Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH2:25][CH3:26])[C:9]1[CH:14]=[CH:13][C:12]([C:15]([OH:24])([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C(=O)N([Cl:34])C(=O)C1>CC(O)C>[CH2:1]([N:8]([CH2:25][CH3:26])[C:9]1[CH:14]=[CH:13][C:12]([C:15]([OH:24])([C:16]([F:17])([F:18])[F:19])[C:20]([F:21])([F:22])[F:23])=[CH:11][C:10]=1[Cl:34])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(Cc1ccccc1)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(C)O
Product: CCN(Cc1ccccc1)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1Cl
Temperature: 80 °C
Reaction time: 10 h
Yield: 82.6 %

Procedure:
A solution of 20 mg (0.05 mmol) of 2-[4-(benzyl-ethyl-amino)-phenyl]-1,1,1,3,3,3-hexafluoro-propan-2-ol (example 1.2) in 0.5 mL of 2-propanol was treated with 7 mg (0.05 mmol) of NCS. The mixture was stirred at 80° C. for 10 hours and the solvent was evaporated. Column chromatography on silicagel with n-heptane/EtOAc 9:1 yielded 17 mg (82%) of 2-[4-(benzyl-ethyl-amino)-3-chloro-phenyl]-1,1,1,3,3,3-hexafluoro-propan-2-ol, colorless oil, MS: 412 (MH+, 1Cl).
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]1[N:23]=[C:6]2[CH:7]=[C:8]([NH:11][C:12]([C:14]3[N:18]([CH3:19])[N:17]=[CH:16][C:15]=3[C:20](O)=[O:21])=[O:13])[CH:9]=[CH:10][N:5]2[N:4]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1.CCCP(=O)=O.C(N(C(C)C)CC)(C)C>O1CCCC1>[CH3:1][N:2]([CH3:24])[C:3]1[N:23]=[C:6]2[CH:7]=[C:8]([NH:11][C:12]([C:14]3[N:18]([CH3:19])[N:17]=[CH:16][C:15]=3[C:20]([N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:21])=[O:13])[CH:9]=[CH:10][N:5]2[N:4]=1
Reactant: C1CCNC1
Reactant: CN(C)c1nc2cc(NC(=O)c3c(C(=O)O)cnn3C)ccn2n1
Agent: CCCP(=O)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)c1nc2cc(NC(=O)c3c(C(=O)N4CCCC4)cnn3C)ccn2n1
Temperature: 70 °C
Reaction time: 18 h
Yield: 89.1 %

Procedure:
A mixture of 5-(2-(dimethylamino)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid (150 mg, 455 μmol), pyrrolidine (226 μl, 2.73 mmol), propylphosphonic anhydride (50% in ethyl acetate, 671 μl, 1.14 mmol) and diisopropylethylamine (239 μl, 1.37 mmol) in tetrahydrofurane (8 ml) is stirred for 18 hours at 70° C. under nitrogen atmosphere. The solvent is evaporated and the residue triturated with sat. aqueous sodium hydrogencarbonate solution. The precipitated solid is collected by filtration, washed with water and dried affording N-(2-(dimethylamino)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-(pyrrolidine-1-carbonyl)-1H-pyrazole-5-carboxamide (155 mg, 89%) as a light brown solid. Mp.: 199-201° C. MS: m/z=383.4 (M+H+).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH:4]([CH2:7][CH:8]=O)[CH2:3]1.[Br-].[C:11]1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)CCC)[CH:16]=CC=C[CH:12]=1>>[CH2:7]([CH:4]1[CH2:5][CH2:6][CH:2]([OH:1])[CH2:3]1)[CH:8]=[CH:12][CH2:11][CH3:16]
Reactant: O=CCC1CCC(O)C1
Reactant: CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: CCC=CCC1CCC(O)C1
Yield: 24.9 %

Procedure:
Using the procedure of Example 3, 5 g of 3-hydroxy cyclopentyl-acetaldehyde and 20 g of triphenyl propyl phosphonium bromide were reacted and the product was chromatographed over silica gel. Elution with a 7-3 cyclohexane-ethyl acetate mixture yielded 1.5 g of 3-(2-pentenyl)-cyclopentanol.
Reaction SMILES: FC(F)(F)[C:3](O)=[O:4].[NH2:8][C@@H:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][C@H:10]1[NH:18][C:19]([C:21]1[NH:25][C:24]2[C:26]([Cl:30])=[C:27]([Cl:29])[S:28][C:23]=2[CH:22]=1)=[O:20].C(O)=O.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[Cl:29][C:27]1[S:28][C:23]2[CH:22]=[C:21]([C:19]([NH:18][C@@H:10]3[CH2:11][C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C@H:9]3[NH:8][CH:3]=[O:4])=[O:20])[NH:25][C:24]=2[C:26]=1[Cl:30]
Reactant: O=C(O)C(F)(F)F
Reactant: N[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2sc(Cl)c(Cl)c2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=CO
Product: O=CN[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2sc(Cl)c(Cl)c2[nH]1
Reaction time: 0.08 h
Yield: 88.8 %

Procedure:
N-[(1R,2R)-1-Amino-2,3-dihydro-1H-inden-2-yl]-2,3-dichloro-4H-thieno[3,2-b]pyrrole-5-carboxamide trifluoroacetic acid salt (Method 8, 240 mg, 0.5 mmol), formic acid (50 μL, 1.4 mmol), DIPEA (174 μL, 1.0 mmol) and HOBT (67 mg, 0.5 mmol) were dissolved in DCM (5 ml), stirred for 5 mins, EDCI (120 mg, 0.625 mmol) added and the reaction stirred for 1 hr. Formic acid (50 μL, 1.4 mmol) and EDCI (240 mg, 1.25 mmol) were added, the reaction stirred for 2 hours and the volatiles removed by evaporation under reduced pressure. The residue was dissolved in EtOAc (20 mL), washed with water (2×10 mL), brine (10 mL), dried (MgSO4) and the volatiles removed by evaporation under reduced pressure. The residue was purified by column chromatography (2:1 EtOAc:Hexane) to afford the title compound (175 mg, 89%) as a white foam.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].[Cl:17][CH2:18][CH2:19][CH2:20][S:21](Cl)(=[O:23])=[O:22]>>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][S:21]([CH2:20][CH2:19][CH2:18][Cl:17])(=[O:23])=[O:22])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: CCOC(=O)c1oc2cccc(N)c2c1C
Product: CCOC(=O)c1oc2cccc(NS(=O)(=O)CCCCl)c2c1C
Yield: 70 %

Procedure:
4-(3-Chloro-propane-1-sulfonylamino)-3-methyl-benzofuran-2-carboxylic acid ethyl ester was prepared from 4-amino-3-methyl-benzofuran-2-carboxylic acid ethyl ester (Example 60, Step 1), and 3-chloropropanesulfonyl chloride according to the procedure of Example 68, Step 1. Yield: 70%. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.4 (m, 3 H) 2.2 (m, 2 H) 2.8 (s, 3 H) 3.3 (m, 2 H) 3.8 (t, J=6.4 Hz, 2 H) 4.4 (q, J=7.2 Hz, 2 H) 7.2 (d, J=7.3 Hz, 1 H) 7.5 (m, 1 H) 7.7 (m, 1 H) 9.7 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[C:8]([N+]([O-])=O)=[CH:7][C:5](N)=[C:4]([I:12])[CH:3]=1.S(=O)(=O)(O)O.[N:18]([O-:20])=[O:19].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([I:12])[CH:5]=[C:7]([N+:18]([O-:20])=[O:19])[CH:8]=1
Reactant: O=N[O-]
Reactant: Nc1cc([N+](=O)[O-])c(Cl)cc1I
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])c1cc(Cl)cc(I)c1
Temperature: 0 °C
Yield: 42.1 %

Procedure:
To a solution of 4-chloro-2-iodo-5-nitroaniline (8.5 g) in ethanol (38 ml) was added concentrated sulphuric acid (4.4 ml) dropwise, then the solution was heated to reflux and solid sodium nitrite (4.9 g) added in small amounts over 30 minutes. The mixture was refluxed a further one hour and poured into ice water, the product extracted into ethyl acetate, washed with water and brine and the organic layer was dried over sodium sulfate. The solution was evaporated and the residue purified by column chromatography to give 5-chloro-3-iodonitrobenzene (3.4 g). δ (360 MHz, DMSO-d6) 8.28 (1H, d, 2-H), 8.35 (1H, d, 6-H) and 8.46 (1H, d, 4-H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[C:9]([CH3:11])[NH:8][C:6]=2[N:7]=1.[CH:13]1([NH2:17])[CH2:16][CH2:15][CH2:14]1.C(N(CC)CC)C>C(O)CCC>[Cl:1][C:2]1[N:3]=[C:4]([NH:17][CH:13]2[CH2:16][CH2:15][CH2:14]2)[C:5]2[CH:10]=[C:9]([CH3:11])[NH:8][C:6]=2[N:7]=1
Reactant: NC1CCC1
Reactant: Cc1cc2c(Cl)nc(Cl)nc2[nH]1
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: Cc1cc2c(NC3CCC3)nc(Cl)nc2[nH]1
Yield: 44.9 %

Procedure:
A solution of 2,4-dichloro-6-methyl-7H-pyrrolo[2,3-d]pyrimidine (190 mg, 0.94 mmol), cyclobutylamine (0.160 mL, 1.88 mmol) and triethylamine (0.200 mL, 1.44 mmol) in nBuOH (6 mL) was stirred at 70° C. overnight. It was then purified by HPLC to give 2-chloro-N-cyclobutyl-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (100 mg).
Reaction SMILES: [H-].[Na+].[C:3]1(=[O:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.C(OCC)=O.C1(C)C=CC(S([N:30]=[N+:31]=[N-])(=O)=O)=CC=1>C(OCC)C.C(O)C.O>[N+:30](=[C:4]1[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:3]1=[O:15])=[N-:31]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: O=C1CCCCCCCCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CCOC=O
Product: [N-]=[N+]=C1CCCCCCCCCCC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.6 %

Procedure:
A suspension of 1.3 gm (33 mmole) of sodium hydride dispersion (60%) in 12 mL of diethyl ether and one drop of absolute ethanol was cooled in an ice bath under nitrogen. A mixture was prepared of 2.0 gm (11 mmole) cyclododecanone and 2.4 gm (33 mmole of ethyl formate in 20 mL of diethyl ether. This second solution was added, dropwise, to the sodium hydride suspension. The resulting mixture was stirred in the ice bath for about 3 hours after which time it was allowed to come to room temperature. After stirring at room temperature overnight, a solution of 3.99 gm (33 mmole) p-toluenesulfonyl azide in 25 mL of diethyl ether was added dropwise. The resulting mixture was stirred at room temperature for about 3 hours. Ten mL of water was added and the organic layer removed. This organic layer was then washed with 100 mL of 10% NaOH. The aqueous layer was extracted with three portions of ethyl acetate. The combined organic phases were dried over sodium sulfate and then concentrated in vacuo (less than 30° C.). The residue was subjected to flash chromatography on 40 microns silica gel to give 1.0 gm of 2-diazocyclododecan-1-one as a bright yellow-orange solid, MP 43°-44° C. Elemental analysis calculated for C12H20N2O: C: 69.19; H: 9.68; N: 13.45. Found: C: 69.13; H: 9.69; N: 13.57. Pmr, cmr, ir, and UV spectra consistent with the desired product were obtained.
Reaction SMILES: Cl.FC(C1C=CC=CC=1C1(NC2C=C3C(=CC=2)NC(=O)CC3)C=CN=CN1)(F)F.[Cl:30]C1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.C[Si](N([Si](C)(C)C)C(=O)C(F)(F)F)(C)C.CO[C:61]1[CH:70]=[CH:69][C:68]2[C:63](=[CH:64][C:65]([NH:71][C:72]3[CH:77]=[C:76]([C:78]4[CH:83]=[CH:82][C:81]([C:84]([F:87])([F:86])[F:85])=[CH:80][CH:79]=4)[N:75]=[CH:74][N:73]=3)=[CH:66][CH:67]=2)[N:62]=1>O1CCOCC1>[Cl:30][C:61]1[CH:70]=[CH:69][C:68]2[C:63](=[CH:64][C:65]([NH:71][C:72]3[CH:77]=[C:76]([C:78]4[CH:83]=[CH:82][C:81]([C:84]([F:87])([F:86])[F:85])=[CH:80][CH:79]=4)[N:75]=[CH:74][N:73]=3)=[CH:66][CH:67]=2)[N:62]=1
Reactant: COc1ccc2ccc(Nc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)cc2n1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: C[Si](C)(C)N(C(=O)C(F)(F)F)[Si](C)(C)C
Agent: Cl
Agent: O=C1CCc2cc(NC3(c4ccccc4C(F)(F)F)C=CN=CN3)ccc2N1
Solvent: C1COCCO1
Product: FC(F)(F)c1ccc(-c2cc(Nc3ccc4ccc(Cl)nc4c3)ncn2)cc1
Temperature: 25 °C

Procedure:
7-[6-(4-(Trifluoromethylphenyl)pyrimidin-4-ylamino]-3,4-dihydro-1H-quinolin-2-one hydrochloride, Example 9(c), (500 mg, 1.2 mmol) was suspended in anhydrous 1,4-dioxane (10 mL), under N2, in a flame-dried, round-bottomed flask equipped with a reflux condenser. The suspension was magnetically stirred at 25° C. and treated with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (350 mg, 1.5 mmol, Aldrich) followed by bis(trimethylsilyl)trifluoroacetamide (1.4 mL, 5.3 mmol, Aldrich). The reaction mixture was stirred in a 105° C. oil bath for 15 min, then allowed to cool to 25° C. and partitioned between EtOAc (150 mL) and 1% aq NaHSO3 (100 mL). The resulting emulsion was allowed to settle, and the organic phase was separated and concentrated in vacuo to a brown solid (1.1 g). The solid was treated with phosphorous oxychloride (10 mL, Aldrich) and stirred in a 100° C. oil bath for 1 h. After cooling to room temp, the reaction was quenched by slow addition to MeOH (200 mL), then concentrated in vacuo. The residue was treated with a mixture of 30% NHOH and ice (200 mL), then extracted with EtOAc (2×100 mL). The combined organic extract was washed with satd NaCl (50 mL), dried over Na2SO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (30% EtOAc in hexane) provided a mixture of the title product and (2-methoxyquinolin-7-yl)-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine (Example 12), and the pure title product as a white solid. MS (ESI, pos. ion) m/z: 401 (M+1). MP: 233° C.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([CH:7]2[CH2:11][O:10][C:9]([CH3:13])([CH3:12])[O:8]2)[N:6]=1.CCCCCC.C([Li])CCC.CN(C)[CH:27]=[O:28].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[CH3:12][C:9]1([CH3:13])[O:8][CH:7]([C:5]2[N:6]=[C:2]([CH:27]=[O:28])[S:3][CH:4]=2)[CH2:11][O:10]1
Reactant: CN(C)C=O
Reactant: CC1(C)OCC(c2csc(Br)n2)O1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC1(C)OCC(c2csc(C=O)n2)O1
Temperature: -70 °C
Reaction time: 1 h
Yield: 42.5 %

Procedure:
To a solution of 2-bromo-4-(2,2-dimethyl-1,3-dioxolan-4-yl)-1,3-thiazole (3.00 g) in tetrahydrofuran (40 mL) was slowly added a 1.6M n-butyllithium hexane solution (7.8 mL) at −70° C. under a nitrogen atmosphere. The reaction mixture was stirred at −70° C. for 1 hr, and N,N-dimethylformamide (2.50 g) was added. The reaction mixture was warmed to room temperature, 10% aqueous citric acid solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography, and the title compound (1.03 g, yield 42%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:5, volume ratio).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][C:7]2[O:11][C:10]([C:12](O)=[O:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:19])=O>CN(C=O)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][C:7]2[O:11][C:10]([C:12]([Cl:19])=[O:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Cc2ccc(F)cc2)o1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(Cc2ccc(F)cc2)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.6 %

Procedure:
To 5-(4-fluorobenzyl)-2-furan carboxylic acid (450 mg, 2 mmol) were added thionylchloride (1 ml, 13.7 mmol) and DMF (0.025 ml). The mixture was stirred for 30 minutes at room temperature. The excess amount of thionylchloride was evaporated. The precipitated residue was washed with n-hexane to give crude 5-(4-fluorobenzyl)-2-furan carboxylic acid chloride (480 mg). NMR(CDCl3) δ: 4.03(2H, s), 6.20(1H, d, J=3.6 Hz), 7.03(2H, t, J=8.7 Hz), 7.19-7.24(2H, m), 7.42(1H, d, J=3.6 Hz).
Reaction SMILES: [CH3:1][N:2]([CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C(=O)C(F)(F)F.[BH4-].[Na+]>C(O)C.O>[C:12]1([CH2:11][CH2:10][CH2:9][NH:2][CH3:1])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CN(CCCc1ccccc1)C(=O)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CNCCCc1ccccc1
Reaction time: 15 h
Yield: 102.7 %

Procedure:
To a solution of 4.0 g (16.3 mM) of N-methyl-N-(3-phenylpropan-1-yl)trifluoroacetamide in ethanol (30 ml) was added 1.23 g (32.5 mM) of sodium borohydride at room temperature and the mixture was stirred at the prevailing temperature for 15 hours. This reaction mixture was diluted with water and extracted with methylene chloride. The organic layer was washed with saturated aqueous solution of sodium chloride and dried over MgSO4. The solvent was then distilled off under reduced pressure to provide crude (3-phenylpropan-1-yl)methylamine (2.5 g) as light-yellow oil. A solution of 2.6 g (<16.3 mM) of this (3-phenylpropan-1-yl)methylamine, 4.81 g (17.9 mM) of N-(3-bromopropyl)phthalimide, and 3.0 ml (21.5 mM) of triethylamine was refluxed for 20 hours. The solvent was then distilled off under reduced pressure and the residue was diluted with water and extracted with methylene chloride. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over MgSO4, and purified by column chromatography (methanol-ethyl acetate 20%) to provide the title compound.
Reaction SMILES: [CH:1]1([CH2:4][C@H:5]([NH:23][C:24](=[O:35])[C@@H:25]([NH:27]C(=O)OC(C)(C)C)[CH3:26])[C:6]([NH:8][C@@H:9]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]([C@@:12]2([CH3:15])[CH2:14][O:13]2)=[O:11])=[O:7])[CH2:3][CH2:2]1.[C:36]([OH:42])([C:38]([F:41])([F:40])[F:39])=[O:37]>C(Cl)Cl>[OH:42][C:36]([C:38]([F:41])([F:40])[F:39])=[O:37].[NH2:27][C@@H:25]([CH3:26])[C:24]([NH:23][C@@H:5]([CH2:4][CH:1]1[CH2:3][CH2:2]1)[C:6]([NH:8][C@@H:9]([CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:10]([C@@:12]1([CH3:15])[CH2:14][O:13]1)=[O:11])=[O:7])=[O:35]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC1CC1)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@@]1(C)CO1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](N)C(=O)N[C@@H](CC1CC1)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@@]1(C)CO1
Reaction time: 0.5 h

Procedure:
To tert-butyl ((S)-1-(((S)-3-cyclopropyl-1-(((S)-1-((R)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)amino)-1-oxopropan-2-yl)amino)-1-oxopropan-2-yl)carbamate (380 mg, 0.779 mmol) was added DCM (2.5 mL) and TFA (2.5 mL). The mixture was allowed to stand at ambient temperature for 30 min before it was concentrated to provide (S)-2-((S)-2-aminopropanamido)-3-cyclopropyl-N-((S)-1-((R)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)propanamide TFA salt (377 mg, quant.) as a yellow oil that was carried forward without further purification. MS (EI) for C23H29F3N3O5, found 388.3 [M-TFA]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[C:14]([O:15][C:16]3[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH:23]4OCC[O:24]4)[CH:17]=3)=[C:13]([CH:28]([CH3:30])[CH3:29])[C:12](=[O:31])[NH:11][C:10]2=[O:32])[CH:5]=[C:4]([NH:33][CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)[N:3]=1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>O.CC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[C:14]([O:15][C:16]3[CH:17]=[C:18]([CH:19]=[C:20]([CH3:22])[CH:21]=3)[CH:23]=[O:24])=[C:13]([CH:28]([CH3:29])[CH3:30])[C:12](=[O:31])[NH:11][C:10]2=[O:32])[CH:5]=[C:4]([NH:33][CH2:34][C:35]2[CH:36]=[CH:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=2)[N:3]=1
Reactant: COc1ccc(CNc2cc(Cn3c(Oc4cc(C)cc(C5OCCO5)c4)c(C(C)C)c(=O)[nH]c3=O)cc(Cl)n2)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(CNc2cc(Cn3c(Oc4cc(C)cc(C=O)c4)c(C(C)C)c(=O)[nH]c3=O)cc(Cl)n2)cc1
Temperature: 25 °C
Yield: 41.7 %

Procedure:
A mixture of (15) (908 mg, 1.53 mmol), PPTS (77 mg, 0.31 mmol), and water (7 drops) in acetone (10 ml) was heated under reflux for 3 hr. After cooling to room temperature, the mixture was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, EA:hexanes (1:2)) to afford 350 mg (50%) of a white foam; 1H NMR (200 MHz, CDCl3) δ 1.11 (6H, d, J=6.8 Hz), 2.40 (3H, s), 2.68 (1H, m), 3.80 (3H, s), 4.29 (2H, d, J=5.4 Hz), 4.72 (2H, s), 5.02 (1H, t, J=5.4 Hz), 6.01 (1H, s), 6.26 (1H, s), 6.85-6.89 (3H, m), 7.09 (1H, s), 7.21-7.27 (2H, m), 7.40 (1H, s), 8.98 (1H, s), 9.89 (1H, s).
Reaction SMILES: Cl.[CH3:2][NH:3][C:4]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:13][CH2:12][C:7]2(OCC[O:8]2)[CH2:6][CH2:5]1>O>[CH3:2][NH:3][C:4]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:13][CH2:12][C:7](=[O:8])[CH2:6][CH2:5]1
Reactant: CNC1(c2ccccc2)CCC2(CC1)OCCO2
Agent: Cl
Solvent: O
Product: CNC1(c2ccccc2)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A mixture of conc. HCl (15 ml) and water (8 ml) was poured over methyl-(8-phenyl-1,4-dioxaspiro[4.5]dec-8-yl)amine (2.1 g, 8.4 mmole) and the mixture was stirred for 5 days at RT. The reaction mixture was worked up by dilution with water (20 ml) and extraction with ether (3×30 ml). The ethereal phase was discarded. The aqueous phase was then made alkaline with 2N NaOH and extracted with dichloromethane (3×30 ml). The organic phase thereby obtained was dried over Na2SO4 and then concentrated by evaporation on a rotary evaporator. The ketone Ket-3 was obtained by chromatographic purification on silica gel with ethyl acetate/ethanol (4:1) in a yield of 1.38 g (81%) as a solid with a melting point of 32°-38° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClCCl.C1(C)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.O[CH2:43][CH2:44][O:45][CH2:46][C:47](=[O:63])[O:48][CH2:49][CH2:50][O:51][CH2:52][C:53](=[O:62])[O:54][CH2:55][CH2:56][O:57][CH2:58][C:59]([OH:61])=[O:60]>C1(C)C=CC=CC=1>[O:60]1[CH2:43][CH2:44][O:45][CH2:46][C:47](=[O:63])[O:48][CH2:49][CH2:50][O:51][CH2:52][C:53](=[O:62])[O:54][CH2:55][CH2:56][O:57][CH2:58][C:59]1=[O:61]
Reactant: O=C(O)COCCOC(=O)COCCOC(=O)COCCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C1COCCOC(=O)COCCOC(=O)COCCO1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.3 %

Procedure:
To a stirred solution of triphenylphosphine (4.68 g, 17.85 mmol) in a dichloromethane/toluene 1/1 mixture (1.5 l) was added at room temperature DEAD (8.2 ml, 44.63 mmol). Reaction mixture stirred at room temperature for 10 min then a toluene solution of hydroxyacid 12 (1.18 g, 3.57 mmol) was added. Mixture was stirred at room temperature and concentrated. Careful flash chromatography on silica gel (EtOAc/pentane 1/1 then 2/1 then EtOAc 100%) afforded cyclic 14 as a white solid (670 mg, 60%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].Cl[CH2:20][C:21]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)[NH:23][N:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>CN(C)C=O>[C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:20][C:21]3[CH:25]=[C:24]([C:26]4[CH:27]=[CH:28][C:29]([C:32]([F:34])([F:33])[F:35])=[CH:30][CH:31]=4)[NH:23][N:22]=3)[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Cn1ccc2ccc(O)cc21
Reactant: FC(F)(F)c1ccc(-c2cc(CCl)n[nH]2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cn1ccc2ccc(OCc3cc(-c4ccc(C(F)(F)F)cc4)[nH]n3)cc21
Temperature: 80 °C
Reaction time: 4 h
Yield: 6.7 %

Procedure:
A mixture of (6-hydroxy-indol-1-yl)-acetic acid tert-butyl ester (37 mg, 0.15 mmol), 3-chloromethyl-5-(4-trifluoromethyl-phenyl)-1H-pyrazole (43 mg, 0.16 mmol), cesium carbonate (54 mg, 0.16 mmol) and a trace of potassium iodide were suspended in N,N-dimethylformamide (4 ml). The suspension was stirred at ambient temperature for 14 h and for 4 h at 80° C. The solvent was evaporated under reduced pressure and the residue dissolved in 1 N HCl/ice water 1/1 and ethyl acetate. The layers were separated and the aqueous layer was extracted two times with ethyl acetate. The combined organic layers were washed two times with brine and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography (silica gel, heptane/AcOEt) to give 5 mg (10 μmol, 7%) of the title compound as orange oil.
Reaction SMILES: COC[O:4][C:5]1[CH:14]=[CH:13][C:12]2[O:11][CH:10]([C:15]3[CH:20]=[CH:19][C:18]([O:21]COC)=[CH:17][CH:16]=3)[CH:9]3[CH2:25][C:26](=[O:28])[CH2:27][CH:8]3[C:7]=2[CH:6]=1>C1COCC1.Cl.CCOC(C)=O>[OH:4][C:5]1[CH:14]=[CH:13][C:12]2[O:11][C@@H:10]([C:15]3[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=3)[C@H:9]3[CH2:25][C:26](=[O:28])[CH2:27][C@H:8]3[C:7]=2[CH:6]=1
Reactant: COCOc1ccc(C2Oc3ccc(OCOC)cc3C3CC(=O)CC32)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1C[C@H]2[C@@H](C1)c1cc(O)ccc1O[C@H]2c1ccc(O)cc1
Yield: 102.6 %

Procedure:
Stir a solution of cyclopentanone 23 (384 mg, 1.0 mmol) in 10 mL of THF and 8 mL of 3 M HCl overnight. Dilute the solution with EtOAc. Separate the aqueous solution and extract 2× with EtOAc. The combined organic solutions were washed with saturated aqueous sodium bicarbonate, brine, dried over Na2SO4, filtered, and concentrated to afford 304 mg of cyclopentanone 24. The material was purified by preparative chiral chromatography (Chiralpak AD, 65/35 heptane/ethanol).