Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([F:17])=[CH:10][C:9]=1[NH:18][C:19](=[O:42])[CH2:20][C:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]2[C:32]([CH2:33][O:34]C3CCCCO3)=[CH:31][N:30]=[N:29]2)[CH:23]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][N:14]([CH3:16])[C:12]1[C:11]([F:17])=[CH:10][C:9]2[NH:18][C:19](=[O:42])[CH2:20][C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([N:28]4[C:32]([CH2:33][OH:34])=[CH:31][N:30]=[N:29]4)[CH:23]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1cc2c(cc1F)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2

Procedure:
The title compound was prepared from (RS)-[5-dimethylamino-4-fluoro-2-(3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionyl-amino)-phenyl]-carbamic acid tert.-butyl ester (Example M38) (375 mg, 0.63 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (115 mg).
Reaction SMILES: C[Li].[C:3]([O:7][C:8]([NH:10][C:11]1[CH:16]=[C:15]([CH2:17][C:18]([O:20]CC)=O)[CH:14]=[CH:13][N:12]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH:23](O)(C)C>C1COCC1>[O:20]=[C:18]([CH3:23])[CH2:17][C:15]1[CH:14]=[CH:13][N:12]=[C:11]([NH:10][C:8](=[O:9])[O:7][C:3]([CH3:4])([CH3:5])[CH3:6])[CH:16]=1
Reactant: CCOC(=O)Cc1ccnc(NC(=O)OC(C)(C)C)c1
Reactant: CC(C)O
Agent: [Li]C
Solvent: C1CCOC1
Product: CC(=O)Cc1ccnc(NC(=O)OC(C)(C)C)c1
Yield: 21 %

Procedure:
A solution of methyllithium (1.6 M in diethyl ether, 17.4 mL, 27.9 mmol) was added dropwise over 12 min to a stirred solution of ethyl 2-(2-(tert-butoxycarbonylamino)pyridin-4-yl)acetate (45) (1.56 g, 5.58 mmol) in THF (140 mL) under nitrogen at −78° C. After 3 hr isopropanol (5.0 mL) was added and the reaction mixture was partitioned between water and EtOAc. The aqueous layer was extracted twice with EtOAc and the combined organic extracts were washed with brine then dried (MgSO4) and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, 80 g, 0-80% EtOAc in isohexane, gradient elution) to afford the title compound (46) (300 mg, 21%) as a white solid: m/z 251.0 (M+H)+ (ES+).
Reaction SMILES: COC(=O)CN[C:6](=[O:43])[CH2:7][NH:8][C:9](=[O:42])[C@H:10](C(C)C)[NH:11][C:12](=[O:38])[C@H:13]([CH:35]([CH3:37])[CH3:36])[NH:14][C:15](=[O:34])[C@H:16]([CH2:25][O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[NH:17]C(OC(C)(C)C)=O.[C:45]([OH:51])([C:47]([F:50])([F:49])[F:48])=[O:46]>C(Cl)Cl>[F:48][C:47]([F:50])([F:49])[C:45]([OH:51])=[O:46].[CH3:45][O:46][C:6](=[O:43])[CH2:7][NH:8][C:9](=[O:42])[CH2:10][NH:11][C:12](=[O:38])[C@H:13]([CH:35]([CH3:36])[CH3:37])[NH:14][C:15](=[O:34])[C@H:16]([CH2:25][O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[NH2:17]
Reactant: COC(=O)CNC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C)C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)CNC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](N)COCc1ccccc1)C(C)C
Yield: 92 %

Procedure:
N-tert-butoxycarbonyl O-benzyl L-seryl L-valyl L-valyl glycyl glycine methyl ester 24 (SEQ ID NO: 7) (0.525 g, 0.844 mmol) was dissolved in a 50% (v/v) solution of TFA in CH2Cl2 (12 mL) at room temperature. The reaction mixture was stirred for 1 h 30 min before the solvent and bulk of excess TFA were evaporated. Et2O (10 mL) was added to the liquid residue, which resulted in precipitation of a white solid. The Et2O was decanted off and the residue washed with additional portions of Et2O (2×10 mL) and dried under reduced pressure overnight affording the title compound as a white solid (0.494 g, 92%); δH (300 MHz; d6-DMSO) 8.47 (1H, d, J 9, NH(Valx)), 8.29-8.20 (5H, m, NH3+/NH(Glyx)/NH(Glyy)), 8.00 (1H, d, J 8, NH(Valy)) 7.38-7.27 (5H, m, Ph), 4.51 (2H, s, CH2Ph), 4.34 (1H, dd, J 7 and 9, CαH(Valx)), 4.17-4.12 (2H, m, CαH(Valy)/CαH(Ser(Bn))), 3.85 (2H, dd, J 4 and 6, CαH2(Glyx)), 3.76-3.64 (4H, m, CH2(Ser(Bn))/CαH2(Glyy)), 3.62 (3H, s, OCH3), 2.04-1.89 (2H, m, CH(CH3)2), 0.89-0.81 (12H, m, CH3); δC (75 MHz; d6-DMSO) 171.1, 170.6, 170.1, 169.2, 166.2, 158.3 (q, JCF 32) 137.5, 128.2, 127.6, 127.5, 116.9 (q, JCF 291), 72.5, 68.6, 58.1, 57.9, 52.2, 51.6, 41.6, 40.5, 30.6, 30.2, 19.1, 19.1, 18.2, 18.0; m/z (ESI) 522.2920 (M+; C25H40N5O7 requires 522.2927)
Reaction SMILES: I[C:2]1[CH:19]=[N:18][C:5]2[NH:6][CH2:7][CH2:8][N:9]([C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:11])[C:4]=2[CH:3]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22](B(O)O)[CH:21]=1>>[C:12]1([C:10]([N:9]2[CH2:8][CH2:7][NH:6][C:5]3[N:18]=[CH:19][C:2]([C:22]4[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=4)=[CH:3][C:4]2=3)=[O:11])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(c1ccccc1)N1CCNc2ncc(I)cc21
Reactant: OB(O)c1cccnc1
Product: O=C(c1ccccc1)N1CCNc2ncc(-c3cccnc3)cc21
Yield: 25 %

Procedure:
(7-Iodo-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-1-yl)phenylmethanone (50 mg) was reacted with pyridine 3-boronic acid as in General Procedure 4A to give the title compound as a yellow solid (25% yield). M.p. 219-220° C., LCMS: m/z=317.40 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 3.45-3.50 (m, 2H), 4.02 (t, J=4.8 Hz, 2H), 5.39 (s, 1H), 7.20-7.22 (m, 2H), 7.40-7.44 (m, 3H), 7.47-7.51 (m, 3H), 8.03 (s, 1H), 8.30 (s, 1H), 8.47 (d, J=4.3 Hz, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]([NH:20][NH2:21])=[O:19])[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH2:22]1[CH2:27][CH2:26][CH:25]([CH2:28][N:29]=[C:30]=[O:31])[CH2:24][CH2:23]1>C1(C)C=CC=CC=1>[CH:25]1([CH2:28][NH:29][C:30]([NH:21][NH:20][C:18](=[O:19])[CH2:17][CH2:16][N:13]2[CH2:14][CH2:15][N:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[CH2:11][CH2:12]2)=[O:31])[CH2:26][CH2:27][CH2:22][CH2:23][CH2:24]1
Reactant: O=C=NCC1CCCCC1
Reactant: NNC(=O)CCN1CCN(c2cccc([N+](=O)[O-])c2)CC1
Solvent: Cc1ccccc1
Product: O=C(CCN1CCN(c2cccc([N+](=O)[O-])c2)CC1)NNC(=O)NCC1CCCCC1
Temperature: 70 °C
Yield: 86.5 %

Procedure:
A solution of 3-[4-(3-nitrophenyl)piperazino]propanohydrazide D7 (0.55 g, 1.87 mmol) in toluene (30 mL) was heated at 70° C. and cyclohexanemethyl isocyanate (0.28 g, 0.30 mL, 1.96 mmol) was added at once. The slurry was heated at 70° C. until all solid went into solution (15 min) and then cooled to room temperature. The resulting solid was filtered and washed with toluene to afford 0.70 g (95%) N-(cyclohexylmethyl)-2-{3-[4-(3-nitrophenyl)piperazin-1-yl]propanoyl}hydrazine carboxamide D8 as an orange semi-solid.
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[N:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[F:17][C:18]1[CH:19]=[C:20]([C:25]2[O:29][C:28]([CH3:30])=[N:27][C:26]=2[C:31](O)=[O:32])[CH:21]=[C:22]([F:24])[CH:23]=1>>[F:4][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[N:15]=[C:14]([NH:16][C:31]([C:26]3[N:27]=[C:28]([CH3:30])[O:29][C:25]=3[C:20]3[CH:21]=[C:22]([F:24])[CH:23]=[C:18]([F:17])[CH:19]=3)=[O:32])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:1])[CH3:3]
Reactant: Cc1nc(C(=O)O)c(-c2cc(F)cc(F)c2)o1
Reactant: CC(F)(F)c1ccc(Cn2ncc(N)n2)o1
Product: Cc1nc(C(=O)Nc2cnn(Cc3ccc(C(C)(F)F)o3)n2)c(-c2cc(F)cc(F)c2)o1

Procedure:
Following general procedure Z2, starting from 2-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3,5-difluoro-phenyl)-2-methyl-oxazole-4-carboxylic acid.
Reaction SMILES: C([O:8][C@H:9]1[C@H:14]([OH:15])[C@@H:13]([CH2:16][OH:17])[CH2:12][NH:11][CH2:10]1)C1C=CC=CC=1.C(O[C:22](=[O:24])[CH3:23])(=O)C>N1C=CC=CC=1>[C:9]([O:15][CH:14]1[CH:13]([CH2:16][O:17][C:14](=[O:15])[CH3:13])[CH2:12][N:11]([C:22](=[O:24])[CH3:23])[CH2:10][CH:9]1[OH:8])(=[O:8])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: OC[C@H]1CNC[C@@H](OCc2ccccc2)[C@@H]1O
Solvent: c1ccncc1
Product: CC(=O)OCC1CN(C(C)=O)CC(O)C1OC(C)=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 55 %

Procedure:
(3R,4R,5R)-3-Benzyloxy-5-hydroxymethyl4-piperidinol (0.1 g, 0.4 mmol) was dissolved in pyridine (0.5 ml) at 0° C. by and acetic anhydride (0.5 ml) was added dropwise over 1 min. Stirring at room temperature for 20 h and evaporation to dryness gave a crude product which was purified on silica gel using ethanol as eluent (yield 55%). The purified 3-benzyloxy-3-acetoxy-5-acetoxymethyl-1-acetylpiperidine (75 mg) was debenzylated in methanol at room temperature using 10% Pd/C as catalyst. Filtration and evaporation to dryness gave 50 mg of crude 4-acetoxy-5-acetoxymethyl-1-acetyl-3-piperidinol which was dissolved in dry methanol (4 ml) containing 50 μl of a 1% sodium methoxide in methanol. After stirring at room temperature for 4 days the solution was evaporated to dryness to give (3R,4R,5R)-1-acetyl-5-hydroxymethyl-3,4-piperidinediol (Yield: 35 mg).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]3[NH:18][CH:19]=[CH:20][C:13]=23)[C:9]([CH:21]=[O:22])=[N:8]1.[OH-].[K+].Cl.[CH3:26]O>>[CH3:26][O:22][CH:21]1[C:20]2[C:13]3[C:14]([NH:18][CH:19]=2)=[N:15][CH:16]=[CH:17][C:12]=3[C:10]2[C:9]1=[N:8][N:7]([CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)[CH:11]=2
Reactant: CO
Reactant: O=Cc1nn(C2CCCCO2)cc1-c1ccnc2[nH]ccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: COC1c2nn(C3CCCCO3)cc2-c2ccnc3[nH]cc1c23
Temperature: 25 °C
Reaction time: 42 h

Procedure:
To a stirred solution of 1-(oxan-2-yl)-4-{1H-pyrrolo[2,3-b]pyridin-4-yl}-1H-pyrazole-3-carbaldehyde (1.88 g, 6.35 mmol) in MeOH (280 mL, a concentration of 0.023 mol/L), was added KOH (3.56 g, 27.68 mmol). The reaction mixture was stirred at room temperature for 42 hours. When TLC showed completion of reaction, the pH was adjusted to 7 by addition of HCl (4 M in MeOH).
Reaction SMILES: C(O[C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][S:8][C:7]=1[NH2:17])=[O:5])C.[O-:18][C:19]#[N:20].[K+].C(O)(=O)C>O>[C:11]1([C:10]2[C:6]3[C:4](=[O:5])[NH:20][C:19](=[O:18])[NH:17][C:7]=3[S:8][CH:9]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)c1c(-c2ccccc2)csc1N
Reactant: N#C[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]c(=O)c2c(-c3ccccc3)csc2[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-Amino-4-phenyl-thiophene-3-carboxylic acid ethyl ester (2.0 g, 8.1 mmol), and Potassium Cyanate (Aldrich, 2.0 g, 24.3 mmol) were added to glacial acetic acid (VWR, 20 ml) and stirred at ambient temperature for 18 h. The reaction was diluted with water (50 ml) and the resultant precipitate filtered, washed with water and dried to a damp cake. The solid was suspended in water (100 ml) and made alkaline to pH 12-14 by the addition of concentrated sodium hydroxide. The resultant suspension was heated at 100° C. for 2 h with stirring, then cooled to ambient temperature and acidified by the addition of glacial acetic acid. The resulting solid was collected by filtration, washed with water and dried in vacuo at 40° C. to give 5-Phenyl-1H-thieno[2,3-d]pyrimidine-2,4-dione as a white solid. Yield=(1.1 g, 56%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:22]=[C:21]2[C:12]([N:13]3[C:18]([CH2:19][O:20]2)=[N:17][NH:16][C:15](=[O:23])[C@H:14]3[CH3:24])=[CH:11][C:10]=1[N:25]([CH3:31])[C:26]1([CH3:30])[CH2:29][NH:28][CH2:27]1.CCN(C(C)C)C(C)C.[C:41](Cl)(=[O:43])[CH3:42]>C(Cl)Cl>[C:41]([N:28]1[CH2:27][C:26]([N:25]([CH3:31])[C:10]2[CH:11]=[C:12]3[C:21](=[CH:22][C:9]=2[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[F:2])[O:20][CH2:19][C:18]2[N:13]3[C@H:14]([CH3:24])[C:15](=[O:23])[NH:16][N:17]=2)([CH3:30])[CH2:29]1)(=[O:43])[CH3:42]
Reactant: C[C@@H]1C(=O)NN=C2COc3cc(-c4ccccc4F)c(N(C)C4(C)CNC4)cc3N21
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CC(C)(N(C)c2cc3c(cc2-c2ccccc2F)OCC2=NNC(=O)[C@@H](C)N23)C1
Temperature: 25 °C
Reaction time: 0.1 h
Yield: 17.7 %

Procedure:
(R)-7-(2-fluoro-phenyl)-4-methyl-6-[methyl-(3-methyl-azetidin-3-yl)-amino]-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one hydrochloride acid (0.125 g, 0.30 mmol) was dissolved in DCM (1 mL) and DIPEA (98 μl, 0.561 mmol) was added. The reaction mixture was stirred at room temperature for 6 min then acetyl chloride (59.8 μl, 0.841 mmol) was added. The reaction mixture was stirred at rt for 10 min and concentrated in vacuo. The residue was purified by basic prep-HPLC (Table 3, Method 32) to give (R)-6-[(1-acetyl-3-methyl-azetidin-3-yl)-methyl-amino]-7-(2-fluoro-phenyl)-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.024 g, 18%). 1H NMR (CD3OD, 400 MHz) δ 7.36-7.33 (m, 2H), 7.25-7.22 (m, 1H), 7.17-7.14 (m, 1H), 6.95-6.92 (m, 2H), 4.80 (m, 1H), 4.68-4.62 (m, 2H), 4.09-4.05 (m, 1H), 3.85-3.73 (m, 2H), 3.55-3.50 (m, 1H), 2.58 (m, 3H), 1.79 (s, 3H), 1.50 (m, 3H), 1.44 (m, 3H). LC/MS (Table 1, Method 4), Rt=2.300 min., MS m/z: 452 [M+H]+.
Reaction SMILES: [Br:1][CH2:2][C:3](=[O:25])[C@@H:4]([NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([Cl:13])[CH:7]=1>C1COCC1.C(O)C>[Br:1][CH2:2][C@@H:3]([OH:25])[C@@H:4]([NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:5][C:6]1[CH:7]=[C:8]([Cl:13])[CH:9]=[C:10]([Cl:12])[CH:11]=1
Reactant: O=C(N[C@@H](Cc1cc(Cl)cc(Cl)c1)C(=O)CBr)OCc1ccccc1
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(N[C@@H](Cc1cc(Cl)cc(Cl)c1)[C@H](O)CBr)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 79.7 %

Procedure:
Step BF (6): A 1M solution of LiAlH(OtBu)3 in THF (22.9 mL, 22.9 mmol) was diluted with THF (30.5 mL) and ethanol (56 mL) and cooled to −78° C. A solution of (S)-benzyl 4-bromo-1-(3,5-dichlorophenyl)-3-oxobutan-2-ylcarbamate (5.093 g, 11.45 mmol) in THF (56 mL) was then added dropwise down the side of the flask. After 15 min, TLC indicated no starting material remained. The reaction was carefully quenched with 1M HCl and let warm to rt. The organic solvents were removed in vacuo. The residue was taken up in EtOAc, and the aluminum salts removed via filtration. The organic layer was dried over MgSO4, and concentrated to afford benzyl (2S,3S)-4-bromo-1-(3,5-dichlorophenyl)-3-hydroxybutan-2-ylcarbamate (4.08 g, 80% yield). 1H NMR (500 MHz, DMSO-d6) δ 7.05-7.50 (m, 9H) 5.55 (d, J=5.80 Hz, 1H) 4.99 (d, J=12.8 Hz, 1H) 4.87 (d, J=12.8 Hz, 1H) 3.66-3.77 (m, 1H) 3.56-3.65 (m, 2H) 3.36-3.45 (m, 1H) 3.01 (dd, J=13.73, 3.05 Hz, 1H) 2.59 (dd, J=13.43, 10.38 Hz, 1H).
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH2:10][C:11]1[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=1.[CH3:18][C:19]([C:22]1[CH:27]=[CH:26][C:25]([S:28]([N:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:33][C@H:32]2[C:40](Cl)=[O:41])(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])[CH3:20]>ClCCl>[CH3:21][C:19]([C:22]1[CH:23]=[CH:24][C:25]([S:28]([N:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:33][C@H:32]2[C:40]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=2)=[O:41])(=[O:30])=[O:29])=[CH:26][CH:27]=1)([CH3:18])[CH3:20]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N2c3ccccc3C[C@H]2C(=O)Cl)cc1
Reactant: NCc1cccc(O)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)c1ccc(S(=O)(=O)N2c3ccccc3C[C@H]2C(=O)NCc2cccc(O)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
54 mg (0.53 mmol) of triethylamine are added to a suspension of 42.26 mg (0.265 mmol) of 3-(aminomethyl)phenol hydrochloride in 8 ml of dichloromethane at ambient temperature, then a solution of 100 mg (0.265 mmol) of 1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-(2S)-1H-indole-2-carbonyl chloride in 2 ml of dichloromethane is added over 10 minutes. This is left to agitate at ambient temperature for 1 hour. The reaction medium is washed with water, dried on magnesium sulfate, the solvents are evaporated and the evaporation residue is purified by silica column chromatography eluting with the help of a toluene/ethyl acetate mixture (8/2; v/v). The expected product is obtained in the form of a white solid with a yield of 51%.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].C(N(CC)CC)C.[C:16]([NH:26][C@H:27]([C:35](O)=[O:36])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>C(Cl)(Cl)Cl>[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH:7][C:35](=[O:36])[C@H:27]([CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[NH:26][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[CH3:3]
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
Glycine ethyl ester.hydrochloride in an amount of 20.6 g was dissolved in 500 ml of chloroform and 20 ml of triethylamine was added thereto. Then, 57.2 g of carbobenzoxyphenylalanine p-nitorphenyl ester was added to the resulting mixture and the reaction was carried out overnight at room temperaure. The resulting mixture was washed with IN-NaHCO3, water, IN-HCl and water in this order and the chloroform layer was dried over magnesium sulfate MgSO4). After removing the solvent by distillation, the residue was recrystallized from ethyl acetate and petroleum ether to give carbobenzoxy-phenylalanyl-glycine ethyl ester having a melting point of 110°-112° C. in yield of 40.5 g (81%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH:9](OS(C)(=O)=O)[CH2:8][C@H:7]1[CH2:16][O:17][C:18]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:5])[CH3:2].[Br:37][C:38]1[CH:43]=[CH:42][C:41]([SH:44])=[C:40]([C:45]([F:48])([F:47])[F:46])[CH:39]=1>>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@@H:9]([S:44][C:41]2[CH:42]=[CH:43][C:38]([Br:37])=[CH:39][C:40]=2[C:45]([F:48])([F:46])[F:47])[CH2:8][C@H:7]1[CH2:16][O:17][C:18]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CC(OS(C)(=O)=O)C[C@H]1COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: FC(F)(F)c1cc(Br)ccc1S
Product: CCOC(=O)[C@@H]1C[C@@H](Sc2ccc(Br)cc2C(F)(F)F)C[C@H]1COC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
The title compound was prepared in analogy to example 68 step 8 using (1R,2R)-4-methanesulfonyloxy-2-trityloxymethyl-cyclopentanecarboxylic acid ethyl ester (epimeric mixture, example 152 step 3) and 4-bromo-2-trifluoromethyl-benzenethiol (example 58, intermediate 1). Colorless oil (43%). MS (EI): 691.0 (M+Na)+.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]([F:16])([F:15])[F:14])=[C:11]([CH3:17])[C:10]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[F:25])=[C:9]1[C:26]([O:28]CC)=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>O.CCO>[CH2:1]([N:8]1[C:12]([C:13]([F:14])([F:15])[F:16])=[C:11]([CH3:17])[C:10]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[F:25])=[C:9]1[C:26]([OH:28])=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(-c2ccc(Cl)cc2F)c(C)c(C(F)(F)F)n1Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1c(-c2ccc(Cl)cc2F)c(C(=O)O)n(Cc2ccccc2)c1C(F)(F)F
Temperature: 25 °C

Procedure:
To a mixture of ethyl 1-benzyl-3-(4-chloro-2-fluorophenyl)-4-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylate (1.55 g, 3.5 mmol) in H2O (20 mL) and EtOH (20 mL) was added NaOH (2.82 g, 71 mmol) and the mixture stirred at reflux for 2 h. The reaction mixture cooled to room temperature and concentrated. The reaction mixture was acidified using aqueous 5N HCl and the solids which had been formed were filtered off to give 1.45 g (100%) of ACI-04 as an off white solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([N:6]([CH2:15][C@@H:16]2[O:20][C:19](=[O:21])[N:18]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH2:33][CH2:32][N:31]([CH:34]=[O:35])[CH2:30][CH:29]=4)=[C:24]([F:36])[CH:23]=3)[CH2:17]2)C(OCC(Cl)(Cl)Cl)=O)=[N:2]1>C(O)(=O)C.[Zn]>[O:1]1[CH:5]=[CH:4][C:3]([NH:6][CH2:15][C@@H:16]2[O:20][C:19](=[O:21])[N:18]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH2:33][CH2:32][N:31]([CH:34]=[O:35])[CH2:30][CH:29]=4)=[C:24]([F:36])[CH:23]=3)[CH2:17]2)=[N:2]1
Reactant: O=CN1CC=C(c2ccc(N3C[C@H](CN(C(=O)OCC(Cl)(Cl)Cl)c4ccon4)OC3=O)cc2F)CC1
Agent: [Zn]
Solvent: CC(=O)O
Product: O=CN1CC=C(c2ccc(N3C[C@H](CNc4ccon4)OC3=O)cc2F)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 5(R)-[N-isoxazol-3-yl-N-(2,2,2-trichloroethyloxycarbonyl)-aminomethyl]-3-[3-fluoro-4-(1-formyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl]oxazolidin-2-one (110 mg, 0.2 mM) in acetic acid (3 ml) was added zinc dust (130 mg, 2.0 mM). The mixture was held in an ultrasonic bath for 10 min. and then stirred vigorously for 48 hours under a nitrogen atmosphere at ambient temperature. The mixture was filtered through celite and the filtrate was evaporated. The residue was taken into 5% MeOH/CH2Cl2 (5 ml) with filtration of inorganic material and the title compound was isolated by MPLC (4% MeOH/CH2Cl2). It was obtained as a brittle glass on evaporation under high vacuum (22 mg, 28%). NMR: 2.41(s, 2H), 3.45(m, 2H), 3.60(m, 2H), 3.84(t, 1H), 4.08(m, 2H), 4.19(t,1H), 4.91 (m, 1H), 6.00(m, 2H), 6.53(m, 1H), 7.36(m, 2H), 7.54(d, 2H), 8.11 & 8.19(2s, 1H), 8.37(s, 1H); m/z ES+(M+H)=387.
Reaction SMILES: CCN(C(C)C)C(C)C.[Li]CCCC.[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][C:17]=1[F:25].[Br:26]C(Cl)(Cl)C(Br)(Cl)Cl>C1COCC1>[Br:26][C:18]1[C:17]([F:25])=[C:16]([Cl:15])[CH:24]=[CH:23][C:19]=1[C:20]([OH:22])=[O:21]
Reactant: O=C(O)c1ccc(Cl)c(F)c1
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Agent: [Li]CCCC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(O)c1ccc(Cl)c(F)c1Br
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 82.8 %

Procedure:
To a cooled (−78° C.) solution of DIEA (4.9 mL, 48 mmol) in THF was added dropwise n-BuLi (132 mL, 2.3 eq, 2.5 M). The mixture was stirred at −30° C. for 30 min. Again the reaction mixture was cooled to −78° C., and a solution of 4-chloro-3-fluorobenzoic acid (25 g, 143 mmol) in THF was added over 1 h. The reaction was stirred at −78° C. overnight. The next day a solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (87 g, 267 mmol) in THF was added and the reaction was stirred at −78° C. for further 2 h and then rt for 4 h. The reaction mixture was quenched with H2O, organic layer was separated and aqueous layer washed with Et2O. Aqueous layer acidified with 1.5 N HCl and extracted in EtOAc (2×200 mL), dried over anhydrous Na2SO4, filtered and concentrated to afford Intermediate 12A (30 g, 83.3%). MS (ESI) m/z: 252.6 (M−H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]([OH:18])=[CH:6]2.[OH-].[K+].Cl[CH2:22][C:23]1[CH:35]=[CH:34][C:26]2[O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:25]=2[CH:24]=1>C1(C)C=CC=CC=1.C(Cl)Cl>[CH:24]1[C:25]2[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[O:27][C:26]=2[CH:34]=[CH:35][C:23]=1[CH2:22][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]=1[OH:18]
Reactant: ClCc1ccc2oc3ccccc3c2c1
Reactant: CCCc1nc(O)cc2cc(OC)c(OC)cc12
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCc1nc(O)c(Cc2ccc3oc4ccccc4c3c2)c2cc(OC)c(OC)cc12
Temperature: 150 °C
Reaction time: 1.5 h
Yield: 8 %

Procedure:
To a solution of 6,7-dimethoxy-1-propylisoquinolin-3-ol RBO 35142 (75 mg, 303 μmol) in toluene (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added a 2 N aq. KOH solution (0.15 mL, 0.30 mmol) at RT followed by 2-(chloromethyl)dibenzo[b,d]furan CCH 34116-2 (70 mg, 323 μmol) and the mixture was stirred at 150° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2:MeOH=9:1 (50 mL), washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 96:4) gave, after evaporation and drying, 4-(dibenzo[b,d]furan-2-ylmethyl)-6,7-dimethoxy-1-propylisoquinolin-3-ol (11 mg, 8% yield). This free base was dissolved in MeOH (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.20 M HCl solution in MeOH (0.25 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to afford 4-(dibenzo[b,d]furan-2-ylmethyl)-6,7-dimethoxy-1-propylisoquinolin-3-ol hydrochloride 7 as a pale brown solid (11 mg, 8% yield).