Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16](Cl)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1.Cl.[CH2:26]([O:28][C:29](=[O:33])[CH2:30][CH2:31][NH2:32])[CH3:27]>CS(C)=O>[CH2:26]([O:28][C:29](=[O:33])[CH2:30][CH2:31][NH:32][C:16]1[CH:15]=[CH:14][C:13]2[C:18](=[CH:19][CH:20]=[C:21]([Cl:22])[C:12]=2[C:10](=[O:11])[NH:9][CH2:8][CH:5]2[CH2:6][CH2:7][C:2]([F:24])([F:1])[CH2:3][CH2:4]2)[N:17]=1)[CH3:27]
Reactant: CCOC(=O)CCN
Reactant: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Agent: Cl
Solvent: CS(C)=O
Product: CCOC(=O)CCNc1ccc2c(C(=O)NCC3CCC(F)(F)CC3)c(Cl)ccc2n1

Procedure:
The title compound was synthesized according to the procedure described in example 1 by heating 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide, DIEPA and 3-Amino-propionic acid ethyl ester hydrochloride in DMSO at 140° C. 1H NMR (400 MHz, DMSO-d6) δ 4.16 (s, 1H), 4.00 (t, J=13.2 Hz, 2H), 3.78 (t, J=7.60 Hz, 2H), 3.28 (d, J=6.04 Hz, 2H), 8.81 (s, 1H), 7.68-7.77 (m, 2H), 6.93-7.02 (m, 1H), 4.05-4.10 (m, 2H), 3.68-3.80 (m, 2H), 3.23 (t, J=6.03 Hz, 2H), 2.01-2.03 (m, 2H), 1.73-1.88 (m, 5H), 1.22-2.27 (m, 2H), 1.15-1.19 (m, 3H). m/z: 454.0 [M+H]+
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[F-].[K+].C(=O)([O-])[O-].[K+].[K+].[CH:21]1([NH2:24])[CH2:23][CH2:22]1>ClCCl>[CH:21]1([NH:24][C:2]2[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=2[N+:10]([O-:12])=[O:11])[CH2:23][CH2:22]1
Reactant: NC1CC1
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [F-]
Agent: [K+]
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(F)c(F)cc1NC1CC1
Temperature: 90 °C

Procedure:
2,4,5-Trifluoronitrobenzene (2.00 g, 11.3 mmol), potassium fluoride (0.656 g, 11.3 mmol), potassium carbonate (1.561 g, 11.29 mmol), and cyclopropylamine (0.93 ml, 13.55 mmol) were added to a vial and heated in a microwave at 90° C. for 10 min. The reaction was then diluted with dichloromethane, washed with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure. Purification by flash chromatography on silica gel (0-15% ethyl acetate in hexanes) provided the title compound: 1H NMR (500 MHz, CDCl3) δ 8.04 (dd, J=10.4, 8.5 Hz, 1 H), 7.09 (dd, J=12.6, 7.0 Hz, 1 H), 2.55-2.54 (m, 1 H), 0.97-0.93 (m, 2 H), 0.69-0.66 (m, 2 H).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:20][CH2:19][C@@H:18]([NH:21][CH3:22])[C@@H:17]2[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Br[CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36].CCN(C(C)C)C(C)C>C(#N)C>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:20][CH2:19][C@@H:18]([N:21]([CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])[CH3:22])[C@@H:17]2[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH3:14])[CH:4]=[C:3]([C:2]([F:1])([F:30])[F:31])[CH:8]=1
Reactant: COC(=O)CCBr
Reactant: CN[C@@H]1CC[C@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]1c1ccc(F)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCN(C)[C@@H]1CC[C@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]1c1ccc(F)cc1
Temperature: 50 °C
Reaction time: 60 h

Procedure:
To a solution of 40 mg of 1-(S)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)-2-(S)-(4-fluorophenyl)-3-(R)-(methylamino)cyclopentane from Example 15 in 1 mL of acetonitrile was added 0.011 mL of methyl 3-bromo-proprionate and 0.046 mL of DIPEA. The reaction was heated at 50° C. for 24 hours, then an additional 0.011 mL of methyl 3-bromoproprionate and 0.030 mL of DIPEA were added and heating continued at 80° C. for 60 hours. The reaction was evaporated under a stream of nitrogen and the residue purified by prep TLC (5% methanol in methylene chloride) to give 39 mg of title compound. Mass spec (ESI): 536 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14](O)=[N:13][C:12]([C:19]3[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=3)=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:31])=O.C(N(CC)C1C=CC=CC=1)C>>[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([Cl:31])=[N:13][C:12]([C:19]3[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=3)=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1nc(-c2ccc(C(F)(F)F)nc2)nc2c1CCN(Cc1ccccc1)C2
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)c1ccccc1
Product: FC(F)(F)c1ccc(-c2nc(Cl)c3c(n2)CN(Cc2ccccc2)CC3)cn1
Temperature: 110 °C
Reaction time: 4 h

Procedure:
A mixture of 232 mg (0.6 mmol) of 7-benzyl-2-[6-(trifluoromethyl)pyridin-3-yl]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ol from Step A and 1.0 mL of phosphorous oxychloride in a 25-mL round bottom flask was treated with 90 mg (0.095 mL, 0.6 mmol) of N,N-diethylaniline. The mixture was warmed to 110° C. After 4 h, it was cooled to ambient temperature and concentrated in vacuo. Water (15–20 mL) was added. The mixture was neutralized by the addition of solid sodium bicarbonate and extracted with 2 portions of ethyl acetate. The combined organic phases were washed with brine, dried, and concentrated. Purification by flash chromatography (silica gel, 0 to 20% ethyl acetate/hexane step gradient) gave 220 mg of a light yellow oil. LC-MS 405.2 (M+1).
Reaction SMILES: [OH:1][CH:2]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)[CH2:3][C:4]#[N:5].C(OC=C)(=O)C>C(OC(C)C)(C)C>[OH:1][C@H:2]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)[CH2:3][C:4]#[N:5]
Reactant: N#CCC(O)c1cccs1
Solvent: C=COC(C)=O
Solvent: CC(C)OC(C)C
Product: N#CC[C@H](O)c1cccs1
Yield: 42 %

Procedure:
Enzymatic Transesterification of 3-hydroxy-3-(2-thienyl) propanenitrile (1): To a solution of 3-hydroxy-3-(2-thienyl) propanenitrile (1) (5 mmol) dissolved in diisopropyl ether (100 mL), Pseudomonas cepacia lipase immobilized on diatomite (PS-D) (500 mg) and vinyl acetate (25 mmol) were added successively and incubated at 25° C. in an orbital shaker. After 50% completion of the reaction (14 h) as indicated by HPLC, the reaction mixture was filtered and solvent was evaporated under reduced pressure. The residue was subjected to column chromatography to separate the acetate formed and the unreacted alcohol. The optical purity of these compounds were determined by HPLC. (S)-3-hydroxy-3-(2-thienyl) propanenitrile (S-1) 42% yield, ee>99%; [α]30D=−33.5 (c 1, CHCl3); IR (Neat) 3475, 3075, 2878, 2251, 1105, 698 cm−1; 1H NMR (200 MHz, CDCl3) δ 2.82 (dd, 2H, J=3.0 Hz, J=6.6 Hz), 3.0 (s, 1H) 5.25 (t, 1H, J=5.5 Hz), 6.98 (t, 1H, J=4.9 Hz), 7.05 (d, 1H, J=3.7 Hz), 7.28 (d, 1H, J=4.9 Hz); 13C NMR (75 MHz) δ 28.1, 66.0, 117.0, 124.6, 125.6, 127.0, 144.4; Mass (EI) 153 127, 113, 85.
Reaction SMILES: [CH3:1][C:2]([C@@H:4]1[C@@:8]2([CH3:23])[CH2:9][CH2:10][C@@H:11]3[C@@:16]4([CH3:22])[CH2:17][CH2:18][C@H:19]([OH:21])[CH2:20][C:15]4=[CH:14][CH2:13][C@H:12]3[C@@H:7]2[CH2:6][CH2:5]1)=[O:3].[I:24]I.[I-].[NH+:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.I.[NH+]1C=CC=CC=1>N1C=CC=CC=1>[I-:24].[OH:21][C@H:19]1[CH2:18][CH2:17][C@@:16]2([CH3:22])[C:15](=[CH:14][CH2:13][C@@H:12]3[C@@H:11]2[CH2:10][CH2:9][C@@:8]2([CH3:23])[C@H:7]3[CH2:6][CH2:5][C@@H:4]2[C:2](=[O:3])[CH2:1][N+:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:20]1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: II
Reactant: c1cc[nH+]cc1
Agent: I
Agent: [I-]
Solvent: c1ccncc1
Product: C[C@]12CC[C@H]3[C@@H](CC=C4C[C@@H](O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)C[n+]1ccccc1
Temperature: 100 °C
Reaction time: 1.75 h

Procedure:
In a large beaker clamped in an oil bath maintained at 100° C. and containing 100 ml. of pyridine are placed 50 g. of pregnenolone. The beaker is capped with a watch glass and the mixture is stirred until solution is complete. To this mixture is added 43.3 g. of crushed iodine as quickly as possible, and the opaque black-brown solution is quickly stirred to fully dissolve the iodine as much as possible before obvious reaction, and in particular, crystallization begins. Within a few minutes a gentle but brisk reaction begins as indicated by bubbling. Heating is continued for about 1.5 to 2 hours. The reaction mixture is allowed to cool, and the granular reaction product is gently broken up with a spatula and transferred to a sintered glass funnel, crushed to a firm layer, and sucked dry. The beaker is rinsed with pyridine and added to the cake; the cake is resuspended, pressed to a layer again, and sucked dry again. One or two more washes are usually suffient to remove the bulk of contaminating pyridinium hydroiodide present. The cake is now sucked dry under a nitrogen atmosphere to give from 72 g. to 78 g. of the pyridinium iodide compound, having a m.p. of 223°-225° C. Theoretical yield is 83 g. The product is usually contaminated with pyridinium hydroiodide, but since this contaminant does not appear to interfere with the next step, no attempt is made to remove it.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:19]=[C:18]3[C:13]([CH2:14][CH2:15][C@H:16]([CH2:20][NH2:21])[O:17]3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:23]([C@H:25]([O:27][C:28](=[O:30])[CH3:29])[CH3:26])=[O:24]>C(Cl)Cl>[C:1]1([S:7]([C:10]2[CH:19]=[C:18]3[C:13]([CH2:14][CH2:15][CH:16]([CH2:20][NH:21][C:23]([C@H:25]([O:27][C:28](=[O:30])[CH3:29])[CH3:26])=[O:24])[O:17]3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC[C@H]1CCc2ccc(S(=O)(=O)c3ccccc3)cc2O1
Reactant: CC(=O)O[C@H](C)C(=O)Cl
Solvent: ClCCl
Product: CC(=O)O[C@H](C)C(=O)NCC1CCc2ccc(S(=O)(=O)c3ccccc3)cc2O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(R)—C-(7-Benzenesulfonyl-chroman-2-yl)-methylamine (57 mg, 0.19 mmol) triethylamine (0.02 mL) and acetic acid 1-(R)-chlorocarbonyl-ethyl ester were added to 1 mL methylene chloride, and the mixture was stirred for two hours at room temperature. The reaction was quenched by addition of water, and the mixture was extracted with methylene chloride. The combined organic layers were washed with water and brine, dried (Na2SO4), filtered and contrated under reduced pressure. Purification of the residue by flash chromatography gave 7.59 mg of (R)-acetic acid 1-[(7-benzenesulfonyl-chroman-2-ylmethyl)-carbamoyl]-ethyl ester.
Reaction SMILES: [CH3:1][N:2]1[CH2:27][CH2:26][C:5]2[N:6]([CH2:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][CH:19]=3)([OH:17])[CH3:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][N:2]1[CH2:27][CH2:26][C:5]2[N:6]([CH2:14][C:15]([C:18]3[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=3)([OH:17])[CH3:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: COc1ccc(C(C)(O)Cn2c3c(c4cc(C)ccc42)CN(C)CC3)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2ccc(O)cc2)CCN(C)C1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-2-(4-methoxyphenyl)propan-2-ol (0.145 g, 0.39 mmol) in DCM (10 mL) at −78° C. was added borontribromide (0.293 g in 5 mL DCM). The reaction mixture was stirred at −78° C. for 30 min. and then at 25° C. for 1 h. The solution was poured into ice water, saturated NaHCO3 was added, and the mixture extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (silica gel, 0-75% MeOH:DCM) to give the product as an off white solid, 20 mg. 1H NMR (CDCl3, freebase) δ (ppm): 7.25 (d, 1H), 7.10 (m, 3H), 6.98 (d, 1H), 6.70 (d, 2H), 4.10 (m, 2H), 3.82 (m, 2H), 2.80 (m, 2H), 2.60 (s, 3H), 2.42 (s, 3H), 2.38 (m, 2H), 1.60 (s, 3H).
Reaction SMILES: [C:1](=[O:3])=[O:2].C([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12]C)=[O:11])=O.C(OC)(=O)CCCCC([O-])=O>>[CH3:6][CH:7]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[C:1]([OH:3])=[O:2]
Reactant: COC(=O)CCCCC=O
Reactant: O=C=O
Agent: COC(=O)CCCCC(=O)[O-]
Product: CC(CCC(=O)O)C(=O)O
Yield: 96 %

Procedure:
The cleavage in stage (c) is advantageously carried out in the presence of molecular oxygen or a gas which contains molecular oxygen and an inert gas, such as nitrogen, carbon dioxide, argon or steam. A molar ratio of formylvaleric esters to molecular oxygen of from 1:0.05 to 1:3, in particular from 1:0.2 to 1:1.5, e.g., from 1:0.25 to 1:1.25, is advantageously used. This increases the catalyst life and in particular the yield of pentenoic esters. The presence of molecular oxygen was not indicated since methyl 5-formylvalerate is oxidized to monomethyl adipate in a yield of 96% by molecular oxygen at as low as 50° C., as disclosed in European Patent 131,860, and it was therefore to be expected that 4- and 3-formylvaleric esters would be oxidized in a similar manner to give 2-methylglutaric acid and 3-ethylsuccinic esters.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:12]2[C:17](=[O:18])[C:16]3[CH:19]=[C:20]([CH2:22][CH3:23])[S:21][C:15]=3[NH:14][C:13]2=[O:24])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].Br[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:39]2[N:43]=[C:42](C(Cl)(Cl)Cl)[O:41][N:40]=2)=[CH:29][CH:28]=1.C(=O)([O-])[O-:49].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:12]2[C:17](=[O:18])[C:16]3[CH:19]=[C:20]([CH2:22][CH3:23])[S:21][C:15]=3[N:14]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[C:39]4[NH:43][C:42](=[O:49])[O:41][N:40]=4)=[CH:29][CH:28]=3)[C:13]2=[O:24])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: ClC(Cl)(Cl)c1nc(-c2ccccc2-c2ccc(CBr)cc2)no1
Reactant: CCc1cc2c(=O)n(-c3ccc(Cl)cc3C(=O)OC)c(=O)[nH]c2s1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCc1cc2c(=O)n(-c3ccc(Cl)cc3C(=O)OC)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 50 °C
Reaction time: 2 h
Yield: 38.1 %

Procedure:
A mixture of methyl 5-chloro-2-(6-ethyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)benzoate (0.67 g), 3-[4′-(bromomethyl)biphenyl-2-yl]-5-(trichloromethyl)-1,2,4-oxadiazole (0.96 g), potassium carbonate (0.38 g) and acetonitrile (80 mL) was stirred at 50° C. for 2 hr. Insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography and dissolved in tetrahydrofuran (10 mL) and acetone (10 mL). 1N Aqueous potassium carbonate solution (20 mL) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was adjusted to pH 5 with water and 1N hydrochloric acid, and extracted with chloroform. The obtained chloroform layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as colorless crystals (0.43 g, 38%).
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1.ClC1C(Cl)=CC2=NC(=O)N=C2C=1.C(O[C@@H:29]1[O:41][C@H:40]([CH2:42][O:43][C:44](=[O:46])[CH3:45])[C@@H:35]([O:36][C:37](=[O:39])[CH3:38])[C@H:30]1[O:31][C:32](=[O:34])[CH3:33])(=O)C.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C>CCOC(C)=O>[Br:1][C:2]1[N:3]([C@@H:29]2[O:41][C@H:40]([CH2:42][O:43][C:44](=[O:46])[CH3:45])[C@@H:35]([O:36][C:37](=[O:39])[CH3:38])[C@H:30]2[O:31][C:32](=[O:34])[CH3:33])[C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: Clc1cc2nc(Br)[nH]c2cc1Cl
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C1N=c2cc(Cl)c(Cl)cc2=N1
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of (7) (47.867 g, 180 mmol) in 540 mL of dry. MeCN, was added 45 mL (180 mmol) of BSA. The reaction mixture was stirred at room temperature for 15 min to give a clear solution. A small amount of solid impurity remained unsilylated, believed to be 5,6-dichlorobenzimidazol-2-one from the starting material(7). 1,2,3,5-Tetra-O-acetyl-β-D-ribofuranose (60.14 g, 189 mmole) was added to this solution and then TMSOTf (38.267 mL 198 mmol) was added dropwise over 20 min. After the addition had been completed, stirring was continued at room temperature for 30 min. The reaction mixture was diluted with 2 L of EtOAc. The EtOAc solution was washed with 1:1 saturated aquenous NaHCO3 /saturated aquenous NaCl (1.5 L×2), dried (Na2SO4, 100 g), decolorized (activated charcoal, 6 g), and filtered through Celite. The filtrate was evaporated and the residue was recrystallized from MeOH to give 82.21 g (4 crops, 87%) of 52a as white needles. MP: 140°-144° C. This product was pure by 1H NMR.
Reaction SMILES: [CH:1]1([Si:6]([O:11][CH3:12])([O:9][CH3:10])[O:7][CH3:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.O[CH:14]1C[CH2:17][O:16][CH2:15]1.C[Si](C)(C)Cl>C[O-].[Na+]>[CH:1]1([Si:6]([O:11][CH3:12])([O:7][CH3:8])[O:9][CH:10]2[CH2:14][CH2:15][O:16][CH2:17]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: OC1CCOC1
Reactant: CO[Si](OC)(OC)C1CCCC1
Agent: C[O-]
Agent: C[Si](C)(C)Cl
Agent: [Na+]
Product: CO[Si](OC)(OC1CCOC1)C1CCCC1
Yield: 54 %

Procedure:
In a 100 ml three-neck flask provided with a magnetic stirrer and a reflux condenser were charged 7.7 g (0.0404 mole) of cyclopentyl trimethoxysilane, 35.7 g (0.405 mole) of 3-hydroxy tetrahydrofurane and 53.0 mg (0.98 m mole) of sodium methoxide, which were then reacted with each other in an oil bath of 80° C. for 2 hours under stirring. After cooled, trimethylchlorosilane was added to neutralize the alkali. Then, 5.37 g (0.0218 mole) of cyclopentyl dimethoxy oxa-3-cyclopentyloxysilane were obtained by vacuum distillation. Its structure was confirmed as in Example 1. The yield was 54%.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]([F:28])([F:27])[F:26])[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:32]O.Cl>CO.O.C(Cl)Cl>[O:3]=[C:4]1[CH:5]=[C:6]([C@H:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])[CH2:9]2)[O:7][NH:32]1
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](Cc2ccccc2C(F)(F)F)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccccc1C(F)(F)F
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 68.2 %

Procedure:
Cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(2-(trifluoromethyl)benzyl)piperidine-1-carboxylate (2.062 g, 4.96 mmol) was dissolved in MeOH (16 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.199 g, 4.96 mmol) dissolved in water (1.600 mL) was added during 10 min and the colourless solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.304 mL, 4.96 mmol) was added during 8 min. The resulting solution was stirred at −40° C. for 3.5 h. The mixture was then transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (25 mL, 150.00 mmol) and the mixture continued to stir at 80° C. for 20 min. DCM and water were added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield a yellow semi-solid. The compound was purified by preparative HPLC in 3 injections on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 5-30% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. Cis-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(2-(trifluoromethyl)benzyl)piperidine-1-carboxylate (1.30 g, 68%) was isolated as a white solid. 1H NMR (600 MHz, cdcl3) δ 1.79-1.95 (m, 2H), 1.95-2.14 (m, 2H), 2.79-2.98 (m, 3H), 3.17-3.27 (m, 1H), 3.34 (s, 3H), 4.04 (dd, 1H), 4.30-4.41 (m, 1H), 5.68 (s, 1H), 7.14 (d, 1H), 7.19-7.28 (m, 1H), 7.39 (t, 1H), 7.57 (d, 1H). MS m/z 385 (M+H)+
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[S:15]([Cl:18])(=[O:17])=[O:16])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[NH:26]1[CH2:32][CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.Cl>C(Cl)Cl>[ClH:18].[CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[S:15]([N:26]2[CH2:32][CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)(=[O:17])=[O:16])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1
Reactant: C1CNCCNC1
Reactant: O=S(=O)(Cl)c1c2ccccc2cc2ccccc12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1c2ccccc2cc2ccccc12)N1CCCNCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 69 %

Procedure:
Add the product from step 2 (0.35 g, 1.28 mmol) in methylene chloride (20 mL) to a mixture of triethyl amine (0.605 mL, 4.34 mmol) and hexahydro-2H-1,4-diazepine (also known as homopiperazine) (0.326 g, 3.25 mmol) in methylene chloride (7 mL) cooled to 0° C. over 5 min. Stir the reaction mixture for 15 min at 0° C. Add aqueous HCl (25 mL, 1N) to the reaction mixture. Filter the solid and recrystallize from absolute ethanol to give the title compound (0.33 g, 69%) as light yellow needles. Rf=0.54 (5% MeOH in methylene chloride (v/v), 0.2% ammonium hydroxide buffer).
Reaction SMILES: [CH:1]1([CH:4]([CH:6]2[CH2:8][CH2:7]2)[OH:5])[CH2:3][CH2:2]1.[N+](=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N-]>ClCCl.CCCCCCC.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH2:15]([O:14][C:12](=[O:13])[CH2:11][O:5][CH:4]([CH:6]1[CH2:8][CH2:7]1)[CH:1]1[CH2:3][CH2:2]1)[CH3:16]
Reactant: OC(C1CC1)C1CC1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCCCCCC
Product: CCOC(=O)COC(C1CC1)C1CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 52.1 %

Procedure:
To a solution of dicyclopropylmethan-1-ol (1.5 mL, 12.7 mmol) in dichloromethane (20 mL) is added rhodium (II) acetate dimer (10 mg) followed by ethyl diazoacetate (1.26 mL, 12.0 mmol). The reaction mixture is stirred at rt for 48 h. The reaction mixture is diluted with heptane, and filtered. The filtrate is evaporated, and the residue is vacuum distilled at 170° C. to give 1.24 g of the product 448.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:16])=O>ClCCl.CN(C=O)C>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:16])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(F)c(Cl)c1Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(F)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
2,3-dichloro-4-fluorobenzoic acid (I32) (5.76 g, 27.6 mmol) was suspended in dichloromethane (DCM) (150 mL) at 0° C. and treated with oxalyl chloride (2.89 mL, 33.1 mmol). The mixture was stirred at 0° C. for 10 minutes before 5 drops of DMF were added. The mixture was stirred to room temperature over 4 h. Solvents were removed in vacuo and the residue was azeotroped with toluene (3×100 mL). The residue was used directly in subsequent steps without further purification, assuming 100% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([S:9]([NH2:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[S:13]([NH2:16])(=[O:15])=[O:14].[CH3:17][N:18]([CH3:26])[CH:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1>Cl>[CH3:17][N:18]([CH3:26])[CH:19]1[CH2:24][CH2:23][C:22]2([NH:1][C:2]3[CH:7]=[C:6]([Cl:8])[C:5]([S:9]([NH2:12])(=[O:10])=[O:11])=[CH:4][C:3]=3[S:13](=[O:15])(=[O:14])[NH:16]2)[CH2:21][CH2:20]1
Reactant: CN(C)C1CCC(=O)CC1
Reactant: Nc1cc(Cl)c(S(N)(=O)=O)cc1S(N)(=O)=O
Agent: Cl
Product: CN(C)C1CCC2(CC1)Nc1cc(Cl)c(S(N)(=O)=O)cc1S(=O)(=O)N2

Procedure:
A mixture of 4-amino-6-chloro-1,3-benzenedisulfonamide (5.72 g., 0.02 mole) and 4-dimethylaminocyclohexanone (3.38 g., 0.022 mole) in 2 N ethanolic HCl (100 ml) is refluxed for one hour and cooled. 4'-Dimethylamino-6-chlorospiro[2H-1,2,4-benzothiadiazine-3(4H),1'-cyclohexane]-7-sulfonamide-1,1-dioxide hydrochloride is filtered, dissolved in warm water (200 ml.) and treated with aqueous ammonia (1.0 ml.) to give 4'-dimethylamino-6-chlorospiro[2H-1,2,4-benzothiadiazine-3(4H),1'-cyclohexane]-7-sulfonamide-1,1-dioxide which melts at 255° C. after recrystallization from dimethylsulfoxide--H2O.