Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[N+:17]([O-:19])=[O:18])=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[B-].[Na+].O>CS(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N+:17]([O-:19])=[O:18])=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])/C=C/c1ccc(OCc2ccccc2)nc1
Agent: [B-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: O=[N+]([O-])CCc1ccc(OCc2ccccc2)nc1
Reaction time: 0.5 h
Yield: 40.7 %

Procedure:
To a solution of 2-benzyloxy-5-((E)-2-nitro-vinyl)-pyridine described in Manufacturing Example 231-1-3 (44.0 g, 172 mmol) and acetic acid (44.0 mL) in dimethyl sulfoxide (200 mL) was added sodium borohydrate (11.0 g, 275 mmol) at room temperature while cooling appropriately under nitrogen atmosphere, which was stirred for 30 minutes. Water was added to this reaction solution at room temperature while cooling appropriately, which was then partitioned into water and ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:4) to obtain the title compound (18.1 g, 40.7%).
Reaction SMILES: [C:1]([C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].[ClH:10]>C(O)C.[Pd]>[ClH:10].[ClH:10].[NH2:2][CH2:1][C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: N#Cc1ncccc1F
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: NCc1ncccc1F
Yield: 90 %

Procedure:
Dissolve 2-cyano-3-fluoropyridine (300 mg, 2.457 mmol) in absolute ethanol (12 mL). Add 10% Pd/C (93 mg) and concentrated HCl (0.614 mL, 7.37 mmol). Hydrogenate at 40 psi overnight. Filter through Celite® and concentrate in vacuo to give the title compound as a solid (440 mg, 90%). MS (ES+) m/z: 127 (M+H)+.
Reaction SMILES: B.C1COCC1.[CH2:7]([N:14]([CH2:16][CH2:17][O:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:20]=1[C:21]#[N:22])[CH3:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl>C1COCC1.CCOCC>[CH2:7]([N:14]([CH2:16][CH2:17][O:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:20]=1[CH2:21][NH2:22])[CH3:15])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CN(CCOc1cccc(Cl)c1C#N)Cc1ccccc1
Agent: B
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN(CCOc1cccc(Cl)c1CN)Cc1ccccc1

Procedure:
A solution of borane/THF (80 ml, 1M solution) was added to a solution of 2-[2-(N-benzyl-N-methylamino) ethoxy]-6-chlorobenzonitrile (6.02 g) in THF (60 ml) at ambient temperature under nitrogen with stirring. The mixture was stirred at ambient temperature for 4 hours and then boiled under reflux for 1 hour. The mixture was evaporated to dryness and the residue was heated on a steam bath under nitrogen for 1 hour and then 1M hydrochloric acid (100 ml) was added and the mixture was heated for a further 2 hours. The mixture was cooled, washed with ethyl acetate, basified with concentrated sodium hydroxide solution and extracted with dichloromethane to give an oil. The oil was dissolved in ether and treated with ethereal hydrogen chloride to give a solid which was collected by filtration. The solid was stirred with 2M sodium hydroxide solution and then extracted with dichloromethane to give an oil which was distilled under vacuum. The oil which boiled at 140° C. at 0.04 mbar was dissolved in ether and treated with ethereal hydrogen chloride. The precipitated solid was collected by filtration and dried to give 2-[2-(N-benzyl-N-methylamino)ethoxy]-6-chlorobenzylamine, m.p. 85° C.
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1.[CH3:14][Si:15]([CH3:22])([CH3:21])[CH2:16][CH2:17][O:18][CH2:19]Cl>CN(C=O)C.C1COCC1>[CH3:14][Si:15]([CH3:22])([CH3:21])[CH2:16][CH2:17][O:18][CH2:19][O:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1
Reactant: Oc1cccnc1
Reactant: C[Si](C)(C)CCOCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCOc1cccnc1
Temperature: 25 °C
Yield: 69.7 %

Procedure:
Add potassium tert-butoxide (2.69 g, 24 mmol) to a 0° C. solution of 3-hydroxy-pyridine (1.90 g, 20 mmol) in DMF (30 mL) and THF (30 mL) stirring under N2. Add 2-(trimethylsilyl)ethoxy-methyl chloride (3.72 mL, 21 mmol) dropwise and allow to warm slowly to RT overnight. Add water to quench, stir for 5 minutes and concentrate. Dissolve in 20% i-PrOH/CHCl3, wash with saturated NaHCO3 solution (2×) and brine. Dry the combined organic layers over MgSO4 and concentrate. Purify the residue by flash chromatography on silica gel eluting with 0-50% EtOAc/hexanes to afford the title compound (3.14 g, 70%) as yellow liquid. MS(IS) 226 (M+1). TLC: Rf=0.43 (50% EtOAc/hexanes).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([SH:16])[CH:13]=[CH:14][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH:38]1[CH2:43][CH:44]=[O:45]>O.O1CCCC1>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([S:16][CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH:38]2[CH2:43][CH:44]=[O:45])[CH:13]=[CH:14][CH:15]=1
Reactant: O=CCC1CCCCC1Br
Reactant: COc1cccc(S)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: COc1cccc(SC2CCCCC2CC=O)c1
Reaction time: 1 h
Yield: 134.9 %

Procedure:
Triethylamine 481 ml is added to the mixture of 3-methoxythiophenol 322.5 g, triphenylphosphine 241.3 g, water 204 ml and tetrahydrofuran 2.3 liter under nitrogen atmosphere while cooling with ice under stirring, and then 2-bromocyclohexylacetaldehyde 518.9 g is dropwise added. Stirring is carried out at a room temperature for one hour, and then stirring is further continued at 60° C. for 2.5 hours. Water 200 ml is added, and the mixture is shaken. The organic layer is separated and washed twice with 10% hydrochloric acid 500 ml and twice with saturated brine 400 ml, and then it is dried on magnesium sulfate anhydrous. The solvent is distilled off under reduced pressure, and the residue is dissolved in hexane 2 liter and stirred at a room temperature for 13 hours. After cooling with ice, deposited crystals are filtered off, and the solvent is distilled off under reduced pressure, whereby yellow oily 2-(3-methoxyphenylthio)cyclohexylacetaldehyde 820.3 g is obtained.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([OH:23])[C:9]2[C:10]3[CH:11]=[C:12]([CH3:22])[CH:13]=[CH:14][C:15]=3[C:16]([CH3:21])([CH3:20])[O:17][C:18]=2[CH:19]=1.Cl.CN(C)CCCN=C=NCC>CO.O>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([OH:23])[C:9]2[C@@H:10]3[CH:11]=[C:12]([CH3:22])[CH2:13][CH2:14][C@H:15]3[C:16]([CH3:21])([CH3:20])[O:17][C:18]=2[CH:19]=1
Reactant: CCCCCc1cc(O)c2c(c1)OC(C)(C)c1ccc(C)cc1-2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CO
Solvent: O
Product: CCCCCc1cc(O)c2c(c1)OC(C)(C)[C@@H]1CCC(C)=C[C@@H]21

Procedure:
One hundred mg of a cannabinol derivative having the formula ##STR3## were dissolved in 20 ml of 30% methanol at pH 4.5. To this solution, 84 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added and the pH was adjusted to 4.5. After mixing at room temperature for 30 minutes, 100 mg of methylated bovine serum albumin were added in 20 ml of water with mixing, and the pH was again adjusted to 4.5. The solution was mixed for 1 hour at room temperature and then overnight at 4° C., after which any unconjugated cannabinol derivative was removed by dialysis against 1000-ml volume changes of sodium phosphate buffer at 4° C., to produce a THC-methylated albumin conjugate.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:5][CH:4]=1.Br>C(O)(=O)C>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:7][CH:8]=1
Reactant: COc1ccc(CCCC(=O)O)cc1
Agent: Br
Solvent: CC(=O)O
Product: O=C(O)CCCc1ccc(O)cc1
Reaction time: 1 h
Yield: 92.1 %

Procedure:
4-(4-Methoxyphenyl)butanoic acid (0.97 g, 5 mmol) was mixed with HBr (50 mL) and acetic acid galacial (80 mL). The mixture was refluxed for 12 h (monitored by TLC), poured into ice, stirred for 1 h, and then extracted with DCM. The solvent was evaporated in vacuo to give the title compound (0.83 g, 92%). NMR (400 MHz in CDCl3, Bruker AVANCE-400): δ 1.72 (m, 2H, CH2), 2.16 (t, 2H, CH2, J=7.4 Hz), 2.45 (t, 2H, CH2, J=7.6 Hz), 6.65 (d, 2H, Ar—H, J=8.3 Hz), 6.95 (d, 2H, Ar—H, J=8.3 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13]C=O)[CH2:10][C@H:9]1[C:16]([O:18][CH3:19])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([OH:13])[CH2:10][C@H:9]1[C:16]([O:18][CH3:19])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H]1C[C@H](OC=O)CN1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)[C@@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Reaction time: 0.33 h
Yield: 89.2 %

Procedure:
To a solution of (2S,4S)-1-t-butoxycarbonyl-4-formyloxy-2-methoxycarbonylpyrrolidine (5.12 g: 18.7 mmole) in methanol (51.0 ml), aqueous 1N-sodium hydroxide (18.7 ml) is added under ice cooling. The mixture is stirred at the same temperature for 20 minutes to give (2S,4S)-1-t-butoxycarbonyl-4-hydroxy-2-methoxycarbonylpyrrolidine (4.09 g). Yield: 89%. Colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10]C)=[O:9])=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl>O1CCCC1.O.[Cl-].[Na+]>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1
Reactant: COC(=O)c1cnc(Cl)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cnc(Cl)cn1
Temperature: 25 °C
Reaction time: 42 h
Yield: 98.5 %

Procedure:
A solution of methyl 5-chloropyrazine-2-carboxylate (30.00 g, 0.17 mol) in tetrahydrofuran (87 mL) was treated with a solution of potassium carbonate (72.08 g, 0.52 mol) in water (261 mL). The resulting reaction mixture stirred at 25° C. for 42 h. The reaction mixture was then acidified to a pH=2 with concentrated hydrochloric acid, diluted with a saturated aqueous sodium chloride solution (300 mL), and was continuously extracted with ethyl acetate (4 L total) until no product was present in the aqueous layer. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to afford 5-chloro-pyrazine-2-carboxylic acid (26.54 g, 96%) as an off-white solid: mp 150–151° C.; EI-HRMS m/e calcd for C5H3ClN2O2 (M+) 157.9883, found 157.9877.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].[BH4-].[Na+]>CCO>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[OH:11]
Reactant: O=C1CCc2c(Br)cccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC1CCc2c(Br)cccc21
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a stirring solution of 4-bromoindanone (3 g, 14.2 mmol) in anhydrous EtOH (30mL) was added sodium borohydride (0.36 g, 9.5 mmol) and silica gel (2 g) at 0° C. The reaction was stirred at 0° C. for 20 min and was allowed to stir at room temperature for 2 h. The reaction mixture was quenched with saturated NaHCO3 solution (10 mL) and concentrated to remove EtOH. The aqueous layer was extracted with EA (3×20 mL) and the organic phase was dried over MgSO4. After concentration, the crude product was purified by chromatography (EA/hexane) to yield (±)-4-bromo-2,3-dihydro-1H-inden-1-ol IND INT-5 (2.56 g, 85%) as a white solid. LCMS-ESI (m/z) calculated for C9H9BrO: 213.07; found 195.0 [M−H2O]+, tR=3.07 min. 1H NMR (400 MHz, CDCl3) δ 7.35 (d, J=7.9, 1H), 7.27 (d, J=7.4, 1H), 7.05 (t, J=7.7, 1H), 5.23 (t, J=6.2, 1H), 3.00 (ddd, J=16.6, 8.8, 4.6, 1H), 2.84-2.66 (m, 1H), 2.45 (dddd, J=13.2, 8.4, 7.0, 4.6, 1H), 1.96-1.70 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH2:5]Cl.[C-:11]#[N:12].[Na+]>CS(C)=O.C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][C:11]#[N:12])[CH:7]=[C:8]([Cl:10])[CH:9]=1
Reactant: [C-]#N
Reactant: ClCc1cc(Cl)cc(Cl)c1
Agent: [Na+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: N#CCc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 51.8 %

Procedure:
3,5-Dichlorobenzyl chloride (315.6 mg, 1.615 mmol), 0.2 molar in DMSO, was treated with sodium cyanide (158.2 mg, 3.229 mmol) and allowed to stir at ambient temperature for 24 hours. After 24 hours the reaction mixture was diluted with diethyl ether and partitioned between saturated aqueous sodium chloride. The organic layer was dried with magnesium sulfate, filtered, and concentrated to provide the title compound (155.5 mg, 0.836 mmol, 51.8% yield) as a dark red oil.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=[O:7]>C(O)(=O)C.[Pd]>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH2:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: O=C(O)C=Cc1ccccc1Cl
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C(O)CCc1ccccc1Cl
Yield: 100 %

Procedure:
2-Chlorocinnamic acid (26 g) (ex Aldrich) in glacial acetic acid (250 ml) was subjected to hydrogenation at 45 psi in the presence of 10% palladium/charcoal. Conventional work-up gave 3-(2-chlorophenyl)propanoic acid (26.3 g) which was added to polyphosphoric acid (220 g) at 80° under nitrogen. After stirring for 2 hours at 80° the mixture was allowed to cool and added to water, ether extraction and conventional work up gave 4-chloroindan-1-one as a brown solid (10 g).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:13]C1C=CC(C(F)(F)F)=CC=1N.ClC(Cl)C.S(Cl)(Cl)(=O)=O.[OH-].[Na+]>O.CN1C(=O)CCC1>[Cl:1][C:2]1[CH:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:6]=[C:5]([Cl:13])[C:3]=1[NH2:4]
Reactant: Nc1ccc(C(F)(F)F)cc1Cl
Reactant: Nc1cc(C(F)(F)F)ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(Cl)Cl
Solvent: CN1CCCC1=O
Product: Nc1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 55 °C

Procedure:
A mixture (740 g) containing 2-chloro-4-trifluoromethyaniline, 2-chloro-5-trifluoromethylaniline and NMP (0.686 m/m) was charged with 400 ml dichloroethane in to the reactor. It was then heated to 55° C. and reacted with 430 g of sulfuryl chloride at 55-60° C. over a period of 4 hrs & further maintained at 65-70° C. for 2 hrs. The reaction mixture was worked up by adding water & treating with 5N NaOH, the organic layer was fractionated under reduced pressure to get 504.9 g of distilled 2,6-dichloro-4-trifluoromethylaniline. The yield of 2,6-dichloro-4-trifluoromethyl aniline was 93.5% on 2-chloro-4-trifluoromethylaniline.
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH2:17][CH2:18][CH:19]([OH:23])[CH:20]([CH3:22])[CH3:21])[C:7]([N:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])(=O)C.C(SCC(CSC)C(N1CCC[C@H]1C(O)=O)=O)(=O)C>>[SH:4][CH2:5][CH:6]([CH2:17][CH2:18][CH:19]([OH:23])[CH:20]([CH3:21])[CH3:22])[C:7]([N:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8]
Reactant: CC(=O)SCC(CCC(O)C(C)C)C(=O)N1CCC[C@H]1C(=O)O
Agent: CSCC(CSC(C)=O)C(=O)N1CCC[C@H]1C(=O)O
Product: CC(C)C(O)CCC(CS)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
By substituting 1-[2-(acetylthiomethyl)-5-hydroxy-6-methylheptanoyl]-L-proline for the 1-[3-acetylthio-2-(methylthiomethyl)propanoyl]-L-proline in the procedure of Example 17, 1-[2-mercaptomethyl-5-hydroxy-6-methylheptanoyl]-L-proline is obtained.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Br:10][C:11]1[CH:16]=[CH:15][C:14](O)=[CH:13][CH:12]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.C(OCC)(=O)C>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([O:9][CH2:8][CH2:7][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:13][CH:12]=1
Reactant: Oc1ccc(Br)cc1
Reactant: OCCN1CCOCC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Brc1ccc(OCCN2CCOCC2)cc1
Temperature: 110 °C
Reaction time: 17 h
Yield: 144.6 %

Procedure:
To a mixture of 2-(morpholin-4-yl)ethanol (197 mg, 1.5 mmol) in THF (5 mL) was added 4-bromophenol (200 mg, 1.16 mmol), polymeric triphenylphosphine (0.5 g, 1.5 mmol) and DIAD (305 mg, 1.5 mmol). The mixture was degassed with nitrogen for 2 min and stirred at 110° C. for 17 hours. The cooled reaction mixture was filtered and the filtrate was concentrated in vacuo to give a residue, which was dissolved with ethyl acetate (50 mL), washed with 2 M aqueous NaOH (3×15 mL) and brine (2×20 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to give a residue, which was purified by flash chromatography on silica gel to give 4-[2-(4-bromophenoxy)ethyl]morpholine (480 mg, 100%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.35 (d, 2H), δ 6.70 (d, 2H), 4.07 (t, 2H), 3.74-3.71 (m, 4H), 2.78 (t, 2H), 2.57-2.55 (m, 4H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH:11]([NH2:14])([CH3:13])[CH3:12]>C(O)C>[CH:11]([NH:14][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9])([CH3:13])[CH3:12]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CC(C)N
Solvent: CCO
Product: CC(C)Nc1ccccc1[N+](=O)[O-]
Temperature: 55 °C
Reaction time: 3 h

Procedure:
To a solution of 1-fluoro-2-nitrobenzene (14.11 g, 100 mmol) in ethanol (50 mL) was added isopropylamine (30 mL, 350 mmol, 3.5 equiv.) and the mixture was heated at 55° C. with stirring in a sealed reaction vessel for 3 hours. All volatiles were removed under reduced pressure. The residue was dissolved in diethyl ether (300 mL) and the solution was washed with a saturated aqueous sodium bicarbonate solution, brine, dried (anhydrous sodium sulfate), and concentrated to give N-isopropyl-2-nitroaniline as a bright orange liquid. This was in ethanol (50 mL) and Raney nickel (2.8 g) was added. The mixture was stirred under a hydrogen atmosphere (30 psi) until all starting material was consumed (as evidenced by the disappearance of the bright orange color, ˜3 h). The reaction mixture was filtered through a pad of celite and concentrated to give 14.92 g (98%) N-isopropyl-1,2-phenylenediamine as a viscous black liquid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14]([OH:16])=O)[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.OC(C(F)(F)F)=O.[NH2:24][CH2:25][C:26]1[C:27](=[O:39])[NH:28][C:29]([CH3:38])=[CH:30][C:31]=1[CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.ON1C2N=CC=CC=2N=N1.CN1CCOCC1.N1C=CC=CC1=O.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.O.C(Cl)CCl>[Br:1][C:2]1[CH:3]=[C:4]([C:14]([NH:24][CH2:25][C:26]2[C:27](=[O:39])[NH:28][C:29]([CH3:38])=[CH:30][C:31]=2[CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[O:16])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:12])[CH3:13])[C:9]=2[CH:10]=1
Reactant: Cc1cc(C2CCCCC2)c(CN)c(=O)[nH]1
Reactant: CC(C)n1ncc2c(C(=O)O)cc(Br)cc21
Agent: O=C([O-])[O-]
Agent: O=c1cccc[nH]1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Solvent: CS(C)=O
Product: Cc1cc(C2CCCCC2)c(CNC(=O)c2cc(Br)cc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-bromo-1-(1-methylethyl)-1H-indazole-4-carboxylic acid (237 mg, 0.84 mmol), 3-(aminomethyl)-4-cyclohexyl-6-methyl-2(1H)-pyridinone TFA (378 mg, 1.13 mmol) and 1-hydroxy-7-azabenzotriazole (171 mg, 1.26 mmol) were stirred in 10 mL of DMSO for 10 min under nitrogen. N-methylmorpholine (0.37 ml, 3.35 mmol) was added along with EDC (241 mg, 1.26 mmol) and the mixture was stirred at rt overnight. An additional 0.2 eq of pyridinone, HOAt, NMM and EDC were added and the contents were stirred at rt overnight. The reaction mixture was then poured onto ice-water. A solution of 10% K2CO3 in water was added to afford a pH ˜8-9 solution. The reaction mixture was stirred at rt for 30 min and then allowed to stand at rt for 30 min. Precipitated solids were filtered and air-dried. The collected solid was treated with EtOAc (not soluble) and hexanes, and then concentrated in vacuo. To the isolated solid was then added DMF followed by heating and sonication. Water was added and beige solids crashed out. The precipitated solids were filtered, washed with water, air-dried, and dried in vacuum oven for 2 hours. The title compound was collected as a solid (308 mg, 74%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.53 (s, 1H) 8.63 (t, J=4.80 Hz, 1H) 8.37 (s, 1H) 8.20 (s, 1H) 7.68 (d, J=1.26 Hz, 1H) 6.01 (s, 1H) 5.05 (dt, J=13.14, 6.57 Hz, 1H) 4.43 (d, J=4.80 Hz, 2H) 2.84 (t, J=11.24 Hz, 1H) 2.15 (s, 3H) 1.70 (d, J=13.39 Hz, 2H) 1.60 (d, J=12.13 Hz, 3H) 1.47 (s, 3H) 1.45 (s, 3H) 1.42 (br. s., 1H) 1.17-1.39 (m, 4H); LCMS: 485.2/487.2 (Br pattern).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH:6]([C:12](=[O:14])[CH3:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:3])[CH3:2].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[C:1]([NH:4][CH2:5][C@@H:6]([C@H:12]([OH:14])[CH3:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(CNC(C)=O)C(C)=O
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: ClCCl
Product: CCOC(=O)[C@@H](CNC(C)=O)[C@@H](C)O
Yield: 83.6 %

Procedure:
In 100 ml-volume stainless steel autoclave whose atmosphere had been displaced with nitrogen was added a solution of 2.01 g (10 mmole) of ethyl 2-(N-acetylamino)methyl-3-oxobutanoate and 168 mg (0.1 mmole) of ##STR11## ((+)-BINAP) in 15 ml of methylene chloride, and a reaction was conducted at 70 ° C. under a hydrogen pressure of 130 kg/cm2 for 30 hours. The reaction mixture was concentrated, and the residue was purified by silica gel chromatography using a 7/3 (by volume) mixture of hexane and isopropanol as an eluent to give 1.7 g (yield: 85%) of ethyl (2S, 3R)-2-(N-acetylamino)methyl-3-hydroxybutanoate having an optical purity of 93 %ee as determined in the same manner as in Example 2.
Reaction SMILES: [O:1]1[C:5]2=[N:6][CH:7]=[C:8]([CH2:10][OH:11])[CH:9]=[C:4]2[CH:3]=[CH:2]1>C(Cl)Cl>[O:1]1[C:5]2=[N:6][CH:7]=[C:8]([CH:10]=[O:11])[CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: OCc1cnc2occc2c1
Solvent: ClCCl
Product: O=Cc1cnc2occc2c1
Reaction time: 8 h
Yield: 82 %

Procedure:
To a solution of 0.47 g of furo[2,3-b]pyridin-5-yl-methanol in 2 ml of DCM was added 10 ml of a Dess-Martins-Periodinane solution (15% in DCM). The reaction mixture was stirred overnight and then quenched with sat.-NaHCO3 and extracted with DCM. The organic phase was washed with brine, dried over MgSO4 and concentrated in vacuo. The resulting crude material was purified by CC using heptane/EtOAc 30/70 as eluant to yield 0.38 g of furo[2,3-b]pyridine-5-carbaldehyde as white solid.
Reaction SMILES: [OH-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH:19](=[O:27])[C:20]1[C:21](=[CH:23][CH:24]=[CH:25][CH:26]=1)[OH:22].[Cl:28][CH2:29]/[CH:30]=[CH:31]/[CH2:32]Cl.[OH-].[Na+]>O>[Cl:28][CH2:29]/[CH:30]=[CH:31]/[CH2:32][O:22][C:21]1[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=1[CH:19]=[O:27]
Reactant: O=Cc1ccccc1O
Reactant: ClC/C=C/CCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=Cc1ccccc1OC/C=C/CCl

Procedure:
To 2 lt of refluxing water, 3 ml of 40% aqueous tetrabutylammonium hydroxide, 250 ml of salicylaldehyde and 280 ml of trans-1,4-dichloro-2-butene are added while vigorously stirring, followed by the dropwise addition of the solution of 83 g of sodium hydroxide in 400 ml of water at such a rate that the pH of the mixture is kept between 7 and 8 (ca 25 minutes). Thereafter the mixture is refluxed for about 6 minutes until the pH is about 7, cooled to 20° and the aqueous layer is extracted with diethyl ether. The extract is combined with the organic layer, washed with 5% aqueous sodium hydroxide, dried, evaporated, the residue distilled and the fraction boiling at 141°-147°/0.7 mmHg collected, to yield the 2-(4-chloro-trans-2-butenyloxy)-benzaldehyde.