Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[C:6](=[O:7])[CH2:5][C:4]2([CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]2)[O:3]1.[BH4-].[Na+].Cl>C(O)C>[NH3:10].[OH:7][CH:6]1[CH2:5][C:4]2([CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]2)[O:3][CH:2]1[CH3:1]
Reactant: CC1OC2(CCN(C)CC2)CC1=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC1OC2(CCN(C)CC2)CC1O
Product: N
Temperature: 25 °C
Reaction time: 2 h
Yield: 197.8 %

Procedure:
To a solution of 2,8-dimethyl-1-oxa-8-azaspiro[4,5]decan-3-one (200 mg) in 7 ml ethanol, was added 25 mg sodium borohydride at room temperature, and the mixture was stirred at room temperature for two hours. The reaction mixture was cooled in an ice-water bath, acidified by addition of 6N--HCl (to about pH 4), and stirred for about 20 minutes with the ice-water bath removed. Ethanol was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography by using, as eluent, a mixed solvent of chloroform/methanol/conc. ammonia (5:1:0.1 by volume), giving 200 mg of 3-hydroxy-2,8-dimethyl-1-oxa-8-azaspiro[4,5]decane as oil. It was dissolved in ether, and ethanolic hydrogen chloride was added to this solution, thus giving its hydrochloride as white crystals.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][C:16]3=[O:21])=[CH:11][CH:10]=2)[CH2:4]1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:28][C:29]1[S:33][C:32]([C:34](Cl)=[O:35])=[CH:31][CH:30]=1>O.CC(C)=O.C1(C)C=CC=CC=1>[Cl:28][C:29]1[S:33][C:32]([C:34]([NH:1][CH2:2][C@@H:3]2[O:7][C:6](=[O:8])[N:5]([C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][C:16]4=[O:21])=[CH:11][CH:10]=3)[CH2:4]2)=[O:35])=[CH:31][CH:30]=1
Reactant: NC[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1
Reactant: O=C(Cl)c1ccc(Cl)s1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(NC[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1)c1ccc(Cl)s1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
1160 g of 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one (VII) hydrochloride, 350 ml of water and 2.7 l of acetone are successively added to a solution of 464 g of sodium carbonate in 5.95 l of water at 10° C. At 8 to 12° C., 2535 g of 5-chlorothiophene-2-carbonyl chloride (IV) (30% strength solution in toluene) and a further 517 ml of toluene are added. The reaction mixture is then heated to 50° C., 2700 ml of acetone are added, and the mixture is stirred at 50 to 53° C. for a further 30 minutes. After cooling to 26° C., the precipitated reaction product is filtered off with suction and washed with water and acetone.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][CH2:8][CH:9]1[CH2:12][N:11]([CH2:13][C:14]#[C:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][C:21]=2[O:22][C:23]2[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][C:24]=2[F:30])[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[CH3:32][O:33][C:34]1[CH:69]=[CH:68][C:37]([CH2:38][NH:39][C:40]2[N:45]=[CH:44][N:43]=[C:42]([O:46][C:47]3[CH:52]=[CH:51][C:50]([NH:53][C:54]([NH:56][C:57](=[O:66])[CH2:58][C:59]4[CH:64]=[CH:63][C:62]([F:65])=[CH:61][CH:60]=4)=[O:55])=[CH:49][C:48]=3[F:67])[CH:41]=2)=[CH:36][CH:35]=1>>[F:65][C:62]1[CH:61]=[CH:60][C:59]([CH2:58][C:57]([N:56]=[C:54]=[O:55])=[O:66])=[CH:64][CH:63]=1.[CH3:32][O:33][C:34]1[CH:35]=[CH:36][C:37]([CH2:38][NH:39][C:40]2[N:45]=[CH:44][N:43]=[C:42]([O:46][C:47]3[CH:52]=[CH:51][C:50]([NH:53][C:54]([NH:56][C:57](=[O:66])[CH2:58][C:59]4[CH:64]=[CH:63][C:62]([F:65])=[CH:61][CH:60]=4)=[O:55])=[CH:49][C:48]=3[F:67])[CH:41]=2)=[CH:68][CH:69]=1.[C:1]([O:5][C:6](=[O:31])[NH:7][CH2:8][CH:9]1[CH2:12][N:11]([CH2:13][C:14]#[C:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][C:21]=2[O:22][C:23]2[CH:28]=[CH:27][C:26]([NH:29][C:54]([NH:56][C:57](=[O:66])[CH2:58][C:59]3[CH:64]=[CH:63][C:62]([F:65])=[CH:61][CH:60]=3)=[O:55])=[CH:25][C:24]=2[F:30])[CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC1CN(CC#Cc2cnccc2Oc2ccc(N)cc2F)C1
Agent: COc1ccc(CNc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3F)ncn2)cc1
Product: CC(C)(C)OC(=O)NCC1CN(CC#Cc2cnccc2Oc2ccc(NC(=O)NC(=O)Cc3ccc(F)cc3)cc2F)C1
Product: O=C=NC(=O)Cc1ccc(F)cc1
Yield: 57 %

Procedure:
The title compound was prepared from tert-butyl(1-(3-(4-(4-amino-2-fluorophenoxy)pyridin-3-yl)prop-2-ynyl)azetidin-3-yl)methylcarbamate (25 mg, 0.059 mmol) and a 0.3 M solution of 2-(4-fluorophenyl)acetyl isocyanate in toluene (Compound D of Example 11, 0.37 mL, 0.11 mmol) in the same manner as Step D of Example 33 to give the title compound as a white solid (20 mg, 57%). 1H NMR (DMSO-d6) δ 11.04 (s, 1H), 10.58 (s, 1H), 8.63 (s, 1H), 8.37 (d, 1H, J=5.5 Hz), 7.78 (d, 1H, J=12.6 Hz), 7.40-7.33 (m, 4H), 7.16 (dd, 2H, J=8.8, 8.9 Hz), 6.89-6.87 (m, 1H), 6.68 (d, 1H, J=5.5 Hz), 3.73 (s, 2H), 3.45 (s, 2H), 3.26-3.24 (m, 2H), 3.07-3.04 (m, 2H), 2.98-2.96 (m, 2H), 2.38-2.35 (m, 2H), 1.32 (s, 9H); MS(ESI+): m/z 606.26 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][CH:13]([NH:16][CH:17]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[C:18]([O:20][CH3:21])=[O:19])[CH2:12][CH2:11]2)=[CH:2]1.[F:28][C:29]1[CH:30]=[C:31]([CH:37]=[C:38]([F:41])[C:39]=1[F:40])/[CH:32]=[CH:33]/[C:34](O)=[O:35]>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C@H:10]2[CH2:15][CH2:14][C@H:13]([NH:16][CH:17]([CH:22]3[CH2:23][CH2:24][N:25]([C:34](=[O:35])/[CH:33]=[CH:32]/[C:31]4[CH:30]=[C:29]([F:28])[C:39]([F:40])=[C:38]([F:41])[CH:37]=4)[CH2:26][CH2:27]3)[C:18]([O:20][CH3:21])=[O:19])[CH2:12][CH2:11]2)=[CH:2]1
Reactant: COC(=O)C(NC1CCC(c2c[nH]c3ccccc23)CC1)C1CCNCC1
Reactant: O=C(O)/C=C/c1cc(F)c(F)c(F)c1
Product: COC(=O)C(N[C@H]1CC[C@H](c2c[nH]c3ccccc32)CC1)C1CCN(C(=O)/C=C/c2cc(F)c(F)c(F)c2)CC1

Procedure:
The title compound was prepared from methyl 2-((4-(1H-indol-3-yl)cyclohexyl)amino)-2-(piperidin-4-yl)acetate (from Example 24, step A) and trans-3,4,5-trifluorocinnamic acid, by the method of Example 1, step K, and the mixture of product diastereomers was separated by flash chromatography giving a pale yellow solid for the more polar cyclohexyl diastereomer (trans, Example 49a), a tan solid for the less polar cyclohexyl diastereomer (cis, Example 49b). Mass spectrum (LCMS, APCI pos.) calcd. for C31H35F2N3O3: 536 (M+H). Found: 536.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:12]([NH:14][CH2:15][C:16]([NH:18][CH2:19][C:20]([NH2:22])=[O:21])=[O:17])=[O:13])[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].O>CO.[Pd]>[NH2:1][C@H:2]([C:12]([NH:14][CH2:15][C:16]([NH:18][CH2:19][C:20]([NH2:22])=[O:21])=[O:17])=[O:13])[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:9])([CH3:10])[CH3:8]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)NCC(=O)NCC(N)=O
Agent: [Pd]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)CC[C@H](N)C(=O)NCC(=O)NCC(N)=O
Reaction time: 4 h
Yield: 96.8 %

Procedure:
940 mg (2.09 mmol) of Z-Glu(OtBu)-Gly-GlyNH2 was dissolved in 40 mL of 95:5 methanol:de-ionized water in a 250 mL glass PARR hydrogenation shaker flak. 222 mg of 10% palladium on carbon was added to the flask and the contents were hydrogenated with shaking under hydrogen (40 PSI) for 4 hours. The mixture was vacuum filtered though celite filter aid and solvent was removed from the filtrate by rotary evaporation to give 640 mg (94%) of the title compound. 1H NMR (400 MHz, DMSO) δ 4.03 (s, 1H), 3.75 (d, J=3.3, 2H), 3.63 (s, 2H), 3.30-3.22 (m, J=3.6, 1H), 3.14-3.10 (m, 1H), 2.27 (t, J=7.9, 2H), 1.84 (td, J=13.6, 7.4, 1H), 1.63 (td, J=15.0, 7.5, 1H), 1.39 (s, 9H). 13C NMR (101 MHz, MeOD) δ 176.53, 174.24, 172.00, 170.32, 81.82, 55.21, 43.64, 43.16, 40.44, 32.31, 30.45, 28.41. HRMS (M+H+) Calc. 317.1825 found 317.1800.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][C:11]1[O:15][C:14]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][CH:17]=2)=[N:13][N:12]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:46][CH2:47][C:48]([N:50]1[CH2:55][CH2:54][N:53]([C:56](=[O:67])[C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=2[C:63]([F:66])([F:65])[F:64])[CH2:52][CH2:51]1)=[O:49].Cl>CN(C=O)C.O>[CH3:10][C:11]1[O:15][C:14]([C:16]2[CH:17]=[CH:18][C:19]([C:20]([NH:46][CH2:47][C:48](=[O:49])[N:50]3[CH2:51][CH2:52][N:53]([C:56](=[O:67])[C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=4[C:63]([F:64])([F:66])[F:65])[CH2:54][CH2:55]3)=[O:22])=[CH:23][CH:24]=2)=[N:13][N:12]=1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Reactant: Cc1nnc(-c2ccc(C(=O)O)cc2)o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1nnc(-c2ccc(C(=O)NCC(=O)N3CCN(C(=O)c4ccccc4C(F)(F)F)CC3)cc2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.9 %

Procedure:
DIPEA (180 mg, 0.24 mL, 1.4 mmol) was added drop wise to 4-(5-methyl-[1,3,4]oxadiazol-2-yl)-benzoic acid (90 mg, 0.4 mmol) in DMF (3 mL). EDCI (92 mg, 0.48 mmol) and HOBT (65 mg, 0.48 mmol) were added consecutively and, after 10 minutes, 2-Amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone in its HCl salt form (150 mg, 0.4 mmol) was added. The resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue purified by column chromatography (using silica gel of 60-120 mesh and 10% EtOAc in Hexane as eluent to afford 40 mg (19.9% yield) of 4-(5-Methyl-[1,3,4]oxadiazol-2-yl)-N-{2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-benzamide. LCMS Purity: 96.6%. 1H NMR (CDCl3): δ 8.1 (d, 2H), 7.9 (m, 2H), 7.7 (m, 1H), 7.5 (m, 2H), 7.3 (m, 2H), 4.2 (m, 2H), 4.0 (m, 2H), 3.6 (m, 3H), 3.4 (m, 1H), 2.6 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][N:3]=1.[CH2:10]([Mg]Cl)[CH3:11].CCOCC>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]([OH:9])[CH2:10][CH3:11])[CH:5]=[CH:4][N:3]=1
Reactant: O=Cc1ccnc(Br)c1
Reactant: CC[Mg]Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC(O)c1ccnc(Br)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a chilled (−78° C.) solution of 2-bromo-pyridine-4-carbaldehyde (7.0 g, 38 mmol) in THF (200 mL) was added a 2 M solution of ethylmagnesium chloride in ether (23.5 mL, 47.0 mmol) over a 10 minute period. After 15 minutes, the mixture was gradually warmed to room temperature over 1 hour. The reaction was quenched by the slow addition of saturated aqueous NH4Cl (100 mL) and extracted with EtOAc (2×200 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated to afford a brown oil. The crude material was purified by silica gel chromatography eluting with a gradient of 20-40% EtOAc in hexanes to afford 1-(2-bromo-pyridin-4-yl)-propan-1-ol.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].CCCCCCC.O1CCCC1.C(C1C=CC=CC=1)C.CN(C)CCN(C)C.[CH3:37][O:38][C:39](=[O:52])[CH2:40][C:41]1[CH:46]=[CH:45][C:44]([S:47]([CH3:50])(=[O:49])=[O:48])=[C:43]([Cl:51])[CH:42]=1.I[CH2:54][C@@H:55]1[CH2:60][CH2:59][CH2:58][S:57][CH2:56]1>O1CCCC1>[CH3:37][O:38][C:39](=[O:52])[CH:40]([C:41]1[CH:46]=[CH:45][C:44]([S:47]([CH3:50])(=[O:49])=[O:48])=[C:43]([Cl:51])[CH:42]=1)[CH2:54][C@H:55]1[CH2:60][CH2:59][CH2:58][S:57][CH2:56]1
Reactant: IC[C@@H]1CCCSC1
Reactant: COC(=O)Cc1ccc(S(C)(=O)=O)c(Cl)c1
Agent: CC(C)[N-]C(C)C
Agent: CN(C)CCN(C)C
Agent: [Li+]
Solvent: CCc1ccccc1
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: COC(=O)C(C[C@H]1CCCSC1)c1ccc(S(C)(=O)=O)c(Cl)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
A 2.0M solution of lithium diisopropylamide in heptane/tetrahydrofuran/ethylbenzene (564.0 μL, 1.128 mmol) and N,N,N′,N′-tetramethylethylenediamine (157.0 μL, 1.040 mmol) in dry tetrahydrofuran (3 mL) cooled to −78° C. under nitrogen was treated with (3-chloro-4-methanesulfonyl-phenyl)-acetic acid methyl ester (269.4 mg, 1.02 mmol). The reaction mixture was stirred at −78° C. for 1 h and then warmed to 0° C. The reaction was then treated with a solution of 3(R)-iodomethyl-tetrahydro-thiopyran (71.00 mg, 0.293 mmol) in dry tetrahydrofuran (1 mL) and allowed to warm to 25° C., where it was stirred for 19 h. The reaction mixture was then quenched with a saturated aqueous ammonium chloride solution (10 mL) and then concentrated in vacuo to remove tetrahydrofuran. The aqueous residue was extracted with ethyl acetate (2×20 mL), and the combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 12M, Silica, 4/1 hexanes/ethyl acetate) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-3(R)-(tetrahydro-thiopyran-3-yl)-propionic acid methyl ester (96 mg, 86.9%) as a colorless oil: [α]23589=+10.93° (c=0.76, methanol); EI-HRMS m/e calcd for C16H21ClO4S2 (M+) 376.0570, found 376.0574.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)=[O:11].F[C:20]1[C:25]([CH:26]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][F:34])[CH2:28][CH2:27]2)=[N:24][CH:23]=[CH:22][N:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:20]2[C:25]([CH:26]3[CH2:27][CH2:28][N:29]([CH2:32][CH2:33][F:34])[CH2:30][CH2:31]3)=[N:24][CH:23]=[CH:22][N:21]=2)=[CH:14][CH:13]=1)=[O:11]
Reactant: O=C(c1ccc(O)cc1)c1nc2ccccc2[nH]1
Reactant: FCCN1CCC(c2nccnc2F)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: O=C(c1ccc(Oc2nccnc2C2CCN(CCF)CC2)cc1)c1nc2ccccc2[nH]1
Temperature: 80 °C

Procedure:
The mixture of (1H-benzo[d]imidazol-2-yl)(4-hydroxyphenyl)methanone (78 mg, 0.326 mmol), 2-fluoro-3-(1-(2-fluoroethyl)piperidin-4-yl)pyrazine (37 mg, 0.163 mmol), and cesium carbonate (106 mg, 0.326 mmol) in DMSO (0.5 mL) was heated at 80° C. for 20 h. The reaction mixture was partitioned between EtOAc and brine. The aqueous layer was back extracted with EtOAc (3×) and the combined organic layer was dried (Na2SO4) and concentrated. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 100% EtOAc in hexane, followed by reverse-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C18, 110 Å, 150×30 mm, 0.1% TFA in CH3CN/H2O, gradient 5% to 95% over 15 min then neutralization to provide (1H-benzo[d]imidazol-2-yl)(4-(3-(1-(2-fluoroethyl)piperidin-4-yl)pyrazin-2-yloxy)phenyl) as white solid. MS (ESI, pos. ion) m/z: 446.1 (M+1). IC50 (uM) +++++.
Reaction SMILES: N#N.[N+:3]([C:6]1[CH:10]=[N:9][N:8]([CH2:11][C:12]2[O:16][N:15]=[C:14]([C:17](=[O:19])[CH3:18])[CH:13]=2)[N:7]=1)([O-:5])=[O:4].COC([O:25][CH3:26])OC.[C:27]([O-])(O)=O.[Na+]>C(O)CO>[CH3:18][C:17]1([C:14]2[CH:13]=[C:12]([CH2:11][N:8]3[N:7]=[C:6]([N+:3]([O-:5])=[O:4])[CH:10]=[N:9]3)[O:16][N:15]=2)[O:25][CH2:26][CH2:27][O:19]1
Reactant: COC(OC)OC
Reactant: O=C([O-])O
Reactant: CC(=O)c1cc(Cn2ncc([N+](=O)[O-])n2)on1
Agent: N#N
Agent: [Na+]
Solvent: OCCO
Product: CC1(c2cc(Cn3ncc([N+](=O)[O-])n3)on2)OCCO1
Temperature: 95 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 1-[5-(4-nitro-[1,2,3]triazol-2-ylmethyl)-isoxazol-3-yl]-ethanone (122 mg, 0.51 mmol) in ethylene glycol (0.57 mL) was treated with trimethylorthoformate (0.11 mL, 1.03 mmol) followed by LiBF4 (10 mg, 0.10 mmol). The reaction mixture was heated at 95° C. overnight. Sat. aq. NaHCO3 (10 mL) was added and the mixture was extracted with EA (2×10 mL). The combined org. extracts were washed with brine (2×10 mL), dried over MgSO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (40:60 EA-Hept) gave the title compound as a yellow oil. TLC:rf (40:60 EA-Hept)=0.26. LC-MS-conditions 02: tR=0.89 min.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]([C:20]2[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([O:28][CH3:29])[CH:21]=2)(SC2C=CC=CC=2)[C:9]2[C:4](=[CH:5][C:6]([O:30][CH3:31])=[CH:7][CH:8]=2)[CH2:3]1.[BH4-].[Na+]>CO.O1CCCC1.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:1][N:2]1[C:11](=[O:12])[CH:10]([C:20]2[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([O:28][CH3:29])[CH:21]=2)[C:9]2[C:4](=[CH:5][C:6]([O:30][CH3:31])=[CH:7][CH:8]=2)[CH2:3]1
Reactant: COc1cc(OC)cc(C2(Sc3ccccc3)C(=O)N(C)Cc3cc(OC)ccc32)c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(OC)cc(C2C(=O)N(C)Cc3cc(OC)ccc32)c1
Yield: 72.1 %

Procedure:
A solution of 2-methyl-4-(3,5-dimethoxyphenyl)-4-(phenylsulfanyl)-7-methoxy-1,4-dihydro-3(2H)-isoquinolone (2.4 g) and nickel chloride hexahydrate (8.8 g) in methanol-tetrahydro-furan (3:1, 100 ml) was cooled to 0° C. Sodium borohydride (4.2 g) was added in small portions during 30 minutes at a temperature not exceeding 5° C. The slurry was filtered and the filtrate concentrated to dryness. The residue was partitioned between dichloromethane (200 ml) and aqueous sodium hydroxide (2M, 200 ml). The organic phase was dried and concentrated to dryness leaving crude 2-methyl-4-(3,5-dimethoxyphenyl)-7-methoxy-1,4-dihydro-3(2H)-isoquinolinone (1.3 g). Crystallization from methanol afforded the pure compound, m.p. 137-139
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1.[Cl:36][C:37]1[CH:45]=[CH:44][C:40]([C:41](Cl)=[O:42])=[CH:39][CH:38]=1>>[Cl:36][C:37]1[CH:45]=[CH:44][C:40]([C:41]([O:1][CH2:2][CH2:3][O:4][C:5]2[CH:10]=[CH:9][C:8]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:13][CH:12]3[O:24][CH2:25][C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)=[CH:7][CH:6]=2)=[O:42])=[CH:39][CH:38]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCO)cc2)C(OCc2ccc3ccccc3c2)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCOC(=O)c3ccc(Cl)cc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 22(k), by acylating tert-butyl (3RS,4RS)-4-[4-(2-hydroxy-ethoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate with 4-chlorobenzoyl chloride there was obtained tert-butyl (3RS,4RS)-4-[4-[2-(4-chloro-benzoyloxy)-ethoxy]-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless oil; MS : 616 (M+H)+.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]([O:16][CH2:17][CH3:18])(=[O:15])[CH3:14].[CH:19]1([CH:22]=[CH:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:21][CH2:20]1.[Cl-].[NH4+]>CCCCCC.C1COCC1>[CH:19]1([CH:22]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:14][C:13]([O:16][CH2:17][CH3:18])=[O:15])[CH2:21][CH2:20]1
Reactant: CCOC(=O)C=CC1CC1
Reactant: CCOC(C)=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)CC(CC(=O)OCC)C1CC1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
29.1 ml (72.8 mmol) of a 2.5 M solution of n-butyllithium in hexane were added dropwise to a solution, cooled to −40° C., of 10.2 ml (72.8 mmol) of diisopropylamine in 35 ml of abs. THF. After the end of the addition, the mixture was stirred at −40° C. for another 30 min and then cooled to −78° C., and a solution of 7.1 ml (72.8 mmol) of ethyl acetate in 10 ml of abs. THF was added dropwise. The reaction mixture was stirred at −78° C. for 30 min, and a solution of 8.50 g (60.54 mmol) of ethyl 3-cyclopropylacrylate in a little THF was then added dropwise. After 1 h at −78° C., the mixture was slowly warmed to −40° C., then to 0° C., and a saturated aqueous ammonium chloride solution was finally added. After extraction with ethyl acetate, the organic phase was washed with 1 N hydrochloric acid and sat. sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 30:1→6:1). This gave 3.28 g of the target product (23.7% of theory).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:13]=[CH:12][NH:11][N:10]=2)O1.Br.Br[CH2:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1.Br[C:25]1[CH:34]=[C:33]2[C:28]([CH2:29][CH:30]([CH3:49])[N:31]([C:35]3[CH:40]=[C:39]([N:41]4[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]4)[N:38]=[C:37]([NH2:48])[N:36]=3)[CH2:32]2)=[CH:27][CH:26]=1>>[CH3:47][N:44]1[CH2:43][CH2:42][N:41]([C:39]2[CH:40]=[C:35]([N:31]3[CH:30]([CH3:49])[CH2:29][C:28]4[C:33](=[CH:34][C:25]([C:9]5[CH:13]=[CH:12][N:11]([CH2:17][C:18]6[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=6)[N:10]=5)=[CH:26][CH:27]=4)[CH2:32]3)[N:36]=[C:37]([NH2:48])[N:38]=2)[CH2:46][CH2:45]1
Reactant: CC1Cc2ccc(Br)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: CC1(C)OB(c2cc[nH]n2)OC1(C)C
Reactant: BrCc1ccncc1
Agent: Br
Product: CC1Cc2ccc(-c3ccn(Cc4ccncc4)n3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 156 starting from 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Alfa Aesar, Cat. No. H27619), 4-(bromomethyl)-pyridine hydrobromide and 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (Peak 1, Example 49, Step 7). LCMS (M+H)+: m/z=496.3.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:5][C:4]1(F)F.BrCC1CC1.[CH3:13][C:14]1[N:15]=[C:16]([N:24]2[C:28](=[O:29])[NH:27][N:26]=[CH:25]2)[S:17][C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[CH:5]1([CH2:4][N:27]2[C:28](=[O:29])[N:24]([C:16]3[S:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:14]([CH3:13])[N:15]=3)[CH:25]=[N:26]2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1sc(-n2cn[nH]c2=O)nc1C
Reactant: FC1(F)CC1CBr
Agent: BrCC1CC1
Product: CCOC(=O)c1sc(-n2cnn(CC3CC3)c2=O)nc1C
Yield: 83 %

Procedure:
Following the procedure as described in Preparation 13, making variation as required to replace bromomethyl-2,2-difluorocyclopropane with (bromomethyl)cyclopropane to react with ethyl 4-methyl-2-(5-oxo-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylate in place of ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained as a white solid in 83% yield: 1H NMR (300 MHz, CDCl3) δ 8.27 (s, 1H), 4.31 (q, J=7.1 Hz, 2H), 3.63 (d, J=7.1 Hz, 2H), 2.64 (s, 3H), 1.35 (t, J=7.1 Hz, 3H), 1.19-1.04 (m, 1H), 0.53-0.42 (m, 2H), 0.36-0.27 (m, 2H); MS (ES+) m/z 309.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:26])[N:7]([S:13]([C:16]3[CH:17]=[C:18]([NH2:25])[C:19](=[CH:23][CH:24]=3)[C:20]([OH:22])=[O:21])(=[O:15])=[O:14])[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[C:27](Cl)(=[O:30])[CH2:28][CH3:29].O>O1CCOCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:26])[N:7]([S:13]([C:16]3[CH:17]=[C:18]([NH:25][C:27](=[O:30])[CH2:28][CH3:29])[C:19](=[CH:23][CH:24]=3)[C:20]([O:22][C:5]([CH3:10])([CH3:6])[CH3:4])=[O:21])(=[O:15])=[O:14])[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: CCC(=O)Cl
Reactant: Nc1cc(S(=O)(=O)n2c(=O)[nH]c3cc(Cl)ccc3c2=O)ccc1C(=O)O
Solvent: C1COCCO1
Solvent: O
Product: CCC(=O)Nc1cc(S(=O)(=O)n2c(=O)[nH]c3cc(Cl)ccc3c2=O)ccc1C(=O)OC(C)(C)C

Procedure:
840 mg (1.86 mmol) of Compound 17 was dissolved in 8 ml of 1,4-dioxane, 240 μl (2.79 mmol) of propionyl chloride was added dropwise, then the resultant mixture was stirred overnight at 60° C. An excess of water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer thus obtained was washed, dried, and concentrated to obtain a crude product of t-butyl 4-[(7-chloro-2,4(1H,3H)-quinazolinedion-3-yl)sulfonyl]-2-N-propionylanthranilate. The obtained crude product was stirred at room temperature in 3 ml of trifluoroacetic acid for 1 hour, then the reaction solution was concentrated in vacuo to obtain a crude product. This was washed by diethyl ether to obtain 400 mg (yield 48%: 2 steps) of the above-identified compound. Properties: colorless crystal, Melting point: >200° C. (decomposition), PMR (δ ppm, DMSO-d6): 1.10 (3H, t), 2.45 (2H, dd), 7.11 (1H, s), 7.24 (1H, d), 7.85 (1H, d), 7.88 (1H, d), 8.17 (1H, d), 9.18 (1H, s), 11.07 (1H, s), 11.63 (1H, s).