Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.C(N(C(C)C)CC)(C)C.Cl.[N:25]1([C:30]2[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=2)[CH:29]=[CH:28][N:27]=[CH:26]1>CN(C)C1C=CN=CC=1.ClCCl>[N:25]1([C:30]2[CH:31]=[CH:32][C:33]([C:34]([N:7]3[C:8]4[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=4[CH2:10][N:4]4[CH:3]=[CH:2][CH:1]=[C:5]4[CH2:6]3)=[O:35])=[CH:37][CH:38]=2)[CH:29]=[CH:28][N:27]=[CH:26]1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: O=C(Cl)c1ccc(-n2ccnc2)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(-n2ccnc2)cc1)N1Cc2cccn2Cc2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]-benzodiazepine (0.75), diisopropylethylamine (1.20 g), and 4-dimethylaminopyridine (0.1 g) in dichloromethane (50 ml) was added 4-(imidazol-1-yl)benzoyl chloride hydrochloride (1.12 g). After stirring at room temperature for 18 hours, the reaction mixture was washed with water and saturated aqueous sodium bicarbonate. The dichloromethane solution was dried over anhydrous sodium sulfate, filtered through a short column of hydrous sodium magnesium silicate, and further eluted with several volumes of dichloromethane. The combined organic phase was concentrated on a hot plate with the gradual addition of hexane until crystallization occurred. After cooling, the crystals were collected by filtration to yield the title compound (0.57 g), m.p. 171-172° C.; MS, m/z: 354 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]([CH2:29][CH3:30])([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH:22]([OH:27])[C:23]([CH3:26])([CH3:25])[CH3:24])=[C:16]([CH3:28])[CH:15]=2)[CH2:12][CH3:13])=[CH:8][C:9]=1[CH3:10])=[O:4].N1C=CN=C1.CN(C=O)C.[CH3:41][C:42]([Si:45](Cl)([CH3:47])[CH3:46])([CH3:44])[CH3:43]>CCOCC>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH:22]([O:27][Si:45]([C:42]([CH3:44])([CH3:43])[CH3:41])([CH3:47])[CH3:46])[C:23]([CH3:24])([CH3:25])[CH3:26])=[C:16]([CH3:28])[CH:15]=2)([CH2:12][CH3:13])[CH2:29][CH3:30])=[CH:8][C:9]=1[CH3:10])=[O:4]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1cc(C)c(C(=O)OC)s1
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCC(CC)(c1ccc(OCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1cc(C)c(C(=O)OC)s1
Reaction time: 24 h
Yield: 64.6 %

Procedure:
To a mixture of 5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carboxylic acid methyl ester (Example 2) (1.15 g, 2.66 mmol), imidazole (0.27 g, 4.00 mmol), and DMF (15 mL) is added TBSCl (0.54 g, 2.80 mmol). The reaction is stirred for 24 h. The reaction is diluted with Et2O (120 mL) and washed with 0.1 M HCl (3×40 ml). The organic layer is MgSO4 dried and concentrated. The resulting residue is chromatographed to give the title compound (0.94 g, 64%). 1H NMR (CDCl3), δ 0.01 (s, 3H), 0.06 (s, 3H), 0.65 (t, J=7.4 Hz, 6H), 0.85 (s, 9H), 0.91 (s, 9H), 2.00-2.14 (m, 4H), 2.14 (s, 3H), 2.43 (s, 3H), 3.67 (dd, J=5.8, 3.4 Hz, 1H), 3.74 (s, 3H), 3.85 (dd, J=9.8, 5.8 Hz, 1H), 3.98 (dd, J=9.8, 3.4 Hz, 1H), 6.56 (s, 1H), 6.68 (d, J=8.3 Hz, 1H), 6.96-7.03 (m, 2H). LC/MS (m/z): calcd for C31H51O4SSi (M+H)+: 547.9; found: 547.2.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][CH:12]2[O:14][CH2:13]2)=[CH:8][CH:7]=1)(=[O:4])=[O:3].[NH2:17][CH2:18][CH2:19][N:20]1[C:24]2[CH:25]=[CH:26][C:27]([C:29]3[CH2:30][CH2:31][C:32](=[O:35])[NH:33][N:34]=3)=[CH:28][C:23]=2[N:22]=[CH:21]1>>[CH3:1][S:2]([O:5][C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][CH:12]([OH:14])[CH2:13][NH:17][CH2:18][CH2:19][N:20]2[C:24]3[CH:25]=[CH:26][C:27]([C:29]4[CH2:30][CH2:31][C:32](=[O:35])[NH:33][N:34]=4)=[CH:28][C:23]=3[N:22]=[CH:21]2)=[CH:8][CH:7]=1)(=[O:4])=[O:3]
Reactant: NCCn1cnc2cc(C3=NNC(=O)CC3)ccc21
Reactant: CS(=O)(=O)Oc1ccc(OCC2CO2)cc1
Product: CS(=O)(=O)Oc1ccc(OCC(O)CNCCn2cnc3cc(C4=NNC(=O)CC4)ccc32)cc1

Procedure:
Prepared analogously to Example 1 from 1-(4-methylsulphonyloxy-phenoxy)-2,3-epoxypropane and 6-[1(2-aminoethyl)benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[F:15][C:16](=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:17](O)=O>>[CH2:12]([N:4]1[C:3](=[O:14])[C:2]2[NH:1][C:17](/[C:16](/[F:15])=[CH:20]\[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:8][C:7]=2[N:6]([CH2:9][CH3:10])[C:5]1=[O:11])[CH3:13]
Reactant: O=C(O)C(F)=Cc1ccccc1
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Product: CCn1c(=O)c2[nH]c(/C(F)=C\c3ccccc3)nc2n(CC)c1=O
Yield: 57.9 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 1.08 g (5.47 mmol) of 5,6-diamino-1,3-diethyluracil and 1.00 g (6.02 mmol) of α-fluorocinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 1.04 g (yield 58%) of Compound 138 as white plates.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][S:10]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17](=[O:22])[CH2:16]3)(=[O:12])=[O:11])[CH:6]=[CH:7][CH:8]=1.[CH2:23]([N:25]([CH2:40][CH3:41])[CH2:26][CH2:27][NH:28][C:29]([C:31]1[C:35]([CH3:36])=[C:34]([CH:37]=O)[NH:33][C:32]=1[CH3:39])=[O:30])[CH3:24].N1CCCCC1>C(O)C>[CH2:40]([N:25]([CH2:23][CH3:24])[CH2:26][CH2:27][NH:28][C:29]([C:31]1[C:35]([CH3:36])=[C:34](/[CH:37]=[C:16]2\[C:17](=[O:22])[NH:18][C:19]3[C:15]\2=[CH:14][C:13]([S:10]([CH2:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)(=[O:11])=[O:12])=[CH:21][CH:20]=3)[NH:33][C:32]=1[CH3:39])=[O:30])[CH3:41]
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Reactant: COc1cccc(CS(=O)(=O)c2ccc3c(c2)CC(=O)N3)c1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4cccc(OC)c4)cc32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 69.2 %

Procedure:
To a solution of 5-(3-methoxy-phenylmethanesulfonyl)-1,3-dihydro-indol-2-one (100 mg, 0.32 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (84 mg, 0.32 mmol) in ethanol (4 mL) was added piperidine (0.1 mL). The reaction mixture was stirred at 25° C. for three days. The solvent was evaporated and the residue was purified on a silica gel column eluting with MeOH—CH2Cl2 1:9 to provide 125 mg (69%) of 5-[5-(3-methoxy-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide as a pale orange solid.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2([C:33]3[C:38]([F:39])=[CH:37][CH:36]=[CH:35][C:34]=3F)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][C:26]2=[O:32])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1.CN1C(=O)N(C)CCC1>[CH2:11]([O:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]23[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=[C:26]2[O:32][C:34]2[CH:35]=[CH:36][CH:37]=[C:38]([F:39])[C:33]3=2)=[CH:23][CH:24]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1CCCCCC1(c1ccc(OCc2ccccc2)cc1)c1c(F)cccc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CN1CCCN(C)C1=O
Solvent: Cc1ccccc1
Product: Fc1cccc2c1C1(c3ccc(OCc4ccccc4)cc3)CCCCC=C1O2
Temperature: 90 °C

Procedure:
KHMDS (0.2 mL, 0.5 M in toluene) was added to a solution of 2-(4-(benzyloxy)phenyl)-2-(2,6-difluorophenyl)cycloheptanone (50 mg) in toluene (3 mL) and DMPU (1 mL). The reaction mixture was heated at 90° C. for 2 h (TLC indicated some conversion of the starting material). Additional heating for 1 h gave no further conversion of the starting material according to TLC. The organic phase was washed with water (10 mL), brine, dried (Na2SO4) and concentrated in vacuo. Work-up by flash chromatography (eluent heptane dichloromethane 1:1) afforded the title compound 22 in a yield of 20 mg. 1H-NMR (400 MHz, CDCl3): δ ppm 7.49-7.46 (m, 2H), 7.50-7.34 (m, 5H), 7.10-7.00 (m, 1H), 6.96-6.91 (m, 2H), 6.61-6.59 (m, 1H), 6.53-6.48 (m, 1H), 5.73 (dd, J=5, 9 Hz, 1H), 5.02 (s, 2H), 3.07-3.02 (m, 1H), 2.00-1.20 (m, 8H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[N:4]=[CH:3]1.[NH2:10][C@@H:11]([CH3:29])[CH2:12][N:13]1[CH:17]=[C:16]([C:18]#[N:19])[C:15]([C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[C:22]([Cl:28])[CH:21]=2)=[N:14]1>>[Cl:28][C:22]1[CH:21]=[C:20]([C:15]2[C:16]([C:18]#[N:19])=[CH:17][N:13]([CH2:12][C@@H:11]([NH:10][C:7]([C:5]3[N:4]=[CH:3][N:2]([CH3:1])[CH:6]=3)=[O:9])[CH3:29])[N:14]=2)[CH:25]=[CH:24][C:23]=1[C:26]#[N:27]
Reactant: C[C@H](N)Cn1cc(C#N)c(-c2ccc(C#N)c(Cl)c2)n1
Reactant: Cn1cnc(C(=O)O)c1
Product: C[C@@H](Cn1cc(C#N)c(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cn(C)cn1
Yield: 34.1 %

Procedure:
The title compound was prepared using the method of Example 34(d) starting from 1-methyl-1H-imidazole-4-carboxylic acid (53.0 mg, 0.420 mmol) and (S)-1-(2-aminopropyl)-3-(3-chloro-4-cyanophenyl)-1H-pyrazole-4-carbonitrile (100 mg, 0.350 mmol). The product was purified by recrystallization from diethyl ether and diethyl ether/ethanol, respectively. Finally the product was also run through flash chromatography. Yield 34.1%. 1H-NMR (400 MHz; DMSO-d6): δ 1.15 (d, 3H), 3.67 (s, 3H), 4.36-4.51 (m, 3H), 7.56 (d, 1H), 7.69 (d, 1H), 7.98 (dd, 1H), 8.04-8.10 (m, 2H), 8.15 (dd, 1H), 8.69 (s, 1H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[NH:19][C:18](=[O:20])[C:17]([NH:21][C:22](=[O:31])[O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:16][CH:15]=1.[CH:32]1([CH2:35]Br)[CH2:34][CH2:33]1.O>CN(C)C=O>[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[N:19]([CH2:35][CH:32]2[CH2:34][CH2:33]2)[C:18](=[O:20])[C:17]([NH:21][C:22](=[O:31])[O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:16][CH:15]=1
Reactant: BrCC1CC1
Reactant: O=C(Nc1ccc(-c2ccccc2Cl)[nH]c1=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(-c2ccccc2Cl)n(CC2CC2)c1=O)OCc1ccccc1
Reaction time: 4 h
Yield: 38.2 %

Procedure:
Cesium carbonate (1.07 g, 3.30 mmol) was added to a solution of benzyl 6-(2-chlorophenyl)-2-oxo-1,2-dihydropyridin-3-ylcarbamate (J. Med. Chem. 1994, 37, 3303-3312) (585 mg, 1.65 mmol) and cyclopropylmethyl bromide (0.19 mL, 1.98 mmol) in N,N-dimethylformamide (5 mL). After 4 h, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water (2×), saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (hexanes→30% ethyl acetate/hexanes) gave the title compound (258 mg). MS 409.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:26][CH3:27])=[C:16]([CH2:19][NH:20][C@@H:21]([CH3:25])[CH2:22][O:23][CH3:24])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.CC[O:31][C:32]([C@H:34](OS(C(F)(F)F)(=O)=O)[CH3:35])=[O:33]>>[Cl:1][C:2]1[C:3]([F:28])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:26][CH3:27])=[C:16]([CH2:19][N:20]([C@@H:21]([CH3:25])[CH2:22][O:23][CH3:24])[C@H:34]([C:32]([OH:33])=[O:31])[CH3:35])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC[C@H](C)NCc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC
Reactant: CCOC(=O)[C@@H](C)OS(=O)(=O)C(F)(F)F
Product: COC[C@H](C)N(Cc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC)[C@@H](C)C(=O)O

Procedure:
N-(3-Chloro-2-fluorophenyl)-7-methoxy-6-({[(1S)-2-methoxy-1-methylethyl]amino}methyl)quinazolin-4-amine (prepared as described in Example 52) was coupled with ethyl O-trifluoromethanesulfonyl-D-lactate and hydrolysed using analogous methods to those described for the equivalent steps in Example 46 to give N-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)-N-[(1S)-2-methoxy-1-methylethyl]-L-alanine; 1H NMR Spectrum: (DMSO-d6) 1.08 (d, 3H); 1.30 (d, 3H); 3.09 (m, 1H); 3.16 (s, 3H); 3.23 (dd, 1H); 3.39 (dd, 1H); 3.06 (q, 1H); 3.97 (s, 3H); 3.98 (d, 1H); 4.10 (d, 1H); 7.19 (s, 1H); 7.29 (t, 1H); 7.49 (m, 1H); 7.61 (m, 1H); 8.39 (s, 1H); 8.43 (s, 1H); 9.57 (brs, 1H); 12.13 (brs, 1H); Mass Spectrum: (M+H)+ 477.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[C:10]([NH2:11])=[CH:9][S:8][CH:7]=1)=[O:5].C(N(CC)CC)C.[Cl:19][C:20]1[CH:32]=[CH:31][CH:30]=[CH:29][C:21]=1[O:22][CH2:23][CH2:24][CH2:25][C:26](Cl)=[O:27]>ClCCl>[CH3:2][O:3][C:4]([C:6]1[C:10]([NH:11][C:26](=[O:27])[CH2:25][CH2:24][CH2:23][O:22][C:21]2[CH:29]=[CH:30][CH:31]=[CH:32][C:20]=2[Cl:19])=[CH:9][S:8][CH:7]=1)=[O:5]
Reactant: O=C(Cl)CCCOc1ccccc1Cl
Reactant: COC(=O)c1cscc1N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cscc1NC(=O)CCCOc1ccccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.9 %

Procedure:
To 4-amino-thiophene-3-carboxylic acid methyl ester hydrochloride (199 mg, 0.994 mmol) in dichloromethane (1.9 mL) and triethylamine (0.29 mL, 2.08 mmol), was slowly added a crude solution of 4-(2-chloro-phenoxy)-butyryl chloride (271 mg, approximately 1.16 mmol) in dichloromethane (1.9 mL). The reaction mixture was stirred for 3 hours at room temperature. The reaction mixture was then further diluted with dichloromethane (50 mL) and washed with water. The aqueous phase was then extracted with dichloromethane and the combined organic phases were dried with sodium sulfate, and concentrated in vacuo. The residue was then purified by column chromatography (SiO2, Heptane/EtOAc: 0-80%) to yield the title compound as a white solid (281 mg, 80%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6].C(N(CC)C(C)C)(C)C.C([O:23][C:24](=O)[CH:25]=[C:26]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=1)[CH2:27]Br)C>C(#N)C>[CH3:2][O:3][C:4](=[O:11])[C@@H:5]([N:6]1[CH2:27][C:26]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:38])([F:39])[F:37])[CH:31]=2)=[CH:25][C:24]1=[O:23])[CH2:7][CH:8]([CH3:10])[CH3:9]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: CCOC(=O)C=C(CBr)Oc1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CC(C)C)N1CC(Oc2cccc(C(F)(F)F)c2)=CC1=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 58.5 %

Procedure:
A mixture of (L)-leucine methyl ester hydrochloride (0.79 g, 4.34 mmol) in acetonitrile (9.5 mL) was treated with N,N-diisopropylethylamine (0.70 mL, 4.26 mmol). After addition was complete, the mixture was stirred at 60° C. for 1 h. At this time, the reaction was cooled to 25° C., treated with N,N-diisopropylethylamine (0.70 mL, 4.26 mmol) and acetonitrile (9.5 mL) and then heated to 80° C. Upon reaching 80° C., the reaction was treated with a solution of 4-bromo-3-(3-trifluoromethyl-phenoxy)-but-2-enoic acid ethyl ester (1.40 g, 3.96 mmol) in acetonitrile (9.5 mL). After the addition was complete the reaction mixture was heated to 100° C. and stirred overnight. At this time, the reaction mixture was cooled to 25° C. and concentrated in vacuo. The residue was diluted with dichloromethane (100 mL) and was washed with a 2N aqueous hydrochloric acid solution (1×100 mL), a saturated aqueous sodium bicarbonate solution (1×100 mL), a saturated aqueous sodium chloride solution (1×100 mL), dried over magnesium sulfate, filtered, rinsed with dichloromethane and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 15-50% ethyl acetate/hexanes) afforded (S)-4-methyl-2-[2-oxo-4-(3-trifluoromethyl-phenoxy)-2,5-dihydro-pyrrol-1-yl]-pentanoic acid methyl ester (0.86 g, 59%) as a light, brown solid: HR-ES-MS m/z calculated for C18H20NO4F3 [M+H]+ 372.1417, observed 372.1418; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.88 (d, J=6.6 Hz, 3H), 0.93 (d, J=6.6 Hz, 3H), 1.29-1.55 (m, 1H), 1.56-1.68 (m, 1H), 1.73-1.90 (m, 1H), 3.66 (s, 3H), 4.19 (d, J=18.1 Hz, 1H), 4.26 (d, J=18.1 Hz, 1H), 4.75 (dd, J=11.4, 4.6 Hz, 1H), 4.95 (s, 1H), 7.64-7.78 (m, 4H).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[CH2:25]Br>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:25][C:19]2[C:18](=[CH:23][CH:22]=[C:21]([F:24])[CH:20]=2)[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: Fc1ccc(CBr)c(CBr)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Fc1ccc2c(c1)CN(Cc1ccccc1)C2

Procedure:
A solution of benzylamine (64.3 ml) and triethylamine (164 ml) in toluene (1 L) was added to 1,2-bis(bromomethyl)-4-fluorobenzene (164.1 g) (J. Org. Chem., 1988, 53, 1775-9). This mixture was heated to reflux for 4 h under argon. The reaction mixture was then filtered and the solid was washed with toluene (3×150 ml). The filtrate was evaporated in vacuo and the residue dissolved in dichloromethane (1 L). This solution was washed successively with a saturated solution of potassium carbonate (1 L) and water (0.5 L). The organic extract was dried (MgSO4), concentrated to a volume of 0.5 L and cooled in ice. The unwanted precipitate was filtered off and the filtrate evaporated to a residue which was purified by chromatography over silica gel eluting with a gradient of dichloromethane/ethyl acetate to give the title compound (D7) as an oil (49.3 g). MS electrospray (+ion) 228 (MH+). 1H NMR δ (CDCl3): 7.24-7.42 (5H, m), 7.07-7.12 (1H, m), 6.82-6.89 (2H, m), 3.89 (6H, br, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([C@H:18]3[N:23]([CH2:24][C:25]([OH:27])=O)[CH2:22][C:21]([CH3:29])([CH3:28])[O:20][CH2:19]3)=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([C@@H:18]3[CH2:19][O:20][C:21]([CH3:29])([CH3:28])[CH2:22][N:23]3[CH2:24][C:25](=[O:27])[N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: CC1(C)CN(CC(=O)O)[C@H](C(=O)Nc2cc(Cl)cc3c2[nH]c2cnccc23)CO1
Reactant: C1CCNC1
Product: CC1(C)CN(CC(=O)N2CCCC2)[C@H](C(=O)Nc2cc(Cl)cc3c2[nH]c2cnccc23)CO1
Yield: 82 %

Procedure:
The desired compound was prepared according to Method F from [(S)-5-(6-Chloro-9H-beta-carbolin-8-ylcarbamoyl)-2,2-dimethyl-morpholin-4-yl]-acetic acid and pyrrolidine in 82% yield.
Reaction SMILES: [OH-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:10][C:11]1[CH:22]=[CH:21][C:14]2[C:15](=O)[O:16]C(=O)[NH:18][C:13]=2[CH:12]=1.O1CCCC1>C(OCC)(=O)C>[F:10][C:11]1[CH:12]=[C:13]([NH2:18])[C:14](=[CH:21][CH:22]=1)[C:15]([O:9][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:16]
Reactant: Oc1ccccc1
Reactant: O=c1[nH]c2cc(F)ccc2c(=O)o1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1cc(F)ccc1C(=O)Oc1ccccc1

Procedure:
Sodium hydroxide (2 pellets; approx 0.15 g) was added to a mixture of phenol (1.08 g) and 7-fluoro-1H-3,1-benzoxazine-2,4-dione (2 g) followed by tetrahydrofuran (4 ml). The mixture was heated on a steam bath until gas evolution ceased. It was then cooled, diluted with ethyl acetate (100 ml), the liquid collected and washed with aqueous sodium carbonate, dried, treated with charcoal and evaporated. The crude product was recrystallised from diisopropyl ether/light petroleum to give phenyl 4-fluoroanthranilate, m.p. 69°-70°. (Compound 3).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)=[O:4].[OH:15][CH:16]([CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1.C(=O)([O-])O.[Na+]>C(O)C>[OH:15][CH:16]([CH:24]1[CH2:29][CH2:28][N:27]([CH2:2][C:3]([C:5]2[CH:14]=[CH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]=2)=[O:4])[CH2:26][CH2:25]1)[C:17]1[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=1
Reactant: O=C(CBr)c1ccc2ccccc2c1
Reactant: OC(c1ccc(F)cc1)C1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=C(CN1CCC(C(O)c2ccc(F)cc2)CC1)c1ccc2ccccc2c1

Procedure:
5.4 g of 2-bromo-2'-acetonaphthone, 4.6 of 4-(α-hydroxy-p-fluorobenzyl)piperidine and 10 g of sodium hydrogencarbonate were refluxed in ethanol solvent for 2.5 h. After completion of the reaction, the product was treated by an ordinary process. The obtained oily product was purified according to silica gel column chromatography to obtain 5 g of 2-[4-(α-hydroxy-p-fluorobenzyl)piperidinyl]-2'-acetonaphthone; 1 g of this product was stirred together with 1.0 g of acetic anhydride and 0.1 g of dimethylaminopyridine in pyridine solvent at room temperature for 5 h. After completion of the reaction, the oily product was purified according to silica gel column chromatography and converted into its hydrochloride, which was recrystallized from ethyl acetate and methanol.
Reaction SMILES: [Cl-].[CH2:2]([O:4][CH:5]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:3].C1CCN2C(=NCCC2)CC1.[CH2:41]([O:48][C:49]1[C:56]([F:57])=[CH:55][C:52]([CH:53]=O)=[CH:51][C:50]=1[F:58])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>O1CCCC1>[CH2:41]([O:48][C:49]1[C:56]([F:57])=[CH:55][C:52](/[CH:53]=[C:5](\[O:4][CH2:2][CH3:3])/[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:51][C:50]=1[F:58])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: O=Cc1cc(F)c(OCc2ccccc2)c(F)c1
Reactant: CCOC(=O)C(OCC)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCOC(=O)/C(=C/c1cc(F)c(OCc2ccccc2)c(F)c1)OCC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of (1,2-diethoxy-2-oxoethyl)triphenylphosphonium chloride (679) (1.61 g, 3.76 mmol) in tetrahydrofuran (56 mL) was added DBU (0.67 ml, 4.51 mmol) and the reaction was stirred for 10 minutes at room temperature. 4-(benzyloxy)-3,5-difluorobenzaldehyde (1.40 g, 5.64 mmol) was added in one portion and the reaction was stirred at room temperature for 18 hours. The solvent was removed in vacuo, diethyl ether was added and the solids filtered. The filtrate was concentrated in vacuo and the residue oil was purified by flash column chromatography (0-30% EtOAc in hexanes) to provide (Z)-ethyl 3-(4-(benzyloxy)-3,5-difluorophenyl)-2-ethoxyacrylate (680).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.II.[Si]([O:29][C:30]1[CH:63]=[CH:62][C:33]([C:34]([NH:36][NH:37][C:38](=O)[C@H:39]([NH:50][C:51]2[CH:56]=[CH:55][C:54]([C:57]#[N:58])=[C:53]([Cl:59])[C:52]=2[CH3:60])[C@H:40]([O:42][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44])[CH3:41])=[O:35])=[CH:32][C:31]=1[Cl:64])(C(C)(C)C)(C)C>C(Cl)Cl>[Si:43]([O:42][C@H:40]([CH3:41])[C@@H:39]([NH:50][C:51]1[CH:56]=[CH:55][C:54]([C:57]#[N:58])=[C:53]([Cl:59])[C:52]=1[CH3:60])[C:38]1[O:35][C:34]([C:33]2[CH:62]=[CH:63][C:30]([OH:29])=[C:31]([Cl:64])[CH:32]=2)=[N:36][N:37]=1)([C:46]([CH3:48])([CH3:47])[CH3:49])([CH3:44])[CH3:45]
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(O[Si](C)(C)C(C)(C)C)c(Cl)c2)[C@@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(O)c(Cl)c3)o2)[C@@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 106.6 %

Procedure:
To a 25 mL round bottom flask was added polymer supported triphenylphosphine (687 mg, 2.06 mmol, 2.0 equiv., approx. 3 mmol/g) and 10.3 mL of methylene chloride. The reaction was cooled to 0° C. using an ice-water bath and then iodine (523 mg, 2.06 mmol, 2.0 equiv.) was added followed by TEA (0.57 mL, 4.12 mmol, 4.0 equiv.). After stirring for 5 min, 4-(tert-butyldimethylsilyloxy)-N′-((2R,3R)-3-(tert-butyldimethylsilyloxy)-2-(3-chloro-4-cyano-2-methylphenylamino)butanoyl)-3-chloro benzohydrazide (688 mg, 1.03 mmol, 1.0 equiv.) was added. The reaction was allowed to stir at room temperature for 2 h. The mixture was filtered over Celite® in a ground glass fritted funnel and the solids rinsed with methylene chloride several times. The organics were washed with 10% Na2S2O3 (3×10 mL) followed by a wash with brine (1×10 mL). The solution was dried over Na2SO4 and was concentrated in vacuo to yield a brown oil. The product was purified via automated flash chromatography (0→30% EtOAc/hexanes→100% EtOAc, 40 g of silica gel) to provide the desired product as a yellow oil (586 mg, 88% yield). Other data: 1H NMR (400 MHz, acetone-d6, δ in ppm) 7.92 (d, J=2.14 Hz, 1H), 7.80 (dd, J=1.95, 8.4 Hz, 1H), 7.50 (d, J=8.79 Hz, 1H), 7.18 (d, J=8.6 Hz, 1H), 6.93 (d, J=8.79 Hz, 1H), 5.79 (d, J=9.18 Hz, 1H), 5.02 (dd, J=6.65, 9.19 Hz, 1H), 4.65 (m, 1H), 2.34 (s, 3H), 1.41 (d, J=6.05 Hz, 3H), 0.81 (s, 9H), 0.09 (s, 3H), 0.03 (s, 3H); LRMS (ESI-) exact mass calcd for C25H30Cl2N4O3Si [M]+533.5, found 534.2.