Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([C:19]([C:21]3[CH:31]=[CH:30][C:24]4[N:25]([CH3:29])[CH2:26][CH2:27][O:28][C:23]=4[CH:22]=3)=[O:20])[C@@H:11]([CH3:32])[CH2:10]2)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:42](Cl)(=[O:44])[CH3:43]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([C:19]([C:21]3[CH:31]=[CH:30][C:24]4[N:25]([CH3:29])[CH2:26][CH2:27][O:28][C:23]=4[CH:22]=3)=[O:20])[C@@H:11]([CH3:32])[CH2:10]2)[C:42](=[O:44])[CH3:43])=[CH:4][CH:3]=1
Reactant: CC(=O)Cl
Reactant: C[C@H]1C[C@@H](Nc2ccc(Cl)cc2)c2ccccc2N1C(=O)c1ccc2c(c1)OCCN2C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc3c(c2)OCCN3C)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (2S,4R)-[4-(4-Chloro-phenylamino)-2-methyl-3,4-dihydro-2H-quinolin-1-yl]-(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-methanone (540 mg, 1.25 mmol) in methylene chloride (5 mL) was added diisopropylethylamine (0.240 mL, 1.37 mmol) followed by acetyl chloride (2 mL). The mixture was stirred at room temperature 4 hours. The mixture was concentrated under reduced pressure, dissolved in ethyl acetate, washed with sat. aq. NaHCO3, brine and dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (25/75 hexanes/ethyl acetate gradient) to afford the final product.
Reaction SMILES: [N+](C1C=CC([O:10][C:11]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([C:28]4[N:29]=[C:30]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)[O:31][C:32]=4[C:33]([F:36])([F:35])[F:34])=[O:27])=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)=O)=CC=1)([O-])=O.C[O:44][C:45](=[O:54])[CH2:46][CH2:47][CH:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1>>[C:37]1([C:30]2[O:31][C:32]([C:33]([F:35])([F:34])[F:36])=[C:28]([C:26]([NH:25][C:22]3[CH:21]=[CH:20][C:19]([CH:16]4[CH2:15][CH2:14][N:13]([C:11]([N:51]5[CH2:52][CH2:53][CH:48]([CH2:47][CH2:46][C:45]([OH:44])=[O:54])[CH2:49][CH2:50]5)=[O:10])[CH2:18][CH2:17]4)=[CH:24][CH:23]=3)=[O:27])[N:29]=2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: COC(=O)CCC1CCNCC1
Reactant: O=C(Nc1ccc(C2CCN(C(=O)Oc3ccc([N+](=O)[O-])cc3)CC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Product: O=C(O)CCC1CCN(C(=O)N2CCC(c3ccc(NC(=O)c4nc(-c5ccccc5)oc4C(F)(F)F)cc3)CC2)CC1

Procedure:
With a procedure similar to above, 3-[1-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidine-1-carbonyl)-piperidin-4-yl]-propionic acid was prepared from 4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidine-1-carboxylic acid 4-nitro-phenyl ester and 3-piperidin-4-yl-propionic acid methyl ester. LCMS calcd for C31H33F3N4O5 (m/e) 598, obsd 599 (M+H). The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[CH:20]=[C:19]([OH:21])[C:13]3[CH2:14][C:15]([CH3:18])([CH3:17])[O:16][C:12]=3[CH:11]=2)=[O:9])=[N:3]1.Cl[CH2:23][C:24]1[N:29]=[C:28]([C:30]2[CH:35]=[N:34][CH:33]=[CH:32][N:31]=2)[N:27]=[C:26]([OH:36])[CH:25]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[CH:20]=[C:19]([O:21][CH2:23][C:24]3[CH:25]=[C:26]([OH:36])[N:27]=[C:28]([C:30]4[CH:35]=[N:34][CH:33]=[CH:32][N:31]=4)[N:29]=3)[C:13]3[CH2:14][C:15]([CH3:18])([CH3:17])[O:16][C:12]=3[CH:11]=2)=[O:9])=[N:3]1
Reactant: Oc1cc(CCl)nc(-c2cnccn2)n1
Reactant: Cn1ccc(NC(=O)c2cc(O)c3c(c2)OC(C)(C)C3)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cn1ccc(NC(=O)c2cc(OCc3cc(O)nc(-c4cnccn4)n3)c3c(c2)OC(C)(C)C3)n1
Temperature: 60 °C
Yield: 9.8 %

Procedure:
To a solution of 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (31a) (80 mg, 0.280 mmol) and 6-(chloromethyl)-2-(pyrazin-2-yl)pyrimidin-4-ol (124 mg, 0.557 mmol) in 3 mL of DMF was added Cs2CO3 (181 mg, 0.557 mmol). The mixture was heated at 60° C. overnight, then filtered, washed with EtOAc, concentrated, and purified by reverse phase HPLC to give a white solid (13 mg, 10% yield). 1H NMR (400 MHz, CDCl3) δ 9.67 (d, J=1.52 Hz, 1 H) 8.83 (d, J=2.53 Hz, 1 H) 8.65-8.67 (m, 1H) 8.50 (s, 1 H) 7.27-7.31 (m, 1 H) 7.06 (d, J=1.01 Hz, 1 H) 6.88 (s, 1 H) 6.76-6.82 (m, 1 H) 6.72 (s, 1 H) 5.13 (s, 2 H) 3.81 (s, 3 H) 3.11 (s, 2 H) 1.49-1.55 (m, 6 H); LCMS for C24H23N7O4 m/z 474.00 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:26])=[CH:4][C:5]([F:25])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[CH:7]=1.[NH2:27][CH2:28][CH2:29][CH2:30][OH:31].C(N(CC)CC)C>N1C=CC=CC=1>[NH2:1][C:2]1[C:3]([F:26])=[CH:4][C:5]([F:25])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15]([NH:27][CH2:28][CH2:29][CH2:30][OH:31])[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[CH:7]=1
Reactant: NCCCO
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(NCCCO)c(Cl)c32)c(F)cc1F
Temperature: 45 °C
Reaction time: 43 h
Yield: 46.7 %

Procedure:
1-(5-Amino-2,4-difluorophenyl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (150 mg), 3-amino-1-propanol (75 mg) and triethylamine (200 mg) were added to pyridine (350 mg), and the mixture was stirred at 45° C. for 43 hours. The reaction mixture was concentrated under reduced pressure. A process of adding ethanol (2 ml) to the residue and then concentrating the mixture under reduced pressure was conducted twice repeatedly. Concentrated hydrochloric acid (120 mg) was added to the residue, and the mixture was concentrated under reduced pressure. Ethanol (1 ml) was added to the resultant residue, and deposits were collected by filtration and washed with ethanol and diisopropyl ether in that order to obtain the title compound (80 mg) as a colorless powder.
Reaction SMILES: [CH3:1][C:2]([CH2:5][C@H:6]1[NH:10][C@@H:9]([C:11]([NH:13][CH:14]2[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]2)=[O:12])[C@H:8]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=2[F:28])[C@:7]21[C:37](=[O:38])[NH:36][C:30]1[CH:31]=[C:32]([Cl:35])[CH:33]=[CH:34][C:29]2=1)([CH3:4])[CH3:3]>CO.O>[CH3:4][C:2]([CH2:5][C@@H:6]1[NH:10][C@@H:9]([C:11]([NH:13][CH:14]2[CH2:15][CH2:16][CH:17]([OH:20])[CH2:18][CH2:19]2)=[O:12])[C@H:8]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=2[F:28])[C@@:7]21[C:37](=[O:38])[NH:36][C:30]1[CH:31]=[C:32]([Cl:35])[CH:33]=[CH:34][C:29]2=1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)C[C@H]1N[C@@H](C(=O)NC2CCC(O)CC2)[C@H](c2cccc(Cl)c2F)[C@@]12C(=O)Nc1cc(Cl)ccc12
Solvent: CO
Solvent: O
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)NC2CCC(O)CC2)[C@H](c2cccc(Cl)c2F)[C@]12C(=O)Nc1cc(Cl)ccc12
Reaction time: 72 h
Yield: 26 %

Procedure:
In an alternative procedure, MI-773 (77 mg) was dissolved in 15 mL MeOH/H2O (v/v=1:1). After 3 days, the needle crystals that had formed were collected, washed with cold MeOH/H2O (v/v=1:1) and dried in vacuum to give MI-77301 as the free amine (20 mg; >95% purity as determined by HPLC).
Reaction SMILES: [CH3:1][CH:2]([CH3:39])[C:3]([O:5][C@H:6]([O:10][C:11]([O:13]N1C(=O)[C@@H](OC(=O)C2C=CC=CC=2)[C@H](OC(=O)C2C=CC=CC=2)C1=O)=O)[CH:7]([CH3:9])[CH3:8])=[O:4].[NH2:40][CH2:41][CH2:42][CH2:43][P:44]([OH:46])[OH:45].C1COCC1>O>[C:3]([O:5][C@H:6]([O:10][C:11]([NH:40][CH2:41][CH2:42][CH2:43][P:44]([OH:46])[OH:45])=[O:13])[CH:7]([CH3:8])[CH3:9])(=[O:4])[CH:2]([CH3:1])[CH3:39]
Reactant: CC(C)C(=O)O[C@H](OC(=O)ON1C(=O)[C@@H](OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)C1=O)C(C)C
Reactant: NCCCP(O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C(=O)O[C@H](OC(=O)NCCCP(O)O)C(C)C
Temperature: 19 °C
Reaction time: 4 h

Procedure:
To a 3 L three necked round bottom flask fitted with a mechanical stirrer, temperature probe, and nitrogen inlet is added (25) (100 mmol), 3-aminopropylphosphonous acid (100 mmol), THF (1 L), and water (100 mL). The suspension is stirred under a nitrogen atmosphere at 18-20° C. for 4 h during which time the reaction mixture becomes homogeneous. The THF is removed in vacuo and the reaction mixture is diluted with methyl tert-butyl ether (250 mL) and washed with 1N HCl (1×500 mL) and water (2×200 mL). The organic phase is separated and concentrated in vacuo to leave a white solid. The solid is purified by flash chromatography to afford the title compound (39) as a white solid.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][C:18]([C:25]([O:27][CH3:28])=[O:26])=[N:17]1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:30][OH:31]>N1C=CC=CC=1>[Cl:15][C:13]1[CH:12]=[CH:11][C:10]([N:16]2[C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][C:18]([C:25]([O:27][CH3:28])=[O:26])=[N:17]2)=[C:9]([C:1](=[N:30][OH:31])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:14]=1
Reactant: COC(=O)c1cc(C(=O)OC)n(-c2ccc(Cl)cc2C(=O)c2ccccc2)n1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)c1cc(C(=O)OC)n(-c2ccc(Cl)cc2C(=NO)c2ccccc2)n1
Temperature: 25 °C

Procedure:
A mixture of 11.2 g. (28 mmol) of the final product of Example 3, 5.80 g. (84 mmol) of hydroxylamine hydrochloride and 180 ml. pyridine was heated to reflux for 6.5 hours. After cooling to room temperature, the reaction was concentrated in vacuo to remove the pyridine. The crude product, as isolated, was then chromatographed on silica gel, using 10% EtOAc in benzene as eluent, to give the final product. Recrystallization from EtOH/H2O gave an analytical sample as colorless prisms mp: 177°-179°.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([NH:15][C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH3:27])[N:19]=[C:18]([CH3:28])[C:17]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11].I[CH3:36].O>CN(C=O)C>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([N:15]([CH3:36])[C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH3:27])[N:19]=[C:18]([CH3:28])[C:17]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: CI
Reactant: COC(=O)c1cc(OC)ccc1Nc1c(-c2ccccc2)c(C)nn1-c1ccccc1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OC)ccc1N(C)c1c(-c2ccccc2)c(C)nn1-c1ccccc1C
Reaction time: 0.5 h
Yield: 76.4 %

Procedure:
To a suspension of NaH (60% dispersion in mineral oil; 0.28 g, 7 mmol) in DMF (10 mL) at rt was added a solution of methyl 5-methoxy-2-{[3-methyl-1-(2-methylphenyl)-4-phenyl-1H-pyrazol-5-yl]amino}benzoate (1.495 g, 3.5 mmol) in DMF (15 mL) dropwise. The mixture was stirred for 0.5 h, and then iodomethane (0.88 mL, 14 mmol) was added. The reaction mixture was stirred at rt for 1 h. Water (100 mL) was cautiously added, and the mixture was extracted with ethyl acetate (25 mL×3). The combined organic phases were washed with a saturated solution of sodium bicarbonate (50 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (EtOAc/hexanes 1:12) to afford the title compound (1.18 g, 68%) as a pale yellow solid. 1H NMR (400 MHz, acetone-d6) δ 2.1 (s, 3H), 2.3 (s, 3H), 2.9 (s, 3H), 3.65 (s, 3H), 3.7 (s, 3H), 6.87-6.92 (m, 2H), 6.94-6.98 (m, 1H), 7.03-7.09 (m, 1H), 7.15-7.27 (m, 4H), 7.30-7.36 (m, 2H), 7.39-7.43 (m, 2H). ES-MS m/z 442.3 (MH+); HPLC RT (min) 3.96.
Reaction SMILES: [H-].[Na+].[CH2:3]([CH2:10][S:11]([NH:14][CH2:15][CH2:16][OH:17])(=[O:13])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:19]1[N:24]2[CH:25]=[CH:26][N:27]=[C:23]2[CH:22]=[CH:21][CH:20]=1.O>CN(C)C=O>[CH2:3]([CH2:10][S:11]([NH:14][CH2:15][CH2:16][O:17][C:19]1[N:24]2[CH:25]=[CH:26][N:27]=[C:23]2[CH:22]=[CH:21][CH:20]=1)(=[O:13])=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Clc1cccc2nccn12
Reactant: O=S(=O)(CCc1ccccc1)NCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=S(=O)(CCc1ccccc1)NCCOc1cccc2nccn12
Yield: 39.4 %

Procedure:
To a suspension of 60% sodium hydride in oil (0.20 g, 5 mmoles) in dimethylformamide (20 ml) was added 2-(N-benzylmethylsulfonylamino)-1-ethanol (1.14 g, 5 mmoles) with stirring under ice-cooling and the mixture was stirred at room temperature for 30 minutes. To this reaction mixture was added 5-chloroimidazo[1,2-a]pyridine (0.763 g, 5 mmoles) with stirring under ice-cooling, followed by stirring at 80° C. for 16 hours. After cooling, water was added to the reaction mixture, which was extracted with ethyl acetate and dried. After the solvent was distilled off, the residue was purified by column chromatography [eluent: ethyl acetate/hexane (1:1)→ethyl acetate/hexane (2:1)] to obtain 0.68 g of the desired product (39.4%, pale yellow oily product).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[N:19]1[NH:20][C:21]([C:28](O)=[O:29])=[C:22]2[C:27]=1[CH2:26][CH2:25][CH2:24][CH2:23]2>>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:28]([C:21]3[NH:20][N:19]=[C:27]4[C:22]=3[CH2:23][CH2:24][CH2:25][CH2:26]4)=[O:29])[CH3:18])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1[nH]nc2c1CCCC2
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1[nH]nc2c1CCCC2

Procedure:
The title compound was prepared using the method of Example 34(d) starting from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (200 mg, 0.767 mmol) and 4,5,6,7-tetrahydro-2H-indazole-3-carboxylic acid (166 mg, 0.997 mmol). The product was triturated with ethanol. Yield 111 mg (35%). 1H-NMR (400 MHz; d6-DMSO): δ 1.09 (d, 3H), 1.58-1.72 (m, 4H), 2.54-2.61 (m, 4H), 4.24-4.46 (m, 3H), 6.94 (d, 1H), 7.82 (d, 1H), 7.99 (s, 2H), 8.05-8.08 (m, 2H), 12.68 (s, 1H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=2)[CH:3]=[N:2]1.[H-].[Na+].Cl[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:21][CH:22]=1>CN(C)C=O>[O:23]([C:20]1[N:21]=[CH:22][C:17]([CH2:16][N:1]2[CH:5]=[C:4]([C:6]3[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=3)[CH:3]=[N:2]2)=[CH:18][CH:19]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1ncccc1-c1cn[nH]c1
Reactant: ClCc1ccc(Oc2ccccc2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncccc1-c1cnn(Cc2ccc(Oc3ccccc3)nc2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 58.2 %

Procedure:
To an N,N-dimethylformamide (5.00 mL) solution of 3-(1H-pyrazol-4-yl)-pyridin-2-ylamine (20.0 mg, 0.125 mmol) described in Manufacturing Example 32-1-4 was added sodium hydride (5.50 mg, 0.138 mmol, 60% in oil) on an ice bath (0° C.) under nitrogen atmosphere, which was stirred for 10 minutes at room temperature. Thereafter, 5-chloromethyl-2-phenoxy-pyridine (49.7 mg, 0.226 mmol) described in Manufacturing Example 193-1-2 was added to the above mixture, which was stirred for 30 minutes at room temperature. The reaction mixture was partitioned into ethyl acetate and water at room temperature. The organic layer was washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=2:1→ethyl acetate) to obtain the title compound (25.0 mg, 58.2%).
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2[CH:17]=[CH:16][C:13]([CH2:14]Cl)=[CH:12][CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C2C(COC([NH:35][CH2:36][C:37]([NH:39][CH2:40][CH:41]3[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]3)=[O:38])=O)C3C(=CC=CC=3)C=2C=CC=1.C(N(CC)CC)C>C(#N)C>[NH2:35][CH2:36][C:37]([NH:39][CH2:40][CH:41]1[CH2:42][CH2:43][N:44]([CH2:14][C:13]2[CH:16]=[CH:17][C:10]([C:8](=[O:9])[NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:11][CH:12]=2)[CH2:45][CH2:46]1)=[O:38]
Reactant: O=C(Nc1ccccc1)c1ccc(CCl)cc1
Reactant: O=C(CNC(=O)OCC1c2ccccc2-c2ccccc21)NCC1CCNCC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: NCC(=O)NCC1CCN(Cc2ccc(C(=O)Nc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 19 h
Yield: 30.2 %

Procedure:
An acetonitrile (100 mL) solution of 4-(N-phenylcarbamoyl)benzyl chloride (800 mg, 3.26 mmol) was dropped into a mixture of 4-[[N-(9-fluorenylmethyloxycarbonyl)glycyl]aminomethyl]piperidine (1.27 g, 2.96 mmol) with triethylamine (1.25 mL, 8.88 mmol), KI (50 mg, 0.30 mmol) and acetonitrile (200 mL). The resulting mixture was stirred at room temperature for 19 hours and stirred at 60° C. for another 5 hours. After concentrating, the obtained crude product was purified by column chromatography (SiO2, 5% methanol/dichloromethane-triethylamine/methanol/dichloromethane=2:2:96) to provide 4-[(glycylamino)methyl]-1-[4-(N-phenylcarbamoyl)benzyl]piperidine (340 mg, 30%).
Reaction SMILES: BrC1C=C(N[C@@H]2CCCN(C(OC(C)(C)C)=O)C2)C([O:8]C)=NC=1.Cl[CH2:25][C:26]([N:28]1[CH2:33][CH2:32][CH2:31][C@@H:30]([NH:34][C:35]2[C:40](=[O:41])[NH:39][CH:38]=[C:37]([C:42]3[CH:47]=[CH:46][N:45]=[CH:44][CH:43]=3)[CH:36]=2)[CH2:29]1)=O>>[C:33]([N:28]1[CH2:26][CH2:25][C@@H:30]([NH:34][C:35]2[C:40](=[O:41])[NH:39][CH:38]=[C:37]([C:42]3[CH:47]=[CH:46][N:45]=[CH:44][CH:43]=3)[CH:36]=2)[CH2:29]1)(=[O:8])[CH:32]=[CH2:31]
Reactant: O=C(CCl)N1CCC[C@@H](Nc2cc(-c3ccncc3)c[nH]c2=O)C1
Reactant: COc1ncc(Br)cc1N[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Product: C=CC(=O)N1CC[C@@H](Nc2cc(-c3ccncc3)c[nH]c2=O)C1

Procedure:
Following Example 1, but using (R)-tert-butyl 3-aminopyrrolidine-1-carboxylate (Example 1 Step 3) and reaction with acroyl chloride (Example 1 Step 6) provided the desired compound after purification: 1H NMR (300 MHz, DMSO-d6) 11.86 (br s, 1H), 8.52, (d, J=4.8 Hz, 2H), 7.64 (br s 2H), 7.28 (br s, 1H), 6.75 (d, J=7.2 Hz, 1H), 6.50-6.70 (m, 1H), 6.13 (d, J=16.8 Hz, 1H), 6.55-6.75 (m, 2H), 4.10-4.30 (m, 1H), 3.90-4.05 (m, 1H), 3.20-3.65 (m, 3H), 1.85-2.35 (m, 2H); MS (ES) m/z 311 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[C:11]([CH2:13]O)[N:10]=[CH:9]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:35]>C1COCC1>[Br:35][CH2:13][C:11]1[N:10]=[CH:9][N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH:12]=1
Reactant: OCc1cn(-c2ccccc2Cl)cn1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1ccccc1-n1cnc(CBr)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
48 mg (0.16 mmol) of the compound from Example 38A and 63 mg (0.24 mmol) of triphenylphosphine were dissolved in 1.6 ml of THF, and 80 mg (0.24 mmol) of carbon tetrabromide were added at RT. The mixture was then stirred at RT for 16 h. For work-up, the mixture was filtered through 20 g of kieselguhr, the filter residue was rinsed with ethyl acetate and the filtrate was concentrated under reduced pressure. The residue was purified chromatographically on silica gel (mobile phase: cyclohexane/ethyl acetate 5:1, then 1:1). This gave 17 mg (39% of theory) of the target compound which was immediately reacted further.
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[N:8]=[C:9]([CH2:16][CH2:17][CH3:18])[NH:10][C:11]=1[C:12]([O:14][CH3:15])=[O:13])([O:5][CH3:6])=[O:4].Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]2[N:37]([C:38]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:36]=[N:35][N:34]=2)=[CH:23][CH:22]=1>CN(C=O)C>[C:12]([C:11]1[N:10]=[C:9]([CH2:16][CH2:17][CH3:18])[N:8]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[N:37]([C:38]([C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)([C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[N:36]=[N:35][N:34]=3)=[CH:25][CH:26]=2)[C:7]=1[C:3]([O:5][CH3:6])=[O:4])([O:14][CH3:15])=[O:13]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCc1nc(C(=O)OC)c(C(=O)OC)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1nc(C(=O)OC)c(C(=O)OC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 60 °C
Reaction time: 24 h
Yield: 50.8 %

Procedure:
Sodium hydride (1.06 g, 44.2 mmol, 1 eq) was added to a solution of 4,5-dicarbomethoxy-2-n-propylimidazole (10.00 g, 44.2 mmol, 1 eq) in DMF at room temperature. Foaming and gas evolution occurred. The temperature was increased to 60° C. for 15 minutes to dissolve all of the sodium hydride. Gas evolution ceased and the mixture was cooled to room temperature. To this mixture was added a DMF solution of 4-bromomethyl-2'-(N-triphenylmethyl-(1H-tetrazol-5-yl))biphenyl (24.64 g, 44.2 mmol, 1 eq). After 24 h, the solvent was removed in vacuo, and the residue was flash chromatographed in 75:25 hexane/ethyl acetate to 100% ethyl acetate over silica gel to yield 15.78 g (51%) of a white glass which was suitable for further transformation. Recrystallization from ethanol yielded an analytical sample (white crystals); top: 124.0°-125.5° C. NMR (CDCl3) δ 7.91 (d of d,1H,J=3,9 Hz); 7.59-7.20 (m12H); 7.09 (d,2H,J=9Hz); 6.94 (m, 6H); 6.76 (d,2H,J=9Hz); 5.30 (s,2H); 3.89 (s,3H); 2.50 (t,2H,J=7Hz); 1.67 (t of t, 2H,J=7,7Hz); 0.85 (t,3H,J=7Hz). IR (neat) 1718 cm-1. Anal. calcd. for C43H38N6O4 : C, 73.49; H, 5.45; N, 11.96. Found: C, 73.23; H, 5.48; N, 12.22. ##STR78##
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:30]([O:31][CH2:32][CH:33]([F:35])[F:34])=[CH:29][C:14]3[N:15]([CH3:28])[C:16]([NH:18][C:19]4[CH:24]=[C:23]([CH2:25][NH2:26])[CH:22]=[CH:21][C:20]=4[Cl:27])=[N:17][C:13]=3[CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[F:36][C:37]([F:42])([CH3:41])[C:38](O)=[O:39].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:30]([O:31][CH2:32][CH:33]([F:35])[F:34])=[CH:29][C:14]3[N:15]([CH3:28])[C:16]([NH:18][C:19]4[CH:24]=[C:23]([CH2:25][NH:26][C:38]([C:37]([F:42])([F:36])[CH3:41])=[O:39])[CH:22]=[CH:21][C:20]=4[Cl:27])=[N:17][C:13]=3[CH:12]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: CC(F)(F)C(=O)O
Reactant: Cn1c(Nc2cc(CN)ccc2Cl)nc2cc(C(=O)Nc3ccc(Br)cc3)c(OCC(F)F)cc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cn1c(Nc2cc(CNC(=O)C(C)(F)F)ccc2Cl)nc2cc(C(=O)Nc3ccc(Br)cc3)c(OCC(F)F)cc21

Procedure:
The title compound was prepared in accordance with Example 72, step (c) using N-(4-bromo-phenyl)-2-(2-chloro-5-{[amino]-methyl}-phenylamino)-6-(2,2-difluoro-ethoxy)-1-methyl-1H-benzimidazole-5-carboxylic acid amide (170 mg; 0.30 mmol), 2,2-difluoropropanoic acid (33 mg; 0.30 mmol), HBTU (114 mg; 0.30 mmol), TEA (61 mg; 0.60 mmol) and DMF (3 mL). Yield: 63 mg (32%). 400 MHz 1H-NMR (DMSO-d6, ppm) 10.07 (1H, s) 9.30 (1H, t, J=5.8 Hz) 8.35 (1H, s) 7.87-7.82 (1H, m) 7.73-7.60 (3H, m) 7.53-7.39 (3H, m) 7.33-7.27 (1H, m) 6.99-6.90 (1H, m) 6.66-6.34 (1H, m) 4.59-4.44 (2H, m) 4.30 (2H, d, J=5.8 Hz) 3.71 (2.38H, s, major tautomer) 3.43 (0.41H, s, minor tautomer) 1.74 (3H, t, J=19.6 Hz). MS m/z: 656, 658, 660 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18])[N:6]=[C:5]2Cl.[OH:20][C@H:21]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:22]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:23].C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18])[N:6]=[C:5]2[N:27]1[CH2:26][CH2:25][N:24]([C:22](=[O:23])[C@H:21]([OH:20])[CH2:30][CH:31]([CH3:32])[CH3:33])[CH2:29][CH2:28]1
Reactant: CC(C)C[C@@H](O)C(=O)N1CCNCC1
Reactant: Oc1ccccc1-c1nc(Cl)c2cc(Br)ccc2n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C[C@@H](O)C(=O)N1CCN(c2nc(-c3ccccc3O)nc3ccc(Br)cc23)CC1
Yield: 36.4 %

Procedure:
A solution of 6-bromo-4-chloro-2-(2-hydroxyphenyl)quinazoline (75 mg, 0.22 mmol), (R)-2-hydroxy-4-methyl-1-piperazin-1-yl-pentan-1-one (60 mg, 0.3 mmol), triethylamine (42 μL, 0.3 mmol), and CH2Cl2 (2 mL) was stirred at room temperature overnight. After diluting with CH2Cl2, the reaction mixture was washed with H2O, dried over Na2SO4, and concentrated. The crude material was purified by silica gel chromatography using 0-10% MeOH/CH2Cl2 to give (R)-1-{4-[6-bromo-2-(2 hydroxyphenyl)-quinazolin-4-yl]-piperazin-1-yl}-2-hydroxy-4-methyl-pentan-1-one (40 mg, 36%).