Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](OC(C1OC2C=CC=C(C(=O)N)C=2C=1C)=O)C.[H-].[Na+].IC.[CH2:23]([O:25][C:26]([C:28]1[O:29][C:30]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38](=[O:41])[NH:39][CH3:40])[C:31]=2[C:32]=1[CH3:33])=[O:27])[CH3:24]>CN(C=O)C>[CH2:23]([O:25][C:26]([C:28]1[O:29][C:30]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38](=[O:41])[N:39]([CH3:1])[CH3:40])[C:31]=2[C:32]=1[CH3:33])=[O:27])[CH3:24]
Reactant: CCOC(=O)c1oc2cccc(C(=O)NC)c2c1C
Reactant: CCOC(=O)c1oc2cccc(C(N)=O)c2c1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)c1oc2cccc(C(=O)N(C)C)c2c1C
Temperature: 50 °C

Procedure:
To 200 mg of 4-carbamoyl-3-methyl-benzofuran-2-carboxylic acid ethyl ester (0.81 mmol, 1 eq.) in 5 mL of DMF was added 50 mg of NaH (60% in mineral oil, 1.25 mmol, 1.5 eq) under nitrogen. After 30 min of reaction, iodomethane (0.053 mL, 0.85 mmol, 1 eq) was added to the reaction. The mixture was then heated to 50° C. for 12 h. After work up and column chromatography, a mixture of 3-methyl-4-methylcarbamoyl-benzofuran-2-carboxylic acid ethyl ester and 4-dimethylcarbamoyl-3-methyl-benzofuran-2-carboxylic acid ethyl ester was obtained (76 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.3 (t, J=7.1 Hz, 3 H) 2.8 (d, J=4.5 Hz, 6 H) 4.4 (q, J=7.2 Hz, 2 H) 7.3 (dd, J=7.3, 1.0 Hz, 1 H) 7.5 (dd, J=8.3, 7.3 Hz, 1 H) 7.8 (dd, J=8.5, 0.9 Hz, 1 H).
Reaction SMILES: [CH2:1]([OH:23])[C@H:2]1[O:7][C@H:6]([O:8][CH2:9][C@H:10]2[O:15][CH:14]([OH:16])[C@H:13]([OH:17])[C@@H:12]([OH:18])[C@@H:11]2[OH:19])[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22].C>>[CH2:1]([OH:23])[C@H:2]1[O:7][C@H:6]([O:8][CH2:9][C@@H:10]([OH:15])[C@@H:11]([OH:19])[C@H:12]([OH:18])[C@@H:13]([OH:17])[CH2:14][OH:16])[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22]
Reactant: OC[C@H]1O[C@H](OC[C@H]2OC(O)[C@H](O)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O
Product: OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Yield: 80 %

Procedure:
An isomaltose content syrup, obtained by the method in Example A-1, was hydrogenated in accordance with the method in Experiment 36, and the resulting mixture was in a usual manner decolored with an activated charcoal, desalted for purification with ion-exchange resins in H- and OH-forms, and concentrated to give a concentration of about 73%. The concentrate was spray dried in a usual manner to obtain a high isomaltitol content powder, containing 43.3% of isomaltitol, 37.8% of ring-opened tetrasaccharide, 13.8% of cyclotetrasaccharide, and 3.5% of other sugar alcohols, in a yield of about 80%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[NH:14][S:15]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=1)(=[O:17])=[O:16])(=[O:6])=[O:5].CCN(CC)CC.[C:36](OC(=O)C)(=[O:38])[CH3:37]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([S:4]([CH2:3][CH2:2][NH:1][C:36](=[O:38])[CH3:37])(=[O:5])=[O:6])=[C:8]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]([F:26])([F:27])[F:28])[CH:19]=2)(=[O:17])=[O:16])[CH:9]=1
Reactant: CC(=O)OC(C)=O
Reactant: NCCS(=O)(=O)c1ccc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCCS(=O)(=O)c1ccc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-{2-[(2-aminoethyl)sulfonyl]-5-chlorophenyl}-4-chloro-3-(trifluoromethyl)benzenesulfonamide (23 mg, 0.048 mmol) in CH2Cl2 (2 ml) was added Et3N (14 μl, 0.10 mmol), acetic anhydride (5 μl, 0.053 mmol), and catalytic amount of DMAP. The reaction was stirred at room temperature for 1 h and was concentrated. The crude product was purified by column chromatography on silica gel (0→10% MeOH in ethyl acetate), followed by PTLC (10% MeOH in ethyl acetate) to give the title compound.
Reaction SMILES: C1C2C(COC([NH:18][C:19]([CH3:84])([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:80]([CH3:83])[CH2:81][CH3:82])[C@H:33]([O:78][CH3:79])[CH2:34][C:35]([N:37]3[CH2:41][CH2:40][CH2:39][C@H:38]3[C@@H:42]([C@@H:45]([CH3:77])[C:46](=[O:76])[NH:47][C@@H:48]([CH2:69][C:70]3[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=3)[C:49](=[O:68])[NH:50][CH2:51][CH2:52][NH:53][C:54](=[O:67])[CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][C@H:60]3[C@@H:64]([CH3:65])[NH:63][C:62](=[O:66])[NH:61]3)[O:43][CH3:44])=[O:36])[CH3:31])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])[CH3:20])=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>CN(C=O)C>[CH3:20][C:19]([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:80]([CH3:83])[CH2:81][CH3:82])[C@H:33]([O:78][CH3:79])[CH2:34][C:35]([N:37]1[CH2:41][CH2:40][CH2:39][C@H:38]1[C@@H:42]([C@@H:45]([CH3:77])[C:46](=[O:76])[NH:47][C@@H:48]([CH2:69][C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1)[C:49](=[O:68])[NH:50][CH2:51][CH2:52][NH:53][C:54](=[O:67])[CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][C@H:60]1[C@@H:64]([CH3:65])[NH:63][C:62](=[O:66])[NH:61]1)[O:43][CH3:44])=[O:36])[CH3:31])=[O:29])[CH:25]([CH3:26])[CH3:27])=[O:22])([CH3:84])[NH2:18]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)NCCNC(=O)CCCCC[C@@H]1NC(=O)N[C@@H]1C)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)NCCNC(=O)CCCCC[C@@H]1NC(=O)N[C@@H]1C)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)N)C(C)C
Yield: 53.1 %

Procedure:
Following general procedure A using #256 (5 mg, 0.004 mmol, 1.0 eq.) and piperidine (0.02 mL, 0.2 mmol, 50 eq.) in 0.7 mL of DMF followed by purification (Method J) afforded #257 (2 mg, 50%) as a colorless glass. LC-MS (Protocol Q1): m/z 1164.8 [M+H+], retention time=0.99 minutes. 1H NMR (400 MHz, DMSO-d6), δ 8.44-8.52 (m), 8.06-8.20 (m), 7.96-8.01 (m), 7.69-7.83 (m), 7.20-7.28 (m), 7.11-7.19 (m), 3.38-3.83 (m), 3.19-3.26 (m), 3.03-3.12 (m), 2.98 (s), 2.91 (s), 2.75 (s), 2.65-2.70 (m), 2.01-2.36 (m), 1.65-1.87 (m), 1.39-1.57 (m), 1.13-1.37 (m), 1.04-1.08 (m), 0.74-1.01 (m).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:13])[CH2:9][CH:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[F:14][C:15]([F:22])([F:21])[C:16]1[CH:17]=[N:18][NH:19][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cl-].[Na+].O>[CH3:11][CH:10]([CH3:12])[CH2:9][C:8]([C:5]1[CH:6]=[N:7][C:2]([N:18]2[CH:17]=[C:16]([C:15]([F:22])([F:21])[F:14])[CH:20]=[N:19]2)=[CH:3][CH:4]=1)=[O:13]
Reactant: FC(F)(F)c1cn[nH]c1
Reactant: CC(C)CC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CC(=O)c1ccc(-n2cc(C(F)(F)F)cn2)nc1
Temperature: 50 °C
Reaction time: 6 h
Yield: 92.3 %

Procedure:
To a solution of 1-(6-chloropyridin-3-yl)-3-methylbutan-1-one (1.0 g, 5.1 mmol) and 4-(trifluoromethyl)-1H-pyrazole (766 mg, 5.62 mmol) in anhydrous DMF (20 mL) was added potassium carbonate (2.12 g, 15.3 mmol). The mixture was stirred at 50° C. for 6 h. The reaction mixture was poured into brine (30 mL) and extracted with ethyl acetate (30 mL*2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography to give 3-methyl-1-(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)butan-1-one (1.4 g) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 8.92 (d, J=2.0 Hz, 1H), 8.85 (s, 1H), 8.33 (dd, J=2.0, 8.4 Hz, 1H), 8.02 (d, J=8.4 Hz, 1H), 7.88 (s, 1H), 2.79 (d, J=6.8 Hz, 2H), 2.31-2.21 (m, 1H), 0.96 (d, J=6.8 Hz, 6H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N:23]([S:27]([C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=3[F:37])(=[O:29])=[O:28])[CH2:24][O:25][CH3:26])[C:18]=2[F:38])=O)[CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].C1C=C[NH+]=CC=1.Br[Br-]Br.[CH:49]1([N:52]2[CH2:57][CH2:56][CH:55]([C:58](=[S:60])[NH2:59])[CH2:54][CH2:53]2)[CH2:51][CH2:50]1>CN(C=O)C>[CH:49]1([N:52]2[CH2:57][CH2:56][CH:55]([C:58]3[S:60][C:14]([C:12]4[CH:11]=[CH:10][N:9]=[C:8]([NH:7][C:6](=[O:39])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])[CH:13]=4)=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([N:23]([S:27]([C:30]5[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=5[F:37])(=[O:29])=[O:28])[CH2:24][O:25][CH3:26])[C:18]=4[F:38])[N:59]=3)[CH2:54][CH2:53]2)[CH2:50][CH2:51]1
Reactant: COCN(c1cccc(C(=O)Cc2ccnc(NC(=O)OC(C)(C)C)c2)c1F)S(=O)(=O)c1cc(F)ccc1F
Reactant: NC(=S)C1CCN(C2CC2)CC1
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Product: COCN(c1cccc(-c2nc(C3CCN(C4CC4)CC3)sc2-c2ccnc(NC(=O)OC(C)(C)C)c2)c1F)S(=O)(=O)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 60 %

Procedure:
Tert-butyl-{4-[2-(3-{[(2,5-difluorophenyl)sulfonyl](methoxymethyl)amino}-2-fluorophenyl)-2-oxoethyl]pyridin-2-yl}carbamate (prepared as described in Example 9, 374 mg, 0.662 mmol) was dissolved in dry DMF (5 mL) under argon atmosphere. Pyridinium bromide perbromide (190 mg, 0.596 mmol, 0.9 eq) was added and the reaction mixture was stirred at r.t. for 50 min. 1-Cyclopropylpiperidine-4-carbothioamide (146 mg, 0.794 mmol, 1.2 eq) was then added and the mixture was heated to 70° C. After 1 h the reaction was allowed to cool to r.t. overnight. The solvent was concentrated under reduced pressure. The residue was taken up with ethyl acetate and washed with saturated aqueous NaHCO3 and brine. The organic phase was dried over Na2SO4 and evaporated to dryness. The crude product was purified by flash chromatography on silica gel (DCM/MeOH 98:2) to give 290 mg (60%) of tert-butyl {4-[2-(1-cyclopropylpiperidin-4-yl)-4-(3-{[(2,5-difluorophenyl)sulfonyl](methoxymethyl)amino}-2-fluorophenyl)-1,3-thiazol-5-yl]pyridin-2-yl}carbamate as amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:28](I)[CH3:29]>O1CCOCC1.O.CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:28][CH3:29])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=2)[N:3]=1
Reactant: CCI
Reactant: FC(F)(F)c1cccc(Nc2nc(Cl)nc3nc[nH]c23)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Solvent: CN(C)C=O
Product: CCn1cnc2c(Nc3cccc(C(F)(F)F)c3)nc(Cl)nc21

Procedure:
A mixture comprising 1 g (3.2 mmol) of 2-chloro-6-(3-trifluoromethyl-phenyl-amino)-purine, 1.7 g (5.1 mmol) of caesium carbonate and 2.1 ml (25.6 mmol) of ethyl iodide in 7 ml of dioxane/water/DMF (8:2:2) is stirred at RT for 18 h. It is then diluted with ethyl acetate and the organic phase is washed with water. This phase is separated off and dried over sodium sulfate. After removal of the solvent, the residue is recrystallized from ethyl acetate and diethyl ether. 2-Chloro-9-ethyl-6-(3-trifluoromethyl-phenyl-amino)-9H-purine is obtained; m.p. 129–130° C.; FAB-MS: (M+H)+=342; Rf=0.6 (methylene chloride:methanol=9:1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([OH:23])[CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24]I.[H-].[Na+].O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([O:23][CH3:24])[CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC(C(O)CCc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(CCc1ccccc1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 0.218 g (0.68 mmol) of 1-t-butoxy carbonyl-4-(3-phenyl-1-hydroxypropyl)piperidine (Example 239) and 0.3 mL of methyl iodide in 2 mL of DMF was added 0.066 g (1.5 mmol)of NaH (60% dispersion in mineral oil) and the mixture was stirred for 16 h at rt. To the reaction was added 5 mL of water and the mixture was extracted with ethyl acetate. The combined organic fractions were washed with sat'd NaCl solution, dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, hexanes:ethyl acetate, 4:1) to give 1-t-butoxy carbonyl-4-(3-phenyl-1-(RS)-methoxypropyl)piperidine. Removal of the BOC protecting group was achieved as described in Example 233, Step 6 to give the title compound.
Reaction SMILES: [NH2:1][C:2]1([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[C:29]([S:32][CH2:33][CH:34]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:35](O)=[O:36])(=[O:31])[CH3:30]>>[C:29]([S:32][CH2:33][CH:34]([CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:35]([NH:1][C:2]1([C:8]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)=[O:36])(=[O:31])[CH3:30]
Reactant: NC1(C(=O)OCc2ccccc2)CCCCC1
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CC(=O)SCC(Cc1ccccc1)C(=O)NC1(C(=O)OCc2ccccc2)CCCCC1

Procedure:
Benzyl 1-aminocyclohexanecarboxylate·p-toluene-sulfonate and 2-acetylthiomethyl-3-phenylpropionic acid are reacted in the same manner as described in Example 68-(a)-[1] to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][N:23]=1)[C:18]([OH:20])=O.[NH2:24][CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][N:23]=1)[C:18]([NH:24][CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[O:20]
Reactant: NC1CCOCC1
Reactant: Cc1onc(-c2ccccc2)c1COc1cc(C(=O)O)ccn1
Product: Cc1onc(-c2ccccc2)c1COc1cc(C(=O)NC2CCOCC2)ccn1
Yield: 62 %

Procedure:
As described for example 58c, 2-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-isonicotinic acid (78 mg, 0.3 mmol) was converted, using 4-aminotetrahydropyran instead of 2,2,2-trifluoroethylamine, to the title compound (61 mg, 62%) which was obtained as a white solid. MS: m/e=394.3 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[CH3:15][C:16]1[CH:25]=[C:24]([CH2:26][O:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3([N:43]4[CH2:48][CH2:47][N:46](C(OC(C)(C)C)=O)[CH2:45][CH2:44]4)[C:39](=[O:40])[NH:38][C:37](=[O:41])[NH:36][C:35]3=[O:42])=[CH:30][CH:29]=2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:15][C:16]1[CH:25]=[C:24]([CH2:26][O:27][C:28]2[CH:29]=[CH:30][C:31]([C:34]3([N:43]4[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]4)[C:39](=[O:40])[NH:38][C:37](=[O:41])[NH:36][C:35]3=[O:42])=[CH:32][CH:33]=2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1
Reactant: Cc1cc(COc2ccc(C3(N4CCN(C(=O)OC(C)(C)C)CC4)C(=O)NC(=O)NC3=O)cc2)c2ccccc2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(COc2ccc(C3(N4CCNCC4)C(=O)NC(=O)NC3=O)cc2)c2ccccc2n1
Yield: 199.6 %

Procedure:
The product from example 13 (50 mg, 0.0635 mmol) was treated with trifluoacetic acid (2.0 mL) in dichloromethane (2.0 mL) at rt for 1 h. The mixture was concentrated in vacuo to provide the title barbituric acid (50.8 mg, 100%). MS found: (M+H)+=460.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22](O)=[O:23])=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C.Cl.[F:62][C@@H:63]1[CH2:67][CH2:66][NH:65][CH2:64]1>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:26])([F:28])[F:27])=[N:20][C:21]([C:22]([N:65]3[CH2:66][CH2:67][C@@H:63]([F:62])[CH2:64]3)=[O:23])=[C:15]2[CH2:14]1)=[O:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: F[C@@H]1CCNC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CC[C@@H](F)C3)c2C1)Cc1cc(F)c(F)cc1F
Yield: 96.5 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (0.15 g, 0.27 mmol), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.140 g, 0.54 mmol), triethylamine (0.4 mL, 2.6 mmol) and (R)-3-fluoropyrrolidine hydrochloride (68 mg, 0.54 mmol) were dissolved in 10 mL of dichloromethane under stirring. The reaction mixture was reacted at room temperature overnight and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-[1-((R)-3-fluoro-pyrrolidine-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 25a (0.162 g) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:24]3[C:29]([CH:30]=2)=[CH:28][C:27]([CH:31]=O)=[CH:26][CH:25]=3)=[C:18]2[C:14]=1[CH2:15][NH:16][C:17]2=[O:40])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:41][CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:24]3[C:29]([CH:30]=2)=[CH:28][C:27]([CH2:31][N:47]2[CH2:48][CH2:49][N:44]([CH2:43][CH2:42][OH:41])[CH2:45][CH2:46]2)=[CH:26][CH:25]=3)=[C:18]2[C:14]=1[CH2:15][NH:16][C:17]2=[O:40])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCCOc1ccc(-c2cc3cc(C=O)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Reactant: OCCN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCCOc1ccc(-c2cc3cc(CN4CCN(CCO)CC4)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Yield: 68.9 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-[3-(tert-butoxycarbonylamino)propoxy]-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (104 mg, 0.189 mmol) was dissolved in acetonitrile (5.2 mL), and the solution was treated with 1-(2-hydroxyethyl)piperazine (98 mg, 0.756 mmol), acetic acid (0.216 mL, 3.78 mmol) and sodium triacetoxyborohydride (160 mg, 0.756 mmol). The reaction mixture was added with water and sodium carbonate, followed by extracting with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 4-[3-(tert-butoxycarbonylamino)propoxy]-7-{1-(tert-butoxycarbonyl)-5-[4-(2-hydroxyethyl)piperazin-1-ylmethyl]indol-2-yl}isoindolinone (86.5 mg, yield 69%).
Reaction SMILES: [O:1]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:15][C:16]#[N:17]>>[O:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:15][C:16]#[N:17])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CCBr
Reactant: c1ccc(OC2CCNCC2)cc1
Product: N#CCN1CCC(Oc2ccccc2)CC1

Procedure:
The title compound is synthesized by coupling of 4-Phenoxy-piperidine (commercially available from Alfa Aesar) and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a colorless oil; ES-MS: M+H=217.2: CtRet=4.80.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:9][CH2:10][CH2:11][CH2:12]Br)[CH2:8][CH2:7][CH2:6]1)=[O:4].[CH3:14][SH:15].[Na]>>[CH3:1][O:2][C:3]([C:5]1([CH2:9][CH2:10][CH2:11][CH2:12][S:15][CH3:14])[CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: CS
Reactant: COC(=O)C1(CCCCBr)CCC1
Agent: [Na]
Product: COC(=O)C1(CCCCSC)CCC1

Procedure:
1-[4-(Methylthio)butyl]cyclobutane carboxylic acid methyl ester was prepared from 1-(4-bromobutyl)cyclobutane carboxylic acid methyl ester and sodium methylmercaptan using the procedure described in example 172.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:29][C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:29][C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)=[CH:4][CH:3]=1
Reactant: BrCc1cccnc1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccccc21
Product: O=C1OC2(CCN(C(=O)c3cn(Cc4cccnc4)c4cc(Cl)ccc34)CC2)c2ccccc21

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 16) with commercially available 3-bromomethyl-pyridine gave the title compound.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH:9]1([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[F:21][C:22]1[CH:36]=[CH:35][C:25]([C:26]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[O:27])=[CH:24][CH:23]=1>O1CCCC1>[CH:9]1([CH:15]([C:26]([C:25]2[CH:35]=[CH:36][C:22]([F:21])=[CH:23][CH:24]=2)([C:28]2[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=2)[OH:27])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CCOC(=O)CC1CCCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C1CCCCC1)C(O)(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 813.5 %

Procedure:
Lithium diisopropylamide (56 mL of 1.8M, 100 mmol) was added to a solution of ethyl cyclohexylacetate (16.0 g, 100 mmol) in 50 mL tetrahydrofuran at -40° C. and the solution stirred for 0.5 hour. After further cooling to -70° C., 4,4'-difluorobenzophenone (10.9 g, 50 mmol) was added and the solution stirred for 1 hour at -70° C. and then allowed to warm to -10° C. during the next 2 hrs. The reaction was quenched with 2N hydrochloric acid and extracted with diethyl ether. The extracts were dried with magnesium sulfate and concentrated in vacuo. The residue was crystallized from hexane to give 158 g of the title compound; m.p. =118°-119° C.
Reaction SMILES: [N-]=[N+]=[N-].[Na+].Br[CH:6]([CH3:20])[C:7]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([C:16]([F:19])([F:18])[F:17])[CH:10]=1)=[O:8].[N-:21]=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:43]1([CH3:53])[CH:48]=[CH:47][C:46]([S:49]([OH:52])(=[O:51])=[O:50])=[CH:45][CH:44]=1>O1CCCC1>[C:43]1([CH3:53])[CH:44]=[CH:45][C:46]([S:49]([OH:52])(=[O:50])=[O:51])=[CH:47][CH:48]=1.[NH2:21][CH:6]([CH3:20])[C:7]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([C:16]([F:19])([F:18])[F:17])[CH:10]=1)=[O:8]
Reactant: CC(Br)C(=O)c1ccc(F)c(C(F)(F)F)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(N)C(=O)c1ccc(F)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.3 %

Procedure:
Add sodium azide (640.94 mg; 1.05 equiv; 9.76 mmoles) in one portion to a solution of 2-Bromo-1-(4-fluoro-3-trifluoromethyl-phenyl)-propan-1-one (2.78 g; 1.00 equiv; 9.30 mmoles) in tetrahydrofuran (15 mL). Stir the mixture at room temperature overnight. Filter the solids and wash with THF. Add the crude azide (1.00 equiv; 9.30 mmoles; 2.43 g) to a solution of triphenylphosphine (1.06 equiv; 9.86 mmoles; 2.61 g) and p-Toluenesulfonic Acid (2.2 equiv; 20.47 mmoles; 3.56 g) in tetrahydrofuran (15 mL) under 20° C. Stir the mixture overnight. Filter the solid, then wash with THF to obtain 920 mg (24%) of the title compound.