Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]2[CH2:8][CH2:9][O:10][C:6]=2[C:5]([C:11]([O:13][C@H:14]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][C@H:15]2[O:27][CH3:28])=[O:12])=[CH:4][C:3]=1[Cl:29].[NH4+].[OH-]>O1CCCC1.Cl>[NH2:1][C:2]1[C:7]2[CH2:8][CH2:9][O:10][C:6]=2[C:5]([C:11]([O:13][C@H:14]2[CH2:19][CH2:18][NH:17][CH2:16][C@H:15]2[O:27][CH3:28])=[O:12])=[CH:4][C:3]=1[Cl:29]
Reactant: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1OC(=O)c1cc(Cl)c(N)c2c1OCC2
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CO[C@@H]1CNCC[C@@H]1OC(=O)c1cc(Cl)c(N)c2c1OCC2
Yield: 26.1 %

Procedure:
A mixture of intermediate (5) (32 g) in tetrahydrofuran (500 ml) and hydrochloric acid (50 ml) was stirred and refluxed for 30 minutes. The reaction mixture was cooled and alkalized with NH4OH. The layers were separated. The aqueous layer was extracted with tetrahydrofuran. The separated organic layer was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2 /(CH3OH/NH3) 93/7). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from acetonitrile. The precipitate was filtered off and dried (vacuum; 80° C.), yielding 6.4 g of (±)-cis-3-methoxy-4-piperidinyl 4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylate (26%) (intermediate 6).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.[CH3:12][N:13]([CH3:39])[C:14](=O)[C:15]([C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][C:18]=1[C:26]1[C:27]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[N:28][O:29][C:30]=1[CH3:31])=O>O>[CH3:31][C:30]1[O:29][N:28]=[C:27]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]=1[C:18]1[NH:19][C:20]2[C:25]([C:17]=1[CH2:15][CH2:14][N:13]([CH3:39])[CH3:12])=[CH:24][CH:23]=[CH:22][CH:21]=2
Reactant: Cc1onc(-c2ccccc2)c1-c1[nH]c2ccccc2c1C(=O)C(=O)N(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1onc(-c2ccccc2)c1-c1[nH]c2ccccc2c1CCN(C)C
Reaction time: 1 h

Procedure:
To a refluxing suspension of 22.8 g. (0.60 mole) of lithium aluminum hydride in 1100 ml. of tetrahydrofuran under nitrogen, there is added dropwise over approximately 1 to 11/2 hours a warm solution of 56 g. (0.15 mole) of N,N-dimethyl-2-(5-methyl-3-phenyl-4-isoxazolyl)-3-indoleglyoxylamide in 2250 ml. of tetrahydrofuran. The mixture is refluxed for 3 hours after addition is completed. The resulting suspension is cooled to -10° to +5° C. and a solution of 270 ml. of tetrahydrofuran and 90 ml. of water is added dropwise with the temperature maintained between -10° and +5° C. The suspension is stirred for approximately 1 hour without a cooling bath and then allowed to stand overnight without stirring. The mixture is filtered, the filtrate evaporated in vacuo and the residue dissolved in methylene chloride. The methylene chloride is washed with water, dried and evaporated in vacuo. The residue is crystallized from ether to give 2-(5-methyl-3-phenyl-4-isoxazolyl)-3-(dimethylaminoethyl)-indole; m.p. 141.5° to 143.5° C.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[NH:13][C:12]3[N:11]=[CH:10][CH:9]=[CH:8][C:7]=3[C:5]=2[CH:6]=1.[Al+3].[Cl-].[Cl-].[Cl-].[Br:18][CH2:19][C:20](Br)=[O:21]>C(Cl)Cl>[Br:18][CH2:19][C:20]([C:1]1[CH:6]=[C:5]2[C:4](=[CH:3][CH:2]=1)[NH:13][C:12]1[N:11]=[CH:10][CH:9]=[CH:8][C:7]2=1)=[O:21]
Reactant: c1ccc2c(c1)[nH]c1ncccc12
Reactant: O=C(Br)CBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(CBr)c1ccc2[nH]c3ncccc3c2c1
Yield: 61 %

Procedure:
To a 0.2 M stirred suspension of the α-carboline derivative (200 mg) in anhydrous CH2Cl2 was added AlCl3 (4.5 equiv.) and bromoacetyl bromide (2.1 equiv.), at room temperature under inert atmosphere. The mixture was stirred at reflux until completion of the reaction (followed by t.l.c.). The resulting mixture was then cautiously quenched at 0° C. with H2O. It was extracted with the mixture of EtOAc/DMF (99:1). The resulting organic layer was washed with NaHCO3 saturated aqueous solution and brine, dried over MgSO4, filtered and solvents were removed under reduced pressure. 2-Bromo-1-(9H-pyrido[2,3-b]indol-6-yl)ethanone was obtained in 61% yield after trituration of the crude product in MeOH and filtration
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([C:19]([NH2:24])=[N:20][CH:21]=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Br:26]C1C(=O)C(C)(C)C(Br)C1=O>C1COCC1>[C:1]([O:5][C:6](=[O:25])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([C:19]([NH2:24])=[N:20][CH:21]=[N:22]3)=[C:17]([Br:26])[CH:16]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)C(=O)C(Br)C(=O)C1Br
Reactant: CC(C)(C)OC(=O)NCc1cccc(-c2ccc3c(N)ncnn23)c1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1cccc(-c2cc(Br)c3c(N)ncnn23)c1
Temperature: -20 °C
Reaction time: 2 h
Yield: 146.4 %

Procedure:
To a solution of [3-(4-amino-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzyl]-carbamic acid tert-butyl ester (3.3 g, 9.7 mmol) in THF (73 mL) cooled to −20° C. (isopropanol/ice/CO2), 2,5-dibromo-4,4-dimethyl-cyclopentane-1,3-dione (1.4 g, 4.9 mmol) was added in four portions over 15 mins. The mixture was allowed to stir at −20° C. for 2 hours. The mixture was quenched with sodium thiosulfate solution (20 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layer was washed with water, brine, dried by Na2SO4, filtered and concentrated. The residue was purified by Biatage® to give desired product 3 g (72%). NMR (300 MHz, DMSO-d5) δ 7.80-7.7 (m, 3 H), 7.5 (m, 2 H), 7.2 (m, 2 H), 4.0 (m, 2 H), 1.5 (s, 9 H); ES-MS m/z 420 [M+H]+, HPLC RT (min) 2.91.
Reaction SMILES: [Na+].[Br-].[CH3:3]C1(C)N([O])C(C)(C)CCC1.C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O.C([O-])(O)=O.[Na+].C(OO)(=O)C.[OH-].[Na+].[O:46]=[CH:47][C@@H:48]([C@H:50]([C@H:52]([C@@H:54]([C:56]([OH:58])=[O:57])[OH:55])[OH:53])[OH:51])O>O>[O:58]([CH3:3])[C@H:56]1[O:57][C@H:48]([CH2:47][OH:46])[C@@H:50]([OH:51])[C@H:52]([OH:53])[C@H:54]1[OH:55]
Reactant: CC1(C)CCCC(C)(C)N1[O]
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C(=O)O
Agent: CC(=O)OO
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: O=C([O-])O
Solvent: O
Product: CO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reaction time: 8 h

Procedure:
One gram of MGP (5.15 mmol) was dissolved in 60 ml of water at room temperature To this solution were added 200 mg NaBr (1.94 mmol), 20 mg TEMPO (0.13 mmol), 10 mg EDTA (for stabilising the oxidising agent) and 2.5 g NaHCO3. Peracetic acid (1.32 mmol/ml) was added at a rate of 200 μl per 10 minutes until an excess amount, calculated on a theoretical basis for 100% oxidation to 6-carboxylic acid (14.6 mmol), had been added. The pH was maintained at 7 by addition of 1 M NaOH using a pH-stat. The reaction time was 8 hr. The degree of oxidation, determined using the Blumenkrantz method with galacturonic acid as a reference, was 95%. High Performance Anion Exchange Chromatography (HPAEC) shows that the degree of oxidation is greater than 95%. No other peaks than the uronic acid and a trace of starting material were detected.
Reaction SMILES: [Br:1]Br.[CH3:3][CH:4]([CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(OCC)C>[Br:1][CH:11]([CH:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:3])[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13]
Reactant: CC(CC(=O)c1ccccc1)c1ccccc1
Reactant: BrBr
Solvent: CCOCC
Product: CC(c1ccccc1)C(Br)C(=O)c1ccccc1

Procedure:
Bromine (0.02 mol) was added dropwise to a stirred solution of 2-(α-methylbenzyl)acetophenone (0.02 mol) in dry diethyl ether (20 ml) at 5° over one hour. The ether was removed in vacuo and the residue redissolved in ether (100 ml), washed with saturated sodium bicarbonate solution (2 × 100 ml) and then water (4 × 100 ml), and dried over anhydrous sodium sulphate. Removal of the solvent gave a solid which on recrystallisation from petroleum ether (40°-60°) gave 2-bromo-3-phenylbutyrophenone, m.p. 69°-71°.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([NH:21][S:22](=[O:47])(=[O:46])[NH:23][C@@H:24]1[CH2:39][C:38]2=[CH:40][CH:41]=[C:35]([CH:36]=[CH:37]2)[O:34][CH2:33][CH2:32][CH2:31][CH2:30][O:29][CH2:28][C@H:27]([CH:42]([CH3:44])[CH3:43])[NH:26][C:25]1=[O:45])[C:14]([O:16]C(C)(C)C)=[O:15])=O)(C)(C)C>ClCCl.C(O)(C(F)(F)F)=O>[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([NH:21][S:22](=[O:46])(=[O:47])[NH:23][C@@H:24]1[CH2:39][C:38]2=[CH:37][CH:36]=[C:35]([CH:41]=[CH:40]2)[O:34][CH2:33][CH2:32][CH2:31][CH2:30][O:29][CH2:28][C@H:27]([CH:42]([CH3:44])[CH3:43])[NH:26][C:25]1=[O:45])[C:14]([OH:16])=[O:15]
Reactant: CC(C)[C@H]1COCCCCOc2ccc(cc2)C[C@@H](NS(=O)(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)N1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H]1COCCCCOc2ccc(cc2)C[C@@H](NS(=O)(=O)N[C@@H](CCCCN)C(=O)O)C(=O)N1
Reaction time: 2 h
Yield: 56.4 %

Procedure:
A solution of 78 mg (0.114 mmol) of tert-butyl (S)-6-tert-butoxycarbonylamino-2-[((9S,12R)-9-isopropyl-11-oxo-2,7-dioxa-10-azabicyclo[12.2.2]octadeca-1(17),14(18),15-trien-12-ylsulfamoyl)amino]hexanoate in 3 ml of dichloromethane/TFA (1:1, v/v) was left to stand at RT for 2 h and then concentrated. The crude product was purified by prep. HPLC. The required fractions were combined and freeze dried after addition of 1N hydrochloric acid. 34 mg of the title compound were obtained as hydrochloride. LC/MS (method F): Rt=2.97 min, m/z: 529.23 [MH+].
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([C@@H:11]3[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]3[OH:13])[CH:9]=[N:10][C:5]2=[C:4]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:3]=1>O.[Pd]>[NH:20]([C:4]1[CH:3]=[CH:2][N:7]=[C:6]2[N:8]([C@@H:11]3[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]3[OH:13])[CH:9]=[N:10][C:5]=12)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Nc4ccccc4)cc(Cl)nc32)[C@H](O)[C@@H]1O
Agent: [Pd]
Solvent: O
Product: OC[C@H]1O[C@@H](n2cnc3c(Nc4ccccc4)ccnc32)[C@H](O)[C@@H]1O
Yield: 13.6 %

Procedure:
A solution of 5-chloro-7-anilino-3-β-D-ribofuranosyl-3H-imidazo[4,5-b]pyridine (0.104 g, 0.28 mMol) in 150 mL of water containing 0.1 g of 10% palladium on carbon was hydrogenated in a Parr apparatus for 120 h at 45 psi. The catalyst was removed by filtration and washed well with water. The aqueous filtrate was taken to dryness in vacuo and the residue recrystallized from a minimum of boiling water to give 13 mg of 7-anilino-3-β-D-ribofuranosyl-3H-imidazo[4,5-b]pyridine as shown by retention time on reversed phase HPLC and the following: UV max (nm) at pH 1, 304; at pH 13, 301; NMR (DMSO-d6): 9.06 δ (s, 1H, NH); 8.43 (s, 1H, H2); 7.97 (d, 1H, J=5.66 Hz, H5); 7.40-7.07 (m, 5H, Phenyl); 6.88 (d, 1H, J=5.83 Hz, H6); 5.97 (d, 1H, J=6.32 Hz H1').
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][S:12][CH2:13][CH2:14][C:15]#[N:16])[CH:6]=1)[CH3:3].C(Cl)(Cl)Cl.Cl.[S:22]([NH2:26])([NH2:25])(=[O:24])=[O:23]>CO>[S:22]([NH:26][C:15](=[NH:16])[CH2:14][CH2:13][S:12][CH2:11][C:7]1[CH:6]=[C:5]([CH2:4][N:2]([CH3:3])[CH3:1])[CH:10]=[CH:9][N:8]=1)(=[O:24])(=[O:23])[NH2:25]
Reactant: CN(C)Cc1ccnc(CSCCC#N)c1
Reactant: NS(N)(=O)=O
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CN(C)Cc1ccnc(CSCCC(=N)NS(N)(=O)=O)c1

Procedure:
3-(4-Dimethylaminomethyl-2-pyridylmethylthio)propionitrile in a mixture of dry methanol and dry chloroform under nitrogen at 2° C. is treated with dried hydrogen chloride gas and allowed to stand at ca. 0° C. to give after basification with ice cold potassium carbonate solution methyl-3-(4-dimethylaminomethyl-2-pyridylmethylthio)propionimidate which is reacted in methanol with sulphamide under reflux. Evaporation of the solvent at reduced pressure and purification of the product by chromatography yields N-sulphamoyl-3-(4-dimethylaminomethyl-2-pyridylmethylthio)propionamidine.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:12]=[CH:11][N:10]3[N:13]=[C:14]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[C:15]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]5[CH2:27][CH2:26][CH2:25][CH2:24]5)[N:17]=4)=[C:9]3[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([Li])CCC.C(Cl)(Cl)(Cl)[Cl:41]>O1CCCC1>[Cl:41][C:11]1[N:10]2[N:13]=[C:14]([C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)[C:15]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]4[CH2:24][CH2:25][CH2:26][CH2:27]4)[N:17]=3)=[C:9]2[CH:8]=[C:7]([NH:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:12]=1
Reactant: Fc1ccc(-c2nn3ccc(NC4CCCC4)cc3c2-c2ccnc(NC3CCCC3)n2)cc1
Reactant: ClC(Cl)(Cl)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Fc1ccc(-c2nn3c(Cl)cc(NC4CCCC4)cc3c2-c2ccnc(NC3CCCC3)n2)cc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-5-amine (120 mg, 0.26 mmol) in tetrahydrofuran (5 mL) at −78 ° C. was added n-butyllithium (0.8 mL, 1.3 mmol of 1.6 M solution in hexanes). The resulting reaction was stirred at −78° C. for 10 minutes, then carbon tetrachloride (1 mL) was added. The reaction mixture was allowed to warm to room temperature and then quenched by the addition of water. The phase were separated and the organic phase dried over magnesium sulfate, filtered and concentrated. The resulting residue was purified by flash chromatography (1:1 hexanes-ethyl acetate) to give 7-chloro-N-cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-5-amine (12 mg) as a foam. 1H-NMR (CDCl3): δ 7.97 (d, 1H), 7.62 (q, 2H), 7.44 (d, 1H), 7.15 (t, 2H), 6.48 (d, 1H), 6.22 (d, 1H), 5.30 (broad s, 1H), 4.44 (m, 1H), 4.18 (m, 1H), 3.94 (m, 1H), 1.4–2.1 (16H);19F-NMR (CDCl3): δ −113.24; MS m/z 492 (M+1).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[S:6][C:7]([C@H:18]1[CH2:22][CH2:21][CH2:20][O:19]1)=[C:8]2[C:12]([O:14]CC=C)=[O:13])[CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Na].C(C(CCCC)C([O-])=O)C.O>C(Cl)Cl.CC(C)=O>[CH3:3][C@@H:2]([OH:1])[C@H:4]1[C:10](=[O:11])[N:9]2[C:8]([C:12]([OH:14])=[O:13])=[C:7]([C@@H:18]3[O:19][CH2:20][CH2:21][CH2:22]3)[S:6][C@H:5]12
Reactant: C=CCOC(=O)C1=C([C@H]2CCCO2)S[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Agent: CCCCC(CC)C(=O)[O-]
Agent: [Na]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)=O
Solvent: O
Solvent: ClCCl
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C([C@H]3CCCO3)S[C@H]12
Temperature: 10 °C
Reaction time: 1.5 h

Procedure:
Allyl (5R,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-[(2R)-tetrahydrofuran-2-yl]-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (72 g, 0.221 mol) was dissolved in methylene chloride (950 ml). The solution was cooled to 10° C. and triphenyl phosphine (2.0 g, 0.0076 mol), sodium-2-ethylhexanoate (39.71 g, 0.239 mol) and tetrakis triphenylphosphine palladium (0) (2.0 g) were added together at 10° C. The reaction mixture was stirred for 1-2 hours at 10-15° C. After the completion of reaction, water (50 ml) was added to the reaction mixture. The reaction mixture was stirred for 15 minutes, followed by the addition of acetone (332.5 ml) and the reaction mixture was cooled to 0° C. The solid so separated from the reaction mixture was filtered, washed with acetone and dried under reduced pressure to obtain the title compound.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[F:9][CH:10]([F:13])[CH:11]=[O:12]>O>[F:9][CH:10]([F:13])[CH:11]([C:4]1[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=1)[OH:12]
Reactant: Oc1ccccc1
Reactant: O=CC(F)F
Solvent: O
Product: Oc1ccc(C(O)C(F)F)cc1
Temperature: 100 °C

Procedure:
9.3 g (100 mmol) of phenol and 4.9 g (25 mmol) of 50% w/w difluoroacetaldehyde hydrate in water are introduced into a 100 ml reactor. 50 g of MgO are added. The mixture is stirred and is heated at 100° C. for 7 hours. The catalyst is filtered off.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:24])=[C:8]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[NH:9][C:10]=1[CH2:11][C:12]([O:14]CC)=[O:13])=[O:5])[CH3:2].CO.[OH-].[Li+]>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:24])=[C:8]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[NH:9][C:10]=1[CH2:11][C:12]([OH:14])=[O:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)Cc1[nH]c(C(=O)OC(C)(C)C)c(C)c1C(=O)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)c1c(CC(=O)O)[nH]c(C(=O)OC(C)(C)C)c1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 72.6 %

Procedure:
A solution of 5-ethoxycarbonylmethyl-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester (30 g, 88.5 mmol) in tetrahydrofuran (268 ml), and methanol (134 ml) was added with aqueous lithium hydroxide solution (0.465 mol lithium hydroxide in 197 ml of water). Upon completion of the addition, the mixture was stirred for 1.5 hours at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was added with water (200 ml) and extracted with ethyl ether. The water phase was adjusted to pH 1˜3 with 20% hydrochloric acid solution. The resulting solid was filtered, washed with ethyl ether, and dried in vacuo to give 5-carboxymethyl-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester (20 g, 72.3%) as a yellow solid.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:6][OH:7])[CH2:4][OH:5].[C:8]1(=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>>[O:1]1[C:8]2([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[O:5][CH2:4][CH:3]([CH2:6][OH:7])[CH2:2]1
Reactant: OCC(CO)CO
Reactant: O=C1CCCCC1
Product: OCC1COC2(CCCCC2)OC1
Yield: 65 %

Procedure:
The same procedure as in the step (1a) of Example 1 was repeated using 2-(hydroxymethyl)-1,3-propanediol and cyclohexanone to obtain the title compound (2.26 g, yield: 65%) as a light yellow oil.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:21]=[C:20]2[C:15]([C:16]([CH2:22][CH2:23][CH2:24][CH2:25][OH:26])=[CH:17][CH:18]=[N:19]2)=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:11][C:12]1[CH:21]=[C:20]2[C:15]([C:16]([CH2:22][CH2:23][CH2:24][CH:25]=[O:26])=[CH:17][CH:18]=[N:19]2)=[CH:14][CH:13]=1
Reactant: OCCCCc1ccnc2cc(Cl)ccc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=CCCCc1ccnc2cc(Cl)ccc12
Temperature: -78 °C
Reaction time: 0.05 h

Procedure:
Oxalyl chloride (0.42 mL of a 2M solution in dry methylene chloride) was placed in an oven-dried flask, cooled to -78° C. and a solution of 99 mg methylsulfoxide in dry methylene chloride (2 mL) added drop by drop to the oxalyl chloride over 3 minutes and stirred for a further 3 minutes. A solution of 4-(7-chloroquinolin-4-yl)butan-1-ol (100 mg) in dry methylene chloride (1 mL) was added to the reaction flask over approx. 3 minutes followed by anhydrous triethylamine (0.42 mL) and the reaction mixture stirred for another 2.5 hours during which time it was allowed warmed up to room temperature. The reaction was quenched by the addition of saturated brine and then partitioned with methylene chloride. The aqueous layer was discarded and the methylene chloride extract dried over anhydrous sodium sulfate powder, filtered and concentrated in vacuo. The title compound was isolated by flash chromatography on silica gel (ethyl acetate:hexane, 2:1; then ethyl acetate), 57 mg.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([NH:7][CH2:8][CH2:9][O:10][C:11]([F:14])([F:13])[F:12])=[O:6].[H-].[Na+]>C1COCC1>[F:12][C:11]([F:14])([F:13])[O:10][CH2:9][CH2:8][N:7]1[CH2:2][CH2:3][NH:4][C:5]1=[O:6]
Reactant: O=C(NCCCl)NCCOC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1NCCN1CCOC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.4 %

Procedure:
A −20° C. solution of 1-(2-chloroethyl)-3-(2-(trifluoromethoxy)ethyl)urea (0.436 g, 1.858 mmol) in THF (20 mL) was treated with NaH (60% in mineral oil, 0.082 g, 2.044 mmol), warmed to RT and stirred overnight. The mixture was cooled to −20° C., treated with additional NaH (60% in mineral oil, 0.082 g, 2.044 mmol) warmed to RT, stirred for 6 h, then quenched with satd. NH4Cl. The mixture was extracted with EtOAc which was dried over MgSO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford 1-(2-(trifluoromethoxy)ethyl)imidazolidin-2-one (156 mg, 42%). 1H NMR (400 MHz, DMSO-d6): δ 6.41 (s, 1 H), 4.13 (t, J=5.3 Hz, 2 H), 3.35-3.34 (m, 4 H), 3.22-3.20 (m, 2H); MS (ESI) m/z: 199.1 (M+H+).
Reaction SMILES: [CH2:1]([N:4]([CH2:27][CH2:28][CH3:29])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:17][C:16]2[C:11](=[CH:12][C:13]([CH2:18][NH:19][CH2:20][C:21]3[NH:22][CH:23]=[CH:24][N:25]=3)=[CH:14][CH:15]=2)[C:10]1=[O:26])[CH2:2][CH3:3].[CH3:30][N:31]1[CH:35]=[CH:34][N:33]=[C:32]1[CH:36]=O.C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>CO.C(O)(=O)C>[CH2:27]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:17][C:16]2[C:11](=[CH:12][C:13]([CH2:18][N:19]([CH2:20][C:21]3[NH:22][CH:23]=[CH:24][N:25]=3)[CH2:36][C:32]3[N:31]([CH3:30])[CH:35]=[CH:34][N:33]=3)=[CH:14][CH:15]=2)[C:10]1=[O:26])[CH2:28][CH3:29]
Reactant: CCCN(CCC)CCCCN1Cc2ccc(CNCc3ncc[nH]3)cc2C1=O
Reactant: Cn1ccnc1C=O
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN(CCC)CCCCN1Cc2ccc(CN(Cc3ncc[nH]3)Cc3nccn3C)cc2C1=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 88.4 %

Procedure:
The compound (15.1 mg) obtained in Example 8-1 was dissolved in methanol (1.5 ml). The solution was added with 1-methyl-2-imidazole carboxaldehyde (5.0 mg) and sodium cyanoborohydride (4.8 mg). The solution was adjusted to pH 4 by addition of acetic acid, followed by stirring at room temperature for 2.5 hours. Then, the solution was added with a saturated aqueous sodium hydrogen carbonate solution to stop the reaction and then subjected to extraction with chloroform. After that, the organic layer was washed with water and a saturated saline solution and then dried with anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining a hydrochloride (16.5 mg) of the subject compound as a pale-yellow solid.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([C@H:13]([O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[CH2:14][S:15](Cl)(=[O:17])=[O:16])[CH2:9]1)=O)(C)(C)C.[CH3:30][NH2:31].[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33]>C(Cl)Cl>[CH3:30][NH:31][S:15]([CH2:14][C@H:13]([C@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1)(=[O:17])=[O:16].[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33]
Reactant: CN
Reactant: CC(C)(C)OC(=O)N1CC[C@H]([C@@H](CS(=O)(=O)Cl)Oc2ccc(C(F)(F)F)cc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNS(=O)(=O)C[C@@H](Oc1ccc(C(F)(F)F)cc1)[C@H]1CCNC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(S)-3-[(S)-2-Chlorosulfonyl-1-(4-trifluoromethylphenoxy)ethyl]pyrrolidine-1-carboxylic acid t-butyl ester (50 mg, 109 μmol, 1.0 eq.) in DCM (1.0 mL) was combined with a solution of methylamine (2M in THF; 4.0 eq) and the resulting mixture was stirred at room temperature for 2 hours. TFA (1.0 mL) was added and stirred for 1 minute. The mixture was then concentrated and purified by preparative HPLC to yield the title compound as a TFA salt (8.7 mg). MS m/z: [M+H]+ calcd for C14H19F3N2O3S, 353.11. found 353.0.