Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([C:10](O)([CH2:13][CH3:14])[CH2:11][CH3:12])=[CH:8][C:7]([CH3:16])=[N:6][N:5]2[C:17]=1[C:18]1[S:19][C:20]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=2)=[CH:21][C:22]=1[CH3:23].COCCN(S(F)(F)[F:41])CCOC>C(Cl)Cl>[CH2:11]([C:10]([C:9]1[C:4]2[N:5]([C:17]([C:18]3[S:19][C:20]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=4)=[CH:21][C:22]=3[CH3:23])=[C:2]([CH3:1])[N:3]=2)[N:6]=[C:7]([CH3:16])[CH:8]=1)([F:41])[CH2:13][CH3:14])[CH3:12]
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: CCC(O)(CC)c1cc(C)nn2c(-c3sc(-c4cccc(C)n4)cc3C)c(C)nc12
Solvent: ClCCl
Product: CCC(F)(CC)c1cc(C)nn2c(-c3sc(-c4cccc(C)n4)cc3C)c(C)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.4 %

Procedure:
To a −78° C. solution of 3-{2,6-dimethyl-3-[3-methyl-5-(6-methyl-pyridin-2-yl)-thiophen-2-yl]-imidazo[1,2-b]pyridazin-8-yl}-pentan-3-ol (0.23 g, 0.55 mmol) and CH2Cl2 (3 mL) is added a solution of [bis(2-methoxyethyl)amino]sulfur triflouride (0.14 g, 0.60 mmol) and CH2Cl2 (2 mL). The solution is warmed to ambient temperature and stirred overnight. The solution is washed with sat. NaHCO3 (5 mL) and concentrated. The reside is purified by ISCO column chromatography (15%-20% EtOAc/hexane gradient) furnish the title compound (0.13 g, 0.31 mmol, 57%). 1H NMR (CDCl3) δ 0.80 (t, J=7.5 Hz, 6H), 2.14 (s, 3H), 2.16-2.31 (m, 2H), 2.46 (s, 3H), 2.54 (s, 3H), 2.56 (s, 3H), 2.59-2.70 (m, 2H), 6.98 (s, 1H), 7.00 (d, J=7.6 Hz, 1H), 7.45 (d, J=7.8 Hz, 1H), 7.52 (s, 1H), 7.56 (dd, J=7.8, 7.6 Hz, 1H). LC/MS (m/z): calcd. for C24H27FN4S (M+H)+: 423.2; found: 423.4.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([O:26][CH3:27])[C:23]([F:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:3]1.Cl[C:35]([CH2:37][O:38]C(=O)C)=[O:36]>>[OH:38][CH2:37][C:35]([N:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([O:26][CH3:27])[C:23]([F:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:3]1)=[O:36]
Reactant: COc1cc(-c2ncnc3c(C(=O)N[C@@H]4CCCNC4)c[nH]c23)c(OCC2CC2)cc1F
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: COc1cc(-c2ncnc3c(C(=O)N[C@@H]4CCCN(C(=O)CO)C4)c[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from 4-(2-Cyclopropylmethoxy-4-fluoro-5-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-piperidin-3-ylamide hydrochloride (example A164) and acetic acid chlorocarbonyl-methyl ester the title compound is obtained as colorless solid.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][C@H:21]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22]1)=[O:19])C1C=CC=CC=1>[Pd].CO>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][C@H:21]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22]1)=[O:19]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3O)C1
Reaction time: 1 h

Procedure:
Palladium on carbon (335 mg; 10% Pd/C) was added to a solution of the product of Step 1 (1.4 g, 3.15 mmol) in methanol (30 mL) and the resulting mixture was stirred under hydrogen (balloon) for 1 hour. LC-MS analysis showed the reaction was complete. The reaction mixture was filtered and the filtrate was concentrated under vacuum to afford the title compound as an oil which was used without purification in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([C:18]3[CH:23]=[CH:22][C:21]4[O:24][CH2:25][O:26][C:20]=4[CH:19]=3)[CH:10]2[C:27]([O-:29])=[O:28])=[CH:5][CH:4]=1.COC1C=CC(C2C3C(=CC=CC=3)C(C3C=CC4OCOC=4C=3)=C2C(OCC)=O)=CC=1>CCO.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([C:18]3[CH:23]=[CH:22][C:21]4[O:24][CH2:25][O:26][C:20]=4[CH:19]=3)[CH:10]2[C:27]([OH:29])=[O:28])=[CH:5][CH:4]=1
Reactant: COc1ccc(C2c3ccccc3C(c3ccc4c(c3)OCO4)C2C(=O)[O-])cc1
Agent: [Pd]
Agent: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1c1ccc(OC)cc1
Solvent: CCO
Product: COc1ccc(C2c3ccccc3C(c3ccc4c(c3)OCO4)C2C(=O)O)cc1
Reaction time: 56 h
Yield: 95 %

Procedure:
Ethyl (1RS, 2RS, 3SR)-1-(4-Methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indane-2-carboxylate. To a solution of ethyl (RS)-1-(4-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)-indene-2-carboxylate (0.72 g, 1.7 mmol) in EtOH (30 ml) was added 10% palladium on activated carbon (1 g). The resulting suspension was stirred under an atmosphere of H2 for 56 h and filtered. The filtrate was concentrated under reduced pressure to afford the title compound as a yellow solid (0.70 g, 95%), which was used without further purification.
Reaction SMILES: CC(O)(C)[C:3]#[C:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH3:14])=[CH:7][CH:6]=1.[H-].[Na+].O>C1(C)C=CC=CC=1>[CH2:11]([C:8]1[CH:7]=[CH:6][C:5]([C:4]#[CH:3])=[CH:10][CH:9]=1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCc1ccc(C#CC(C)(C)O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: C#Cc1ccc(CCCC)cc1
Temperature: 60 °C
Reaction time: 6 h
Yield: 86.1 %

Procedure:
3-Methyl-1-(4'-butylphenyl)-1-butyne-3-ol (100 g) was dissolved in toluene (900 ml) under nitrogen atmosphere, and then sodium hydride (60% in paraffin liquid; 5.7 g) was added thereto, followed by stirring at 60° C. for 6 hours. The reaction solution was poured into water (500 ml), and then extracted with chloroform, followed by washing with water 3 times. After distilling off toluene and chloroform, the resultant was distilled under reduced pressure (b.p. 62° to 65° C./3 mmHg) to give 4-butylphenylacetylene (63 g).
Reaction SMILES: BrBr.[F:3][C:4]([F:15])([F:14])[C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])[CH3:12])=[CH:7][CH:6]=1.[CH:16]1[C:21]([Cl:22])=[CH:20][C:19]2[NH:23][C:24]([O:26][C:18]=2[CH:17]=1)=[O:25].[H-].[Na+].[Br-]>C(OCC)C.O1CCOCC1.CN(C=O)C.O>[Cl:22][C:21]1[CH:16]=[CH:17][C:18]2[O:26][C:24](=[O:25])[N:23]([CH2:12][C:11](=[O:13])[C:8]3[CH:7]=[CH:6][C:5]([C:4]([F:14])([F:15])[F:3])=[CH:10][CH:9]=3)[C:19]=2[CH:20]=1
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1
Reactant: O=c1[nH]c2cc(Cl)ccc2o1
Agent: BrBr
Agent: [Br-]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Solvent: C1COCCO1
Product: O=C(Cn1c(=O)oc2ccc(Cl)cc21)c1ccc(C(F)(F)F)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 95.2 %

Procedure:
Bromine (0.67 ml, 13 mmol) was added dropwise to a solution of 4'-(trifluoromethyl)acetophenone (2.5 g, 13 mmol) in diethylether (20 ml) and 1,4-dioxane (10 ml) at room temperature. Chlorzoxazone (2.19 g, 13 mmol) was treated with sodium hydride (400 mg, 13 mmol) in DMF for 15 min. under N2 and transferred by cannulation into the freshly prepared solution of bromide. The reaction mixture was stirred at 60° C. for 3 h, and poured into water (1 vol). The product was extracted with ethyl acetate, and the organic layer washed with water and brine and dried. Concentration gave a solid 4.4 g (93%) which was recrystallized from acetonitrile. mp 188°-189° C.; IR(KBr, ν=cm-1) 1776, 1704, 1330, 1226, 1122; 1H NMR (300 MHz, DMSO-d6) δ5.64 (2H, s), 7.20 (1H, dd, J=8.6 Hz, 2.1 Hz), 7.44 (1H, d, J=8.5 Hz), 7.57 (1H, d, J=2.1 Hz), 7.99 (2H, d, J=8.3 Hz), 8.27 (2H, d, J=8.1 Hz); MS(DCl)m/z: 356 (MH+)
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15](O)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.S(Cl)([Cl:22])=O>>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([Cl:22])=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reaction time: 2 h
Yield: 99 %

Procedure:
4′-Trifluoromethyl-biphenyl-2-carboxylic acid (25 g, 94 mmol) was combined with thionyl chloride (35 ml, 470 mmol) and the mixture was heated at reflux. After 2 h, the mixture was concentrated under vacuum to afford 26.5 g of the title product as a light yellow oil.
Reaction SMILES: Br[C:2]1[C:6]([Br:7])=[C:5]([Cl:8])[S:4][C:3]=1[Cl:9].[Li]CCCC.[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=[O:20]>C1COCC1>[Br:7][C:6]1[C:2]([CH:19]([C:18]2[CH:21]=[CH:22][CH:23]=[C:16]([Cl:15])[CH:17]=2)[OH:20])=[C:3]([Cl:9])[S:4][C:5]=1[Cl:8]
Reactant: O=Cc1cccc(Cl)c1
Reactant: Clc1sc(Cl)c(Br)c1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC(c1cccc(Cl)c1)c1c(Cl)sc(Cl)c1Br
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3,4-dibromo-2,5-dichlorothiophene (2.00 g, 6.43 mmol) in THF (18 mL) at −78° C., was added n-BuLi (2.5M in hexane, 2.57 mL, 6.43 mmol) dropwise. After 30 min., 3-chlorobenzaldehyde (0.732 mL, 6.43 mmol) was added dropwise to the yellow solution. The resulting solution was stirred at −78° C. for 30 min. and allowed to warm to 0° C. After 30 min., the reaction was quenched by the addition of 25% aq. NH4OAc. The aqueous layer was extracted with EtOAc and the combined organics were washed with water and brine, dried (Na2SO4) and concentrated. The crude product was purified by chromatography on silica gel (50:50 to 80:20 CHCl3/hexane) to afford the desired product as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)N.C(ON=O)CC(C)C.[Si:17]([O:24][CH2:25][C:26]1[O:27][CH:28]=[CH:29][CH:30]=1)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>CCOCC>[Br:1][C:2]1[CH:3]=[C:4]([C:28]2[O:27][C:26]([CH2:25][O:24][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:18])[CH3:19])=[CH:30][CH:29]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Br)c1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccco1
Agent: CC(C)CCON=O
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OCc1ccc(-c2cccc(Br)c2)o1
Temperature: 50 °C
Yield: 26 %

Procedure:
To a stirred solution of m-bromoaniline (6.88 g; 0.04M) in 42.2 g (0.2M) of 2-(t-butyldimethylsilyloxymethyl)furan at 0° was added isoamylnitrite (10.75 mL: 0.08M) dropwise over a period of 0.5 hr. The resulting mixture was then heated 16 hours at 50° C. The reaction mixture was cooled and diluted with 150 mL of ether and washed with 2×100 mL of ice cold water. The organic phase was dried over anhydrous magnesium sulfate, and the residue was distilled after filtering through 50G of silica gel bed, to give 26% of the desired 2-(3'-bromophenyl)-5-(t-butyldimethylsilyloxymethyl)furan as a colorless liquid boiling at 163°-7°/~0.5 mm.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.OS(O)(=O)=O.[CH3:20][CH2:21]O>C(Cl)Cl>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]([C:12]([O:14][CH2:20][CH3:21])=[O:13])=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: Cc1ccc2c(C(=O)O)cccc2n1
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CCOC(=O)c1cccc2nc(C)ccc12

Procedure:
To a slurry of compound 73a (3.1 g, 16 mmol) in EtOH (50 mL) was added concentrated H2SO4 (1.0 mL) and the resultant slurry was refluxed overnight. The homogeneous solution was cooled, diluted with DCM (300 mL), washed with 1N NaOH (1×100 mL), dried (Na2SO4), and concentrated in vacuo to give compound 73b as an off-white solid. Mass spectrum (LCMS, ESI pos.) Calcd. For C13H13NO2: 216.2 (M+H). found 216.2.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][N:12]1[C:16]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][N:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[CH:24]=2)=[N:15][C:14]([CH2:36][OH:37])=[N:13]1>ClCCl>[CH3:11][N:12]1[C:16]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][N:30]3[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]3)[CH:24]=2)=[N:15][C:14]([CH:36]=[O:37])=[N:13]1
Reactant: Cn1nc(CO)nc1NCCCCOc1cccc(CN2CCCCC2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Product: Cn1nc(C=O)nc1NCCCCOc1cccc(CN2CCCCC2)c1
Reaction time: 0.25 h
Yield: 80.4 %

Procedure:
Dimethyl sulphoxide (304 mg) was added to a solution of oxalyl chloride (254 mg) in dichloromethane (20 ml) at -60° under nitrogen for 2 min. and a solution of 1-methyl-5-[[4-[3-(1-piperidinylmethyl)phenoxy]butyl]amino]-1H-1,2,4-triazole-3-methanol (0.5 g) in dichloromethane (10 ml) was added. The mixture was stirred at -50° to -60° for 15 min. and then quenched with triethylamine (657 mg). The solution was allowed to warm to 25° and was diluted with water. The aqueous phase was extracted with dichloromethane and the combined organic extracts were dried and evaporated to leave the title compound as a pale yellow oil (0.4 g).
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[CH2:4][O:5][C:6]1[N:7]=[CH:8][N:9]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:16]([O:18]C)=[O:17])[C:10](=[O:12])[CH:11]=1.[OH-].[Na+]>O1CCOCC1>[F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[CH2:4][O:5][C:6]1[N:7]=[CH:8][N:9]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:16]([OH:18])=[O:17])[C:10](=[O:12])[CH:11]=1
Reactant: COC(=O)c1ccc(C)c(-n2cnc(OCc3ccc(F)cc3F)cc2=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)O)cc1-n1cnc(OCc2ccc(F)cc2F)cc1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-[4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoate (from Step 1) (7.56 g, 19.6 mmol) in dioxane (30 mL) was added 2N NaOH (14.7 mL). Stirred at ambient temperature for 1 h. Concentrated to ˜20 mL under reduced pressure. Cooled to 0° C. and added 5% citric acid to precipitate solid, filtered the precipitate, rinsed with water, and dried in vacuo overnight. Obtained product as an orange solid (6.62 g, 91%). Used without further purification. 1H NMR (CD3OD/400 MHz) δ8.28 (s, 1H), 8.04 (m, 1H), 7.88 (s, 1H), 7.56 (q, 1H, J=8.4 Hz), 7.50 (d, 1H, J=8.0 Hz), 6.99 (m, 2H), 5.87 (s, 1H), 5.39 (s, 2H), 2.19 (s, 3H). ESHRMS m/z 373.1001 (M+H calculated for C19H15F2N2O4 requires 373.0994).
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[CH2:5]([N:7]([CH2:17][CH3:18])[C:8]1[C:14]([F:15])=[CH:13][C:11]([NH2:12])=[C:10]([F:16])[CH:9]=1)[CH3:6].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.O>[CH2:17]([N:7]([CH2:5][CH3:6])[C:8]1[C:14]([F:15])=[CH:13][C:11]([N:12]=[C:1]=[S:2])=[C:10]([F:16])[CH:9]=1)[CH3:18]
Reactant: S=C(Cl)Cl
Reactant: CCN(CC)c1cc(F)c(N)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCN(CC)c1cc(F)c(N=C=S)cc1F
Yield: 101.6 %

Procedure:
In a manner similar to Step A of Example 8, the reaction of 3.0 g (0.026 mole) of thiophosgene with 2.6 g (0.013 mole) of 4-diethylamino-2,5-difluoroaniline and 7.2 g (0.052 mole) of potassium carbonate in 100 ml of chloroform and 100 ml of water yielded 3.2 g of 4-diethylamino-2,5-difluorophenyl isothiocyanate. The nmr and ir spectra were consistent with the proposed structure.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([CH3:15])[CH2:13]O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].P(Br)(Br)[Br:17]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([CH3:15])[CH2:13][Br:17])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: BrP(Br)Br
Reactant: CC(CO)Cc1ccc(C(C)(C)C)cc1
Product: CC(CBr)Cc1ccc(C(C)(C)C)cc1
Reaction time: 16 h

Procedure:
300.2 g of 3-(p-tert.butyl-phenyl)-2-methyl-propanol are added dropwise over a period of 2 hours at 20°-30° C. to 218.6 g of phosphorus tribromide and the mixture is left to stand for 16 hours. The mixture is subsequently heated to 55°-60° C. over a period of 1.5 hours, cooled to ca 10° C. and cautiously poured on to ice. The aqueous solution is exhaustively extracted with ether, the combined ether phases are washed with saturated sodium bicarbonate solution and water, dried over sodium sulphate and evaporated. By fraction distillation there is obtained pure 3-(p-tert.butyl-phenyl)-2-methyl-propyl bromide of boiling point 104° C./0.025 Torr.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:33]=[CH:32][C:6]([C:7]([O:22][CH2:23][C:24]2[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=2)[CH2:27][NH2:28])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[C:34](=S)=[S:35].C(N(CC)CC)C.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>CCO.CN(C1C=CN=CC=1)C>[CH3:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([C:7]([O:22][CH2:23][C:24]2[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=2)[CH2:27][N:28]=[C:34]=[S:35])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:33][CH:32]=2)=[CH:13][CH:12]=1
Reactant: COc1ccc(C(OCc2cccc(CN)c2)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: S=C=S
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc(C(OCc2cccc(CN=C=S)c2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-(4,4′-Dimethoxytrityloxymethyl)benzylamine (5) (613 mg, 1.39 mmol), carbon disulfide (0.85 mL, 13.9 mmol, 10 eq.), and triethylamine (0.20 mL, 1.39 mmol) were dissolved in EtOH (2 mL). The air was evacuated from the reaction system, and then Ar was charged therein. The reaction mixture was stirred for 2 hours at a room temperature. Then, in an ice bath, to the mixture were added dropwise a solution of di-tert-butyl dicarbonate (3.06 mg, 1.40 mmol) in EtOH (0.6 mL) and a solution of DMAP (6.12 mg, 6 mol %) in EtOH (0.6 mL). The mixture was further stirred for 4 hours at a room temperature. TLC was used to confirm there was no starting material in the mixture. Then, the reaction mixture was evaporated under reduced pressure. The residue was purified by column chromatography (Hex:EtOAc=10:1) to isolate
Reaction SMILES: C([Li])CCC.C(OP([CH2:14][C:15]([OH:17])=[O:16])(OCC)=O)C.[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1/[CH:23]=[CH:24]/[CH:25]=O.Cl>O1CCCC1.CO.O>[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH:23]=[CH:24][CH:25]=[CH:14][C:15]([OH:17])=[O:16]
Reactant: O=C/C=C/c1ccco1
Reactant: CCOP(=O)(CC(=O)O)OCC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)C=CC=Cc1ccco1
Temperature: -65 °C
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
Butyllithium (70 mL of 2.5 N solution) was added to 350 mL of anhydrous tetrahydrofuran (THF) at −65° C. A solution of diethylphosphonoacetic acid (15.9 g) in 130 mL of anhydrous THF was added dropwise to the stirred solution at −65° C. over a period of 75 minutes. The resulting solution was stirred at −65° C. for an additional 30 minutes and then a solution of trans-3-(2-furyl)acrolein (10.0 g) in 85 mL of anhydrous THF was added to the reaction at −65° C. over a period of 2 hours. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was then acidified with 5% hydrochloric acid (85 mL) to a pH of 3.5 followed by addition of 30 mL of water. The aqueous layer was extracted with 50 mL of ether twice and with 50 mL of ethyl acetate once. The combined organic extract was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give an oil. The crude oil was dissolved in 45 mL of hot methanol and then refrigerated overnight. The crystals formed were filtered and dried under vacuum to afford 9.2 g of the desired 5-(2-furyl)-2,4-pentadienoic acid. 1H NMR (acetone-d6, 300 MHz), δ(ppm) 7.64 (broad s, 1H), 7.42 (m, 1H), 6.86 (m, 2H), 6.58 (m, 2H), 6.05 (d, 1H).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([C:7](Cl)=[O:8])=[CH:3][CH:2]=1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:28]=[CH:29][C:30]=1[Cl:31])[CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][C@@H:23]([NH2:27])[CH:24]([CH3:26])[CH3:25])[CH2:18][CH2:17]1>N1C=CC=CC=1>[Cl:11][C:12]1[CH:13]=[C:14]([CH:28]=[CH:29][C:30]=1[Cl:31])[CH2:15][CH:16]1[CH2:17][CH2:18][N:19]([CH2:22][C@@H:23]([NH:27][C:7](=[O:8])[C:4]2[CH:5]=[CH:6][C:1]([CH3:10])=[CH:2][CH:3]=2)[CH:24]([CH3:26])[CH3:25])[CH2:20][CH2:21]1
Reactant: CC(C)[C@H](N)CN1CCC(Cc2ccc(Cl)c(Cl)c2)CC1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)N[C@H](CN2CCC(Cc3ccc(Cl)c(Cl)c3)CC2)C(C)C)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55.9 %

Procedure:
p-Toluoyl chloride (0.14 ml, 1 mmol) was added to a solution of 1-(S)-[4-(3,4-dichlorobenzyl)piperidin-1-ylmethyl]-2-methylpropylamine (0.33 g, 1 mmol) in dry pyridine (7 ml) at 0° C. under argon atmosphere. The solution was stirred for 30 min., at 0° C. and then allowed to warm to room temperature. After 3 h, the reaction mixture was concentrated under reduced pressure and water (10 ml) was added. The product was extracted with ethyl acetate and the organic layer was dried with magnesium sulfate and then concentrated in vacuo. The crude product (0.5 g) was chromatographed by eluting with a gradient of from 1% to 4% methanol/methylene chloride to give N-{1-(S)-[4-(3,4-dichlorobenzyl)piperidin-1-ylmethyl]-2-methylpropyl}-4-methylbenzamide (0.25 g) as partially solidified gum.
Reaction SMILES: Cl[C:2]1(Cl)[CH:9]2[CH:4]([CH2:5][CH2:6][CH:7]=[CH:8]2)[C:3]1=[O:10]>C(O)(=O)C.[Zn]>[CH:9]12[CH2:2][C:3](=[O:10])[CH:4]1[CH2:5][CH2:6][CH:7]=[CH:8]2
Reactant: O=C1C2CCC=CC2C1(Cl)Cl
Agent: [Zn]
Solvent: CC(=O)O
Product: O=C1CC2C=CCCC12
Temperature: 65 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
To a solution of 1.1 g of 8,8-dichlorobicyclo[4.2.0]oct-2-en-7-one in 10 ml of glacial acetic acid was added 2.0 g of zinc dust in portions over a period of 15 minutes. The mixture was then stirred at 65° C. for 1 hour, then a further 0.5 g of zinc dust was added and the mixture stirred at 75° C. for 1 hour. The mixture was cooled, filtered, the solid washed with hexane, the filtrate and combined washings diluted with water and extracted with hexane. The hexane layer was dried over anhydrous sodium sulfate, the solvent removed under reduced pressure and the residue distilled under vacuum to give 500 mg of bicyclo[4.2.0]oct-2-en-7-one, the compound of formula (III), where X and Y are hydrogen.
Reaction SMILES: C(Cl)Cl.[Cl:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=1[NH:15][C@H:16]([CH:20]([CH3:22])[CH3:21])[C:17]([OH:19])=[O:18].[C:23]([C@@H:25](O)[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:27]=1)#[N:24].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[Cl:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=1[NH:15][C@H:16]([CH:20]([CH3:22])[CH3:21])[C:17]([O:19][C@H:25]([C:23]#[N:24])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:27]=1)=[O:18]
Reactant: CC(C)[C@@H](Nc1ccc(C(F)(F)F)cc1Cl)C(=O)O
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(C)[C@@H](Nc1ccc(C(F)(F)F)cc1Cl)C(=O)O[C@H](C#N)c1cccc(Oc2ccccc2)c1
Reaction time: 1 h

Procedure:
Into 4.5 ml of methylene chloride containing 22.5 mg of 4-dimethylaminopyridine are added 439 mg (1.48 mmol) of (R)-2-(2-chloro-4-trifluoromethylphenylamino)-3-methylbutanoic acid and 329 mg (1.46 mmol) of (S)-α-cyano-3-phenoxybenzyl alcohol. The solution is cooled in an ice bath and 380 mg (1.82 mmol) of dicyclohexylcarbodiimide is added. The mixture is stirred at 0° for 1 hour and is then worked up by partition between ether/hexane. The aqueous phase is extracted with ether, and the ether extract is washed with water (2×) and brine, dried over magnesium sulfate, filtered and evaporated. The product is purified by radial thin layer chromatography (2 mm silica gel rotor eluting with 12% ether/hexane). Higher diastereomeric purity is obtained by further radial tlc, yielding the final product (S)-α-cyano-3-phenoxybenzyl (R)-2-(2-chloro-4-trifluoromethylphenylamino)-3-methylbutanoate, specific rotation=+46.3° (in CHCl3), diastereomer purity=~98%.