Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[C:4]([N:24]2[CH2:28][CH2:27][CH2:26][S:25]2(=[O:30])=[O:29])[CH:3]=1.[O:31]1[CH2:35][CH:34]=[N:33][C:32]1=[O:36]>>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:33]3[CH2:34][CH2:35][O:31][C:32]3=[O:36])=[CH:3][C:4]=2[N:24]2[CH2:28][CH2:27][CH2:26][S:25]2(=[O:30])=[O:29])=[O:9])[CH2:11][CH2:12]1
Reactant: O=C1N=CCO1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCOC4=O)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Yield: 88.9 %

Procedure:
By reaction and treatment in the same manner as in Example 149 and using [4-bromo-2-(1,1-dioxoisothiazolidin-2-yl)phenyl][4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (492 mg) described in Preparation Example 181 and oxazolin-2-one (104 mg), the title compound (443 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]=[C:10]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[C:9]3[CH:19]=[CH:20][C:21]([C:23]([F:26])([F:25])[F:24])=[CH:22][C:8]=3[O:7][C:6]=2[CH:27]=1.[BH4-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH:10]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[C:9]3[CH:19]=[CH:20][C:21]([C:23]([F:26])([F:25])[F:24])=[CH:22][C:8]=3[O:7][C:6]=2[CH:27]=1
Reactant: CN1CCN(C2=Cc3ccc(Cl)cc3Oc3cc(C(F)(F)F)ccc32)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CN1CCN(C2Cc3ccc(Cl)cc3Oc3cc(C(F)(F)F)ccc32)CC1

Procedure:
11.9 G. of 1-[3-chloro-7-trifluoromethyl-dibenz[b,f]oxepin-10-yl]-4-methyl-piperazine was reduced with sodium borohydride in glacial acetic acid in a manner analogous to that described in Example 14, and there is obtained crude 1-[3-chloro-10,11-dihydro-7-trifluoromethyl-dibenz[b,f]oxepin-10-yl]-4-methyl-piperazine which is recrystallized from isopropanol and melts at 110° C. The dihydrochloride, prepared in ethanol, melts at 219°-222° C. (with decomposition).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[Na+].Cl[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1>C1(C)C=CC=CC=1.C1(C2(C3C=CC=CC=3)CC2(P(C(C)(C)C)C(C)(C)C)C)C=CC=CC=1>[C:8]1([N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COc1ccc(Cl)cc1
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: CC(C)(C)P(C(C)(C)C)C1(C)CC1(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 96.2 %

Procedure:
To a solution of diphenylamine (0.34 g, 2.0 mmol) in 4 ml of toluene were added sodium tert-butoxide (0.23 g, 2.4 mmol), 4-chloroanisole (0.27 ml, 2.2 mmol), (π-allyl)palladium chloride (3.7 mg, 0.01 mmol) and 2,2-diphenyl-1-(di-tert-butylphosphino)-1-methylcyclopropane (14.1 mg, 0.04 mmol) obtained in Example 4 under a nitrogen atmosphere and the mixture was stirred for 3 hours at 100° C. The reaction mixture was cooled, washed with water, and dried over anhydrous magnesium sulfate. Then, the solvent was removed under reduced pressure, and the concentrate was purified by column chromatography to give the title compound (0.53 g, 95%) as white crystal.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[N:5][N:4]=[C:3]1[C@H:7]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:30]=[C:29]([CH3:31])[C:28]3[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=3[CH:22]=2)=[CH:15][CH:14]=1)[CH2:8][C:9]([O:11]C)=[O:10].[Li+].[OH-]>C1COCC1.CCO>[CH3:1][N:2]1[CH:6]=[N:5][N:4]=[C:3]1[C@H:7]([C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]2[CH:30]=[C:29]([CH3:31])[C:28]3[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=3[CH:22]=2)=[CH:17][CH:18]=1)[CH2:8][C:9]([OH:11])=[O:10]
Reactant: COC(=O)C[C@@H](c1ccc(OCc2cc(C)c3c(c2)CCCC3)cc1)c1nncn1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(COc2ccc([C@H](CC(=O)O)c3nncn3C)cc2)cc2c1CCCC2
Temperature: 23 °C

Procedure:
To a stirred solution of 46.7 (150 mg, 3.6 mmol) in THF/EtOH (6 mL, 3/1, v/v) was added 1N LiOH (aq) (2 mL). The reaction mixture is stirred at 23° C. until TLC confirms consumption of the starting material. The organic solvent is removed in vacuo. 1N HCl is added to neutralize the mixture to pH 7. The mixture is extracted with EtOAc (2×10 mL), concentrated in vacuo. The residue is purified by column chromatography (silica, MeOH/DCM), to afford acid 46.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.F[C:22]1[C:27]([CH:28]2[CH2:32][CH2:31][C:30]([CH3:34])([OH:33])[CH2:29]2)=[CH:26][CH:25]=[CH:24][N:23]=1.CN1C(=O)CCC1>C(OCC)(=O)C>[CH3:34][C:30]1([OH:33])[CH2:31][CH2:32][CH:28]([C:27]2[C:22]([O:20][C:17]3[CH:18]=[CH:19][C:14]([NH:13][C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][N:7]=4)=[CH:15][CH:16]=3)=[N:23][CH:24]=[CH:25][CH:26]=2)[CH2:29]1
Reactant: CC1(O)CCC(c2cccnc2F)C1
Reactant: Oc1ccc(Nc2ccccn2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC1(O)CCC(c2cccnc2Oc2ccc(Nc3ccccn3)cc2)C1
Temperature: 200 °C
Reaction time: 0.25 h

Procedure:
To a 20 mL microwave vial was added cesium carbonate (834 mg, 2.56 mmol), 4-(pyridin-2-ylamino)phenol (191 mg, 1.024 mmol), and 3-(2-fluoropyridin-3-yl)-1-methylcyclopentanol (200 mg, 1.024 mmol) followed by NMP (2049 μL). The slurry was heated to 200° C. for 3 h in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden). The reaction mixture was diluted with ethyl acetate (35 mL) and washed with 5N NaOH (5×30 mL) before drying over magnesium sulfate, filtering, and concentrating to a dark orange oil under reduced pressure. The oil was dissolved in 2 mL DMSO and transferred to a preparative HPLC vial through a 0.45 μm syringe filter. The crude compound was purified in three aliquots over 25 minutes per sample (5% 0.1% TFA in ACN:0.1% TFA in water to 80% over 15 minutes with a ten minute hold at 80%) on a Shimadzu Prominence Prep HPLC. The major peaks were collected and diluted with DCM (40 mL) before washed with saturated aqueous sodium bicarbonate (3×40 mL), drying over magnesium sulfate, filtering, and concentrating under reduced pressure, yielding the product as a yellow oil. MS (ESI, pos. ion) m/z: 362.3 (M+1). IC50 (uM) 0.035.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].C(O[CH:16](OC(C)(C)C)[N:17]([CH3:19])[CH3:18])(C)(C)C>CN(C=O)C>[CH3:16][N:17]([CH:19]=[C:3]1[C:4]2=[N:5][CH:6]=[CH:7][CH:8]=[C:9]2[NH:1][C:2]1=[O:10])[CH3:18]
Reactant: CN(C)C(OC(C)(C)C)OC(C)(C)C
Reactant: O=C1Cc2ncccc2N1
Solvent: CN(C)C=O
Product: CN(C)C=C1C(=O)Nc2cccnc21

Procedure:
This monomer was generated in situ (during library synthesis) from 1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one and dimethylformamide di-t-butylacetal in DMF.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1.C(N(CC)CC)C.[C:29](Cl)(=[O:31])[CH3:30].N(CC)(CC)CC.Cl>C(Cl)Cl.O>[C:29]([NH:2][C:3]1[CH:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:6]=[CH:5][C:4]=1[N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1)(=[O:31])[CH3:30]
Reactant: Nc1cc(C(F)(F)F)ccc1N1CCc2ccccc21
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)Nc1cc(C(F)(F)F)ccc1N1CCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred mixture, under N2, of 6.30 g of 1-(2-amino-4-trifluoromethylphenyl)indoline hydrochloride in 100 ml of dry methylene chloride is added 4.04 g of triethylamine. The mixture is then cooled to 0°-5°, and kept at that temperature while a solution of 1.57 g of acetyl chloride in 25 ml of CH2Cl2 is added dropwise over 1 hour. After stirring at room temperature overnight, water is added to dissolve the precipitated (C2H5)3N.HCl salt, and the layers are separated. The organic phase is washed further with 3N--HCl, 3N--NaOH, with H2O and dried over Na2SO4. The solvent is removed to yield 1-(2-acetamido-4-trifluoromethylphenyl)indoline, m.p. 153°-155° C.
Reaction SMILES: C([O:5][C:6](=[O:27])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:19]2[N:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.I[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].[BrH:35].C(O)(=O)C>C(OCC)C>[BrH:35].[CH2:25]([C:22]1[CH:23]=[N:24][C:19]([N:18]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:17][CH2:16][C:14]2[N:15]=[C:11]([S:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:5])=[O:27])[S:12][CH:13]=2)=[N:20][CH:21]=1)[CH3:26]
Reactant: CCCCCCI
Reactant: CCc1cnc(NCCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)nc1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1ncc(CC)cn1

Procedure:
A compound obtained using 2-[(4-{2-[(5-ethylpyrimidin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester synthesized in Example 265-1 and 1-iodohexane as starting materials and by an operation similar to that of Example 326 was dissolved in diethyl ether, and reacted with 30% hydrobromic acid-acetic acid to give the title compound.
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([N:16]4[CH:20]=[C:19]([C:21]([OH:23])=O)[CH:18]=[N:17]4)[N:12]=[CH:11][C:10]=3[N:9]([CH3:24])[C:8](=[O:25])[C@H:7]2[CH2:26][CH3:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.C[CH2:29][N:30]=[C:31]=NCCCN(C)C.Cl.CNC.C1C=NC2N(O)N=NC=2C=1.C(N(CC)CC)C>C(Cl)Cl>[CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([N:16]4[CH:20]=[C:19]([C:21]([N:30]([CH3:31])[CH3:29])=[O:23])[CH:18]=[N:17]4)[N:12]=[CH:11][C:10]=3[N:9]([CH3:24])[C:8](=[O:25])[C@H:7]2[CH2:26][CH3:27])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(-n3cc(C(=O)O)cn3)nc2N1C1CCCC1
Reactant: CCN=C=NCCCN(C)C
Agent: CNC
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@@H]1C(=O)N(C)c2cnc(-n3cc(C(=O)N(C)C)cn3)nc2N1C1CCCC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
(R)-1-(8-Cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)-1H-pyrazole-4-carboxylic acid (Example 44, 0.14 g, 0.378 mmol) was dissolved in 2 mL of DCM and EDCI (79 mg, 0.415 mmol), dimethylamine hydrochloride (46 mg, 0.567 mmol), HOAt (5 mg, 0.0379 mmol) and triethylamine (115 mg, 1.13 mmol) were added. The resulting solution was stirred at rt for 48 hours after which the reaction mixture was diluted with DCM and washed with 0.1 N aqueous HCl then 1 N aqueous NaOH, dried with Na2SO4, filtered, concentrated under vacuum and purified by preparative HPLC to give the title compound. 1H NMR (CDCl3) δ: 7.55-7.57 (s, 1H), 7.40-7.51 (m, 2H), 4.26-4.51 (m, 2H), 3.11-3.39 (m, 9H), 1.64-2.18 (m, 10H), and 0.97 ppm (m, 3H); LCMS: 398.1 m/z (M+H)+; ret. Time: 3.267 min (Analytical Method A).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]2[CH:23]=[CH:22][C:11]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:10][CH:9]=2)[CH2:3]1.Br[CH2:25][CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:27]1([CH2:26][CH2:25][N:2]2[CH2:7][CH2:6][CH2:5][CH:4]([C:8]3[CH:9]=[CH:10][C:11]([O:12][C:13]4[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=4)=[CH:22][CH:23]=3)[CH2:3]2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: NC(=O)c1ccc(Oc2ccc(C3CCCNC3)cc2)nc1
Reactant: BrCCC1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(Oc2ccc(C3CCCN(CCC4CCCCC4)C3)cc2)nc1
Yield: 41.8 %

Procedure:
Combine 6-(4-Piperidin-3-yl-phenoxy)-nicotinamide (free base compound of example 322) (0.0255 g, 0.0858 mmol), 1-bromo-2-cyclohexylethane (0.0150 mL, 0.0958 mmol), and potassium carbonate (0.0245 g, 0.177 mmol) in dimethylformamide (1.0 mL) and stir for 10 min. Purify the reaction mixture by ion exchange chromatography (SCX resin, methanol→2 M ammonia/methanol) and silica gel chromatography (15:1→10:1 ethyl acetate:methanol) to provide 0.0146 g (42%) of the title compound as an off-white foam: high resolution mass spectrum (electrospray): m/z calc for C25H34N3O2 408.2651, found 408.2661; 1H NMR (methanol-d4): 8.61 (s br, 1H), 8.28 (d, 1H, J=7.8 Hz), 7.36 (d, 2H, J=7.8 Hz), 7.12 (d, 2H, J=7.8 Hz), 7.01 (d, 1H, J=8.3 Hz), 3.07 (d, 2H, J=10.2 Hz), 2.89 (t, 1H, J=11.2 Hz), 2.55-2.42 (m, 2H), 2.15-1.93 (m, 4H), 1.93-1.64 (m, 8H), 1.63-1.43 (m, 4H), 1.40-1.15 (m, 8H), 1.07-0.86 (m, 3H).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:18]([C:25]1[CH:26]=[C:27]([N:31]=[C:32]=[O:33])[CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[O:18]([C:25]1[CH:26]=[C:27]([NH:31][C:32](=[O:33])[O:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]3)[CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C=Nc1cccc(Oc2ccccc2)c1
Reactant: Oc1ccc2c(c1)CCN2Cc1ccccc1
Product: O=C(Nc1cccc(Oc2ccccc2)c1)Oc1ccc2c(c1)CCN2Cc1ccccc1

Procedure:
The title compound was synthesized from 1-benzylindolin-5-ol (30.0 mg, 0.133 mmol) using the same procedure employed for Example 2 (2), but with 3-phenoxyphenylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained having the following characteristics (16.5 mg, 28%).
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:9][CH2:10][NH2:11])[CH:5]=[C:6]([I:8])[N:7]=1)[CH3:2].[CH3:12][C:13]1[CH:14]=[C:15]([CH2:20][CH2:21][CH:22]=O)[CH:16]=[CH:17][C:18]=1[CH3:19]>>[CH3:12][C:13]1[CH:14]=[C:15]([CH2:20][CH2:21][CH:22]2[NH:11][CH2:10][CH2:9][N:4]3[C:3]([CH2:1][CH3:2])=[N:7][C:6]([I:8])=[C:5]23)[CH:16]=[CH:17][C:18]=1[CH3:19]
Reactant: CCc1nc(I)cn1CCN
Reactant: Cc1ccc(CCC=O)cc1C
Product: CCc1nc(I)c2n1CCNC2CCc1ccc(C)c(C)c1

Procedure:
According to the general procedure (GP10), the microwave-assisted Pictet-Spengler reaction (60 W; 100° C.; 8 bars; 10 min.) between 2-(2-ethyl-4-iodo-imidazol-1-yl)-ethylamine (344.6 mg; 1.300 mmol) and 3-(3,4-dimethyl-phenyl)-propionaldehyde (211.4 mg; 1.300 mmol) afforded 8-[2-(3,4-dimethyl-phenyl)-ethyl]-3-ethyl-1-iodo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine which was Boc-protected and finally purified by HPLC.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]([CH3:14])([CH3:13])[C:9]([O:11]C)=[O:10])=[CH:4][CH:3]=1.[OH-].[Na+].CO>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]([CH3:13])([CH3:14])[C:9]([OH:11])=[O:10])=[CH:15][CH:16]=1
Reactant: COC(=O)C(C)(C)COc1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(COc1ccc(Br)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.8 %

Procedure:
In tetrahydrofuran (40 mL) was dissolved methyl 3-(4-bromophenoxy)-2,2-dimethylpropanoate (3.2 g), 2N aqueous sodium hydroxide solution (10 mL) was added to the solution, and the mixture was stirred at room temperature overnight. After adding methanol (10 mL) to the mixture, the resulting mixture was refluxed for 3 hours. To the residue obtained by concentrating the reaction mixture under reduced pressure were added ethyl acetate and 1N hydrochloric acid, and the liquids were separated. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 3-(4-bromophenoxy)-2,2-dimethylpropanoic acid (2.886 g).
Reaction SMILES: [BH4-].[Na+].B(F)(F)F.CCOCC.[CH3:12][N:13]1[C:19]2[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:18]=2[C:17]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:16][CH2:15][C:14]1=O.Cl.N>O1CCCC1>[CH3:12][N:13]1[C:19]2[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:18]=2[C:17]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[N:16][CH2:15][CH2:14]1
Reactant: CN1C(=O)CN=C(c2ccccc2)c2cc(Cl)ccc21
Agent: Cl
Agent: FB(F)F
Agent: N
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN1CCN=C(c2ccccc2)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 103 %

Procedure:
To a suspension of 2.28 g of sodium borohydride in 35ml of tetrahydrofuran was added dropwise with stirring a solution of 13.0 g of boron trifluoride etherate in 10ml of tetrahydrofuran below 10° C, and the mixture was stirred at room temperature for 45 minutes. To the mixture was added dropwise solution of 1.43 g of 1-methyl-5-phenyl-7-chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one in 10 ml of tetrahydrofuran at -15° to -12.5° C over a period of 5 minutes, and then the mixture was stirred at =15° C for 22 hours. The reaction mixture was poured into 100 ml of ice-water, and then 20 ml of concentrated hydrochloric acid was added. The mixture was refluxed for 30 minutes, then cooled, and neutralized with concentrated ammonia. The tetrahydrofuran layer was separated, and the aqueous layer was extracted with ether. The combined organic layer was washed with water and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 1.4 g of 1-methyl-5-phenyl-7-chloro-2,3-dihydro-1H-1,4-benzodiazepine.
Reaction SMILES: C([CH:5]1[CH:9]([OH:10])[CH2:8][CH2:7][N:6]1[C:11]([OH:13])=[O:12])(C)(C)C.[H-].[Na+].[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1>C1COCC1>[C:20]([O:13][C:11]([N:6]1[CH2:7][CH2:8][CH:9]([O:10][CH2:21][C:20]2[CH:23]=[CH:24][C:17]([Cl:16])=[CH:18][CH:19]=2)[CH2:5]1)=[O:12])([CH3:23])([CH3:21])[CH3:19]
Reactant: CC(C)(C)C1C(O)CCN1C(=O)O
Reactant: Clc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(OCc2ccc(Cl)cc2)C1
Yield: 110.6 %

Procedure:
A solution of tert-butyl 3-hydroxy-1-pyrrolidinecarboxylic acid (0.27 g, 1.44 mmol) in dry THF (4 mL) was added dropwise to a cold (0° C.), stirred suspension of sodium hydride (0.078 g, 2.17 mmol, ca. 50% suspension in oil) in THF (10 mL). After 30 min. a solution of 4-chlorobenzyl bromide (0.36 g, 1.74 mmol) in THF (2 mL) was added and the resulting suspension was stirred at R.T. overnight. The reaction mixture was partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate and the combined organic phase was washed with saturated aqueous sodium chloride, dried and concentrated. The residue was subjected to flash chromatography (heptane-ethyl acetate, 6:1) to afford the subtitle compound 3-(4-Chloro-benzyloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester as an oil (0.30 g, 66.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=O.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[C:45]([O:49][C:50]([N:52]1[CH2:57][CH2:56][C:55]([NH2:60])([C:58]#[N:59])[CH2:54][CH2:53]1)=[O:51])([CH3:48])([CH3:47])[CH3:46]>CN(C=O)C.O>[C:45]([O:49][C:50]([N:52]1[CH2:53][CH2:54][C:55]([C:58]#[N:59])([NH:60][C:10](=[O:12])[CH2:9][C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[CH2:56][CH2:57]1)=[O:51])([CH3:48])([CH3:46])[CH3:47]
Reactant: CC(C)(C)OC(=O)N1CCC(N)(C#N)CC1
Reactant: O=C(O)Cc1ccc(Cl)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C#N)(NC(=O)Cc2ccc(Cl)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.8 %

Procedure:
(2,4-Dichloro-phenyl)-acetic acid (218 mg, 1.07 mmol), 1-ethyl-3-(3′-dimethylamino-propyl)carbodiimide hydrochloride (255 mg, 1.33 mmol), 1-hydroxybenzotriazole hydrate (136 mg, 0.88 mmol) and N,N-diisopropylethylamine (0.378 ml, 2.22 mmol) were sequentially added to a solution of 4-amino-4-cyano-piperidine-1-carboxylic acid tert-butyl ester (200 mg, 0.888 mmol) in DMF (4 ml) at room temperature, and the mixture was stirred at room temperature for 16 hours. H2O (20 ml) was added to the reaction mixture, followed by extraction with AcOEt (40 ml and 20 ml). The organic layers were sequentially washed with H2O (20 ml), 1 N HCl (20 ml), H2O (20 ml) and saturated brine (20 ml), and then dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane/AcOEt) to give 4-cyano-4-[2-(2,4-dichloro-phenyl)-acetylamino]-piperidine-1-carboxylic acid tert-butyl ester as a white powder (285 mg, 78%).
Reaction SMILES: [O:1]=[C:2]1[CH:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:5][N:4]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:3]1.CCN(C(C)C)C(C)C.[O:29](S(C(F)(F)F)(=O)=O)[S:30]([C:33]([F:36])([F:35])[F:34])(=O)=[O:31]>C(Cl)Cl>[F:34][C:33]([F:36])([F:35])[S:30]([O:1][C:2]1[CH2:3][N:4]([C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])[CH2:5][CH2:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:31])=[O:29]
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1=O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 1-tert-butyl 4-ethyl 3-oxopiperidine-1,4-dicarboxylate (2.0 g, 7.37 mmol) in DCM (45 mL) was added DIPEA (1.54 ml, 8.84 mmol) and Tf2O (1.36 mL, 8.11 mmol) at −78° C., then the temperature was warmed up to room temperature and the solution was stirred at RT for 1.5 h, the mixture was diluted with DCM (100 mL), organic layer was washed with Sat. NaHCO3, brine, dried and concentrated to give 1-(tert-butyl) 4-ethyl 5-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1,4(2H)-dicarboxylate, which was used for next step without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=2[F:20])=O)=[CH:5][CH:4]=1.Cl.[F:22][C:23]1[CH:24]=[C:25]([CH:30]([NH2:32])[CH3:31])[CH:26]=[CH:27][C:28]=1[F:29].C(N(CC)CC)C.C([BH3-])#N.[Na+]>[Ti](Cl)(Cl)(Cl)Cl.C(O)(=O)C>[F:22][C:23]1[CH:24]=[C:25]([CH:30]([NH:32][CH:9]([C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=2[F:20])[C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH3:31])[CH:26]=[CH:27][C:28]=1[F:29]
Reactant: COc1ccc(C(=O)c2cc([N+](=O)[O-])ccc2F)cc1
Reactant: CC(N)c1ccc(F)c(F)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: COc1ccc(C(NC(C)c2ccc(F)c(F)c2)c2cc([N+](=O)[O-])ccc2F)cc1
Yield: 68.7 %

Procedure:
Following a similar procedure to that described in Example (1a), 828 mg of 2-fluoro-5-nitrophenyl 4-methoxyphenyl ketone, 1.16 g of 1-(3,4-difluorophenyl)ethylamine hydrochloride, 2.52 ml of triethylamine, 0.40 ml of titanium tetrachloride, 840 mg of sodium cyanoborohydride and 0.62 ml of acetic acid were reacted, to obtain 860 mg of the title compound as a yellow oil.
Reaction SMILES: [OH:1][C:2]1([CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])[C:7](=[O:8])[NH:6][C:5](=[O:9])[NH:4][C:3]1=[O:10].N1C=CC=CC=1.Cl.[C:26](Cl)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28]>>[C:26]([O:1][C:2]1([CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])[C:3](=[O:10])[NH:4][C:5](=[O:9])[NH:6][C:7]1=[O:8])(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(c1ccccc1)C1(O)C(=O)NC(=O)NC1=O
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CC(c1ccccc1)C1(OC(=O)C(C)(C)C)C(=O)NC(=O)NC1=O
Temperature: 75 °C

Procedure:
The amount of 5 g. of 5-hydroxy-5-(1-phenylethyl) barbituric acid, prepared following the procedure described in Belgian Pat. No. 775,117, was dissolved in a mixture of pivaloyl chloride (5 ml.) and 60 ml. pyridine. The mixture was heated at 75°C overnight, then cooled and poured into ice containing 60 ml. of concentrated hydrochloric acid. The product was extracted four times with ethyl acetate, and the combined extracts washed with saturated sodium chloride solution, sodium bicarbonate solution, dilute hydrochloric acid and sodium chloride solution. After drying over anhydrous sodium sulfate, solvent was removed by evaporation on a Buchi Rotovapor apparatus. The resulting product was purified by column chromatography (230 g. silica gel). Elution with 5% ethyl acetate in benzene solution followed by recrystallization from benzene provided 5-pivaloyloxy-5-(1-phenylethyl) barbituric acid, m.p. 205°-207°C.