Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH2:16][C:17]1[CH:18]=[C:19]([C:23]#[CH:24])[CH:20]=[CH:21][CH:22]=1>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:24]#[C:23][C:19]2[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=2)[NH2:16])=[CH:3][CH:4]=1
Reactant: C#Cc1cccc(N)c1
Reactant: Fc1ccc(Br)cc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Nc1cccc(C#Cc2ccc(F)cc2)c1
Temperature: 65 °C
Yield: 96.4 %

Procedure:
A multinecked flask as described in Example 1 was charged with 50.0 g (0.28 mol) of p-bromofluorobenzene, 200 ml of dried, degassed triethylamine, 35.0 g (0.30 mol) of 3-aminophenylacetylene, 0.23 g (0.29 mmol) of bis(triphenyl phosphine) palladium II chloride, 1.03 g (3.92 mmol) of triphenylphosphine, and 0.1 g (0.52 mmol) of cuprous iodide. The reaction mixture was heated at 65° C. for 48 hours at which point gas chromatography showed the reaction to be complete. The mixture was cooled to room temperature and diluted with 200 ml of toluene. The toluene/triethylamine solution was decanted and concentrated on the rotary evaporator to give 75 g (0.27 mol, 96% yield) of the product as a bright yellow solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[CH2:14][C:13](=C)[CH2:12][C@@H:11]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[OH:24]>>[CH2:1]([O:8][CH2:9][C@@H:10]1[C@@H:11]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[CH2:12][C:13](=[O:24])[CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO
Reactant: C=C1C[C@H](COCc2ccccc2)[C@@H](c2cccc(F)c2)C1
Product: O=C1C[C@H](COCc2ccccc2)[C@@H](c2cccc(F)c2)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 1-(S)-benzyloxymethyl-2-(S)-(3-fluorophenyl)-4-methylenecyclopentane from Step A (7.1 g, 25.5 mmol) in methanol (300 mL) was cooled in a dry ice/acetone bath and ozone was bubbled into the solution until the blue color persisted. The excess ozone was removed with a stream of nitrogen and then dimethylsulfide (10 mL) was added. After 10 min, the bath was removed and the reaction was allowed to warm to room temperature over 2 h. The mixture was treated with 10 drops of sulfuric acid (c) in water (2 mL) for 1 h before most of the methanol was removed in vacuo. The mixture was diluted with water and extracted twice with ethyl acetate and the organic layers were washed with brine, dried over sodium sulfate, combined and concentrated. The residue was purified by FC (15% ethyl acetate in hexanes) to give the title compound (4.74 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12]/[N:13]=[CH:14]/[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:8][CH:7]=1.[N+]([C:26]([CH2:53][CH2:54][CH2:55][CH3:56])=[CH:27][C:28]1[CH:40]=[CH:39][C:31]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:30][C:29]=1[C:41]([N:43]1[CH2:52][CH2:51][C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH2:44]1)=[O:42])([O-])=O>>[C:35]([O:34][C:32]([C:31]1[CH:39]=[CH:40][C:28]([C:27]2[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:13][N:12]([C:9]3[CH:10]=[CH:11][C:6]([O:5][C:4]4[CH:20]=[CH:21][CH:22]=[C:2]([Cl:1])[CH:3]=4)=[CH:7][CH:8]=3)[C:26]=2[CH2:53][CH2:54][CH2:55][CH3:56])=[C:29]([C:41]([N:43]2[CH2:52][CH2:51][C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[CH2:44]2)=[O:42])[CH:30]=1)=[O:33])([CH3:36])([CH3:37])[CH3:38]
Reactant: CCOC(=O)/C=N/Nc1ccc(Oc2cccc(Cl)c2)cc1
Reactant: CCCCC(=Cc1ccc(C(=O)OC(C)(C)C)cc1C(=O)N1CCc2ccccc2C1)[N+](=O)[O-]
Product: CCCCc1c(-c2ccc(C(=O)OC(C)(C)C)cc2C(=O)N2CCc3ccccc3C2)c(C(=O)OCC)nn1-c1ccc(Oc2cccc(Cl)c2)cc1
Yield: 44.4 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 223E, (E)-ethyl 2-(2-(4-(3-chlorophenoxy)phenyl)hydrazono)acetate (60 mg, 0.19 mmol) and tert-butyl 4-(2-nitrohex-1-enyl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (88 mg, 0.19 mmol) were converted to the title compound (62 mg, 45%) as a pale yellow oil. 1H NMR (CDCl3, 1:1 mixture of amide rotamers) δ 8.10 (dd, J=8, 2 Hz, 1H), 8.05-8.04 (m, 1H), 7.44-6.83 (m, 13H), 5.02-4.98 (m, 1H), 4.48-4.38 (m, 1H), 4.33-4.28 (m, 2H), 4.18-3.98 (m, 1H), 3.58-3.32 (m, 1H), 2.85-2.50 (m, 4H), 1.61 (s, 9H), 1.29 (t, J=8 Hz, 1.5H), 1.19 (t, J=8 Hz, 1.5H), 1.15-0.81 (m, 4H), 0.65-0.61 (m, 3H); MS(ESI+) m/z 734.3 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-])=O)[CH:3]=1.Cl[Sn]Cl.[OH-].[Na+]>CCO>[Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:6])=[CH:7][CH:8]=1
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc(Br)cc1N

Procedure:
A solution of 4-bromo-2-nitroaniline (1.0 eq) and SnCl2 (2.2 eq) in EtOH was heated at reflux for 3 hours. After this time, the solution was poured onto ice, brought to pH 10 with 2M NaOH and extracted with Et2O. The combined organic layers were dried over MgSO4 and concentrated. The resulting brown oil was purified by silica gel chromatography (0-50% EtOAc:hexanes) to provide a light yellow solid. LC/MS m/z 187.1 (MH+), Rt 1.33 minutes.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][C@H:8]1[CH2:32][C:33]#[N:34])=[O:6])[CH:2]=[CH2:3].C(=O)([O-])[O-:36].[K+].[K+].OO.C(OCC)(=O)C>CS(C)=O.O>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][C@H:8]1[CH2:32][C:33](=[O:36])[NH2:34])=[O:6])[CH:2]=[CH2:3]
Reactant: O=C([O-])[O-]
Reactant: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CC#N
Agent: OO
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CC(N)=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 528.3 %

Procedure:
To a solution of (2R,4S)-1-allyloxycarbonyl-2-cyanomethyl-4-(triphenylmethylthio) pyrrolidine (1.17 g) in dimethyl sulfoxide (3.75 ml) were added potassium carbonate (50 mg) and 30% hydrogen peroxide (313 μl). After stirring at 60° C. for 2 hours, the mixture was poured into a mixture of ethyl acetate and water. The separated organic layer was washed with aqueous sodium chloride solution twice, dried over magnesium sulfate and evaporated. The residue was subjected to column chromatography on silica gel (eluent; n-hexane:ethyl acetate=1:1) to give (2R,4S)-1-allyloxycarbonyl-2-carbamoylmethyl-4-(triphenylmethylthio)pyrrolidine (0.93 g).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[C:8](=[O:26])[NH:9][C:10]3[C:15]([C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:14][C:13]([N+:23]([O-])=O)=[CH:12][CH:11]=3)[O:4][N:3]=1>[Pd].CO>[NH2:23][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:26])[C:7]([C:5]1[O:4][N:3]=[C:2]([CH3:1])[CH:6]=1)=[C:16]2[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cc1cc(-c2c(-c3ccccc3)c3cc([N+](=O)[O-])ccc3[nH]c2=O)on1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(-c2c(-c3ccccc3)c3cc(N)ccc3[nH]c2=O)on1
Reaction time: 8 h
Yield: 97.8 %

Procedure:
A flask charged with 3-(3-methyl-isoxazol-5-yl)-6-nitro-4-phenyl-1H-quinolin-2-one (0.2 g, 0.58 mmol)(Example 51), 50 mg of 10% Pd/C, and 10 mL of methanol was shaken on a Parr apparatus under 15 PSI of H2 for 8 hrs. The solution was filtered and concentrated to give 0.18 g (100%) of the title compound as a white solid. 1H NMR (400 MHz, CD3OD) δ 7.44 (m, 3H), 7.22 (m, 3H), 7.04 (m, 1H), 6.50 (m, 1H), 6.34 (s, 1H), 2.20 (s, 3H). Mass spectrum (ESI, m/z) calcd. for C19H15N3O2 317.1, found 318.1 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C@H:7]2[CH2:11][CH2:10][CH2:9][C@H:8]2[NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])=[CH:4][CH:3]=1.Br[C:22]1C=CC(O[C@@H]2CCCC[C@@H]2N)=CC=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C@@H:7]2[CH2:11][CH2:10][CH2:9][CH2:22][C@@H:8]2[NH:12][S:13]([CH:16]([CH3:17])[CH3:18])(=[O:14])=[O:15])=[CH:19][CH:20]=1
Reactant: CC(C)S(=O)(=O)N[C@@H]1CCC[C@@H]1Oc1ccc(Br)cc1
Reactant: N[C@H]1CCCC[C@H]1Oc1ccc(Br)cc1
Product: CC(C)S(=O)(=O)N[C@H]1CCCC[C@H]1Oc1ccc(Br)cc1

Procedure:
The title compound of Step 7 was prepared according to the general procedure for the synthesis of cis-N-[2-(4-bromophenoxy)cyclopentyl]propane-2-sulfonamide in Example 5, except that (1S,2R)-2-(4-bromophenoxy)cyclohexanamine was used in place of cis-2-(4-bromophenoxy)cyclopentan-amine, and the product purification was carried out using a gradient of 0% to 1% methanol in dichloromethane. N-[(1S,2R)-2-(4-bromophenoxy)cyclohexyl]propane-2-sulfonamide was obtained as a white foam. Yield: 1.67 g, 4.44 mmol, 75%. 1H NMR (400 MHz, CDCl3) δ 1.36 (d, J=6.9 Hz, 3H), 1.37 (d, J=6.9 Hz, 3H), 1.37-1.48 (m, 4H), 1.77-1.88 (m, 3H), 2.06 (m, 1H), 3.12 (septet, J=6.8 Hz, 1H), 3.54 (m, 1H), 4.48 (d, J=9.5 Hz, 1H), 4.54 (m, 1H), 6.84 (d, J=9.0 Hz, 2H), 7.39 (d, J=9.0 Hz, 2H). The enantiomer of N-[(1S,2R)-2-(4-bromophenoxy)cyclohexyl]propane-2-sulfonamide was prepared using similar chemistry to that described above in this Step 7, but employing (1S,2S)-2-(4-bromophenoxy)cyclohexanol as starting material instead of (1R,2R)-2-(4-bromophenoxy)cyclohexanol. The absolute stereochemistry of the enantiomer of N-[(1S,2R)-2-(4-bromophenoxy)cyclohexyl]propane-2-sulfonamide was established via X-ray crystallography.
Reaction SMILES: N1C=CC=CC=1S[C:8](=[O:25])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1.[CH:26]1([Mg]Br)[CH2:30][CH2:29][CH2:28][CH2:27]1.CCOCC>C1COCC1>[CH2:18]([O:17][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][CH2:9][C:8]([CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)=[O:25])=[CH:16][CH:15]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(CCc1ccc(OCc2ccccc2)cc1)Sc1ccccn1
Reactant: Br[Mg]C1CCCC1
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(CCc1ccc(OCc2ccccc2)cc1)C1CCCC1
Temperature: -78 °C
Reaction time: 0.58 h
Yield: 84 %

Procedure:
3-(4-Benzyloxyphenyl)thiopropionic acid S-pyridin-2-yl ester (3.00 g, 8.58 mmol) from Step 4 above was dissolved in dry THF (45 mL) and cooled to −78° C. A solution of cyclopentylmagnesium bromide in Et2O (2.0 M, 4.51 mL, 9.02 mmol) was added dropwise along the sides of the reaction vessel. After stirring 35 min, the cooling bath was removed. The reaction mixture was quenched with saturated aq. NH4Cl upon reaching ambient temperature and extracted with Et2O (500 mL). The organic phase was washed with brine (50 mL), dried over MgSO4 and evaporated. The residue was purified by flash column chromatography (10% EtOAc in hexanes) to give the product (2.22 g, 84%) as a white semi-crystalline material. 1H NMR (CDCl3) δ 1.48-1.83 (m, 8H), 2.69-2.77 (m, 2H), 2.79-2.88 (m, 3H), 5.03 (s, 2H), 6.86-6.92 (m, 2H), 7.07-7.12 (m, 2H), 7.28-7.45 (m, 5H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]([S:25]([N:28]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])(=[O:27])=[O:26])[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K].C(C1C=CC(N2S(=O)(=O)NC(=O)C2)=C(O)C=1)C1C=CC=CC=1.OC1C=C(C=CC=1N1CC(=O)NS1(=O)=O)[CH2:69][C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][C:71]=1[O:76][S:77]([CH3:80])(=[O:79])=[O:78]>>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH2:69][C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][C:71]=2[O:76][S:77]([CH3:80])(=[O:79])=[O:78])[CH:12]=[CH:11][C:10]=1[N:16]([S:25]([N:28]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])(=[O:27])=[O:26])[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Oc1ccccc1Cc1ccc(N2CC(=O)NS2(=O)=O)c(O)c1
Reactant: CC(C)(C)OC(=O)CN(c1ccc(I)cc1OCc1ccccc1)S(=O)(=O)N(CC[Si](C)(C)C)C(=O)OC(C)(C)C
Agent: O=C1CN(c2ccc(Cc3ccccc3)cc2O)S(=O)(=O)N1
Agent: [K]
Product: CC(C)(C)OC(=O)CN(c1ccc(Cc2ccccc2OS(C)(=O)=O)cc1OCc1ccccc1)S(=O)(=O)N(CC[Si](C)(C)C)C(=O)OC(C)(C)C

Procedure:
The title compound is prepared analogously to Example 1, Step I, starting with (tert-butyl N-[2-(benzyloxy)-4-iodophenyl]-N-({(tert-butoxycarbonyl)[2-(trimethylsilyl)ethyl]amino}-sulfonyl)glycinate) (intermediate from Example 1) and methanesulfonic acid 2-iodomethylphenyl ester (intermediate from Example 18).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[N:3]=1.C(N(CC)CC)C.Cl.[CH:21]1([NH:27][CH2:28][CH:29]2[CH2:31][CH2:30]2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:5]=[C:6]([N:27]([CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]2)[CH2:28][CH:29]2[CH2:31][CH2:30]2)[N:7]=1
Reactant: C1CCC(NCC2CC2)CC1
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(N(CC2CC2)C2CCCCC2)nc(Cl)n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A cooled (0° C.) solution of methyl 2,4-dichloropyrimidine-6-carboxylate (Apollo, OR2558, 5.00 g; 24.1 mmol) in THF (50 mL) was treated triethylamine (7.38 ml; 53.1 mmol) and cyclohexyl(cyclopropylmethyl)amine hydrochloride (Chembridge, 4.58 g; 24.1 mmol. The reaction mixture was stirred for 2 days at RT. The solvent was evaporated under reduced pressure, the remaining residue was partitioned between 100 ml of ethyl acetate and a saturated aqueous solution of NH4Cl (50 mL). The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated to obtain the crude product, which was purified by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc to give the title product as a yellow oil, which solidified upon standing (6.14 g, 78%).
Reaction SMILES: [CH3:1][N:2]([CH3:40])[C:3](=[O:39])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2([CH2:30][O:31]CC3C=CC=CC=3)[CH2:19][CH2:18][N:17]([C:20]3[C:21]4[C:28]([CH3:29])=[CH:27][NH:26][C:22]=4[N:23]=[CH:24][N:25]=3)[CH2:16][CH2:15]2)=[O:13])[CH:6]=1>C1COCC1.[Pd]>[CH3:40][N:2]([CH3:1])[C:3](=[O:39])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2([CH2:30][OH:31])[CH2:15][CH2:16][N:17]([C:20]3[C:21]4[C:28]([CH3:29])=[CH:27][NH:26][C:22]=4[N:23]=[CH:24][N:25]=3)[CH2:18][CH2:19]2)=[O:13])[CH:6]=1
Reactant: Cc1c[nH]c2ncnc(N3CCC(COCc4ccccc4)(C(=O)Nc4cccc(OC(=O)N(C)C)c4)CC3)c12
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1c[nH]c2ncnc(N3CCC(CO)(C(=O)Nc4cccc(OC(=O)N(C)C)c4)CC3)c12
Reaction time: 8 h
Yield: 4 %

Procedure:
To a solution of 3-(4-(benzyloxymethyl)-1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamido)phenyl dimethylcarbamate from example 15, step E, (30 mg, 0.055 mmol) in THF (2 mL) was added Pd/C (10%). The reaction mixture was stirred under H2 at 60 psi overnight. The mixture was filtered and concentrated under vacuum. The residue was purified by prep HPLC (30×250 mm C18 column, 10-100% MeCN:H2O (10 mM NH4OAc), 18 min, 45 mL/min) to give the title compound (1 mg).
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([S:9](Cl)(=[O:11])=[O:10])=[C:4]([F:13])[CH:3]=1.[NH2:14][CH2:15][CH2:16][OH:17].C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([S:9]([NH:14][CH2:15][CH2:16][OH:17])(=[O:11])=[O:10])=[C:4]([F:13])[CH:3]=1
Reactant: O=S(=O)(Cl)c1cc(F)c(Br)cc1F
Reactant: NCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(NCCO)c1cc(F)c(Br)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.9 %

Procedure:
A solution of 4-bromo-2,5-difluorobenzenesulfonyl chloride (1.17 g, 4 mmol) in CH2Cl2 (3 mL) was added to a solution of 2-aminoethanol (0.36 mL, 6 mmol) and triethylamine (1.67 mL, 12 mmol) in CH2Cl2 (12 mL) at ambient temperature. The mixture was stirred at ambient temperature for 1 h and concentrated. The crude product was purified by chromatography on a silica gel column using 0 to 10% MeOH/CH2Cl2 to give 884 mg (70%) of 4-bromo-2,5-difluoro-N-(2-hydroxyethyl)benzenesulfonamide as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.67 (dd, 1H, Ja=7.2 Hz, Jb=6.0 Hz), 7.47 (dd, 1H, Ja=8.7 Hz, Jb=5.1 Hz), 5.39-5.14 (m, 1H), 3.78-3.64 (m, 2H), 3.26-3.10 (m, 2H), 1.73 (bs, 1H); LRMS (ESI), m/z 314/316 (M−H).
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:13][CH2:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][PH:18](=[O:22])[O:19][CH2:20][CH3:21])=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(O)C.[Pd]>[Si:1]([O:8][C@@H:9]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][CH2:16][CH2:17][PH:18](=[O:22])[O:19][CH2:20][CH3:21])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCO[PH](=O)CCCCC1=CC(O[Si](C)(C)C(C)(C)C)CC1
Agent: [Pd]
Solvent: CCO
Product: CCO[PH](=O)CCCC[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)C1

Procedure:
A solution of (±)-ethyl [3-(t-butyldimethylsilyloxy)cyclopentenyl]butylphosphinate (8) (3.20 g, 9.23 mmol) in ethanol (30 cm3) was hydrogenated over palladium on carbon (50 mg) at 40 psi for 3 hours. The catalyst was removed by filtration through celite, which was washed with methanol (3×30 cm3). The solvent was removed in vacuo to yield the desired title compound (9) in quantitative yield (>90% cis isomer (9) by NMR spectroscopy) as a colourless oil, which was used in the next step without further purification (2.55g, 79%) (data for cis isomer only is reported): 1H-NMR (300 MHz, CDCl3) δH 0.05 (6H, s, Si(CH3)2), 0.89 (9H, s, SiC(CH3)3), 0.90 and 0.92 (3H, 2×d, J=7.2 and 9.3 Hz, PCH2CH2CH2CH3), 1.23-2.21 (16H, m, C(1)—H, C(2)—H, C(2)—H′, C(4)—H, C(4)—H′, C(5)—H and C(5)—H′, POCH2CH3, PCH2CH2CH2CH3, PCH2CH2CH2CH3, PCH2CH2CH2CH3), 3.99-4.35 (3H, m, POCH2CH3, C(3)—H); 13C-NMR (75 MHz, CDCl3) δC −4.89 and −4.87 (d, 6JPC=1.43 Hz, Si(CH3)2), 13.51 (s, PCH2CH2CH2CH3), 16.63 and 16.70 (d, 6JPC=5.4 Hz, SiC(CH3)3), 17.98 (s, POCH2CH3), 23.60 and 23.77 (2×d, 3JPC=12.75 and 13.13 Hz, PCH2CH2CH2CH3), 23.91 (s, C(5)), 24.10 (s, PCH2CH2CH2CH3), 25.74 (s, SiC(CH3)3), 25.26 and 26.47 (2×d, JPC=89.10 and 92.18 Hz, PCH2CH2CH2CH3), 34.88 and 36.51(2×d, JPC=4.50 and 94.73 Hz, C(1)), 35.78 and 35.58 (d, 3JPC=15.38 Hz, C(4)), 35.86 (s, C(2)), 60.05 (2×d, 2JPOC=5.93 and 6.30 Hz, POCH2CH3), 73.81 and 73.97 (2×d, 3JPC=11.93 and 11.93 Hz, C(3)); 31P-NMR (121 MHz, CDCl3) δP 60.26 and 60.43; MS (CI, CH4) m/z 349.2 (100%) (MH+), 333.3 (40), 291.2 (36), 350.2 (23). Synthesis of (±)-cis-ethyl (3-hydroxycyclopentanyl)butylphosphinate (10)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH2:11])([CH3:10])[CH3:9])=[C:4]([CH3:12])[CH:3]=1.[CH2:13]([O:16][CH2:17][CH2:18]Br)[CH2:14]Br.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:11]2[CH2:18][CH2:17][O:16][CH2:13][CH2:14]2)([CH3:9])[CH3:10])=[C:4]([CH3:12])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C(C)(C)N
Reactant: BrCCOCCBr
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Br)ccc1C(C)(C)N1CCOCC1
Temperature: 25 °C

Procedure:
A solution of 1-(4-Bromo-2-methyl-phenyl)-1-methyl-ethylamine (preparation 48, 544 mg, 2 mmol), 2,2′-dibromodiethylether (579.8 mg, 2.5 mmol) and N,N-diisopropylethylamine (1.027 ml, 6 mmol) in DMF (7 ml) is heated to 100° C. for 16 h and then allowed to cool to RT. The reaction mixture is partitioned between water and CH2Cl2. The aqueous phase is re-extracted twice, the combined organic phases are dried over Na2SO4 and concentrated in vacuo. The residue is purified by flash chromatography (silicagel, CH2Cl2: EtOAc=1:0=>0:1) to afford the title compound as a pale yellow oil, Rt=0.786 min (Acquity HPLC BEH C18, 2.1×50 mm, 1.7 micron, detection 215 nM, 0.1 min 2% CH3CN in H2O, 2% to 100% CH3CN in H2O in 1.5 min, 0.4 min 100% CH3CN+0.1% TFA, flow rate 1.0 ml/min); MS: 298 (M+1, 79Br)+.
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].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22](Cl)=[O:23])=[CH:17][CH:16]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:22](=[O:23])[CH2:21][C:18]2[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCN)cc1OC
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Product: COc1ccc(CCNC(=O)Cc2ccc(Cl)cc2)cc1OC

Procedure:
prepared by reaction of 3,4-dimethoxyphenylethylamine with 4-chlorophenyl acetyl chloride.
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([NH:17][C@@H:18]([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)[C:19]([F:29])([F:28])[O:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[CH2:11][S:12][CH2:13][CH:14]1[CH2:16][CH2:15]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(OCC)C>[CH:14]1([CH2:13][S:12][CH2:11][C@H:10]([NH:17][C@@H:18]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[C:19]([F:28])([F:29])[O:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:9][OH:8])[CH2:16][CH2:15]1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](CSCC1CC1)N[C@@H](c1ccc(F)cc1)C(F)(F)Oc1ccc(F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: OC[C@H](CSCC1CC1)N[C@@H](c1ccc(F)cc1)C(F)(F)Oc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 50.2 %

Procedure:
To a solution of [2-(tert-butyldimethylsilanyloxy)-1(R)-cyclopropylmethylsulfanylmethyl-ethyl]-[2,2-difluoro-2-(4-fluorophenoxy)-1(S)-(4-fluorophenyl)ethyl]amine (1.06 g, 1.94 mmol) in dry THF (10 ml) at 0° C., a 1M solution of tetrabutylammonium fluoride (2.3 ml, 2.3 mmol) was added. After stirring for 3 h at 0° C., the reaction mixture was diluted with ethyl ether (20 ml) and washed with sat. ammonium chloride solution (20 ml), brine (10 ml) and dried over sodium sulfate. After removal of the solvent under vacuum, the crude was purified by flash chromatography using ethyl acetate/hexanes (2/8) as eluent to give 3-cyclopropylmethylsulfanyl-2(R)-[2,2-difluoro-2-(4-fluorophenoxy)-1(S)-(4-fluorophenyl)ethylamino]propan-1-ol as an oil (0.418 g, 74%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](=O)[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]([CH2:14][C:15]([O:17][CH3:18])=[O:16])#[N:13].C(O)(=O)C.C([O-])(=O)C.[NH4+]>C1(C)C=CC=CC=1>[C:12]([C:14](=[C:9]([CH3:10])[CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:15]([O:17][CH3:18])=[O:16])#[N:13]
Reactant: CC(=O)CCc1ccccc1
Reactant: COC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COC(=O)C(C#N)=C(C)CCc1ccccc1
Yield: 87.3 %

Procedure:
A mixture of 4-phenyl-2-butanone (1 g), methyl cyanoacetate (0.77 g), acetic acid (0.29 mL), ammonium acetate (0.11 g) and toluene (10 mL) was heated for reflux overnight removing the generated water. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=3/1) to give methyl 2-cyano-3-methyl-5-phenyl-2-pentenate (1.35 g). To this material were added methanol (10 mL) and N,N-dimethylformamide dimethyl acetal (0.95 mL), and the mixture was heated for reflux overnight. The reaction mixture was concentrated under reduced pressure. To the residue were added acetic acid (8 mL) and a solution of 30% hydrobromic acid in acetic acid (5.9 g), and the mixture was stirred at room temperature for 6 hours. The reaction mixture was poured into ice water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water twice, a saturated aqueous sodium hydrogen carbonate solution twice, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=6/1) to give the title compound (1.7 g)