Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][N:16]([CH3:19])[C:15](=[O:20])[CH2:14]3)=[N:10][CH:9]=2)[CH:5]=[CH:4][CH:3]=1.[NH2:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][N:23]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:19][N:16]1[CH2:17][CH2:18][N:13]([C:11]2[S:12][C:8]([C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([NH:21][C:22]4[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][N:23]=4)[N:7]=3)=[CH:9][N:10]=2)[CH2:14][C:15]1=[O:20]
Reactant: Cc1ccnc(N)c1
Reactant: CN1CCN(c2ncc(-c3cccc(Br)n3)s2)CC1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccnc(Nc2cccc(-c3cnc(N4CCN(C)C(=O)C4)s3)n2)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 38.2 %

Procedure:
4-[5-(6-bromopyridin-2-yl)thiazol-2-yl]-1-methylpiperazin-2-one obtained in Step 5 (188 mg, 0.53 mmol) was dissolved in toluene (5 ml), and after 2-amino-4-methylpyridine (58 mg, 0.53 mmol) was added, 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (66 mg, 0.11 mmol), palladium acetate (18 mg, 0.08 mmol) and cesium carbonate (260 mg, 0.80 mmol) were added and the mixture was stirred overnight at 100° C. Water was added to the reaction solution and extracted with ethyl acetate and the organic layer was washed with a saturated saline solution. The organic layer was dried over sodium sulfate and after vacuum concentration, the residue was washed with methanol and the title compound (77 mg, 38%) was obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[NH:8][C:7]2[CH:9]=[C:10]([NH:16][C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])=[O:18])[CH:11]=[C:12]([C:13]([OH:15])=O)[C:6]=2[N:5]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:53][C:54]1[C:55]([CH3:61])=[C:56]([CH:58]=[CH:59][CH:60]=1)[NH2:57].C(=O)(O)[O-].[Na+]>CN(C=O)C.C(N(CC)CC)C>[Cl:53][C:54]1[C:55]([CH3:61])=[C:56]([NH:57][C:13]([C:12]2[C:6]3[N:5]=[C:4]([CH2:3][O:2][CH3:1])[NH:8][C:7]=3[CH:9]=[C:10]([NH:16][C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:26])([F:28])[F:27])=[O:18])[CH:11]=2)=[O:15])[CH:58]=[CH:59][CH:60]=1
Reactant: Cc1c(N)cccc1Cl
Reactant: COCc1nc2c(C(=O)O)cc(NC(=O)c3ccccc3C(F)(F)F)cc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCc1nc2c(C(=O)Nc3cccc(Cl)c3C)cc(NC(=O)c3ccccc3C(F)(F)F)cc2[nH]1
Temperature: 25 °C

Procedure:
To a solution of 2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxylic acid (153 mg) in DMF (5 mL), were added HBTU (178 mg) and triethylamine (65 μL). To the mixture was added 3-chloro-2-methylaniline (56 μL) under stirring at room temperature, and the mixture was stirred overnight. The reaction mixture was poured into saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The ethyl acetate layer was washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified on silica gel column chromatography to obtain N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (165 mg) as colorless powder.
Reaction SMILES: [C:1]([C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[CH:5]=[C:6]([C:11]([CH:13]([O:16][CH3:17])[O:14][CH3:15])=O)[C:7]([O:9][CH3:10])=[O:8])#[N:2].[NH2:22]/[C:23](/[CH3:31])=[CH:24]\[C:25]([O:27]C(C)C)=[O:26]>C(OCC)(=O)C>[C:1]([C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[CH:5]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:11]([CH:13]([O:16][CH3:17])[O:14][CH3:15])[NH:22][C:23]([CH3:31])=[C:24]1[C:25]([OH:27])=[O:26])#[N:2]
Reactant: C/C(N)=C/C(=O)OC(C)C
Reactant: COC(=O)C(=Cc1ccccc1C#N)C(=O)C(OC)OC
Solvent: CCOC(C)=O
Product: COC(=O)C1=C(C(OC)OC)NC(C)=C(C(=O)O)C1c1ccccc1C#N
Temperature: 120 °C
Reaction time: 8 h
Yield: 68.9 %

Procedure:
A mixture of methyl 2-(2-cyanobenzylidene)-4,4-dimethoxyacetoacetate (10.1 g) and isopropyl 3-aminocrotonate (5.51 g) was heated for 40 minutes at 78° C. and for 5.5 hours at 120° C. with stirring, followed by heating for an hour at 125° C. without the stirring. After the reaction mixture was allowed to stand overnight, it was dissolved in ethyl acetate. This solution was washed twice with water, dried and then evaporated to dryness under reduced pressure to give a residue, which was crystallized from ethyl ether. The crystals were collected by filtration and washed with a small amount of ethyl ether to give crude powder of isopropyl ester of 4-(2-cyanophenyl)-5-methoxycarbonyl-6-dimethoxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid (8.96 g). Further, the crude product (0.77 g) was recovered from the filtrate. 0.5 g of this crude product was recrystallized from isopropyl ether to give purified white powder of the same product (0.37 g), mp 171°-172.5° C.
Reaction SMILES: [H-].[Na+].[OH:3][C@@H:4]([CH2:15][O:16][CH:17]([CH3:19])[CH3:18])[C:5]([NH:7][C:8]1[CH:13]=[N:12][C:11]([CH3:14])=[CH:10][N:9]=1)=[O:6].Cl[C:21]1[N:26]=[CH:25][N:24]=[C:23]2[N:27]([C:30]3[C:35]([CH3:36])=[N:34][CH:33]=[CH:32][N:31]=3)[N:28]=[CH:29][C:22]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O.CCOC(C)=O>[CH:17]([O:16][CH2:15][C@H:4]([O:3][C:21]1[N:26]=[CH:25][N:24]=[C:23]2[N:27]([C:30]3[C:35]([CH3:36])=[N:34][CH:33]=[CH:32][N:31]=3)[N:28]=[CH:29][C:22]=12)[C:5]([NH:7][C:8]1[CH:13]=[N:12][C:11]([CH3:14])=[CH:10][N:9]=1)=[O:6])([CH3:19])[CH3:18]
Reactant: Cc1nccnc1-n1ncc2c(Cl)ncnc21
Reactant: Cc1cnc(NC(=O)[C@@H](O)COC(C)C)cn1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cnc(NC(=O)[C@H](COC(C)C)Oc2ncnc3c2cnn3-c2nccnc2C)cn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 47.4 %

Procedure:
Sodium hydride (22.06 mg, 0.55 mmol) was added to (S)-2-hydroxy-3-isopropoxy-N-(5-methylpyrazin-2-yl)propanamide (Intermediate C8) (110 mg, 0.46 mmol) in anhydrous THF (5 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 4-chloro-1-(3-methylpyrazin-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate I4) (125 mg, 0.51 mmol) in THF (2 mL) was added. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. Further sodium hydride (22.06 mg, 0.55 mmol) was added and the reaction stirred for another hour at room temperature. The reaction mixture was neutralised with 1M citric acid, and then diluted with water (20 mL) and EtOAc (50 mL). The organic layer was separated and the aqueous layer re-extracted with EtOAc (2×50 mL). The combined organics were washed with saturated brine (75 mL), dried (MgSO4), filtered and evaporated. The residue was purified by flash silica chromatography, elution gradient 50 to 100% EtOAc in isohexane to afford (2S)-3-isopropoxy-N-(5-methylpyrazin-2-yl)-2-(1-(3-methylpyrazin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanamide (98 mg, 47.4%).
Reaction SMILES: C[Si](C)(C)[O:3][C:4]1[CH:9]=C[CH2:7][CH2:6][CH:5]=1.C([O:15][C:16](=[CH2:19])[C:17]#N)(=O)C.C[O-].[Na+]>CO>[CH:17]12[CH2:7][CH2:6][CH:5]([C:4](=[O:3])[CH2:9]1)[CH2:15][C:16]2=[O:19]
Reactant: C[Si](C)(C)OC1=CCCC=C1
Reactant: C=C(C#N)OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1CC2CCC1CC2=O
Temperature: 150 °C
Reaction time: 3 h

Procedure:
25 mL of 2-(trimethylsilyloxy)-1,3-cyclohexadiene and 13 mL of α-acetoxyacrylonitrile were mixed and heated at 150° C. in a closed vessel for 22 h. The obtained dark orange viscous oil was dissolved in 200 mL of MeOH. After dropwise addition of a solution of 2.2 g of sodium methoxide in 150 mL of MeOH the reaction mixture was stirred for 3 h at rt, poured into ice/water and extracted with DCM. The organic phases were concentrated in vacuo and the crude residue was purified by CC with EtOAc-Hept (1:2) to yield 7.9 g of rac-(1R*,4R*)-bicyclo[2.2.2]octane-2,5-dione.
Reaction SMILES: [C:1]1([CH2:7][NH:8][C:9]2[NH:13][N:12]=[C:11]([C:14]3[CH:15]=[CH:16][C:17]4[O:23][CH2:22][CH2:21][N:20]([C:24](OC(C)(C)C)=[O:25])[CH2:19][C:18]=4[CH:31]=3)[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:39][CH:40]1[CH2:45][CH2:44][N:43](C(Cl)=O)[CH2:42][CH2:41]1>C(#N)C.Cl.O1CCOCC1.CO>[CH3:39][CH:40]1[CH2:45][CH2:44][N:43]([C:24]([N:20]2[CH2:19][C:18]3[CH:31]=[C:14]([C:11]4[CH:10]=[C:9]([NH:8][CH2:7][C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[NH:13][N:12]=4)[CH:15]=[CH:16][C:17]=3[O:23][CH2:22][CH2:21]2)=[O:25])[CH2:42][CH2:41]1
Reactant: CC1CCN(C(=O)Cl)CC1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(-c3cc(NCc4ccccc4)[nH]n3)cc2C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: CC#N
Product: CC1CCN(C(=O)N2CCOc3ccc(-c4cc(NCc5ccccc5)[nH]n4)cc3C2)CC1
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 57.1 %

Procedure:
STEP 6 A mixture of 1,1-dimethylethyl 7-{5-[(phenylmethyl)amino]-1H-pyrazol-3-yl}-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (92 mg, 0.22 mmol) in acetonitrile (2 mL) and 4 M hydrogen chloride in 1,4-dioxane (2 mL) was stirred at 70° C. for 10 minutes. The reaction mixture was allowed to cool then concentrated and the residue suspended in N,N-dimethylformamide (2 mL). Triethylamine (123 mg, 1.21 mmol), then 4-methylpiperidine-1-carbonyl chloride (reagent preparation 37) (35 mg, 0.22 mmol) were added and the resulting mixture was stirred at room temperature for 18 hours. The crude mixture diluted with methanol (6 mL) and purified by preparative reverse phase HPLC to give 3-{4-[(4-methylpiperidin-1-yl)carbonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}-N-(phenylmethyl)-1H-pyrazol-5-amine (56 mg, 57% yield), (400 MHz, methanol-d4): 7.49 (br, 1H), 7.45 (dd, 1H), 7.39 (d, 2H), 7.30 (t, 2H), 7.22 (dd, 1H), 6.96 (d, 1H), 5.81 (s, 1H), 4.43 (s, 2H), 4.33 (s, 2H), 4.17 (m, 2H), 3.66 to 3.59 (m, 4H), 2.80 (t, 2H), 1.67 to 1.50 (m, 3H), 1.24 to 1.12 (m, 2H), 0.96 (d, 3H); MS (EI) for C26H31N5O2: 446 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:20]([NH:23][C:24](=[O:37])[C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)=[CH:27][CH:26]=2)(=[O:22])=[O:21])[CH:7]=[CH:8][C:9]=1[NH:10][CH2:11][CH2:12][S:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O-:3])=[O:2].[CH2:38]([N:46]=[C:47]=[O:48])[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>CN1C(=O)CCC1.O>[N+:1]([C:4]1[CH:5]=[C:6]([S:20]([NH:23][C:24]([C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:36][CH2:35][N:34]([C:47]([NH:46][CH2:38][CH2:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[O:48])[CH2:33][CH2:32]3)=[CH:27][CH:26]=2)=[O:37])(=[O:21])=[O:22])[CH:7]=[CH:8][C:9]=1[NH:10][CH2:11][CH2:12][S:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([O-:3])=[O:2]
Reactant: O=C(NS(=O)(=O)c1ccc(NCCSc2ccccc2)c([N+](=O)[O-])c1)c1ccc(N2CCNCC2)cc1
Reactant: O=C=NCCc1ccccc1
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(NS(=O)(=O)c1ccc(NCCSc2ccccc2)c([N+](=O)[O-])c1)c1ccc(N2CCN(C(=O)NCCc3ccccc3)CC2)cc1
Reaction time: 18 h

Procedure:
A solution of Example 173A (54.1 mg, 0.1 mmol) in NMP (2 mL) at room temperature was treated with phenethylisocyanate (0.2 mmol), stirred for 18 hours, diluted with water, and centrifuged. The solid was purified by flash column chromatography on silica gel with 0-5% methanol/dichloromethane to provide the desired product. MS (ESI(−)) m/e 687 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ8.75 (t, 1H), 8.58 (d, 1H), 7.90 (dd, 1H), 7.75 (d, 2H), 7.39-7.34 (m, 2H), 7.31-7.14 (m, 9H), 6.94 (d, 2H), 6.71 (t, 1H), 3.66 (q, 2H), 3.42-3.39 (m, 4H), 3.30-3.21 (m, 8H), 2.72 (dd, 2H).
Reaction SMILES: [OH:1][N:2]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH2:23]([O:27][C:28]1[CH:33]=[CH:32][C:31]([S:34]([CH2:37][NH:38][CH2:39][CH:40]([N:44]2[CH2:49][CH2:48][N:47]([S:50]([CH3:53])(=[O:52])=[O:51])[CH2:46][CH2:45]2)[C:41](O)=[O:42])(=[O:36])=[O:35])=[CH:30][CH:29]=1)[C:24]#[C:25][CH3:26].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[CH2:23]([O:27][C:28]1[CH:33]=[CH:32][C:31]([S:34]([CH2:37][NH:38][CH2:39][CH:40]([N:44]2[CH2:45][CH2:46][N:47]([S:50]([CH3:53])(=[O:51])=[O:52])[CH2:48][CH2:49]2)[C:41]([NH:2][OH:1])=[O:42])(=[O:36])=[O:35])=[CH:30][CH:29]=1)[C:24]#[C:25][CH3:26]
Reactant: On1nnc2ccccc21
Reactant: CC#CCOc1ccc(S(=O)(=O)CNCC(C(=O)O)N2CCN(S(C)(=O)=O)CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN(C)C=O
Product: CC#CCOc1ccc(S(=O)(=O)CNCC(C(=O)NO)N2CCN(S(C)(=O)=O)CC2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51.2 %

Procedure:
63 mg (0.5 mmol) of 1-hydroxybenzotriazole and then 88 mg (0.5 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride are added to a solution of 200 mg (0.4 mmol) of 3-[(4-but-2-ynyloxybenzenesulfonyl)methylamino]-2-(4-methanesulfonylpiperazin-1-yl)propanoic acid in 6 ml of dimethylformamide. The reaction medium is stirred for 10 min at ambient temperature and then 68 mg (0.5 mmol) of O-tert-butyldimethysilylhydroxylamine are added. The reaction medium is then stirred at ambient temperature for 24 h, hydrolyzed by adding 2 ml of a 5% aqueous citric acid solution, and stirred for a further 30 minutes. After extraction with ethyl acetate, the organic phase is washed with water, dried over magnesium sulfate, filtered and concentrated. The crude residue is purified by chromatography on silica gel, elution being carried out with a 95/5 dichloromethane/methanol mixture. 100 mg (50%) of 3-[(4-but-2-ynyloxybenzenesulfonyl)methylamino]-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)propionamide are obtained in the form of a white solid with a melting point of 86° C.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:6]2[N:5]=1)=O.C(N(CC)C(C)C)(C)C.[NH2:30][C:31]1[CH:32]=[CH:33][C:34]2[O:45][C:38]3([CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]3)[CH:37]=[CH:36][C:35]=2[CH:46]=1.COCC(O)C>>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[N:6]2[C:7]([CH:8]=[N:9][C:4]([CH:42]3[CH2:43][C:38]4([CH:37]=[CH:36][C:35]5[CH:46]=[C:31]([NH2:30])[CH:32]=[CH:33][C:34]=5[O:45]4)[CH2:39][CH2:40][N:41]3[CH3:44])=[N:5]2)=[CH:10][CH:11]=1
Reactant: CN1CCC2(C=Cc3cc(N)ccc3O2)CC1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Solvent: CCN(C(C)C)C(C)C
Solvent: COCC(C)O
Product: COc1ccccc1-c1ccc2cnc(C3CC4(C=Cc5cc(N)ccc5O4)CCN3C)nn12
Yield: 12.8 %

Procedure:
2-Methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (87.49 mg, 0.0003045 mol), N,N-Diisopropylethylamine (0.175 mL, 0.00100 mol) and 6-amino-1′-methyl-spiro(2H-1-benzopyran-2,4′-piperidine) (0.141 g, 0.000609 mol) were dissolved in 1-Methoxy-2-propanol (0.350 mL, 0.00358 mol) and the reaction was irradiated at 300 watts, 180° C. for 40 minutes or until HPLC showed consumption of starting material. The reaction mixture was then reduced en vacuo and the product was isolated and purified by Gilson prep HPLC to afford 17.67 mg of 7-(2-methoxy-phenyl)-pyrrolo(2,1-f)(1,2,4)triazin-2-yl-6-amino-1′-methyl-spiro(2H-1-benzopyran-2,4′-piperidine) as a lyophilized powder. (M+H)=456.1. 1H NMR (400 MHz, DMSO, d6) δ 9.19 (s, 1H), 8.91 (s, 1H), 7.81 (d, 1H, J=7.24 Hz), 7.57 (m, 1H), 7.45 (m, 1H), 7.34 (m, 1H), 7.21 (m, 1H), 7.11 (m, 1H), 6.90 (d, 2H, J=7.65 Hz), 6.70 (d, 1H, J=8.56 Hz), 3.79 (s, 3H), 3.33 (m, 2H), 3.18 (m, 2H), 2.83 (m, 3H), 2.62 (m, 2H), 1.92 (m, 2H), 1.79 (m, 4H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-].[Cl:11][C:12]1[CH:13]=[C:14]([C:19]([OH:33])([CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[CH2:20][C:21]#[N:22])[CH:15]=[CH:16][C:17]=1[Cl:18]>C(OCC)C.C1COCC1>[NH2:22][CH2:21][CH2:20][C:19]([C:14]1[CH:15]=[CH:16][C:17]([Cl:18])=[C:12]([Cl:11])[CH:13]=1)([OH:33])[CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1
Reactant: COc1ccc(OCC(O)(CC#N)c2ccc(Cl)c(Cl)c2)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(OCC(O)(CCN)c2ccc(Cl)c(Cl)c2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91.3 %

Procedure:
To a solution of lithium aluminum hydride (2.53 g) in diethyl ether (50 mL) was added aluminum chloride (2.96 g), and the mixture was stirred at 0° C. for 30 min. To the reaction mixture was added dropwise a solution of (3RS)-3-(3,4-dichlorophenyl)-3-hydroxy-4-(4-methoxyphenoxy)butanenitrile (11.7 g) in THF (50 mL), and the mixture was stirred at 0° C. for 15 min, and then stirred while warming to room temperature for 2 hr. To the reaction mixture was added ice, and the precipitate was filtered off through celite. The filtrate was diluted with water, and the mixture was extracted with ethyl acetate. The obtained extract was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (10.8 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:7][CH:6]=1)=[O:4].[C:16]([C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1)(=[O:18])[CH3:17].C(N(CC)CC)C.O>ClCCl>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:11][CH2:12][N:13]([S:25]([C:22]3[CH:21]=[CH:20][C:19]([C:16](=[O:18])[CH3:17])=[CH:24][CH:23]=3)(=[O:27])=[O:26])[CH2:14][CH2:15]2)=[N:7][CH:6]=1)=[O:4]
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1cnc(N2CCNCC2)s1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1cnc(N2CCN(S(=O)(=O)c3ccc(C(C)=O)cc3)CC2)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.4 %

Procedure:
To a solution of compound 11 (200 mg, 0.886 mmol) in dichloromethane (7.5 mL) were added 4-acetyl-benzenesulfonyl chloride (288 mg, 1.320 mmol) and triethylamine (220 mg, 2.169 mmol) under a N2 atmosphere. The reaction mixture was stirred at room temperature for 4 h. Water (10 mL) followed by dichloromethane (10 mL) were added to the reaction mixture and the organic layer was separated, dried on sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using silica gel to give the compound 12h as a solid (346 mg, 96.2%). HPLC: 99.72% (Rt=6.56 min).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:19])([CH3:18])[CH3:17])=[CH:12][C:11]=2[F:20])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([CH:28]([OH:33])[C:29]([F:32])([F:31])[F:30])[N:23]=1>>[F:20][C:11]1[CH:12]=[C:13]([C:16]([OH:19])([CH3:17])[CH3:18])[CH:14]=[CH:15][C:10]=1[C:4]1[S:3][C:2]([NH:1][C:26]2[CH:27]=[CH:22][N:23]=[C:24]([CH:28]([OH:33])[C:29]([F:32])([F:30])[F:31])[N:25]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: OC(c1nccc(Cl)n1)C(F)(F)F
Product: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3ccnc(C(O)C(F)(F)F)n3)s2)c(F)c1

Procedure:
The title compound was prepared as described in Example 1 using 2-amino-5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (68 mg, 0.23 mmol) and 1-(4-chloropyrimidin-2-yl)-2,2,2-trifluoroethanol (49 mg, 0.23 mmol) as starting materials.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6](OC)=[O:7].C([O-])(O)=O.[Na+].O.CCOC(C)=O>C1COCC1>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[NH:1][C:6](=[O:7])[CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cccc(OC)c1C1CCCC(=O)N1
Temperature: 25 °C
Reaction time: 327 h

Procedure:
A yellow solution of the chlorhydrate salt of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate (14.96 mmol) in THF (92 ml) was treated with a solution of aq. sat. NaHCO3 (23.5 ml). The resulting heterogeneous mixture was further stirred at rt, under nitrogen, for 327 h. This reaction mixture was then treated with a solution of aq. sat. NaHCO3 (25 ml), water (50 ml), and AcOEt (200 ml). The layers were separated and the slightly yellow aq. layer was further extracted with AcOEt (50 ml). The mixed yellow organic layers were then dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=20/1) afforded 6-(2,6-dimethoxyphenyl)-piperidin-2-one as a beige solid. LC-MS (conditions B): tR=0.83 min.; [M+H]+: 236.49 g/mol.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]1=[O:14])=[O:5].[CH:20](OC)(OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C(#N)C>[Br:19][C:16]1[CH:15]=[C:3]2[C:2](=[CH:18][CH:17]=1)[N:1]=[CH:20][N:6]([CH:7]1[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]1=[O:14])[C:4]2=[O:5]
Reactant: Nc1ccc(Br)cc1C(=O)NC1CCC(=O)NC1=O
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: O
Product: O=C1CCC(n2cnc3ccc(Br)cc3c2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
A solution of 2-amino-N-(2,6-dioxo-piperidin-3-yl)-5-bromo-benzamide (0.51 g, 1.5 mmol) and trimethyl orthoformate (2 mL) and p-toluene sulfonic acid (150 mg) in acetonitrile (10 mL) was heated to reflux for 12 hours. To the mixture, was added water (70 mL), and stirred at room temperature for 2 hours. The suspension was filtered and washed with ethyl acetate (10 mL). The solid in NMP (3 mL) was heated at 80° C. To the solution, was added water (1.5 mL), and the mixture was allowed to cool to room temperature. The suspension was filtered and washed with NMP (1 mL) and ethyl acetate (10 mL) to give 3-(6-bromo-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as a white solid (350 mg, 68% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 4.18 min (99.9%); mp: 312-314° C.; 1H NMR (DMSO-d6) δ 2.14-2.21 (m, 1H, C W), 2.60-2.74 (m, 2H, 2CHH), 2.83-2.93 (m, 1H, CHH), 5.51 (brs, 1H, NCH), 7.68 (d, J=9 Hz, 1H, Ar), 8.03 (dd, J=2, 9 Hz, 1H, Ar), 8.24 (d, J=2 Hz, 1H, Ar), 8.42 (s, 1H, CH), 11.19 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.45, 30.93, 55.49, 119.83, 122.96, 128.23, 129.65, 137.61, 146.52, 147.94, 158.66, 169.75, 172.46: LCMS: MH=336, 338; Anal Calcd for C13H11N3O3Br+0.3H2O: C, 45.72; H, 3.13; N, 12.30; Br, 23.39. Found: C, 45.46; H, 2.75; N, 12.15; Br, 22.81.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].[F:18][C:19]([F:29])([F:28])[C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1.C(=O)([O-])O.[Na+]>COCCOC.O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:15])[CH:9]([CH2:24][C:23]2[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:28])[F:29])=[CH:27][CH:26]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)c1ccc(Cl)nc1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
To a solution of ethyl 3-(6-chloro-3-pyridyl)-3-oxopropionate (9.0 g, 39.5 mmol) in 1,2-dimethoxyethane (50 ml) was added sodium hydride (60% in oil, 1.58 g, 39.5 mmol) under ice-cooling, and the mixture was stirred at room temperature for 2 hrs. To the reaction solution was dropwise added a solution of 4-trifluoromethylbenzyl bromide (9.45 g, 39.5 mmol) in 1,2-dimethoxyethane (50 ml), and the mixture was stirred overnight at room temperature. The reaction solution was poured into water (200 ml), saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate (200 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene:ethyl acetate=1:1) to give ethyl 3-(6-chloro-3-pyridyl)-3-oxo-2-((4-(trifluoromethyl)phenyl)methyl)propionate (14.2 g, 93%) as a colorless oil.