Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:11])[C:9]=1[OH:10])[CH:5]=[O:6].[F-].[K+].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[CH2:28](Br)Br>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]2[O:11][CH2:28][O:10][C:9]=12)[CH:5]=[O:6]
Reactant: O=Cc1cc(O)c(O)c(Br)c1
Reactant: BrCBr
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cc(Br)c2c(c1)OCO2
Yield: 76 %

Procedure:
To a stirred solution of 3-bromo-4,5-dihydroxybenzaldehyde (10.50 g, 48.38 mmol) in DMF (145 mL) was added anhydrous KF (14.02 g, 241.9 mmol, dried for 24 hours under high vacuum/P2O5). After 15 minutes CH2Br2 was added all at once and the resulting mixture heated to 100–105° C. for 4 hours. The mixture was evaporated under reduced pressure and the residue was taken up in ether and water. The layers were separated, the aqueous layer was washed with ether (3×). The combined ether layers were washed with water (2×), brine and dried over anhydrous magnesium sulfate. After filtration, the mixture was concentrated under reduced pressure to give 8.42 g of 3-bromo-4,5-methylenedioxybenzaldehyde (76%) as a brownish solid. 1H NMR (500 MHz; CDCl3): δ 6.16 (s, 2H); 7.26 (s, 1H); 7.55 (s, 1H); 9.77 (s, 1H).
Reaction SMILES: [O-2].[Zn+2:2].[P:3](=[O:7])([OH:6])([OH:5])[OH:4]>O>[P:3]([O-:7])([O-:6])([O-:5])=[O:4].[Zn+2:2].[P:3]([O-:7])([O-:6])([O-:5])=[O:4].[Zn+2:2].[Zn+2:2]
Reactant: O=P(O)(O)O
Agent: [O-2]
Agent: [Zn+2]
Solvent: O
Product: O=P([O-])([O-])[O-]

Procedure:
An aqueous corrosion inhibitor is created by filling a mixer with approximately 30-75% by total formula weight of water at a temperature between approximately 18-50° C., adding approximately 10-30% by total formula weight of zinc oxide, and then adding approximately 10-30% by total formula weight of phosphoric acid (approximately 75% concentration) to form zinc phosphate. Approximately 1%-95% by total formula weight of hydrotalcite, Mg2xAl2(OH)4x+4CO3*nH2O, with a surface area of approximately 10-400 m2/g is then added. (The higher the surface area, the greater the ion-exchange capacity of the hydrotalcite, the better the corrosion inhibition.) The batch in the mixer is then allowed to mix for approximately ten (10) minutes. The resultant wet slurry is then dried and milled (for example, in an attrition mill) to an average particle size of approximately 1.0-3.0 microns. The corrosion inhibitive pigment created by this process can then be incorporated into a paint.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:7][OH:8])[C:3]([O:5][CH3:6])=[O:4].[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.N1C=CC=CC=1>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[CH3:1][C:2]([CH3:9])([CH2:7][O:8][S:16]([C:13]1[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=1)(=[O:18])=[O:17])[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(C)(C)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COC(=O)C(C)(C)COS(=O)(=O)c1ccc(C)cc1
Reaction time: 20 h
Yield: 108 %

Procedure:
A mixture of methyl 2,2-dimethyl-3-hydroxypropionate (100 g, 0.76 mol), 4-toluenesulfonyl chloride (151 g, 0.80 mol), 4-dimethylaminopyridine (4.6 g, 0.038 mol), and pyridine (200 mL) was stirred for 20 hrs and then was diluted with 200 mL toluene, stirred for 30 min and filtered. The filtrate was concentrated to 250 mL at aspirator pressure, diluted with 100 mL toluene, filtered, and concentrated. The residue was suspended in 200 mL hexanes, and the solvent was removed at aspirator pressure to yield the title compound (235 g, 100%) contaminated by a trace of toluenesulfonyl chloride.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].[BrH:11]>C1C=CC=CC=1>[Br:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9]
Reactant: Br
Reactant: OCCCCCCCCO
Solvent: c1ccccc1
Product: OCCCCCCCCBr
Yield: 71 %

Procedure:
1,8-Octanediol (14.62 g, 0.1 mole) was dissolved in benzene (200 mls) and 12.5 mls of conc (46.48%) aqueous HBr added. The mixture was then heated overnight at reflux whilst removing the water using a Dean & Stark apparatus. About 12 mls of water were rapidly removed within the first 4 hours. The crude mixture was washed with 6N NaOH (100 mls), 10% aq HCl (100 mls), water (2×200 mls) and brine (150 mls). The solvent was removed to give a colourless liquid, (14.8 g, 71%) 1-bromooctan-8-ol.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:37])[NH:5][C:6](=[O:36])[N:7]([CH:35]=1)[C@@H:8]1[O:33][C@H:11]([CH2:12][O:13]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C@@H:10]([I:34])[CH2:9]1)[CH3:2]>CCOCC>[CH2:1]([C:3]1[C:4](=[O:37])[NH:5][C:6](=[O:36])[N:7]([CH:35]=1)[C@@H:8]1[O:33][C@H:11]([CH2:12][OH:13])[C@@H:10]([I:34])[CH2:9]1)[CH3:2]
Reactant: CCc1cn([C@H]2C[C@H](I)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)c(=O)[nH]c1=O
Solvent: CCOCC
Product: CCc1cn([C@H]2C[C@H](I)[C@@H](CO)O2)c(=O)[nH]c1=O
Temperature: 100 °C

Procedure:
A mixture of 5-ethyl-3'-Iodo-5'-O-trityl-2',3'-dideoxyuridine (1.73 g, 2.8 mmole) and 80% HAc (25 ml) is heated at 100° C. for 50 min. After heating, acetic acid is evacuated in vacuo to obtain an amorphous solid. Ether is added, the product is triturated, and the resulting yellowish solid is filtered for collection (350 mg). Another 250 mg is obtained from the filtrate after repeating the above procedure, m.p. 162°-164° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[N:9]=[C:10](Cl)[C:11]2[CH:16]=[CH:15][S:14][C:12]=2[N:13]=1>>[Cl:7][C:8]1[N:9]=[C:10]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[C:11]2[CH:16]=[CH:15][S:14][C:12]=2[N:13]=1
Reactant: C1COCCN1
Reactant: Clc1nc(Cl)c2ccsc2n1
Product: Clc1nc(N2CCOCC2)c2ccsc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.3 %

Procedure:
Morpholine (85.1, 0.977 mol, 2.2 equiv.) was added to a solution of 2,4-dichlorothieno[2,3-d]pyrimidine 17 (91 g, 0.444 mol, 1.0 equiv.). The reaction mixture was stirred at ambient temperature for 1 h and the resulting slurry was filtered, rinsed with water (500 ml). The cake was dried in vacuum oven at 55° C. for 24 hours to give 4-(2-chlorothieno[2,3-d]pyrimidin-4-yl)morpholine 18 as an off-white solid (100.3 g, 88% yield).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4](O)=[O:5].CSC>C1COCC1>[Cl:1][C:2]1[C:3]([CH2:4][OH:5])=[CH:7][C:8]([F:12])=[C:9]([Cl:11])[N:10]=1
Reactant: O=C(O)c1cc(F)c(Cl)nc1Cl
Solvent: CSC
Solvent: C1CCOC1
Product: OCc1cc(F)c(Cl)nc1Cl
Temperature: 25 °C
Yield: 99.7 %

Procedure:
To a stirred mixture of 2,6-dichloro-5-fluoro-nicotinic acid (1.0 g, 4.76 mmol) in dry THF (50 mL) under argon was added neat BH3.DMS (1.35 mL, 14.29 mmol) dropwise. The resulting mixture was heated to reflux for 3 hours, cooled to room temperature and quenched by the dropwise addition of water (4 mL). The reaction mixture was concentrated in vacuo. The crude alcohol was diluted with EtOAc, washed with 1N NaOH, 1N HCl, saturated aqueous NaHCO3 solution and brine. The EtOAc layer was dried (MgSO4), filtered and concentrated in vacuo to give 1A (0.93 g, 97%). HPLC Rt=1.79 min (Column: YMC ODS-A 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA); LCMS Found: (M+H)+=210.
Reaction SMILES: Br[C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[Cl:10].[Cu][C:12]#[N:13].CN1C(=O)CCC1.N>O>[NH2:6][C:5]1[CH:7]=[C:8]([F:9])[C:2]([C:12]#[N:13])=[C:3]([Cl:10])[CH:4]=1
Reactant: Nc1cc(F)c(Br)c(Cl)c1
Reactant: N#C[Cu]
Agent: N
Solvent: O
Solvent: CN1CCCC1=O
Product: N#Cc1c(F)cc(N)cc1Cl
Temperature: 160 °C
Reaction time: 3 h
Yield: 70.4 %

Procedure:
4-Bromo-3-Chloro-5-fluoroaniline (980 mmol, 220 g), copper(I)cyanide (980 mmol, 88 g) and NMP (1000 ml) were added into the reaction flask, heated up to 160° C. and stirred for 3 h to complete the reaction. The reaction mixture was cooled to RT. Water and 25% ammonia solution was added keeping the mixture at RT. The mixture was stirred overnight and the formed precipitate was separated by filtration and flushed with water. The filtered precipitate was dried under vacuum to give 117.7 g of the title compound. 1H-NMR (400 MHz, DMSO-d6): δ 6.41-6.47 (m, 1H), 6.58-6.62 (m, 1H), 6.86 (bs, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13])[NH:8][CH:7]=[CH:6]2.C([BH3-])#N.[Na+].[OH-].[Na+]>C(O)(=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[C:12]([F:15])([F:13])[F:14])[NH:8][CH2:7][CH2:6]2
Reactant: COc1cc2cc[nH]c2cc1C(F)(F)F
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc2c(cc1C(F)(F)F)NCC2
Yield: 99 %

Procedure:
The indole (D2) (67.63 g, 0.315 mol) in glacial acetic acid (500 ml) was treated with sodium cyanoborohydride (40 g, 0.637 mol) portionwise at room temperature with stirring. After 3 h at room temperature the reaction mixture was diluted with water (500 ml) and basified with 40% aqueous NaOH with cooling. The mixture was then extracted with dichloromethane (3×500 ml) and the combined extracts were dried (Na2SO4) and evaporated to give the title compound (67.73 g, 99%) as an off-white solid.
Reaction SMILES: [O:1]1[CH:6]([CH2:7][OH:8])[CH2:5][O:4][C:3]2=[CH:9][S:10][CH:11]=[C:2]12.N#N.[H-].[Na+:15].[CH2:16]1[S:21](=[O:23])(=[O:22])[O:20][CH2:19][CH2:18][CH2:17]1>O1CCCC1>[Na+:15].[O:1]1[CH:6]([CH2:7][O:8][CH2:19][CH2:18][CH2:17][CH2:16][S:21]([O-:23])(=[O:22])=[O:20])[CH2:5][O:4][C:3]2=[CH:9][S:10][CH:11]=[C:2]12
Reactant: OCC1COc2cscc2O1
Reactant: O=S1(=O)CCCCO1
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)([O-])CCCCOCC1COc2cscc2O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(2,3-Dihydro-thieno[3,4-b][1,4]dioxin-2-yl)-methanol (6.9 g, 40 mmol) was dissolved into tetrahydrofuran (100 mL) and blanketed by N2. NaH (1.76 g) was added and stirring was continued for 30 min. Then butanesultone (6.0 g) was added dropwise after which the reaction mixture was brought to reflux for 3 h. Then it was cooled to 25° C. again, the solvent was removed, methanol was added, the mixture was stirred, filtered and the filtrate was concentrated. The remaining oil was solidified by addition of hexane and ethanol, followed by stirring. Final filtration and drying resulted in pure 4-(2,3-dihydro-thieno[3,4-b][1,4]dioxin-2-ylmethoxy)-butane-1-sulphonic acid sodium salt as was demonstrated by NMR and mass spectroscopy.
Reaction SMILES: [C:1]1([CH2:7][OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][N:13]=1>CN(C)C=O>[CH2:7]([O:8][C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][N:13]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCc1ccccc1
Reactant: Brc1ccc(Br)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1ccc(OCc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a solution of phenyl-methanol (20.5 g, 190 mmol) in N,N-dimethylformamide (200 mL) was added sodium hydride (7.6 g, 190 mmol) under nitrogen atmosphere on an ice bath (0° C.), which was stirred for 30 minutes at room temperature. 2,5-Dibromopyridine was then added thereto on the ice bath (0° C.), and stirred for 60 minutes at room temperature. The reaction mixture was partitioned into is water and ethyl acetate on the ice bath (0° C.). The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:20 then 1:10) to obtain the title compound (15.1 g, 90%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][NH2:20]>CN(C=O)C>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][NH:20][C:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[N:7][CH:6]=2)[N:1]=1)=[O:13]
Reactant: COc1cccc(CN)c1
Reactant: O=C(O)c1ccc2cnccc2n1
Solvent: CN(C)C=O
Product: COc1cccc(CNC(=O)c2ccc3cnccc3n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
To a stirring mixture of 2-[1,6]naphthyridinecarboxylic acid (50 mg, 0.287 mmol) in anhydrous DMF (10 mL) at room temperature was added sequentially 1-hydroxyhenzotriazole hydrate (42.7 mg, 0.316 mmol), 3-methoxybenzylamine (56.6 μL, 0.431 mmol) and 1-(3-dimethylaminopropyl-3-ethylcarboiimide hydrochloride (61.8 mg, 0.316 mmol). The resulting mixture was allowed to stir at room temperature overnight and it was found to be clear. The solvent was removed under vacuum. Flash column chromatography of the residue (50% hexane/ethyl acetate to 100% ethyl acetate) afforded the desired product as a clear oil (79.1 mg, 94%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[OH:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:14]2[CH2:15][CH2:16][CH:11]([OH:10])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: OC1CCN(Cc2ccc(Br)cc2)CC1
Yield: 62.5 %

Procedure:
4-Bromobenzylbromide (3 g) was stirred with 4-hydroxypiperidine (1.21 g) and potassium carbonate (1.99 g) in dimethylacetamide (15 ml) at 50° C. for 3 h The reaction mixture was then allowed to cool, poured into water (80 ml) and extracted with ethyl acetate (3×50 ml). The combined extracts were washed with water, dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography, eluting with a gradient of 0-3% methanol in dichloromethane, to afford the product as a viscous, colourless oil (2.02 g).
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[CH3:10][NH2:11].[OH-].[Na+]>CC#N.O>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([NH:11][CH3:10])[N:7]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CNc1nc(Cl)nc(Cl)n1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A mixture of cyanuric chloride (184 mg, 1.00 mmol, 1.00 equiv) in CH3CN/H2O (1/1, 33 ml) was cooled to 0° C. Methylamine (40 w % in H2O) (0.252 ml, 3.25 mmol, 1.00 equiv) was added. The reaction mixture was adjusted to a pH of about 9-10 using 1 N NaOH. After being stirred at 0° for 10 min, the reaction was complete. The resulting suspension was used in the next step without workup or purification.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:17])[C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH:23]=O.O>CO>[OH:16][C:8]1[CH:7]=[CH:6][C:5]([C@@H:3]([OH:4])[C@@H:2]([NH:1][CH2:23][C:22]2[CH:25]=[C:26]([O:30][CH3:31])[C:27]([O:28][CH3:29])=[C:20]([O:19][CH3:18])[CH:21]=2)[CH3:17])=[CH:10][C:9]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13]
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: C[C@H](N)[C@H](O)c1ccc(O)c(NS(C)(=O)=O)c1
Solvent: CO
Solvent: O
Product: COc1cc(CN[C@@H](C)[C@H](O)c2ccc(O)c(NS(C)(=O)=O)c2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 35.4 %

Procedure:
To a solution of the amine (4) (111 mg, 0.43 mmol) and 3,4,5-trimethoxybenzaldehyde (111 mg, 0.55 mmol) in methanol (4 mL) was added borane-pyridine complex (135 μL, 1.28 mmol) at 40° C. and the resulting mixture was stirred for 1.5 hours. The reaction mixture was cooled to room temperature and water was added thereto, followed by extraction with a mixed solvent (ethyl acetate:methanol=10:1) and subsequent washing of the organic layer with saturated brine. The organic layer was dried and concentrated and the obtained crude product was purified by amine silica gel column chromatography (eluent; chloroform:methanol=7:1) to obtain the desired amine (8) as a white solid (67 mg, Yield: 36%).
Reaction SMILES: CO.O=[C:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[C:15]1([C@@H:21]([NH2:23])[CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[C:15]1([C@@H:21]([NH:23][C:4]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)C1CCCCC1=O
Reactant: C[C@H](N)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CO
Product: CCOC(=O)C1=C(N[C@@H](C)c2ccccc2)CCCC1

Procedure:
In another embodiment, (1S,2S)-2-[(S)-1-phenylethyl amino]cyclohexyl)methanol (11) is produced from a starting material comprising ethyl 2-oxocyclohexane carboxylate (6). This embodiment comprises reacting ethyl 2-oxocyclohexane carboxylate (6) with (S)-(−)-1-phenylethylamine (7) in the presence of toluene to produce (S)-Ethyl 2-(1-phenylethylamino)cyclohex-1-enecarboxylate (8). Further, reduction of the amine (8) with sodium borohydride in the presence of isobutyric acid will produce (1R,2S)-Ethyl 2-((S)-1-phenylethylamino)cyclohexanecarboxylate (9), as illustrated in FIG. 4. Additionally, the conversion of the amine (8) to the cis-cyclohexane derivative (9) is further treated with hydrogen bromide and ethyl acetate in propionic acid to create the hydrobromide salt of the cis-cyclohexane derivative (9). The production of the cis-cyclohexane derivative (9) is followed by epimerization of the chiral center adjacent to the ethyl ester functionality using sodium tert-butoxide to afford the trans-cyclohexane derivative (10) as a major diastereomer. After conversion to trans-cyclohexane derivative (10), the compound is subjected to reduction of the ester functionality in compound (10), using potassium borohydride in the presence of lithium chloride, to yield (1S,2S)-2-[(S)-1-phenylethyl amino]cyclohexyl)methanol (11). Generally, the conversion from compound (10) to compound (11) may incorporate tetrahydrofuran as a co-solvent and may be refluxed to afford the desired compound (11) in good overall yield.
Reaction SMILES: [OH-].[Na+].[O:3]1[CH2:8][CH2:7][CH:6]([C:9]([O:11]C)=[O:10])[CH2:5][CH2:4]1>CO.O>[O:3]1[CH2:8][CH2:7][CH:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1
Reactant: COC(=O)C1CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C1CCOCC1
Temperature: 50 °C
Reaction time: 7 h
Yield: 69.3 %

Procedure:
Add 40% w/w sodium hydroxide in water (264.5 mL, 1.15 eq) to a solution of methyl tetrahydro-2H-pyran-4-carboxylate (500 g, 3.47 mol) in methanol (2.26 L). Stir at 50° C. for seven hours. Evaporate solvent, dissolve residue in water (2 L) and wash with methyl-tert-butyl ether (2×1.2 L). Add aqueous 35% hydrochloric acid to the aqueous layer (adjusting pH to 4) and extract with methyl tert-butyl ether (2×1.2 L). Dry over anhydrous magnesium sulfate and concentrate in vacuo. As material still contains water, dissolve the solid in dichloromethane and discard the aqueous layer. Dry the organics with anhydrous sodium sulfate and concentrate in vacuo to give tetrahydro-2H-pyran-4-carboxylic acid (312.76 g, 69%). 1H NMR (300 MHz, DMSO-d6) δ 11.21 (br s, 1H), 3.97 (m, 2H), 3.44 (m, 2H), 2.56 (m, 1H), 1.81 (m, 4H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]#[CH:6])[CH3:3].[F:7][C:8]1[C:9](I)=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:23][CH:22]=[N:21][C:20]=1[CH3:24]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[CH3:1][N:2]([CH2:4][C:5]#[C:6][C:9]1[C:8]([F:7])=[CH:16][CH:15]=[C:14]2[C:10]=1/[C:11](=[CH:18]/[C:19]1[NH:23][CH:22]=[N:21][C:20]=1[CH3:24])/[C:12](=[O:17])[NH:13]2)[CH3:3]
Reactant: C#CCN(C)C
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#CCN(C)C)c21

Procedure:
Using Method C above, N,N-dimethyl propargylamine (42.2 mg, 0.51 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (75 mg, 0.203 mmol) (Starting Material 3 supra) using (Ph3P)4Pd (23.5 mg) and CuI (4 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 6 h to give (Z)-1,3-dihydro-4-[3-(N,N-dimethylamino)-1-propynyl]-5-fluoro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one. (Yield 40 mg, 61%).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=2[OH:11])[CH2:3][CH2:2]1.ClC1C=CC=CC=1Cl.CC(C)([O-])C.[K+].[OH:26][C:27]1[CH:32]=[C:31]([Cl:33])[N:30]=[N:29][C:28]=1Cl>C(O)(C)(C)C>[Cl:33][C:31]1[N:30]=[N:29][C:28]([O:11][C:5]2[C:6]([CH3:10])=[CH:7][CH:8]=[CH:9][C:4]=2[CH:1]2[CH2:3][CH2:2]2)=[C:27]([OH:26])[CH:32]=1
Reactant: Oc1cc(Cl)nnc1Cl
Reactant: Cc1cccc(C2CC2)c1O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Clc1ccccc1Cl
Solvent: CC(C)(C)O
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.7 %

Procedure:
To a mixture of 1.34 g (9.05 mmol) of 2-cyclopropyl-6-methylphenol and 1,2-dichlorobenzene (7.00 mL) was added 1.20 g (9.05 mmol) of 85% potassium t-butoxide at room temperature. The resultant mixture was heated to 180° C. and subjected to azeotropic dehydration under reflux while stirring for 30 minutes. To the resultant solution was added dropwise the preliminarily prepared solution of 4.97 g (purity: 96.0%; 2.89 mmol) of 4-hydroxy-3,6-dichloropyridazine in t-butanol (35.0 g) at 170° C. over 2 hours. (The t-butanol was distilled off simultaneously with the dropwise addition of the solution.) After stirring at 180° C. for another 2 hours, the reaction mixture was cooled to room temperature, and a 1 N aqueous hydrochloric acid solution and methanol were added to the reaction mixture to obtain a uniform solution. The obtained solution was quantitatively determined by an HPLC internal standard analysis method, which showed that 701 mg of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 88%) and 6.9 mg of 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 0.9%) were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(CC)CC)C.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH2:31][C:32](Cl)=[O:33])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:32](=[O:33])[CH2:31][C:25]2[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:23]([O:22][CH3:21])[CH:24]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCN)cc1OC
Reactant: COc1ccc(CC(=O)Cl)cc1OC
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(CCNC(=O)Cc2ccc(OC)c(OC)c2)cc1OC
Yield: 84 %

Procedure:
21.7 g of 2-(3,4-dimethoxyphenyl)ethylamine are dissolved in 150 cc of anhydrous chloroform and then the solution is added to 15.2 g of anhydrous triethylamine. The solution is cooled at a temperature between 5° and 10° C. and then, under stirring, there is added the 3,4-dimethoxyphenylacetyl chloride prepared in part (a), 26 g, dissolved in 80 cc of anhydrous chloroform. The temperature is allowed to rise to room temperature. It is then warmed under reflux for eight hours. After cooling the mixture, by addition of an additional portion of chloroform, 200 cc, the organic phase is washed with water and then with 5% hydrochloric acid and an additional amount of water, then 5% sodium hydroxide and finally water. The organic phase is dried over anhydrous sodium sulfate and after filtering, the solvent is evaporated under reduced pressure. The solid thus obtained is recrystallized from absolute ethanol. The pure amide, 36 g, is obtained in a yield of 84%, m.p. 128° C. The substance gives a single spot on chromatography using ethanol as eluent.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)[Cl:2].[CH2:6]([NH2:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1CCCCC1>[CH2:6]([NH:13][CH2:4][CH:3]([OH:5])[CH2:1][Cl:2])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NCc1ccccc1
Reactant: ClCC1CO1
Solvent: C1CCCCC1
Product: OC(CCl)CNCc1ccccc1
Yield: 55 %

Procedure:
46.25 g of epichlorohydrin, 33.5 g of benzylamine and 250 ml of cyclohexane were stirred together at ambient temperature for 24 hours. The precipitate formed was filtered off and recrystallized from toluene to give N-benzyl-3-amino-1-chloropropan-2-ol (1A), as a crystalline solid, m.p.: 70°-71° C., in 55% yield.