Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH2:12][CH:13](OC)OC)[C:5]([O:7][CH3:8])=[O:6].O=[C:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>C(O)(=O)C>[CH2:28]([O:27][C:25]([N:22]1[CH2:23][CH2:24][CH:19]([N:1]2[C:2]3[C:11](=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:3]=3)[CH:12]=[CH:13]2)[CH2:20][CH2:21]1)=[O:26])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: COC(=O)c1ccc(CC(OC)OC)c(N)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1ccc2ccn(C3CCN(C(=O)OCc4ccccc4)CC3)c2c1
Temperature: 25 °C
Yield: 88.9 %

Procedure:
44.3 g of methyl 3-amino-4-(2,2-dimethoxyethyl)benzoate synthesized according to the publication (Tetrahedron Letters, Vol. 37, No. 34, pp. 6045-6048) and 64.9 g of benzyl 4-oxo-1-piperidinecarboxylate were dissolved in 485 ml of acetic acid, followed by stirring at room temperature. Approximately 20 minutes later, 58.9 g of sodium triacetoxyborohydride was added to the reaction solution. Then, the reaction solution was further stirred for 2 hours. Thereafter, 485 ml of water was added to the reaction solution, and the obtained mixture was heated to a temperature between 100° C. and 115° C. Approximately 3 hours later, the reaction solution was cooled, and then concentrated under a reduced pressure. Thereafter, water and ethyl acetate were added thereto, so as to separate an organic layer. The obtained organic layer was washed with a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. After removing the drying agent by filtration, the organic layer was concentrated under a reduced pressure, and the residue was then purified by NH silica gel column chromatography (hexane/ethyl acetate). The obtained solid was suspended in a mixed solvent consisting of hexane and t-butylmethyl ether, followed by filtration, so as to obtain 64.6 g of the subject compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[N:12]=[C:11]([C:20]([OH:22])=[O:21])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.[Cl:23]C1N=C(NN)C=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:23])[N:15]=3)[N:12]=[C:11]([C:20]([OH:22])=[O:21])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: NNc1cccc(Cl)n1
Reactant: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Product: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2cccc(Cl)n2)n1

Procedure:
1.30 g (3.97 mmol) of the compound of Example 1A is reacted analogously to the synthesis of the compound of Example 20A with 854 mg (5.95 mmol) of 6-chloropyridin-2-yl-hydrazine. After hydrolysis, 815 mg (58% of theory) of the title compound is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(CC)CC)C.[NH2:20][C:21]1[CH:43]=[CH:42][C:24]([C:25]([N:27]2[CH2:33][C:32]3[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=3[CH2:30][C:29]3[CH:38]=[CH:39][CH:40]=[CH:41][C:28]2=3)=[O:26])=[CH:23][CH:22]=1>C(Cl)Cl>[CH:38]1[C:29]2[CH2:30][C:31]3[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=3[CH2:33][N:27]([C:25]([C:24]3[CH:23]=[CH:22][C:21]([NH:20][C:4](=[O:5])[C:3]4[CH:7]=[C:8]([Cl:12])[CH:9]=[C:10]([Cl:11])[C:2]=4[Cl:1])=[CH:43][CH:42]=3)=[O:26])[C:28]=2[CH:41]=[CH:40][CH:39]=1
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1Cl
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1)c1cc(Cl)cc(Cl)c1Cl
Reaction time: 1.5 h
Yield: 99.8 %

Procedure:
A mixture of 366 mg of 2,3,5-trichlorobenzoyl chloride and 151 mg of triethylamine in 2 ml of methylene chloride is stirred while 314 mg of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine in 5 ml of methylene chloride is added. Stirring is continued for 1.5 hours. The reaction mixture is partitioned with water and the organic layer is washed with 1N HCl, water, 0.5N NaOH and brine. The organic layer is dried with Na2SO4 and passed through a pad of hydrous magnesium silicate. Hexane is added to the filtrate at the boil to give 0.52 g of white solid residue which is purified by column chromatography on silica gel by elution with 2:1 hexane-ethyl acetate to give 120 mg of the desired product as a crystalline solid, m.p. 225°-230° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Br[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([C:43]2[CH:44]=[N:45][N:46]([CH3:48])[CH:47]=2)=[CH:38][C:37]=1[CH3:49]>>[CH3:49][C:37]1[CH:38]=[C:39]([C:43]2[CH:44]=[N:45][N:46]([CH3:48])[CH:47]=2)[CH:40]=[C:41]([CH3:42])[C:36]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:10]2[C:6]=1[CH2:7][CH2:8][C@H:9]2[O:11][C:12]1[CH:25]=[CH:24][C:15]2[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=2[CH:13]=1
Reactant: Cc1cc(-c2cnn(C)c2)cc(C)c1Br
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6cnn(C)c6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate and 4-(4-bromo-3,5-dimethylphenyl)-1-methyl-1H-pyrazole following a procedure analogous to that described in Step 2 of Intermediate 17. Mass spectrum (ESI+): m/z=527 [M+H]+.
Reaction SMILES: [CH2:1]([C:4]1[C:5]([CH3:16])=[N:6][O:7][C:8]=1[C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][CH:10]=1)[CH:2]=[CH2:3].[CH2:17]([O:19][C:20]([C:22]1([C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][CH:26]=2)[CH2:24][CH2:23]1)=[O:21])[CH3:18]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:17]([O:19][C:20]([C:22]1([C:25]2[CH:30]=[CH:29][C:28]([C:12]3[CH:13]=[CH:14][C:9]([C:8]4[O:7][N:6]=[C:5]([CH3:16])[C:4]=4[CH2:1][CH:2]=[CH2:3])=[CH:10][CH:11]=3)=[CH:27][CH:26]=2)[CH2:23][CH2:24]1)=[O:21])[CH3:18]
Reactant: C=CCc1c(C)noc1-c1ccc(Br)cc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: C=CCc1c(C)noc1-c1ccc(-c2ccc(C3(C(=O)OCC)CC3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using dichlorobis(triphenylphosphine)palladium(II) as the catalyst and using 4-allyl-5-(4-bromo-phenyl)-3-methyl-isoxazole and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.C(N(C(C)C)CC)(C)C.[NH:18]1[CH2:23][CH2:22][S:21](=[O:25])(=[O:24])[CH2:20][CH2:19]1>C(O)CCC>[O:24]=[S:21]1(=[O:25])[CH2:22][CH2:23][N:18]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=2)[CH2:19][CH2:20]1
Reactant: O=S1(=O)CCNCC1
Reactant: Nc1cc(Cl)ncn1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cc(N2CCS(=O)(=O)CC2)ncn1
Temperature: 200 °C
Reaction time: 18 h

Procedure:
6-Chloropyrimidin-4-amine 7-2 (0.4 g, 3.09 mmol) and diisopropylethylamine (0.4 g, 3.09 mmol) were suspended in n-butanol and thiomorpholine 1,1-dioxide (0.417 g, 3.09 mmol) was added. The reaction was stirred at 200° C. for 18 hours, the butanol was evaporated off and the product was purified on a silica column eluted with DCM:MeOH:NH4OH (95:5:0.5). Yield=2.45 mmol (79%). 1H-NMR (CD3OD): 8.03 ppm (s, 1H); 5.87 ppm (s, 1H); 4.10 ppm (t, 4H); 3.09 ppm (t, 4H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]([C@@H:13]3[CH2:17][NH:16][C@H:15]([C:18]([OH:20])=O)[CH2:14]3)[CH:12]=2)=[CH:4][C:3]=1[C:21]1[S:22][C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=1.Cl.[CH3:31][NH:32][CH3:33].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH3:31][N:32]([CH3:33])[C:18]([C@@H:15]1[CH2:14][C@H:13]([N:11]2[CH:12]=[C:8]([C:5]3[CH:6]=[N:7][C:2]([NH2:1])=[C:3]([C:21]4[S:22][C:23]5[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=5[N:25]=4)[CH:4]=3)[CH:9]=[N:10]2)[CH2:17][NH:16]1)=[O:20]
Reactant: Nc1ncc(-c2cnn([C@@H]3CN[C@H](C(=O)O)C3)c2)cc1-c1nc2ccccc2s1
Reactant: CNC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)[C@@H]1C[C@H](n2cc(-c3cnc(N)c(-c4nc5ccccc5s4)c3)cn2)CN1
Reaction time: 0.02 h

Procedure:
To a solution of (2S,4S)-4-[4-(6-amino-5-benzothiazol-2-ylpyridin-3-yl)-pyrazol-1-yl]-pyrrolidine-2-carboxylic acid (5.00 mg, 0.00969 mmol) in DMF (2 mL) at rt were added dimethylamine hydrochloride (20 mg, 0.25 mmol) and DIPEA (0.1 mL, 0.6 mmol), and the mixture was stirred for 1 min. TBTU (6.22 mg, 0.0194 mmol) was then added, and the solution was stirred for 10 min. The material was transferred to a separatory funnel. The organic layer was washed with water, and concentrated in vacuo. The material was loaded onto a prep TLC plate, eluting with 6% (7N NH3 in MeOH)/DCM. The band containing the product was collected and filtered off with 1:1 MeOH/DCM. The filtrate was concentrated in vacuo to afford the title compound as a yellow solid. 1H NMR (400 MHz, CD3OD): δ=2.15-2.21 (m, 1H), 2.82-2.91 (m, 1H), 3.00 (s, 3H), 3.12 (s, 3H), 3.23 (dd, J=12.4, 6.3 Hz, 1H), 3.49 (dd, J=12.0, 3.4 Hz, 1H), 4.15 (t, J=8.3 Hz, 1H), 4.98-5.05 (m, 1H), 7.42-7.47 (m, 1H), 7.53 (td, J=7.7, 1.3 Hz, 1H), 7.85 (s, 1H), 8.02 (dd, J=11.6, 7.8 Hz, 2H), 8.13 (s, 1H), 8.20 (d, J=2.3 Hz, 1H), 8.32 (d, J=2.0 Hz, 1H). MS (ES+): m/z=434.14 (100) [MH+]. HPLC: tR=2.12 min (ZQ2, polar—5 min).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([NH2:7])=O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][NH2:7])[CH:8]=[CH:9][C:10]=1[Cl:11]
Reactant: NC(=O)c1ccc(Cl)c(Br)c1
Solvent: C1CCOC1
Product: NCc1ccc(Cl)c(Br)c1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To 3-bromo-4-chlorobenzamide (1.6 g, 6.8 mmol) in THF (10 mL) was added borane dimethyl sulfide complex (1.36 mL, 13.6 mmol) at room temperature. The mixture was then heated to 60° C. for 8 days. The solvent was pumped off and the reaction cautiously quenched with ethanol. When bubbling ceased, 1N HCl was added until the pH was ˜2. The mixture was stirred at 50° C. for 4 h. The mixture was partitioned between EtOAc and water. The aqueous phase was washed 3× with EtOAc. The aqueous phase was then adjusted to pH 10 with 2N NaOH and extracted 3× with EtOAc. The combined organics phases were washed with brine, dried over anhydrous Na2SO4, filtered, and evaporated to afford the title compound as a clear oil. LC-MS m/z 219.6 (M+H)+, 1.41 min (ret time).
Reaction SMILES: [CH2:1]([C:3]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:25][S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])=[O:24])=[CH:16][CH:15]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].[CH:36]([N-]C(C)C)(C)C.[Li+].CI.P([O-])([O-])([O-])=O>C1COCC1>[CH2:1]([C:3]1[N:13]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][NH:22][C:23]([N:25]([CH3:36])[S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])=[O:24])=[CH:18][CH:19]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: CC(C)[N-]C(C)C
Reactant: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)N(C)S(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 4.8 %

Procedure:
To a stirred solution of 2-ethyl-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine (Example 1, 200 mg, 0.41 mmol) in THF (10 mL) was added dropwise a solution of lithium diisopropylamide (LDA) (2.0 N in heptane/hexane/ethylbenzene, 0.8 mL, 1.6 mmol) with ice-cooling over a period of 10 min. After completion of the addition, the stirring was continued for an additional 20 min at the same temperature. To the resulting mixture was added dropwise MeI (0.5 mL) at 0° C., and stirred at room temperature for 15 h. The mixture was poured into a solution of phosphate buffer (100 mL) and extracted with dichloromethane (100 mL). The organic layer was washed with brine (50 mL), dried (Na2SO4), and concentrated. The residue was purified by flash chromatography on silica gel eluting with dichloromethane/methanol (10:1) to give 10 mg (5%) of the title compound as a colorless oil: 1H-NMR (CDCl3) δ 7.64 (2H, d, J=8.3 Hz), 7.53–7.25 (7H, m), 6.89 (1H, s), 3.65–3.55 (2H, m), 3.14 (3H, s), 2.96 (2H, t, J=6.7 Hz), 2.82 (2H, q, J=7.6 Hz), 2.66 (3H, s), 2.50 (3H, s), 2.40 (3H, s), 1.25 (3H, t, J=7.6 Hz).
Reaction SMILES: C1(C[O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][C:16]([F:21])([F:20])[CH:17]([F:19])[F:18])C=CC=CC=1.[H][H]>CO.[Pd]>[F:20][C:16]([F:21])([O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[OH:8])[CH:17]([F:18])[F:19]
Reactant: [H][H]
Reactant: FC(F)C(F)(F)Oc1ccccc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: Oc1ccccc1OC(F)(F)C(F)F

Procedure:
A solution of 58.6 g of 1-(phenylmethoxy)-2-(1,1,2,2-tetrafluoroethoxy)benzene in 200 ml methanol was blanketed with nitrogen and 1.0 g of 10% palladium on charcoal added. The mixture was hydrogenated at 50 psi hydrogen for 3 hours. The reaction mixture was filtered to remove catalyst and the filtrate concentrated under reduced pressure to give an oil, which darkened on standing. The oil was distilled, bp 25°-32° (0.2 mm), to give the phenol as a colorless oil, which solidified on standing. The infrared spectrum showed OH absorption at 3570 cm-1.
Reaction SMILES: [C:1]([NH:5][C:6]([NH2:8])=[S:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])[C:11](=O)[C:12]([O:14][CH3:15])=[O:13]>CO>[CH3:2][C:1]([NH:5][C:6]1[S:7][C:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])=[C:11]([C:12]([O:14][CH3:15])=[O:13])[N:8]=1)([CH3:4])[CH3:3]
Reactant: CC(C)(C)NC(N)=S
Reactant: COC(=O)C(=O)C(Cl)c1ccccc1Cl
Solvent: CO
Product: COC(=O)c1nc(NC(C)(C)C)sc1-c1ccccc1Cl
Temperature: 25 °C
Yield: 94.2 %

Procedure:
A reaction vessel was charged with 50 ml methanol and 4 g (30 mmol) of tert-butyl thiourea. With this mixture stirred and cooled in an ice bath, there was added over a 5-minute period 7.41 g of (30 mmol) methyl 3-chloro-3-(o-chlorophenyl)pyruvate. The reaction mixture was refluxed for 16 hours. The mixture was cooled to ambient temperature and concentrated under reduced pressure to yield 9.18 g of a yellow solid which became a hard, glass-like material. This material was recrystallized from an acetone-water solution to yield 7.0 g of a yellow solid product (m.p.=159°-161° C.) identified in Table I.
Reaction SMILES: C(O)(=O)C.[F:5][C:6]([F:26])([F:25])[O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:18][CH2:17][C:16]3([CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:15]2=[O:24])=[CH:10][CH:9]=1.[CH2:27]([O:34][CH2:35][C:36](Cl)=[O:37])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([O:34][CH2:35][C:36]([N:21]1[CH2:20][CH2:19][C:16]2([C:15](=[O:24])[N:14]([C:11]3[CH:12]=[CH:13][C:8]([O:7][C:6]([F:5])([F:25])[F:26])=[CH:9][CH:10]=3)[CH2:18][CH2:17]2)[CH2:23][CH2:22]1)=[O:37])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Reactant: O=C(Cl)COCc1ccccc1
Solvent: CC(=O)O
Product: O=C(COCc1ccccc1)N1CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O

Procedure:
The title compound was prepared in analogy to example 7 step A from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one acetic acid salt (described in example 180 step C) and benzyloxy-acetyl chloride. Off-white solid. MS (ESI): 463.3 (MH+).
Reaction SMILES: [OH:1][C:2]1([CH3:22])[CH:8](Br)[CH:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[O:6][C:4](=[O:5])[CH2:3]1.C([SnH](CCCC)CCCC)CCC>O1CCCC1>[OH:1][C:2]1([CH3:22])[CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[O:6][C:4](=[O:5])[CH2:3]1
Reactant: CC1(O)CC(=O)OC(c2ccc(-c3ccccc3)cc2)C1Br
Agent: CCCC[SnH](CCCC)CCCC
Solvent: C1CCOC1
Product: CC1(O)CC(=O)OC(c2ccc(-c3ccccc3)cc2)C1
Yield: 51.2 %

Procedure:
The product obtained by reducing 0.50 g of 3-hydroxy-3-methyl-4-bromo-5-(4-biphenylyl)-5-pentanolide with 1.62 g of tri-n-butyltin hydride in 10 ml of anhydrous tetrahydrofuran according to the method described in Example 2 (a), was recrystallized from a mixture of n-hexane and acetone (10:1) to give 0.20 g of the desired compound melting at 151°-153° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][CH:7]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[C:6]=2[CH:18]=1.[Cl:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[Cl:19][C:20]1[CH:25]=[C:24]([C:2]2[CH:3]=[CH:4][C:5]3[NH:11][C:10](=[O:12])[CH2:9][O:8][CH:7]([C:13]4[S:14][CH:15]=[CH:16][CH:17]=4)[C:6]=3[CH:18]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: O=C1COC(c2cccs2)c2cc(Br)ccc2N1
Product: O=C1COC(c2cccs2)c2cc(-c3cccc(Cl)c3)ccc2N1

Procedure:
Prepared from 7-bromo-5-thien-2-yl-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and 3-chlorobenzeneboronic acid generally according to the procedure described in example 1. 1H-NMR (CDCl3) δ 8.26 (br s, 1H), 7.51 (dd, J=8.3, 2.1 Hz, 1H), 7.45 (d, J=0.9 Hz, 1H), 7.42 (dd, J=5.1, 0.9 Hz, 1H), 7.36 (m, 3H), 7.24 (d, J=2.0 Hz, 1H), 7.05 (m, 2H), 6.93 (d, J=3.5 Hz, 1H), 6.24 (s, 1H), 4.56 (d, J=Hz, 1H), 4.47 (d, J=17.0 Hz, 1H); MS (ES) m/z 356 (M+H)+; Anal. Calc. For C19H14ClNO2S: C, 64.13; H, 3.97; N, 3.94. Found: C, 64.1; H, 3.83; N, 3.99.
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([C:24](=[O:39])[N:25]([CH2:30][CH2:31][C:32](=[O:38])[NH:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH:26]2[CH2:29][CH2:28][CH2:27]2)[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(C)(C)C.[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44]>ClCCl>[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44].[C:34]([NH:33][C:32]([CH2:31][CH2:30][N:25]([CH:26]1[CH2:27][CH2:28][CH2:29]1)[C:24](=[O:39])[C:19]1[CH:18]=[C:17]([O:16][CH2:15][CH2:14][NH:7][C:8]2[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=2)[CH:22]=[C:21]([Cl:23])[CH:20]=1)=[O:38])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)NC(=O)CCN(C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1)C1CCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)NC(=O)CCN(C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1)C1CCC1
Reaction time: 64 h

Procedure:
A solution of (2-{3-[(2-tert-butylcarbamoyl-ethyl)-cyclobutyl-carbamoyl]-5-chloro-phenoxy}-ethyl)-pyridin-4-yl-carbamic acid tert-butyl ester (0.021 g) in a mixture of dichloromethane (1 ml) and trifluoroacetic acid (1 ml) was stored at room temperature for 64 h and then concentrated under reduced pressure to give the title compound (0.020 g) as a colourless gum.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]3[CH2:15][C@H:14]([C:16]([O:18]CCCC)=O)[O:13][C:12]3=[O:23])=[CH:10][C:5]=2[S:4][C:3]1=[O:24].Cl.[F:26][CH2:27][CH2:28][NH2:29]>N1C=CC=CC=1.C(Cl)Cl>[F:26][CH2:27][CH2:28][NH:29][C:16]([C@@H:14]1[O:13][C:12](=[O:23])[N:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[C:3](=[O:24])[S:4][C:5]=3[CH:10]=2)[CH2:15]1)=[O:18]
Reactant: NCCF
Reactant: CCCCOC(=O)[C@H]1CN(c2ccc3c(c2)sc(=O)n3C)C(=O)O1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cn1c(=O)sc2cc(N3C[C@H](C(=O)NCCF)OC3=O)ccc21
Temperature: 90 °C

Procedure:
A solution of butyl(5R)-3-(2,3-dihydro-3-methyl-2-oxo-6-benzothiazolyl)-2-oxo-5-oxazolidinecarboxylate (EXAMPLE 29, Step 2, 985 mg, 2.81 mmol) in pyridine (5.5 mL) in a thick-walled, screw-cap vial is treated with fluoroethylamine hydrochloride (2.20 g, 22.1 mmol), and the stirred reaction mixture is placed in an oil bath maintained at 90° C. for 24 h. The mixture is then cooled to ambient temperature, diluted with CH2Cl2 (50 mL), washed with 0.2 M hydrochloric acid (25 mL portions, until the washings are at pH<2) and saline (25 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue is chromatographed on a Flash 40M 90 g silica gel cartridge with MeOH/CH2Cl2 (1/99-2.5/97.5). Those fractions with an Rf=0.32 by TLC (MeOH/CHCl3, 5/95) are pooled and concentrated and the residue triturated and filtered from MeOH to give the title compound, mp 201-203° C.; MS (ESI−) for C14H14N3O4FS m/z 338 (M−H)−.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[Cl:7][C:8]1[N:13]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=C)[CH:11]=[C:10]([CH2:19][O:20][CH2:21][C:22]([F:25])([F:24])[F:23])[N:9]=1.[Mn]([O-])(=O)(=O)=[O:27].[K+]>O.O1CCOCC1>[Cl:7][C:8]1[N:13]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:27])[CH:11]=[C:10]([CH2:19][O:20][CH2:21][C:22]([F:25])([F:24])[F:23])[N:9]=1
Reactant: C=C(OCC)c1cc(COCC(F)(F)F)nc(Cl)n1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(COCC(F)(F)F)nc(Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium metaperiodate (701 mg, 3.28 mmol) was suspended in water (10 mL) and sonicated until a clear solution was obtained. 2-Chloro-4-(1-ethoxyvinyl)-6-((2,2,2-trifluoroethoxy)methyl)pyrimidine (486 mg, 1.64 mmol) in 1,4-dioxane (20 mL) and potassium permanganate (39 mg, 0.25 mmol) were added and the mixture was stirred at rt for 30 min. The mixture was filtered, precipitate was washed by dioxane and DCM. DCM an solid sodium bicarbonate (s) were added to the filtrate. The mixture was extracted with DCM (×2). The organic phase was dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica eluting with DC ti give the title compound as a solid, 385 mg (79%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([NH:13][C:14]([C:16]2[CH:17]=[CH:18][CH:19]=[C:20]3[C:24]=2[N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]3)=[O:15])[CH3:12])=[CH:7][CH:6]=1)=[O:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:23]1[C:24]2[C:20](=[CH:19][CH:18]=[CH:17][C:16]=2[C:14]([NH:13][C@H:11]([C:8]2[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][CH:9]=2)[CH3:12])=[O:15])[CH2:21][CH2:22]1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cccc3c2N(C(=O)OC(C)(C)C)CC3)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cccc3c2NCC3)cc1
Reaction time: 1 h

Procedure:
tert-butyl 7-[({(1S)-1-[4-(methoxycarbonyl)phenyl]ethyl}amino)carbonyl]indoline-1-carboxylate (510 mg, 1.2 mmol) was dissolved in CH2Cl2 (5 ml) and TFA (5 ml) was added, the solution was stirred for 1 hour. The solvent was removed. NaHCO3 (sat.) was added and extracted 3× with EtOAc. The combined organic layers were washed with water and brine, then dried over MgSO4. 1H NMR (500 MHz, DMSO-d6): δ 8.50 (d, 1H), 7.90 (d, 2H), 7.55 (m, 3H), 7.10 (d, 1H), 6.50 (m, 2H), 5.15 (m, 1H), 3.85 (s, 3H), 3.50 (m, 2H), 2.90 (m, 2H), 1.40 (d, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][CH2:7][CH2:6][CH:5]2[OH:12].[Cl:13][C:14]1[CH:15]=[C:16](O)[CH:17]=[CH:18][CH:19]=1>CO.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][CH2:7][CH2:6][CH:5]2[O:12][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:13])[CH:19]=1
Reactant: OC1CCNc2ncc(Br)cc21
Reactant: Oc1cccc(Cl)c1
Solvent: CO
Solvent: ClCCl
Product: Clc1cccc(OC2CCNc3ncc(Br)cc32)c1
Yield: 60 %

Procedure:
6-Bromo-1,2,3,4-tetrahydro-[1,8]naphthyridin-4-ol (225 mg) was reacted with 3-chlorophenol (0.30 mL) as in General Procedure 12. Basic alumina chromatography using a gradient of 0-1% methanol/methylene chloride as the eluting solvent gave the title compound as a white film (60% yield). LCMS: m/z=339 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.00 (m, 1H), 2.21 (m, 1H), 3.40 (m, 1H), 3.51 (m, 1H), 5.04 (s, 1H), 5.27 (t, J=3.9 Hz, 1H), 6.87 (d, J=8.3 Hz, 1H), 7.00 (m, 2H), 7.24 (m, 1H), 7.48 (d, J=2.1 Hz, 1H), 8.06 (d, J=2.1 Hz, 1H).