Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[B:9]([C:11]1[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=1[CH3:19])F.[C:21]1([B:27]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)OC(C)C)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:1]1([CH3:20])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[B:9]([C:11]1[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=1[CH3:19])[C:1]1[CH:6]=[CH:5][C:4]([B:27]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[CH:3][CH:2]=1
Reactant: Cc1cc(C)c(B(F)c2c(C)cc(C)cc2C)c(C)c1
Reactant: CC(C)OB(c1ccccc1)c1ccccc1
Product: Cc1cc(C)c(B(c2ccc(B(c3ccccc3)c3ccccc3)cc2)c2c(C)cc(C)cc2C)c(C)c1

Procedure:
The compound is prepared in accordance with Method B described above, using 1 equivalent of dimesitylfluoroborane and 1 equivalent of diphenylisopropoxyborane. The crude product is obtained by concentrating the reaction mixture under a high vacuum and treating the solid residue, under argon, with hexane. Filtration, concentration of the filtrate and recrystallization of the residue from acetonitrile give 3.0 g (61% of theory) of the pale yellow title product, which is sensitive to air. Physical data are given in Tabelle 1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][OH:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl[C:13]1[CH:14]=[C:15]2[N:22]([CH3:23])[C:21]([CH3:25])([CH3:24])[CH2:20][N:16]2[C:17](=[O:19])[N:18]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:8])[CH:7]=1)[CH2:9][CH2:10][O:11][C:13]1[CH:14]=[C:15]2[N:22]([CH3:23])[C:21]([CH3:25])([CH3:24])[CH2:20][N:16]2[C:17](=[O:19])[N:18]=1
Reactant: OCCc1cc(F)cc(F)c1
Reactant: CN1c2cc(Cl)nc(=O)n2CC1(C)C
Product: CN1c2cc(OCCc3cc(F)cc(F)c3)nc(=O)n2CC1(C)C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from 2-(3,5-difluorophenyl)ethanol and 7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])=[CH:8][CH:7]=1)[CH3:2].C=O.[C:26](=O)([O-])[O-].[K+].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:23])[C:5]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14])=[CH:8][CH:7]=1)=[CH2:26])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)Cc1ccc(NC(=O)OCc2ccccc2)cc1
Agent: C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: Cc1ccccc1
Product: C=C(C(=O)OCC)c1ccc(NC(=O)OCc2ccccc2)cc1
Yield: 40.1 %

Procedure:
A solution of 2-(4-(benzyloxycarbonylamino)phenyl)ethanoic acid ethyl ester (6.5 g, 23.3 mmol), paraformaldehyde (1.05 g), potassium carbonate (5.15 g, 37.3 mmol) and tetrabutylammonium iodide (0.172 g, 0.5 mmol) in 230 mL of toluene was heated at 100° C. for 4 hours with stirring. The reaction mixture was filtered and the filtrate was washed with water, 1 M sodium hydrogen sulfate, and brine. The organic layer was evaporated in vacuo to afford 5.2 g of crude product. The product was purified by flash chromatography through silica gel (5/1 hexanes/ethyl acetate) to afford 2-(4-(benzyloxycarbonylamino)phenyl)prop-2-enoic acid ethyl ester 3.04 g (45%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[N:6][CH:7]=1.[O:24]1[CH2:28][CH2:27][NH:26][C:25]1=[O:29]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[N:6]=[CH:7][C:2]([N:26]4[CH2:27][CH2:28][O:24][C:25]4=[O:29])=[CH:3][CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cn3)CC2)c(C)c1
Reactant: O=C1NCCO1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCOC4=O)cn3)CC2)c(C)c1
Yield: 49.8 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (5-bromopyridin-2-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (375 mg) described in Preparation Example 150 and oxazolidin-2-one (96 mg), the title compound (190 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([OH:11])=O)[CH:6]=[CH:5][N:4]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[CH3:36][C:37]1[C:45]2[C:44]([N:46]3[CH2:51][CH2:50][CH:49]([NH2:52])[CH2:48][CH2:47]3)=[N:43][CH:42]=[N:41][C:40]=2[NH:39][CH:38]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([NH:52][CH:49]2[CH2:48][CH2:47][N:46]([C:44]3[N:43]=[CH:42][NH:41][C:40]4=[N:39][CH:38]=[C:37]([CH3:36])[C:45]=34)[CH2:51][CH2:50]2)=[O:11])[CH:6]=[CH:5][N:4]=1
Reactant: COc1cc(C(=O)O)ccn1
Reactant: Cc1c[nH]c2ncnc(N3CCC(N)CC3)c12
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NC2CCN(c3nc[nH]c4ncc(C)c3-4)CC2)ccn1
Reaction time: 0.17 h

Procedure:
A mixture of 2-(methyloxy)-4-pyridinecarboxylic acid (40 mg, 0.261 mmol), EDC (80 mg, 0.418 mmol), HOBt (64.1 mg, 0.418 mmol) and DIPEA (0.114 mL, 0.654 mmol) in DCM (1 mL) was prestirred for 10 minutes before adding 1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinamine hydrochloride D11 (70 mg) and the mixture was stirred at room temperature for 18 hours. The reaction mixture was then partitioned between DCM (4 mL) and 2M NaOH (4 mL) and the organic phase dried (phase separator) before it was concentrated in vacuo. The crude material was then purified by MDAP. After concentrating the product-containing fractions in vacuo the mixture was triturated with Et2O and filtered to give the title compound E23 as white solid (16 mg), 1H NMR (d6-DMSO) δ 11.54 (1H, s), 8.59 (1H, d), 8.28 (1H, d), 8.22 (1H, s), 7.36 (1H, d), 7.21 (1H, s), 7.07 (1H, s), 4.14-3.99 (3H, m), 3.89 (3H, s), 3.05 (2H, t), 2.36 (3H, s), 1.94 (2H, d), 1.73 (2H, ddd), MS(ES+) 367 [M+H]+.
Reaction SMILES: ClC(OCC)=O.[Cl:7][C:8]1[CH:18]=[CH:17][C:11]([CH:12]=[CH:13][C:14](O)=[O:15])=[CH:10][CH:9]=1.[BH4-].[Na+]>C1COCC1>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([CH:12]=[CH:13][CH2:14][OH:15])=[CH:17][CH:18]=1
Reactant: O=C(O)C=Cc1ccc(Cl)cc1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCC=Cc1ccc(Cl)cc1
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
The title compound was prepared according to the general procedure described by K. Ishizumi et al. (Chem. Pharm. Bull., 1968, 16, 492-497). A solution of ethyl chloroformate (5.2 mL, 55 mmol) in THF (15 mL) was added over 30 min to a solution of 4-chlorocinnamic acid (10 g, 55 mmol) and TEA (7.6 mL, 55 mmol) in THF (80 mL) while cooled to −5° C. The reaction was stirred for another 30 min at 0° C. and then sodium borohydride (4.2 gm, 110 mmol) was added. After 30 min., the reaction was slowly quenched with 2N hydrochloric acid and extracted twice with methylene chloride. The organic layers were washed with a portion of brine containing some aq. sodium bicarbonate, dried over sodium sulfate, and evaporated to give the title compound as a white solid. 1HNMR (CDCl3): δ 4.345 (dd, J=1.5 and 5.7 Hz, 2H), 6.36 (dt, J=5.7 and 15.8 Hz, 1H), 6.59 (br dt, J=1.5 and 15.8 Hz, 1H), 7.32 (Abq, 4H).
Reaction SMILES: [CH:1]12[N:7]([C:8](=[O:48])[C:9]([C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[NH:17][C:16]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[CH:22]=3)=[C:15]4[C@H:29]([CH3:47])[CH2:30][NH:31][S:32]([C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][C:36]=3[N+:44]([O-:46])=[O:45])(=[O:34])=[O:33])([CH3:11])[CH3:10])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[N:49]1([CH2:55][CH2:56]O)[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH:4]12[N:7]([C:8](=[O:48])[C:9]([C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[NH:17][C:16]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[CH:22]=3)=[C:15]4[C@H:29]([CH3:47])[CH2:30][N:31]([CH2:56][CH2:55][N:49]3[CH2:54][CH2:53][O:52][CH2:51][CH2:50]3)[S:32]([C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][C:36]=3[N+:44]([O-:46])=[O:45])(=[O:33])=[O:34])([CH3:10])[CH3:11])[CH:1]([CH2:2][CH2:3]1)[CH2:6][CH2:5]2
Reactant: OCCN1CCOCC1
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)N4C5CCC4CC5)cc3c2[C@H](C)CNS(=O)(=O)c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)N4C5CCC4CC5)cc3c2[C@H](C)CN(CCN2CCOCC2)S(=O)(=O)c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])c1
Reaction time: 0.33 h
Yield: 155.3 %

Procedure:
To a solution of (S)-N-{2-[5-[2-(7-azabicyclo[2.2.1]hept-7-yl)-1,1-dimethyl 2-oxo-ethyl]-2-(3,5-dimethylphenyl)-1H-indol-3-yl]-propyl}-2,4-dinitrobenzenesulfonamide (52.5 mg in 1.6 mL dry benzene) was added 20.3 mg 2-morpholin-4-yl-ethanol followed by 40.8 mg triphenylphosphine and 0.025 mL of diethyl azodicarboxylate added dropwise. After 20 minutes, the mixture was concentrated and the crude reaction product purified by flash chromatography on silica gel (ethyl acetate:hexane, 1:3) to give the title compound (95.2 mg).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])[C@H:11]([CH2:27]I)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH:29]1[CH:33]=[CH:32][N:31]=[CH:30]1>>[Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])[C@:11]([CH3:27])([N:29]2[CH:33]=[CH:32][N:31]=[CH:30]2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CI)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: c1c[nH]cn1
Product: CC(C)(C)[Si](C)(C)O[C@H]1CN(C(=O)OCc2ccc([N+](=O)[O-])cc2)[C@](C)(n2ccnc2)C1
Temperature: 0 °C
Reaction time: 5 h
Yield: 59.1 %

Procedure:
A mixture of (2S,4R)-4-t-butyldimethylsilyloxy-2-iodomethyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (3.00 g) and imidazole (15.0 g) was fused at 100-110° C. for 5 hours with stirring. The mixture was poured into ice-water (150 ml) and extracted with chloroform (50 ml ×3). The organic layers were combined, washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (30 g) and eluted with a mixture of methanol and chloroform (1:99, V/V) to give (2S,4R)-4-t-butyldimethylsilyloxy-2-(imidazol-1-yl)-methyl-1-(4-nitrobenzyloxycarbonyl) pyrrolidine (1.57 g).
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23](I)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O>>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=5[NH2:26])=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccccc1B(O)O
Reactant: C[C@H](Nc1nccc(-n2cnc3cc(I)ccc32)n1)c1ccccc1
Product: C[C@H](Nc1nccc(-n2cnc3cc(-c4ccccc4N)ccc32)n1)c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in EXAMPLE 397, starting from 2-[(S)-1-Phenylethylamino]-4-[5-iodobenzimidazol-1-yl]pyrimidine and 2-aminophenylboronic acid. Mass spectrum (ESI) 437.3 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH3:58])([CH2:10][C:11]([O:13][C@H:14]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@@H:16]([CH2:17][CH2:18][C@:19]3([CH3:55])[C@@H:28]2[CH2:27][CH2:26][C@H:25]2[C@@:20]3([CH3:54])[CH2:21][CH2:22][C@@:23]3(/[CH:40]=[CH:41]/[C:42]([NH:44][C@H:45]([C:47]4[CH:52]=[CH:51][CH:50]=[C:49]([Cl:53])[CH:48]=4)[CH3:46])=[O:43])[CH2:35][C:34](=[O:36])[C:33]([CH:37]([CH3:39])[CH3:38])=[C:24]32)[C:15]1([CH3:57])[CH3:56])=[O:12])[C:3]([O:5]C(C)(C)C)=[O:4].C(O)(C(F)(F)F)=O>ClCCl>[Cl:53][C:49]1[CH:48]=[C:47]([C@@H:45]([NH:44][C:42](=[O:43])/[CH:41]=[CH:40]/[C@:23]23[CH2:35][C:34](=[O:36])[C:33]([CH:37]([CH3:39])[CH3:38])=[C:24]2[C@@H:25]2[C@@:20]([CH3:54])([CH2:21][CH2:22]3)[C@@:19]3([CH3:55])[C@@H:28]([C@:29]4([CH3:32])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:56])([CH3:57])[C@@H:14]([O:13][C:11](=[O:12])[CH2:10][C:2]([CH3:1])([CH3:58])[C:3]([OH:5])=[O:4])[CH2:31][CH2:30]4)[CH2:27][CH2:26]2)[CH3:46])[CH:52]=[CH:51][CH:50]=1
Reactant: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)OC(C)(C)C)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)N[C@@H](C)c2cccc(Cl)c2)CC1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)N[C@@H](C)c2cccc(Cl)c2)CC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.9 %

Procedure:
To a solution of 1-tert-butyl 4-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((E)-3-(((S)-1-(3-chlorophenyl)ethyl)amino)-3-oxoprop-1-en-1-yl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) 2,2-dimethylsuccinate (12 g, 14.66 mmol) in dichloromethane (130 mL) was added TFA (80 mL, 14.66 mmol). The reaction mixture was stirred at rt for 2 hr and diluted with DCM, washed with water twice. And the organic layer was concentrated, diluted with MeCN/H2O (1:5, 36 mL) and freeze-dried under high vacuo to give the title compound (9.9 g, 12.89 mmol, 88%). This material was combined with several batches made under similar conditions and freeze dried together for characterization (31 g, 41 mmol) as a light yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ=7.38-7.13 (m, 4H), 6.97 (d, J=15.6 Hz, 1H), 5.82-5.59 (m, 2H), 5.26-5.06 (m, 1H), 4.50 (dd, J=5.3, 11.0 Hz, 1H), 3.29-3.09 (m, 1H), 2.81-2.48 (m, 3H), 2.37-2.00 (m, 3H), 2.00-0.68 (m, 47H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].C([Li])CCC.[C:12](Cl)(=[O:15])[CH2:13][CH3:14]>CCCCCC>[C:12]([N:3]1[CH2:4][CH2:5][O:1][C:2]1=[O:6])(=[O:15])[CH2:13][CH3:14]
Reactant: O=C1NCCO1
Reactant: CCC(=O)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CCC(=O)N1CCOC1=O

Procedure:
Following the cyclization reaction, the formed oxazolidinone is N-acylated to form the nucleophilic precursor of the molecule. The oxazolidinone is reacted with butyllithium in hexane, to form the conjugate base and then reacted with an acyl halide such as propionyl chloride at -71° C., for 0.5-1 hour to yield the N-propionyloxazolidinone.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br:18]N1C(=O)CCC1=O.C(Cl)(Cl)(Cl)Cl>>[Br:18][CH2:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2c1ncn2C(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)n1cnc2c(CBr)cccc21
Yield: 42.4 %

Procedure:
A mixture of 4-methylbenzimidazole-1-carboxylic acid, 1,1-dimethylethyl ester (6.50 g, 28.0 mmol) and N-bromosuccinimide (5.50 g, 30.9 mmol) in carbon tetrachloride (75 mmol) was stirred and irradiated with a 250 W flood lamp for 1 h. The reaction mixture was allowed to cool and the solid was filtered off and discarded. The filtrate was evaporated and purified by HPLC (20% ethyl acetate/hexanes) to give 4-(bromomethyl)benzimidazole-1-carboxylic acid, 1,1-dimethylethyl ester (3.69 g, 42%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)(O)[CH3:4].N1C=CC=CC=1.S(Cl)([Cl:25])(=O)=O>C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:25][C:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)([CH3:4])[C:2]([F:15])([F:14])[F:1]
Reactant: O=S(=O)(Cl)Cl
Reactant: COc1ccc(C(C)(O)C(F)(F)F)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1ccc(C(C)(Cl)C(F)(F)F)cc1
Temperature: 55 °C

Procedure:
A solution of 1,1,1-trifluoro-2-(4-methoxyphenyl)propan-2-ol (22.5 g, 102 mmol) in 150 ml of anhydrous toluene was treated sequentially with pyridine (8.26 ml, 102 mmol) and dropwise sulfuryl dichloride (11.2 ml, 153 mmol) at 0° C. The resulting mixture was then heated at 55° C. for 18 h. The reaction was diluted with 100 ml of EtOAc, washed with 100 ml of H2O and 100 ml of 1N HCl, dried over Na2SO4, and concentrated to give an oil which was filtered through a silica gel pad eluting with 0-5% EtOAc in hexanes to afford the title compound.
Reaction SMILES: [C:1](Cl)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[OH:21][CH2:22][C@@H:23]([C@H:25]([C@@H:27]([C@@H:29]([CH2:31][OH:32])[OH:30])[OH:28])[OH:26])[OH:24].Cl>C1(C)C=CC=CC=1.N1C=CC=CC=1>[C:1]([OH:19])(=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[OH:32][CH2:31][C@@H:29]([C@H:27]([C@@H:25]([C@@H:23]([CH2:22][OH:21])[OH:24])[OH:26])[OH:28])[OH:30]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Agent: Cl
Agent: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCC(=O)O
Temperature: 90 °C

Procedure:
411.5 g (1.358 mols) stearic acid chloride are dissolved in 3 l toluene and heated to 90° C. 41.23 g (0.22 mols) of sorbitol, dissolved in 200 ml pyridine are added dropwise to this mixture over 25 minutes. The solution is boiled (at approx. 110° C.) for 1 hour under reflux. After cooling, dilute hydrochloric acid is added to acidify the mixture, which is then washed with water until neutral and dried with dehydrated sodium sulphate. After concentration of the organic phase the sorbitol stearate crystallizes. It is recrystallized from methanol.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([CH3:12])=[N:9][C:8]=2[CH:13]=1)([OH:3])=O.P(Cl)(Cl)(Cl)=O.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O>[C:20]1([NH:19][C:1]([C:4]2[CH:5]=[CH:6][C:7]3[O:11][C:10]([CH3:12])=[N:9][C:8]=3[CH:13]=2)=[O:3])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1nc2cc(C(=O)O)ccc2o1
Reactant: Nc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cc1nc2cc(C(=O)Nc3ccccc3)ccc2o1
Temperature: 100 °C
Reaction time: 0.75 h
Yield: 594.6 %

Procedure:
5-Carboxy-2-methylbenzoxazole (2.0 g, 1.1 mmol) and phosphorous oxychloride (10 mL) were combined and heated at 100° C. for 1 hr. The reaction mixture was evaporated and the resulting oil was dissolved in 20 mL of acetonitrile and poured into a mixture of ice and water. The solid formed was collected, dissolved in 40 mL of acetonitrile and combined with aniline (2.0 g, 2.2 mmol). After stirring 45 min. the reaction mixture was poured into 500 mL of a mixture of ice and water. The resulting solid was collected and dried affording 1.65 g (58% yield) of 5-(Phenylcarbamoyl)-2-methylbenzoxazole, mp 137.5-139.0° C. Anal. Calcd for C15H12N2O2 : C, 71.42; H, 4.79; N, 11.10. Found: C, 71.16; H, 4.83; N, 10.96.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:22]=[CH:21][C:14]3[N:15]([CH3:20])[C:16](=[O:19])[CH2:17][O:18][C:13]=3[CH:12]=2)[CH2:6]1)=O.[NH3:23]>CO.CCOCC>[CH3:20][N:15]1[C:14]2[CH:21]=[CH:22][C:11]([N:7]3[CH2:6][C@H:5]([C:3]([NH2:23])=[O:2])[O:9][C:8]3=[O:10])=[CH:12][C:13]=2[O:18][CH2:17][C:16]1=[O:19]
Reactant: N
Reactant: COC(=O)[C@H]1CN(c2ccc3c(c2)OCC(=O)N3C)C(=O)O1
Solvent: CO
Solvent: CCOCC
Product: CN1C(=O)COc2cc(N3C[C@H](C(N)=O)OC3=O)ccc21
Reaction time: 16 h
Yield: 81 %

Procedure:
To a stirred solution of (5R)-3-(3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazin-7-yl)-2-oxo-oxazolidine-5-carboxylic acid methyl ester (Step 2, 2.41 g, 7.87 mmol) in MeOH (25 mL) is added 2M NH3 in MeOH (25 mL, 50 mmol). The resulting clear solution becomes turbid after ˜10 min. This mixture is stirred for 16 h at which time the reaction is diluted with ether (20 mL) and the resulting white solid filtered off. This white solid is washed with several portion of ether (50 mL) and dried under high vacuum to give the title compound (1.87 g, 81%), 1H NMR (300 MHz, DMSO) δ 7.85 (br s, 1H), 7.60 (br s, 1H), 7.31-7.14 (m, 3H), 5.00 (dd, 1H), 4.65 (s, 2H), 4.21 (t, 1H), 3.97 (dd, 1H), 3.32 (s, 3H); MS for C14H13N3O5 m/z 292.5 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:28]([O:30][CH2:31][CH2:32]O)[CH3:29].B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:29][CH2:28][O:30][CH2:31][CH3:32])=[O:5]
Reactant: CCOCCO
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)O)c(F)c1
Agent: FB(F)F
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OCCOCC)c(F)c1
Reaction time: 120 h

Procedure:
A solution of 11.8 g of 2-fluoro-4-(hexadecylamino)-benzoic acid, 1.00 g. of 2-ethoxyethanol and 5.35 ml of boron trifluoride etherate in 200 ml of toluene is stirred under reflux for 48 hours. The solution is treated with an additional 5.35 ml of boron trifluoride etherate and refluxing is continued for 120 hours. Dilution with water and methylene chloride followed by filtration affords 2-ethoxyethyl 2-fluoro-4-(hexadecylamino)benzoate as a white solid.
Reaction SMILES: Cl.[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:12][NH:11]2)=[O:9])[CH2:6][CH2:5]1)#[N:3].[CH3:25][N:26]1[CH2:31][CH2:30][CH:29]([C:32](O)=[O:33])[CH2:28][CH2:27]1>>[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:12][N:11]2[C:32]([CH:29]2[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]2)=[O:33])=[O:9])[CH2:6][CH2:5]1)#[N:3]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Reactant: CN1CCC(C(=O)O)CC1
Agent: Cl
Product: CN1CCC(C(=O)N2C[C@H](S(=O)(=O)c3ccccc3Cl)C[C@H]2C(=O)NC2(C#N)CC2)CC1

Procedure:
L31. (2S,4R)-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide hydrochloride from experiment K4 was coupled with 1-methyl-piperidine-4-carboxylic acid in analogy to experiment A1 to give (2S,4R)-4-(2-chloro-benzenesulfonyl)-1-(1-methyl-piperidine-4-carbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide as a white solid. MS: 479.1 [M+H]+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:13]=[CH:14][C:15]2[N:21]([CH:22]([CH3:24])[CH3:23])[C:20](=[O:25])[C@@H:19]([CH2:26][CH2:27][OH:28])[O:18][C@H:17]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:35])[C:16]=2[CH:36]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]2[N:21]([CH:22]([CH3:23])[CH3:24])[C:20](=[O:25])[C@@H:19]([CH2:26][CH:27]=[O:28])[O:18][C@H:17]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:35])[C:16]=2[CH:36]=1
Reactant: CC(C)N1C(=O)[C@@H](CCO)O[C@H](c2ccccc2Cl)c2cc(Cl)ccc21
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)N1C(=O)[C@@H](CC=O)O[C@H](c2ccccc2Cl)c2cc(Cl)ccc21
Reaction time: 0.08 h
Yield: 92.5 %

Procedure:
A solution of oxalyl chloride (0.72 ml) in methylene chloride (10 ml) was cooled to -65° C., to which was added dropwise a solution of dimethyl sulfoxide (0.63 ml) in methylene chloride (2 ml) taking 5 minutes, followed by stirring for 5 minutes. To the mixture was added dropwise, taking 15 minutes, a solution of trans-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-ethanol (2.5 g) obtained in Example 47 in methylene chloride (15 ml), which was stirred for 10 minutes. To the resultant mixture was added triethylamine (3.45 ml) taking 5 minutes, then the cooling bath was removed. The mixture was stirred for 10 minutes at room temperature, to which was then added 1N hydrochloric acid (50 ml), followed by stirring. The methylene chloride layer was dried over anhydrous magnesium sulfate, then the solvent was distilled off under reduced pressure to leave trans-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetaldehyde (2.3 g) as an oily product.