])[CH2:4][CH2:3]1
Reactant: NO
Reactant: CC1(C)CCC(C=O)CC1
Agent: Cl
Product: CC1(C)CCC(C=NO)CC1

Procedure:
4,4-Dimethylcyclohexanecarbaldehyde oxime (I-9C) was prepared by reaction of 4,4-dimethylcyclohexanecarbaldehyde and hydroxylamine hydrochloride by following the same protocol as described for I-6C. MS m/z 156.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([OH:15])=[C:8]([CH2:12][CH2:13][CH3:14])[CH:9]=[C:10]([Cl:11])[C:5]=2[O:4][C:3]=1[C:16]([OH:18])=[O:17].C(=O)([O-])[O-].[K+].[K+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CC(C)=O>[CH3:1][C:2]1[C:6]2[C:7]([OH:15])=[C:8]([CH2:12][CH2:13][CH3:14])[CH:9]=[C:10]([Cl:11])[C:5]=2[O:4][C:3]=1[C:16]([O:18][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:17]
Reactant: BrCc1ccccc1
Reactant: CCCc1cc(Cl)c2oc(C(=O)O)c(C)c2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1cc(Cl)c2oc(C(=O)OCc3ccccc3)c(C)c2c1O
Yield: 29.3 %

Procedure:
A mixture of 3-methyl-4-hydroxy-5-propyl-7-chloro-benzofuran-2-carboxylic acid (0.5 gm; 1.9 mmole), potassium carbonate (0.26 gm; 1.9 mmole) and benzyl bromide (0.22 ml; 1.9 mmole) in acetone (100 ml) was refluxed for a period of 2 hours. The solids were filtered off and the filtrate was concentrated in vacuo. The residue was chromatographed on silica gel and eluted with 15% ethyl acetate in hexane to yield 200 mg (30%) of benzyl 3-methyl-4-hydroxy-5-propyl-7-chlorobenzofuran-2-carboxylate, m.p. 119°-120° C.
Reaction SMILES: C([Li])CCC.[Cl-].[CH3:7][O:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O=[C:30]1[CH2:35][N:34]2[CH2:36][CH2:37][CH:31]1[CH2:32][CH:33]2[C:38]([O:40][CH3:41])=[O:39]>CCOCC>[CH3:41][O:40][C:38]([CH:33]1[CH2:32][CH:31]2[CH2:37][CH2:36][N:34]1[CH2:35][C:30]2=[CH:7][O:8][CH3:9])=[O:39]
Reactant: COC(=O)C1CC2CCN1CC2=O
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOCC
Product: COC=C1CN2CCC1CC2C(=O)OC
Reaction time: 2 h
Yield: 59.2 %

Procedure:
n-Butyllithium (13,67 ml of a 1.5M solution; 20.5 mmol) was added at 20° to a suspension of methoxymethyltriphenyl phosphonium chloride (7 g, 20.5 mmol) stirred in ether (150 ml) under nitrogen. After 2 h, the mixture was cooled to -35° and a solution of methyl 5-oxoquinuclidine-2-carboxylate (3 g, 16.4 mmol; prepared as described in Zhur. Obshchei. Khim., (1960), 30, 519;see Chem. Abs. (1960), 54: 24723) in ether (20 ml) added. The mixture was allowed to warm to 20° over 1 h and then stirred at this temperature for 16 h. After removing the precipitated triphenylphosphine oxide by filtration, the ether was evaporated off and the resulting oil subjected to chromatography on silica in 3% methanol in dichloromethane to afford the title compound (2.05 g) as a mixture of isomers: m/e 211 (M+); δ(360 MHz, CDCl3) 1.2-2.0 (4H, m, 2×CH2); 2.18-2.34 (1H, m, 4-CH); 2.5-3.4 (5H, m, 2×NCH2 and NCH); 3.50-3.56 (3H, m, OCH3); 3.78-3.82 (3H, m, CO2CH3) and 5.73-5.83 (1H, m, CH).
Reaction SMILES: [CH2:1]1[O:5][C@@H:4]2[C@@H:6]([OH:9])[CH2:7][O:8][C@@H:3]2[C@@H:2]1[OH:10].C1O[C@@H]2[C@H](O)CO[C@@H]2[C@@H]1O.C1O[C@@H]2[C@@H](O)CO[C@@H]2[C@H]1O.[OH:31][CH2:32][C@@H:33]([C@H:35]([C@@H:37]([C@@H:39]([CH2:41][OH:42])[OH:40])[OH:38])[OH:36])[OH:34].C(O)[C@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O>>[CH2:1]1[O:5][C@@H:4]2[C@@H:6]([OH:9])[CH2:7][O:8][C@@H:3]2[C@H:2]1[OH:10].[O:31]=[CH:32][C@@H:33]([C@H:35]([C@@H:37]([C@H:39]([CH2:41][OH:42])[OH:40])[OH:38])[OH:36])[OH:34]
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Reactant: O[C@@H]1CO[C@H]2[C@@H]1OC[C@@H]2O
Agent: OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2O
Agent: O[C@H]1CO[C@H]2[C@@H]1OC[C@@H]2O
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO

Procedure:
Isohexide starting materials can be obtained by known methods of making respectively isosorbide, isomannide, or isoidide. Isosorbide and isomannide can be derived from the dehydration of the corresponding sugar alcohols, D-sorbitol and D mannitol. As a commercial product, isosorbide is also available easily from a manufacturer. The third isomer, isoidide, can be produced from L-idose, which rarely exists in nature and cannot be extracted from vegetal biomass. For this reason, researchers have been actively exploring different synthesis methodologies for isoidide. For example, the isoidide starting material can be prepared by epimerization from isosorbide. In L. W. Wright, J. D. Brandner, J. Org. Chem., 1964, 29 (10), pp. 2979-2982, epimerization is induced by means of Ni catalysis, using nickel supported on diatomaceous earth. The reaction is conducted under relatively severe conditions, such as a temperature of 220° C. to 240° C. at a pressure of 150 atmosphere. The reaction reaches a steady state after about two hours, with an equilibrium mixture containing isoidide (57-60%), isosorbide (30-36%) and isomannide (5-7-8%). Comparable results were obtained when starting from isoidide or isomannide. Increasing the pH to 10-11 was found to have an accelerating effect, as well as increasing the temperature and nickel catalyst concentration. A similar disclosure can be found in U.S. Pat. No. 3,023,223, which proposes to isomerize isosorbide or isomannide. More recently, P. Fuertes proposed a method for obtaining L-iditol (precursor for isoidide), by chromatographic fractionation of mixtures of L-iditol and L-sorbose (U.S. Patent Publication No. 2006/0096588; U.S. Pat. No. 7,674,381 B2). L-iditol is prepared starting from sorbitol. In a first step sorbitol is converted by fermentation into L-sorbose, which is subsequently hydrogenated into a mixture of D-sorbitol and L-iditol. This mixture is then converted into a mixture of L-iditol and L-sorbose. After separation from the L-sorbose, the L-iditol can be converted into isoidide. Thus, sorbitol is converted into isoidide in a four-step reaction, in a yield of about 50%. (The contents of the cited references are incorporated herein by reference.)
Reaction SMILES: COC[O:4][CH:5]([CH3:29])[C:6](=[O:28])[CH2:7][N:8]1[C:13]([C:14]2[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=2)=[CH:12][C:11]([C:21]([F:24])([F:23])[F:22])=[C:10]([C:25]#[N:26])[C:9]1=[O:27].Cl>CO>[OH:4][CH:5]([CH3:29])[C:6](=[O:28])[CH2:7][N:8]1[C:13]([C:14]2[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=2)=[CH:12][C:11]([C:21]([F:24])([F:22])[F:23])=[C:10]([C:25]#[N:26])[C:9]1=[O:27]
Reactant: COCOC(C)C(=O)Cn1c(-c2cccc(C)c2)cc(C(F)(F)F)c(C#N)c1=O
Agent: Cl
Solvent: CO
Product: Cc1cccc(-c2cc(C(F)(F)F)c(C#N)c(=O)n2CC(=O)C(C)O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.4 %

Procedure:
1-(3-Methoxymethoxy-2-oxo-butyl)-2-oxo-6-m-tolyl-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile (0.191 g, 0.47 mmoles) was dissolved into 25 mL of anhydrous MeOH and to this solution was added HCl (2.0 M solution in diethyl ether, 5.0 mL). The mixture was then stirred at room temperature for 2 hours. After this period the reaction mixture was evaporated in vacuo and was purified using flash silica chromatography (0-60% EtOAc/Hexane) to yield 0.16 g (93% yield) of 1-(3-Hydroxy-2-oxo-butyl)-2-oxo-6-m-tolyl-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile as a yellow residue. 1H-NMR (CDCl3): δ7.42-7.35 (m, 2H), 7.14-7.08 (m, 2H), 6.50 (m, 1H), 5.06 (d, J=17.2 Hz, 1H), 4.92 (d, J=17.2 Hz, 1H), 4.39-4.31 (m, 1H), 3.48 (bs, 1H), 2.40 (s, 3H), 1.28 (d, J=6.8 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]([C:25]1[CH:26]=[CH:27][C:28]2[S:32][CH:31]=[CH:30][C:29]=2[CH:33]=1)[C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]([C:25]2[CH:26]=[CH:27][C:28]3[S:32][CH:31]=[CH:30][C:29]=3[CH:33]=2)[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CCOC(=O)C(N)c1ccc2sccc2c1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Product: CCOC(=O)C(NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)c1ccc2sccc2c1

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and ethyl 2-amino-2-(benzothiophen-5-yl)acetate (prepared as described in S. Kukolja et al., J. Med. Chem., 1985, 28, 1896-1903), the title compound was prepared as a solid (mp=126.5-127.5° C.). The product was purified by preparative LC 2000 chromatography using 1:1 hexanes/EtOAc as the eluent.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C:7]([C:14]([F:17])([F:16])[F:15])([CH:12]=[CH2:13])[C:6]=2[CH:18]=1.[H-].[Na+].[CH3:21]I.[Cl-].[NH4+]>CN(C=O)C.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:21])[C:9](=[O:11])[O:8][C:7]([C:14]([F:15])([F:16])[F:17])([CH:12]=[CH2:13])[C:6]=2[CH:18]=1
Reactant: CI
Reactant: C=CC1(C(F)(F)F)OC(=O)Nc2ccc(Cl)cc21
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CC1(C(F)(F)F)OC(=O)N(C)c2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 6-chloro-4-(trifluoromethyl)-4-vinyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (100 mg, 0.36 mmol) in DMF (1 mL), sodium hydride (60%, 29 mg, 0.72 mmol) were added at 0° C. After the mixture was stirred at 0° C. for 30 minutes, methyl iodide (44.8 μL, 0.72 mmol) was added dropwise thereto. After the reaction solution was stirred overnight at room temperature, water was added thereto. The solution was diluted with ethyl acetate and a saturated aqueous ammonium chloride solution was added thereto. The organic layer was separated and washed with saturated brine and then dried over magnesium sulfate. After the drying agent was removed by filtration, the solvent was evaporated under reduced pressure, whereby the objective compound (107 mg, quant.) was obtained as a pale brown solid.
Reaction SMILES: C([O:4][C:5]([CH3:7])=[CH2:6])(=O)C.[Cl:8][C:9]1[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[C:10]=1N.C(=O)([O-])[O-].[K+].[K+].N(OC(C)(C)C)=O>CC(C)=O>[Cl:8][C:9]1[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[C:10]=1[CH2:4][C:5](=[O:6])[CH3:7]
Reactant: Nc1c(Cl)cc(Cl)cc1Cl
Reactant: C=C(C)OC(C)=O
Agent: CC(C)(C)ON=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)Cc1c(Cl)cc(Cl)cc1Cl
Reaction time: 0.5 h
Yield: 58 %

Procedure:
A mixture of isopropenyl acetate (12.2 g, 122 mmol), 2,4,6-trichloroaniline (16.0 g, 81.4 mmol), potassium carbonate (100 mg, 0.7 mmol), and acetone (100 g) was cooled to 10° C. tert-Butyl nitrite (90%, 10 g, 87.3 mmol) was dosed over 30 minutes. The reaction was stirred for further 90 minutes, and it was concentrated to a black oil. The residue was triturated with water, and the pH was adjusted to 10.5 with sodium hydroxide solution. The precipitate was filtered and recrystallized from methanol-water 1:1. The solid was filtered, washed with methanol-water 1:1, and dried. The product was obtained as dark-brown crystalline material (15.9 g, 70.7% purity, 47.3 mmol, 58% yield). Further purification was achieved by recrystallization from hexanes. 1H NMR (400 MHz, CDCl3): δ 2.23 (s, 3H, CH3), 4.02 (s, 2H, CH2), 7.31 (s, 2H, CH).
Reaction SMILES: [NH2:1][C@H:2]([C:15]([NH2:17])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=1.[CH:18](=O)[CH3:19].[BH4-].[Na+]>O>[NH:1]([CH2:18][CH3:19])[C@H:2]([C:15]([NH2:17])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:12])[CH3:13])[CH:5]=1
Reactant: CC=O
Reactant: CC(C)(C)c1cc(C[C@H](N)C(N)=O)ccc1O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CCN[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O
Yield: 72.3 %

Procedure:
A mixture of Tyr(3-tBu)-NH2 (1.6 g, 6.8 mmol) and acetaldehyde (7.6 ml, 0.14 mol) was stirred under cooling with ice for 10 min. The reaction mixture was concentrated under reduced pressure under cooling with ice; the thus obtained residue was mixed with methanol (34 ml) and then under cooling with ice with sodium borohydride (0.28 g, 7.4 mmol) and stirred at the same temperature for 15 min. The resultant was mixed with water and extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (CHCl3:MeOH=20:1), giving N-Et-Tyr(3-tBu)-NH2 (T7) (1.3 g, 73%).
Reaction SMILES: [C:1](Cl)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[CH:21][N:22]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=[CH:15][CH:14]=1>>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[C:21]([C:1]([O:3][CH2:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[O:2])[N:22]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=[CH:15][CH:14]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C[Si](C)(C)CCOCn1cnc(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1
Product: C[Si](C)(C)CCOCn1c(C(=O)OCc2ccccc2)nc(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1

Procedure:
Using essentially the same procedure as Example 25, Step B, but using CBZ-Cl (0.030 mL, 1.2 mmol) in Step B, 4,5-di-(4-chlorophenyl)-1-(2-(trimethylsilyl)ethoxymethyl)imidazole (31 mg, 0.074 mmol) from Example 25, Step A was converted to the title compound. HPLC/MS: 553 (M+1), 555 (M+3); Rt=5.2 min.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[CH3:24][O:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29].C(N(CC)C(C)C)(C)C>O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:28](=[O:29])[C:27]3[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=3[O:25][CH3:24])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: COc1ccccc1C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccccc1C(=O)Nc1ccc2c(c1)C(C)(c1ccccc1)CC(C)(C)N2C(C)=O

Procedure:
Acylation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (0.60 g) with 2-methoxybenzoyl chloride (1.0 g) and N,N-diisopropylethylamine (1.7 ml) in tetrahydrofuran (60 ml) was performed according to the method described in example 6.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[C:7]([CH:17]1[CH2:19][CH2:18]1)=[CH:6]2)#[N:2].[F:24][C:25]([F:36])([F:35])[C:26]1[CH:31]=[CH:30][N:29]=[C:28]([C:32](O)=O)[CH:27]=1>>[CH:17]1([C:7]2[N:8]([CH2:12][C:13]3[N:16]=[C:32]([C:28]4[CH:27]=[C:26]([C:25]([F:35])([F:24])[F:36])[CH:31]=[CH:30][N:29]=4)[O:15][N:14]=3)[C:9]3[C:5]([CH:6]=2)=[C:4]([C:20]([F:22])([F:23])[F:21])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)[CH2:19][CH2:18]1
Reactant: O=C(O)c1cc(C(F)(F)F)ccn1
Reactant: N#Cc1ccc2c(cc(C3CC3)n2CC(=N)NO)c1C(F)(F)F
Product: N#Cc1ccc2c(cc(C3CC3)n2Cc2noc(-c3cc(C(F)(F)F)ccn3)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 72 from 2-[5-cyano-2-cyclopropyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (Example 364B) and 4-(trifluoromethyl)-2-pyridinecarboxylic acid: 1H NMR (400 MHz, CDCl3) δ 9.01 (d, J=4.7 Hz, 1H), 8.33 (s, 1H), 7.75 (d, J=4.7 Hz, 1H), 7.68 (d, J=8.5 Hz 1H), 7.56 (d, J=8.5 Hz 1H), 6.49 (s, 1H), 5.70 (s, 2H), 2.14 (m, 1H), 1.16 (m, 2H), 0.90 (m, 2H); MS (ES) m/z 478 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14]O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Br)(Br)(Br)[Br:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][Br:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (2.30 g, 10.7 mmol) and carbon tetrabromide (4.43 g, 13.4 mmol) in CH2Cl2 (40 mL) is cooled to 0° C. Triphenylphosphine (4.21 g, 16.0 mmol) is added and the reaction is stirred at 25° C. for 1 h. The reaction is concentrated and ether is added to the residue. The mixture is filtered and washed with ether. The filtrate is concentrated and purified by column chromatography (silica, 20% EtOAc/hexane) to provide 4-bromomethyl-piperidine-1-carboxylic acid tert-butyl ester as a crystaline solid upon standing. Mp 48-50° C.; 1H NMR (300 MHz, CDCl3) δ 4.13 (bm, 2H), 3.29 (d, 2H), 2.70 (dd, 2H), 1.85-1.73 (m, 3H), 1.46 (s, 9H), 1.28-1.13 (m, 2H); MS (EI) 277 (M)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH2:6])=[O:5].C(Cl)(=O)[C:13](Cl)=[O:14]>ClC(Cl)C>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([N:6]=[C:13]=[O:14])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: NC(=O)c1c(F)cccc1F
Solvent: CC(Cl)Cl
Product: O=C=NC(=O)c1c(F)cccc1F
Temperature: 110 °C
Yield: 76.3 %

Procedure:
In 150 ml of dichloroethane was suspended 13.5 g of 2,6-difluorobenzamide, and 14.0 g of oxalyl chloride was little by little added to the suspension, followed by heating under reflux at about 110° C. for 15 hours. The reaction mixture was concentrated under reduced pressure, and the resultant oily substance was distilled under reduced pressure to give 12 g of the subject compound as an oily material of boiling point of 123° C./60 mmHg.
Reaction SMILES: N1C=CC=CC=1.[S:7]([O:11][S:12]([OH:15])(=[O:14])=[O:13])([OH:10])(=[O:9])=[O:8].[OH:16][CH2:17]/[C:18](/[CH2:27][CH2:28]/[CH:29]=[C:30](\[CH3:37])/[CH2:31][CH2:32][CH:33]=[C:34]([CH3:36])[CH3:35])=[CH:19]/[CH2:20][CH2:21]/[C:22](/[CH3:26])=[CH:23]/[CH2:24][OH:25].C(C(CCCC)C([O-])=O)C.[Na+:48]>C(OCC)(=O)C>[Na+:48].[S:7]([O:11][S:12]([O-:15])(=[O:14])=[O:13])([O-:10])(=[O:9])=[O:8].[OH:16][CH2:17]/[C:18](/[CH2:27][CH2:28]/[CH:29]=[C:30](\[CH3:37])/[CH2:31][CH2:32][CH:33]=[C:34]([CH3:36])[CH3:35])=[CH:19]/[CH2:20][CH2:21]/[C:22](/[CH3:26])=[CH:23]/[CH2:24][OH:25].[Na+:48]
Reactant: O=S(=O)(O)OS(=O)(=O)O
Agent: CC(C)=CCC/C(C)=C/CC/C(=C\CC/C(C)=C/CO)CO
Agent: CCCCC(CC)C(=O)[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=S(=O)([O-])OS(=O)(=O)[O-]

Procedure:
Following the procedures of Example 27, a solution of 2.2 g of (E,Z,E) and (E,E,E)-7-hydroxymethyl-3,11,15-trimethyl-2,6,10,14-hexadecatetraen-1-ol disulfate pyridine salt prepared in Example 28 in 20 ml of ethyl acetate was treated with 6.0 ml (2 mM/ml) of sodium 2-ethylhexanoate to afford 1.4 g of the end product as a white powder.