Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][NH2:5].Cl[C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8].C(N(CC)CC)C>ClCCl>[CH:10]([O:9][C:7](=[O:8])[NH:5][CH2:4][CH2:3][Br:2])([CH3:12])[CH3:11]
Reactant: NCCBr
Reactant: CC(C)OC(=O)Cl
Agent: Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)NCCBr
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of bromoethylamine hydrobromide (5.0 g, 24.4 mmol), isopropyl chloroformate (1.0 M in tetrahydrofuran, 16.3 ml, 16.3 mmol), and anhydrous dichloromethane (100 ml) was treated with triethylamine (4.5 ml, 33 mmol) and stirred at ambient temperature for 18 hr. The mixture was diluted with dichloromethane (200 ml), washed with 1 M hydrochloric acid, 1 M sodium hydroxide, and brine, dried over sodium sulfate and evaporated to give (2-bromo-ethyl)-carbamic acid isopropyl ester clear oil. 1H-NMR δ (CDCl3) 5.01 (1H, br s), 4.92 (m, 1H), 3.58 (m, 2H), 3,48 (m, 2H), 1.25 (m, 6H).
Reaction SMILES: [CH3:1][Si:2]([CH3:52])([CH3:51])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:43][O:44][CH2:45][CH2:46][Si:47]([CH3:50])([CH3:49])[CH3:48])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]2)[C:9]=1Br.C([Sn](CCCC)(CCCC)[C:58]([O:60][CH2:61][CH3:62])=[CH2:59])CCC>O1CCOCC1>[CH3:1][Si:2]([CH3:52])([CH3:51])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:43][O:44][CH2:45][CH2:46][Si:47]([CH3:50])([CH3:49])[CH3:48])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]2)[C:9]=1[C:58]([O:60][CH2:61][CH3:62])=[CH2:59]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)CC1
Solvent: C1COCCO1
Product: C=C(OCC)c1c(C2CCN(C(=O)OC(C)(C)C)CC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N(COCC[Si](C)(C)C)COCC[Si](C)(C)C
Temperature: 100 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
To a pressure flask were charged compound tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate (13.66 g, 16.86 mmol), tributyl(1-ethoxyvinyl)tin (11.4 mL, 33.74 mmols) and dioxane (150 ml). The flask was degassed with Ar briefly, capped and heated at 100° C. with stirring overnight. After cooling, the reaction mixture was concentrated. The residue was taken into ether (200 ml), washed with 0.5 M KF (50 ml), brine and dried (MgSO4). After solvent was removed under reduced pressure, the residue was purified on silica. Elution with DOM in hexanes (0-30%) gave compound tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-(1-ethoxyvinyl)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate (11.55 g, 85%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]2[O:21][CH2:20][CH2:19][O:18]2)=[CH:9][CH:8]=1)(=O)=O.[C:24]([O:28][CH2:29][CH3:30])(=[O:27])[CH:25]=[CH2:26].C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:29]([O:28][C:24]([CH:25]=[CH:26][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]2[O:21][CH2:20][CH2:19][O:18]2)=[CH:9][CH:8]=1)=[O:27])[CH3:30]
Reactant: O=S(=O)(Oc1ccc(C2OCCO2)c2ccccc12)C(F)(F)F
Reactant: C=CC(=O)OCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C=Cc1ccc(C2OCCO2)c2ccccc12
Temperature: 90 °C
Yield: 53.7 %

Procedure:
Nitrogen was passed through a solution of 2-(4-trifluoromethylsulfonyloxynaphthyl) dioxolane (2.46 g, 7.06 mmol), ethyl acrylate (2.3 mL, 2.1 g, 21.2 mmol), triethylamine (4.3 g, 42.3 mmol) in DMF (6 mL) for 15 min, and bis(triphenylphosphine)palladium dichloride was added. The well stirred solution was heated at 90° C. for 8 hr, and concentrated. The residue was dissolved in ethyl acetate (50 mL), washed with brine (2×50 mL), dried (Na2SO4), and concentrated. Purification by flash chromatography using hexane/ethyl acetate 9:1 as eluent provided a yellow solid (1.13 g, 53%).
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][C:4](=[O:23])[CH:3]=1.[C:24]([C:28]1[CH:33]=[C:32]([CH2:34][OH:35])[C:31]([CH3:36])=[CH:30][C:29]=1[S:37]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:27])([CH3:26])[CH3:25].C([O-])([O-])=O.[K+].[K+].Cl>CCOC(C)=O.CN(C=O)C>[C:24]([C:28]1[CH:33]=[C:32]([CH2:34][OH:35])[C:31]([CH3:36])=[CH:30][C:29]=1[S:37][C:3]1[C:4](=[O:23])[O:5][C:6]([CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][C:2]=1[OH:1])([CH3:27])([CH3:26])[CH3:25]
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(CO)cc2C(C)(C)C)cc1
Reactant: O=C1C=C(O)CC(CCc2ccc(O)cc2)(c2ccccc2)O1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(SC2=C(O)CC(CCc3ccc(O)cc3)(c3ccccc3)OC2=O)c(C(C)(C)C)cc1CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound was prepared as described in General Method 9 using 4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-phenyl-5,6-dihydro-pyran-2-one (0.2 g, 0.64 mmol) from Example TT, toluene-4-thiosulfonic acid S-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl) ester (prepared in Example FFF; 0.26 g, 0.71 mmol), K2CO3 (0.35 g, 2.5 mmol), and DMF (3 mL). The solution was stirred overnight at room temperature and then poured into 1N HCl and EtOAc. The organic phase was dried (MgSO4), and concentrated. Purification by silica gel chromatography, eluting with MeOH:CH2Cl2 :hexane (5:80:20 to 5:95:0) gave the title compound, m.p. 196-199° C. 1H NMR (DMSO-d6) δ 1.44 (s, 9 H), 1.76 (s, 3 H), 2.08-2.21 (m, 3 H), 2.42 (m, 1 H), 3.41 (dd, 2 H), 4.32 (s, 2 H), 4.91 (br s, 1 H), 6.16 (s, 1 H), 6.61 (d, 2 H), 6.86 (d, 2 H), 7.21 (s, 1 H), 7.34-7.46 (m, 5 H), 9.14 (s, 1 H), 12.15 (bs, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[OH:11][C:12]([C@H:15]1[CH2:19][CH2:18][NH:17][C@H:16]1[CH3:20])([CH3:14])[CH3:13].C(=O)([O-])[O-].[Li+].[Li+]>>[Br:1][C:2]1[CH:9]=[C:8]([N:17]2[CH2:18][CH2:19][C@H:15]([C:12]([OH:11])([CH3:14])[CH3:13])[C@@H:16]2[CH3:20])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(F)cc1Br
Reactant: C[C@@H]1NCC[C@@H]1C(C)(C)O
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: C[C@H]1[C@@H](C(C)(C)O)CCN1c1ccc(C#N)c(Br)c1

Procedure:
Using 2-bromo-4-fluorobenzonitrile (497 mg), (2S,3S)-3-(1-hydroxy-1-methylethyl)-2-methylpyrrolidine 1/2 oxalate (659 mg) and lithium carbonate (259 mg), the title compound was obtained as a yellow solid (yield: 608 mg) by an operation similar to that in Example 3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:5][N:6]1[N:15]=[C:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:13]2[C:8](=[C:9](F)[CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:23].[Na].[CH2:29]([OH:31])[CH3:30]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:5][N:6]1[N:15]=[C:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:13]2[C:8](=[C:9]([O:31][CH2:29][CH3:30])[CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:23]
Reactant: CCO
Reactant: CCOC(=O)Cc1nn(Cc2ccc(Cl)c(Cl)c2)c(=O)c2c(F)cccc12
Agent: [Na]
Product: CCOC(=O)Cc1nn(Cc2ccc(Cl)c(Cl)c2)c(=O)c2c(OCC)cccc12

Procedure:
Ethyl 2-(3,4-dichlorobenzyl)-8-fluoro-1,2-dihydro-1-oxophthalazin-4-ylacetate (1.8 g.) was added to a solution of sodium (1.5 g.) in dry ethanol (150 ml.). The solution obtained was heated under reflux for 3 hours and then evaporated. Water (100 ml.) was added to the residue and the solid obtained was collected by filtration and dried to give ethyl 2(3,4-dichlorobenzyl)-8-ethoxy-1,2-dihydro-1-oxophthalazin-4-ylacetate (0.5 g.).
Reaction SMILES: [CH:1]1([C@:4]([OH:32])([CH3:31])[CH2:5][NH:6][C:7]([C:9]2[CH:14]=[N:13][C:12]([C:15]#[C:16][Si](CC)(CC)CC)=[C:11]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[N:10]=2)=[O:8])[CH2:3][CH2:2]1.[F-].[NH4+]>CO>[CH:1]1([C@:4]([OH:32])([CH3:31])[CH2:5][NH:6][C:7]([C:9]2[CH:14]=[N:13][C:12]([C:15]#[CH:16])=[C:11]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[N:10]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: CC[Si](C#Cc1ncc(C(=O)NC[C@](C)(O)C2CC2)nc1-c1ccc(Cl)cc1)(CC)CC
Agent: [F-]
Agent: [NH4+]
Solvent: CO
Product: C#Cc1ncc(C(=O)NC[C@](C)(O)C2CC2)nc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.40 g 6-(4-chloro-phenyl)-5-triethylsilanylethynyl-pyrazine-2-carboxylic acid ((R)-2-cyclopropyl-2-hydroxy-propyl)-amide in 10 ml methanol was added at room temperature 0.40 g ammonium fluoride and the mixture was stirred at room temperature for 30 min. The orange reaction mixture was partitioned between water and ethyl acetate, the phases were separated and the organic phase was purified by chromatography on silica gel with heptane:ethyl acetate=1:1 to yield 6-(4-chloro-phenyl)-5-ethynyl-pyrazine-2-carboxylic acid ((R)-2-cyclopropyl-2-hydroxy-propyl)-amide as light yellow foam.
Reaction SMILES: [C:1]([C@@H:5]1[CH2:9][C:8](=[CH2:10])[CH2:7][C@H:6]1[C:11]([O:13]C)=[O:12])([O:3]C)=[O:2].[OH-].[Na+]>>[CH2:10]=[C:8]1[CH2:7][C@@H:6]([C:11]([OH:13])=[O:12])[C@H:5]([C:1]([OH:3])=[O:2])[CH2:9]1
Reactant: C=C1C[C@@H](C(=O)OC)[C@H](C(=O)OC)C1
Agent: [Na+]
Agent: [OH-]
Product: C=C1C[C@@H](C(=O)O)[C@H](C(=O)O)C1
Yield: 77.6 %

Procedure:
A diester, trans-1,2-di-carbomethoxy-4-methylenecyclopentane, (1.48g, 7.47 mmol) prepared by the method of Trost (J. Am. Chem. Soc. 105 2315 (1983) was heated under reflux for 2 hours with 2N sodium hydroxide (11 ml, 22 mmol). The resulting solution was cooled in an ice bath and acidified with concentrated (37%) hydrochloric acid (8.0 ml) until a pH of 0.6 was attained. The resulting slurry was filtered, washed with water, and dried in vacuo to give the diacid 2 (0.987g, 77.7%) as a colorless powder: mp 178°-179° C.; Anal. calcd for C8H10O4 : C, 56.47; H, 5.92. Found: C, 56.08; H, 5.87.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.[NH2:44][CH2:45][CH:46]([OH:58])[CH2:47][N:48]1[CH2:57][CH2:56][C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH2:49]1>C(Cl)Cl>[CH2:49]1[C:50]2[C:55](=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH2:56][CH2:57][N:48]1[CH2:47][CH:46]([OH:58])[CH2:45][NH:44][C:11](=[O:13])[C:10]1[CH:9]=[CH:8][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:15][CH:14]=1
Reactant: NCC(O)CN1CCc2ccccc2C1
Reactant: O=C(O)c1ccc(-c2ccccn2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCC(O)CN1CCc2ccccc2C1)c1ccc(-c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 15.5 %

Procedure:
To a solution of 4-(pyridin-2-yl)benzoic acid (100 mg, 0.5 mmol) in DCM (5 mL) was added EDCI (144 mg, 0.75 mmol), HOBt (101 mg, 0.75 mmol), Et3N (152 mg, 1.5 mmol) and 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (103 mg, 0.5 mmol). The mixture was stirred at 25° C. for 16 h. The reaction solution was washed with water and extracted with DCM. The organic layer was concentrated, and the residue was purified by prep-HPLC to give the title compound (30 mg, Yield 15.5%). 1H NMR (CD3OD, 400 MHz): δ 8.70-8.60 (m, 1H), 8.01-7.84 (m, 6H), 7.45-7.36 (m, 1H), 7.16-6.99 (m, 4H), 4.20-4.10 (m, 1H), 3.79 (s, 2H), 3.62-3.46 (m, 2H), 2.92 (s, 4H), 2.78-2.65 (m, 2H). LCMS (m/z): 388.2 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:26][CH2:25][C@:4]2([N:8]=[C:7]([C:9]3[CH:14]=[C:13]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=4)[CH:12]=[CH:11][N:10]=3)[CH2:6][CH2:5]2)[C:3]1=[O:27].[B-](F)(F)(F)[F:29].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.FC(F)(F)C(O)=O.[OH-].[Na+]>CC#N>[F:29][CH:6]1[CH2:5][C@@:4]2([CH2:25][CH2:26][N:2]([CH3:1])[C:3]2=[O:27])[N:8]=[C:7]1[C:9]1[CH:14]=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=2)[CH:12]=[CH:11][N:10]=1
Reactant: CN1CC[C@@]2(CCC(c3cc(-c4ccc(C(F)(F)F)cc4)ccn3)=N2)C1=O
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CN1CC[C@@]2(CC(F)C(c3cc(-c4ccc(C(F)(F)F)cc4)ccn3)=N2)C1=O
Temperature: 90 °C
Reaction time: 0.17 h

Procedure:
Anhydrous MeCN (5 mL) was added to a dry vial charged with (5S)-7-methyl-2-[4-[4-(trifluoromethyl)phenyl]-2-pyridyl]-1,7-diazaspiro[4.4]non-1-en-6-one (which may be prepared as described in Description 118) (339.99 mg, 0.9100 mmol). Selectfluor (1500 mg, 4.23 mmol) was added to the solution followed by trifluoroacetic acid (0.04 mL, 0.5300 mmol). The vial was sealed under nitrogen and was heated to 90° C. for 24 h. The reaction mixture was allowed to cool to room temperature whence it was poured onto 0.5M sodium hydroxide. The mixture was left to stir for 10 min and extracted with ether. The combined organic layer was dried (sodium sulfate), filtered and the filtrate was evaporated to give an amber oil. The crude residue was purified by silica gel chromatography (10 g SiO2) eluting with ethyl acetate in iso-hexane (10-100%). Evaporation of desired fractions gave (5R)-3-fluoro-7-methyl-2-[4-[4-(trifluoromethyl)phenyl]-2-pyridyl]-1,7-diazaspiro[4.4]non-1-en-6-one, as an amber oil, a 2:1 mixture of epimers. The isomers were separated by chiral semi-prep hplc using a ChiralPak AD-H column eluting with ethanol/n-heptane (20%:80%) to obtain a faster running epimer (D119a) (28 mg);
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:14][OH:15])=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]([C:20]1[N:21]([CH3:26])[N:22]=[C:23](O)[CH:24]=1)=[O:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:23]2[CH:24]=[C:20]([C:18]([O:17][CH3:16])=[O:19])[N:21]([CH3:26])[N:22]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(O)nn1C
Reactant: Cn1nnc(-c2ccc(F)cc2)c1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(OCc2c(-c3ccc(F)cc3)nnn2C)nn1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.9 %

Procedure:
To a solution of [5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-yl]-methanol (290 mg, 1.4 mmol) in THF (30 mL) was added 5-hydroxy-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (218 mg, 1.4 mmol) and triphenylphosphine (477 mg, 1.82 mmol) at ambient temperature under an argon atmosphere. Then diethyl azodicarboxylate (641 μL, 3.5 mmol) was added and the reaction mixture was stirred for 16 h at room temperature. Concentration and purification by chromatography (silica, 20 to 50% ethyl acetate in heptane) afforded the title compound (483 mg, 100%) as a white solid. MS: m/e=346.2 [M+H]+.
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3]O.[CH3:11][S:12](Cl)(=[O:14])=[O:13]>>[C:5]1([C@@H:2]2[CH2:3][CH2:11][S:12](=[O:14])(=[O:13])[NH:1]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CS(=O)(=O)Cl
Reactant: N[C@@H](CO)c1ccccc1
Product: O=S1(=O)CC[C@@H](c2ccccc2)N1

Procedure:
Using (R)-2-amino-2-phenylethanol (1.37 g) and methanesulfonyl chloride (1.6 mL) and by the reaction and treatment in the same manner as in Preparation Example 1, the title compound (391 mg) was obtained.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH3:9][S:10][C:11]1[N:12]=[CH:13][N:14]2[CH:18]=[CH:17][S:16][C:15]=12>ClCCl.[Cl-].[Na+].O>[I:1][C:13]1[N:14]2[C:15]([S:16][CH:17]=[CH:18]2)=[C:11]([S:10][CH3:9])[N:12]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CSc1ncn2ccsc12
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CSc1nc(I)n2ccsc12
Temperature: 25 °C
Yield: 95.3 %

Procedure:
N-Iodosuccinimide (3.08 g) was added under ice cooling to a solution of 2.28 g of 7-methylthioimidazo[5,1-b]thiazole in dichloromethane. The mixture was stirred at room temperature for7 hr. Saturated brine was added to the reaction mixture, followed by separation. The organic layer was washed with a dilute aqueous sodium thiosulfate solution and saturated brine in that order, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation. The residue was purified by column chromatography on silica gel (ethyl acetate:dichloromethane=1:1) to give 3.78 g of 5-iodo-7-methylthioimidazo[5,1-b]thiazole.
Reaction SMILES: [Br:1][CH:2]1[C:6](=[O:7])[C:5]2[CH:8]=[CH:9][C:10]([O:12][CH2:13][CH2:14][Cl:15])=[CH:11][C:4]=2[O:3]1.FC(F)(F)S(O[Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])(=O)=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[O:3][C:4]2[CH:11]=[C:10]([O:12][CH2:13][CH2:14][Cl:15])[CH:9]=[CH:8][C:5]=2[C:6]=1[O:7][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: O=C1c2ccc(OCCCl)cc2OC1Br
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)Oc1c(Br)oc2cc(OCCCl)ccc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1.50 g (5.15 mmol) of the hydrate of 2-bromo-6-(2-chloroethoxy)benzofuran-3-one (Example 43A) are concentrated three times with toluene under argon in order to remove water azeotropically. The residue is then dissolved under argon in 25 ml of diethyl ether and cooled to 0° C. 0.79 ml (5.66 mmol) of TEA and 1.30 ml (5.66 mmol) of tert-butyldimethylsilyl trifluoromethanesulfonate are successively slowly added dropwise, and the mixture is stirred at 0° C. for 10 min and at RT for 1 h. The diethyl ether phase is then separated off, the residue is extracted twice with diethyl ether, and the combined diethyl ether phases are concentrated. Column chromatography on silica gel 60 (mobile phase: cyclohexane) results in 2.00 g (96% of theory) of the product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17](=[O:18])[CH2:16][C@H:15]([C:19](O)=[O:20])[CH2:14]2)=[CH:9][CH:8]=1.C[N:26]1CCOCC1.ClC(OCC)=O>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17](=[O:18])[CH2:16][C@H:15]([C:19]([NH2:26])=[O:20])[CH2:14]2)=[CH:9][CH:8]=1
Reactant: CN1CCOCC1
Reactant: O=C(O)[C@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Product: NC(=O)[C@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 87.8 %

Procedure:
To (S)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid (2.0 g, 6.07 mmol; enantiomeric purity (S):(R)>99.9:0.1) in tetrahydrofuran (40 mL), N-methylmor-pholine (676 mg, 6.68 mmol) was added at 0° C. After stirring for 20 min, a solution of ethyl chloroformate (725 mg, 6.68 mmol) was added dropwise over 10 min, and stirring at 0° C. was continued for another 20 min. Ammonia (excess) was then bubbled for 15 min through the resulting suspension. The reaction mixture was warmed up to room temperature and stirred for 15 min. Water (50 mL) was added, and the tetrahydrofuran was evaporated in vacuo. The product, which precipitated, was collected by filtration, washed with water and tert-butyl methyl ether and dried at 45° C. in vacuo to afford (S)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid amide (1.75 g, 88%). The purity of the product by HPLC was 98.9% (area) and the enantiomeric ratio (S):(R) was determined as 99.8:0.2.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:13][C:14]([CH3:30])=[C:15]([CH2:17][CH2:18]OS(C3C=CC(C)=CC=3)(=O)=O)[N:16]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[CH3:31][CH:32]1[CH2:36][CH2:35][CH2:34][NH:33]1>>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[O:13][C:14]([CH3:30])=[C:15]([CH2:17][CH2:18][N:33]3[CH2:34][CH2:35][CH2:36][CH:32]3[CH3:31])[N:16]=2)=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC1CCCN1
Reactant: CCCCOc1ccc(-c2nc(CCOS(=O)(=O)c3ccc(C)cc3)c(C)o2)cc1
Product: CCCCOc1ccc(-c2nc(CCN3CCCC3C)c(C)o2)cc1

Procedure:
Starting with Toluene-4-sulfonic acid 2-[2-(4-butoxy-phenyl)-5-methyl-oxazol-4-yl]-ethyl ester [CAS 478540-91-9] and racemic 2-methylpyrrolidine, follow procedures significantly analogous to Example 8 to provide the free base of the titled compound. The free base is converted to the titled compound significantly in accordance with the procedure of Example 23. MS (m/e): 343.3 (M+1)
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=O)[C:13]([N:15]([CH3:24])[N:16]=[C:17]([CH3:23])[CH2:18][S:19]([CH3:22])(=[O:21])=[O:20])=[O:14])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:14])[N:15]([CH3:24])[N:16]=[C:17]([CH3:23])[C:18]=1[S:19]([CH3:22])(=[O:21])=[O:20])[CH3:2]
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N=C(C)CS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCc1cc(C)cc(CC)c1-c1c(S(C)(=O)=O)c(C)nn(C)c1=O

Procedure:
To a test tube (outside diameter: 21 mm Φ×overall length: 160 mm), 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methyl-2-(1-methylsulfonyl-2-propylidene)hydrazine ((4-34-(1)-39) (201.0 mg), potassium carbonate (115.1 mg), and methanol (757 μl) were added under ice-cooling.
Reaction SMILES: [C:1](N1C=CN=C1)([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[O:2].[OH:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][N:19]([C:22](=[O:24])[CH3:23])[CH2:18][CH2:17]1.O>C(Cl)Cl>[N:3]1([C:1]([O:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22](=[O:24])[CH3:23])[CH2:18][CH2:17]2)=[O:2])[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(=O)N1CCN(CCO)CC1
Solvent: ClCCl
Solvent: O
Product: CC(=O)N1CCN(CCOC(=O)n2ccnc2)CC1
Yield: 95.8 %

Procedure:
A solution of 1,1′-carbonyldiimidazole (5 g, 31 mmol) in DCM (200 mL) was treated with a solution of 1-[4-(2-hydroxyethyl)-1-piperazinyl]-1-ethanone (see step (i) above; 5 g, 29 mmol) in DCM (50 mL). The reaction mixture was stirred at rt overnight before water was added. The layers were separated, and the organic layer was washed with water, dried and concentrated in vacuo to yield 7.4 g (96%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[C:16]([F:24])[CH:15]=2)=[CH:4][CH:3]=1.[O:25]1[CH:29]=[CH:28][CH:27]=[C:26]1B(O)O.C([O-])(O)=O.[Na+]>COCCOC.O>[F:24][C:16]1[CH:15]=[C:14]([C:9]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([C:26]4[O:25][CH:29]=[CH:28][CH:27]=4)=[CH:3][CH:4]=3)[C:12]([CH3:13])=[CH:11][CH:10]=2)[CH:19]=[CH:18][C:17]=1[S:20]([CH3:23])(=[O:22])=[O:21]
Reactant: Cc1ccc(-c2ccc(S(C)(=O)=O)c(F)c2)n1-c1ccc(Br)cc1
Reactant: OB(O)c1ccco1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(-c2ccc(S(C)(=O)=O)c(F)c2)n1-c1ccc(-c2ccco2)cc1
Yield: 60.7 %

Procedure:
To a stirred suspension of 1-(4-bromophenyl)-2-[3-fluoro-4-(methylsulfonyl)phenyl]-5-methyl-1H-pyrrole (0.41 g, 1 mmol), 2-furanboronic acid (0.14 g, 1.26 mmol), NaHCO3 (0.19 g, 2.3 mmol) in DME-water (6 mL-2 mL) was added dichlorobis(triphenylphosphine) palladium (80 mg, 0.115 mmol) at room temperature under nitrogen. The mixture was heated at reflux temperature for 6 hours. After cooling, volatiles were removed by evaporation. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate/hexane (1/2) to give the title compound (0.24 g, 61% yield).