Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7](B(O)O)[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.Br[C:38]1[C:46]([CH3:47])=[CH:45][CH:44]=[C:43]2[C:39]=1[CH:40]=[C:41]([CH3:48])[CH2:42]2>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:48][C:41]1[CH2:42][C:43]2[C:39]([CH:40]=1)=[C:38]([C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=1)[C:46]([CH3:47])=[CH:45][CH:44]=2
Reactant: CC1=Cc2c(ccc(C)c2Br)C1
Reactant: CC(C)(C)c1cc(B(O)O)cc(C(C)(C)C)c1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC1=Cc2c(ccc(C)c2-c2cc(C(C)(C)C)cc(C(C)(C)C)c2)C1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
3,5-Di-t-butylphenylboronic acid (4.4 g, 19 mmol), prepared as described under (j) above, cesium carbonate (7.3 g, 22 mmol), and Pd2(dba)3 (0.24 g, 262 μmol) (dba=dibenzylidene acetone) were dissolved in 60 ml of 1,4-dioxane. To this solution were added P(t-Bu)3 (170 μL, 830 μmol) and 4-bromo-2,5-dimethylindene (3.1 g, 19 mmol), followed by stirring at 80° C. for five hours. After this time, the solvent was removed in vacuo and the residue was taken up in 150 ml of diethyl ether and filtered through a celite-packed frit to remove cesium salts. Then the solvent was removed in vacuo and the residue was loaded onto a silica gel column and eluted with hexane. Yield: 3.4 g (54%).
Reaction SMILES: [F:1][C:2]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:3]=1[CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[C:19]([F:27])[CH:18]=3)=[C:12]([O:15][CH3:16])[CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:28].C([Li])CCC.CCCCCC.Br[CH2:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48]>O1CCCC1>[F:1][C:2]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:3]=1[CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[C:19]([F:27])[CH:18]=3)=[C:12]([O:15][CH3:16])[CH:13]=2)[CH2:8][CH:7]([CH2:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[C:6]1=[O:28]
Reactant: COc1cc2c(cc1-c1ccc(C(F)(F)F)c(F)c1)CCC(=O)N2Cc1ccc(F)cc1F
Reactant: CC(C)(C)OC(=O)CBr
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cc2c(cc1-c1ccc(C(F)(F)F)c(F)c1)CC(CC(=O)OC(C)(C)C)C(=O)N2Cc1ccc(F)cc1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 66.7 %

Procedure:
To a solution of 1-(2,4-difluorobenzyl)-6-(3-fluoro-4-(trifluoromethyl)phenyl)-7-methoxy-3,4-dihydroquinolin-2(1H)-one (14 mg, 0.03 mmol) in anhydrous tetrahydrofuran (1 mL) at −78° C. in a dry flask equipped with an inlet of dry nitrogen was added fresh 1.6 M n-butyl lithium in n-hexane (40 μL, 0.06 mmol) with stirring. The reaction mixture was stirred at −78° C. for 30 minutes, then at 0° C. for 1 hour. The reaction mixture was re-cooled to −78° C., a solution of tert-butyl bromoacetate (98 mg, 0.50 mmol) in anhydrous tetrahydrofuran added (0.5 mL), and the reaction mixture stirred overnight, allowing it to warm up to room temperature. The reaction was followed by LCMS, and stirring was continued as needed until the starting material was consumed. The reaction mixture was quenched by addition of saturated aqueous ammonium chloride (5 mL) with stirring, concentrated under reduced pressure, diluted with ethyl acetate (10 mL) and diluted with aqueous ammonium chloride (5 mL). The aqueous phase was extracted with ethyl acetate (3×10 mL), and the combined organic phase was successively washed with 2N spdium carbonate (10 mL), 30% ammonium chloride (10 mL), brine (20 mL), and dried over magnesium sulfate. Evaporation of the solvent under reduced pressure gave a crude mixture which was purified by reverse phase HPLC with a gradient of acetonitrile/water (2% to 98%) to afford tert-butyl 2-(1-(2,4-difluorobenzyl)-6-(3-fluoro-4-(trifluoromethyl)phenyl)-7-methoxy-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)acetate (12 mg, 0.02 mmol, 67%). LCMS m/z 524.0 (M-tBu), 602.0 (M+Na), anal HPLC >98% in purity. 1H NMR (400 MHz; acetone-d6) δ7.77 (t, J=8.0 Hz, 1H); 7.60 (m, 2H); 7.38 (m, 2H); 7.11 (m, 1H); 7.00 (m, 1H); 6.81 (s, 1H); 5.35 (s, 2H); 3.80 (s, 3H); 2.70-3.30 (m, 3H); 2.40-2.60 (m, 2H); 1.48 (s, 9H).
Reaction SMILES: CC(C)[C@@H:3]([N:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=4)=[O:24])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]1=[O:36])[C:4]([OH:6])=[O:5].O=C1C2C(=CC(C3C=CC(NC(NC4C=CC=C(C(F)(F)F)C=4)=O)=CC=3)=CC=2)CN1CC(OC)=O>>[O:36]=[C:8]1[C:9]2[C:14](=[CH:13][C:12]([C:16]3[CH:17]=[CH:18][C:19]([NH:22][C:23]([NH:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:34])([F:33])[F:35])[CH:27]=4)=[O:24])=[CH:20][CH:21]=3)=[CH:11][CH:10]=2)[CH2:15][N:7]1[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CC(C)[C@H](C(=O)O)N1Cc2cc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)ccc2C1=O
Agent: COC(=O)CN1Cc2cc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)ccc2C1=O
Product: O=C(O)CN1Cc2cc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)ccc2C1=O

Procedure:
The compound of example 364 was prepared analogous to the compound of example 361 by hydrolysis of the compound of example 363.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][CH2:15][CH3:16])C(C(F)(F)F)=[CH:10][C:9]=1[NH:21][C:22](=[O:39])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([CH3:38])[CH:33]=2)[CH:27]=1)=O)(C)(C)C.[C:41](O)([C:43]([F:46])([F:45])[F:44])=O>C(Cl)Cl>[CH3:38][C:34]1[CH:33]=[C:32]([C:28]2[CH:27]=[C:26]([C:24]3[CH2:23][C:22](=[O:39])[NH:21][C:9]4[CH:10]=[C:41]([C:43]([F:46])([F:45])[F:44])[C:12]([CH2:14][CH2:15][CH3:16])=[CH:13][C:8]=4[N:7]=3)[CH:31]=[CH:30][CH:29]=2)[CH:37]=[CH:36][N:35]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CCCc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(C)c3)c2)cc1C(F)(F)F
Solvent: ClCCl
Product: CCCc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccnc(C)c3)c1)=N2

Procedure:
The title compound was prepared from (2-{3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-propyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M202) (285 mg, 0.51 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (67 mg, 29%).
Reaction SMILES: [CH:1]([N:4]([CH3:26])[C:5]1[CH:10]=[C:9]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:21]=[C:20]([CH3:22])[C:19]([OH:23])=[C:18]([CH3:24])[CH:17]=3)[N:12]=2)[CH:8]=[C:7]([CH3:25])[N:6]=1)([CH3:3])[CH3:2].Cl[CH2:28][C@@H:29]([OH:32])[CH2:30][OH:31]>>[CH:1]([N:4]([CH3:26])[C:5]1[CH:10]=[C:9]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:21]=[C:20]([CH3:22])[C:19]([O:23][CH2:28][C@@H:29]([OH:32])[CH2:30][OH:31])=[C:18]([CH3:24])[CH:17]=3)[N:12]=2)[CH:8]=[C:7]([CH3:25])[N:6]=1)([CH3:3])[CH3:2]
Reactant: OC[C@H](O)CCl
Reactant: Cc1cc(-c2nc(-c3cc(C)c(O)c(C)c3)no2)cc(N(C)C(C)C)n1
Product: Cc1cc(-c2nc(-c3cc(C)c(OC[C@@H](O)CO)c(C)c3)no2)cc(N(C)C(C)C)n1

Procedure:
(S)-3-(4-{5-[2-(Isopropyl-methyl-amino)-6-methyl-pyridin-4-yl]-[1,2,4]oxadiazol-3-yl}-2,6-dimethyl-phenoxy)-propane-1,2-diol is prepared in analogy to Example 3 from 4-{5-[2-(isopropyl-methyl-amino)-6-methyl-pyridin-4-yl]-[1,2,4]oxadiazol-3-yl}-2,6-dimethyl-phenol using (S)-3-chloro-1,2-propanediol; LC-MS: tR=0.78 min; [M+1]+=427.08.
Reaction SMILES: CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-].[Cl:14][CH2:15][C:16](=[O:31])[C@@H:17]([NH:26][C:27](=[O:30])[O:28][CH3:29])[CH2:18][S:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>C(O)(C)C>[Cl:14][CH2:15][C@@H:16]([OH:31])[C@@H:17]([NH:26][C:27](=[O:30])[O:28][CH3:29])[CH2:18][S:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)N[C@@H](CSc1ccccc1)C(=O)CCl
Agent: CC(C)[O-]
Agent: Cl
Agent: [Al+3]
Solvent: CC(C)O
Product: COC(=O)N[C@@H](CSc1ccccc1)[C@H](O)CCl
Temperature: 70 °C
Reaction time: 4 h

Procedure:
To a suspension of 2.15 g aluminium isopropoxide in 35 ml of isopropanol were added 2.88 g of methyl [3-chloro-2-oxo-(R)-1-(phenylthiomethyl)-propyl]-carbamate and the suspension was stirred at 70° C./ 400 mbar for 4 hours. The mixture was cooled to 0° C., the pH was adjusted to 1 by adding hydrochloric acid and the isopropanol was evaporated. The suspension was filtered and the residue was recrystallized from toluene to give 2.18 g (75%) isomerically pure methyl (1R, 2S)-[3-chloro-2-hydroxy-1-(phenylthiomethyl)-propyl]-carbamate, m.p. 113-114° C. IR (KBr): 3389 m and 3327 m (NH, OH), 1695 s (C=O), 1537 s (amide II). MS (EI): 289/35 (M+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].Br[CH2:10][CH:11]1[CH2:24][C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:25][CH3:26])[CH:21]=3)[N:16]=[CH:15][C:14]=2[O:13][CH2:12]1.C(N(CC)C(C)C)(C)C.C1CCCCC1>CN(C)C=O.C(OCC)(=O)C>[CH3:26][O:25][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[N:16]=[CH:15][C:14]1[O:13][CH2:12][CH:11]([CH2:10][N:6]3[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]3)[CH2:24][C:23]2=1
Reactant: COc1ccc2ncc3c(c2c1)CC(CBr)CO3
Reactant: O=[N+]([O-])c1cn[nH]c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: COc1ccc2ncc3c(c2c1)CC(Cn1cc([N+](=O)[O-])cn1)CO3
Temperature: 80 °C
Reaction time: 24 h
Yield: 64 %

Procedure:
4-Nitro-1H-pyrazole (118 mg, 1.02 mmol, 1.0 eq) is added at room temperature to a stirred solution of 3-bromomethyl-6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthrene (350 mg, 1.02 mmol, 1.0 eq) in N,N-dimethylformamide (12 mL), followed by N,N-diisopropylethylamine (196 μL, 1.12 mmol, 1.1 eq). After 24 hours stirring at 80° C., solvent is removed and the residue is extracted with dichloromethane (3×20 mL) and water (20 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by column chromatography (silica gel, eluent: cyclohexane:ethyl acetate, 1:1 to 0:1, v/v) to afford 6-methoxy-3-(4-nitro-pyrazol-1-ylmethyl)-3,4-dihydro-2H-1-oxa-9-aza-phenanthrene as a light yellow viscous oil (222 mg, 61% yield).
Reaction SMILES: [I-].[CH3:2][S+](C)C.[H-].[Na+].[C:8]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)(=[O:10])[CH3:9]>CN(C=O)C.CS(C)=O>[CH3:9][C:8]1([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[CH2:2][O:10]1
Reactant: CC(=O)c1ccncc1
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: CC1(c2ccncc2)CO1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Trimethylsulfonium iodide (43.8 g, 210 mmol) was dissolved in 100 mL DMF and NaH (19.8 g, 495 mmol) was added. The reaction mixture was stirred for 5 min. and a solution of 4-acetylpyridine (20 g, 165 mmol) in 20 mL DMSO was added dropwise at RT. After the addition was complete, reaction mixture was stirred at RT for 2 h after which it was poured into ice water. The product was extracted with EtOAc, organic layer was washed with water, dried over sodium sulfate and concentrated under reduced pressure. Yield: 21 g.
Reaction SMILES: [CH3:1][O-:2].[Na+].[Na].CO.[Br:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](Br)[C:13]=1[CH3:14]>CN(C)C=O.C(OCC)(=O)C>[Br:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([O:2][CH3:1])[C:13]=1[CH3:14]
Reactant: C[O-]
Reactant: Cc1c(Br)cncc1Br
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cncc(Br)c1C
Temperature: 80 °C

Procedure:
To a freshly prepared sodium methoxide from sodium metal (0.165 g, 0.0072 mol) and methanol (2.5 mL), 3,5-dibromo-4-methyl-pyridine (1.0 g, 0.0040 mol) dissolved in N,N-dimethylformamide (10 mL) was added and heated at 80° C. overnight. Reaction was diluted with ethyl acetate and quenched with ice water, and layers were separated. The aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated to provide the title compound. 1H NMR (400 MHz, CDCl3) δ 8.33 (s, 1H), 8.09 (s, 1H), 3.05 (s, 3H), 2.32 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][CH2:14][CH2:15]Cl)[CH:6]=[C:5]2[CH:17]=[O:18].[C:19]([O-:22])(=[O:21])[CH3:20].[Na+]>CS(C)=O.O>[C:19]([O:22][CH2:15][CH2:14][CH2:13][N:7]1[CH:6]=[C:5]([CH:17]=[O:18])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=2)[C:8]1=[O:12])(=[O:21])[CH3:20]
Reactant: CC(=O)[O-]
Reactant: O=Cc1cn(CCCCl)c(=O)c2ccc(Br)cc12
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)OCCCn1cc(C=O)c2cc(Br)ccc2c1=O
Temperature: 70 °C
Reaction time: 10 h

Procedure:
A solution of 6-bromo-2-(3-chloropropyl)-1-oxo-1,2-dihydroisoquinoline-4-carbaldehyde (Example 10b, 0.90 g) in DMSO (10 mL) was treated with sodium acetate (0.45 g) under nitrogen. The resulting mixture was stirred at 70° C. for 10 h. The cooled reaction mixture was diluted with water (250 mL), and extracted with ethyl acetate (250 mL). The organic was dried (MgSO4), filtered and evaporated to afford subtitle compound. (0.91 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:11]2[CH:10]=[C:9]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)[CH:8]=[CH:7][C:6]=2[C:5](=O)[CH2:4][CH2:3]1.[C:27]([C:29]1C=C2C(=[CH:37][CH:38]=1)C(=C(CC)CC)CCC2(C)C)#[CH:28]>>[CH3:26][C:2]1([CH3:1])[C:11]2[CH:10]=[C:9]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)[CH:8]=[CH:7][C:6]=2[C:5](=[C:29]([CH2:38][CH3:37])[CH2:27][CH3:28])[CH2:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3=O)cc1
Reactant: C#Cc1ccc2c(c1)C(C)(C)CCC2=C(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3=C(CC)CC)cc1

Procedure:
Employing the same general procedure as for the preparation of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl]benzoate (Compound 1), 143 mg (0.57 mmol) of 6-ethynyl-3,4-dihydro-1(2H)-(3-pentylidene)-4,4-dimethylnaphthalene (Compound W) was converted into the title compound using 142 mg (0.51 mmol) of ethyl 4-iodobenzoate, 36 mg (0.19 mmol) of cuprous iodide and 130 mg (0.19 mmol) of bis(triphenylphosphine)palladium(II) chloride.
Reaction SMILES: [OH-].[K+].C[O:4][C:5](=[O:36])[C@@H:6]([N:23]1[C:35]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:22])[C:13]1[CH:18]=[CH:17][C:16]([N:19]=[N+:20]=[N-:21])=[CH:15][CH:14]=1.CO.Cl>C1(C)C=CC=CC=1>[N:19]([C:16]1[CH:15]=[CH:14][C:13]([C:12]([NH:11][CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]([N:23]2[C:35]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:29]3[C:24]2=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:5]([OH:36])=[O:4])=[O:22])=[CH:18][CH:17]=1)=[N+:20]=[N-:21]
Reactant: COC(=O)[C@H](CCCCNC(=O)c1ccc(N=[N+]=[N-])cc1)n1c2ccccc2c2ccccc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CO
Product: [N-]=[N+]=Nc1ccc(C(=O)NCCCC[C@@H](C(=O)O)n2c3ccccc3c3ccccc32)cc1
Temperature: 60 °C
Yield: 87.5 %

Procedure:
Methanolic KOH (0.075 g, 1.32 mmol) was added to a stirred solution of (S)-6-(4-azido-benzoylamino)-2-carbazol-9-yl-hexanoic acid methyl ester 13 (0.200 g, 0.44 mmol) in a mixture (2:1) of methanol (6 mL) and toluene (3 mL) at room temperature. The reaction mixture was refluxed at 60° C. for 3.5 h. After cooling to 0° C., 1M HCl solution was added drop-wise for the acidification up to pH=3-4 and extracted with EtOAc (30 mL×2). The combined organic extract was washed with water (20 mL×2) and dried over anhydrous Na2SO4. Removal of solvent under reduced pressure provided (S)-6-(4-azido-benzoylamino)-2-carbazol-9-yl-hexanoic acid 14 (0.170 g, 88%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([N:8]([CH2:20][O:21][CH3:22])[S:9]([C:12]2[CH:16]=[CH:15][S:14][C:13]=2[C:17](Cl)=[O:18])(=[O:11])=[O:10])[O:4][N:3]=1.[C:23]([O:26][CH2:27][C:28]1[C:29]([CH3:37])=[C:30]([C:32]([CH3:36])=[CH:33][C:34]=1[CH3:35])[NH2:31])(=[O:25])[CH3:24].C(N(CC)CC)C.O>ClCCl.CN(C)C1C=CN=CC=1>[C:23]([O:26][CH2:27][C:28]1[C:29]([CH3:37])=[C:30]([NH:31][C:17]([C:13]2[S:14][CH:15]=[CH:16][C:12]=2[S:9]([N:8]([C:5]2[O:4][N:3]=[C:2]([CH3:1])[C:6]=2[CH3:7])[CH2:20][O:21][CH3:22])(=[O:11])=[O:10])=[O:18])[C:32]([CH3:36])=[CH:33][C:34]=1[CH3:35])(=[O:25])[CH3:24]
Reactant: CC(=O)OCc1c(C)cc(C)c(N)c1C
Reactant: COCN(c1onc(C)c1C)S(=O)(=O)c1ccsc1C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCN(c1onc(C)c1C)S(=O)(=O)c1ccsc1C(=O)Nc1c(C)cc(C)c(COC(C)=O)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.7 %

Procedure:
To a solution of 3-[N-(3,4-dimethylisoxazol-5-yl)-N-methoxymethylaminosulfonyl]-2-thiophenecarbonyl chloride (1.1 g, 2.97 mmol) in dichloromethane (9 mL) was added 3-acetoxymethyl-2,4,6-trimethylaniline (0.6 g, 2.97 mmol) at 0° C. Triethylamine (0.46 mL, 3.26 mmol) and 4-dimethylaminopyridine (36 mg, 0.30 mmol) were added. The mixture was stirred at room temperature overnight, then mixed with water (10 mL). The organic material was separated, and the aqueous layer was extracted with dichloromethane (2×10 mL). The extracts were combined and washed with water (20 mL) and saturated sodium chloride (20 mL), dried (MgSO4), then concentrated. The residue was purified by flash chromatography (SiO2, hexane:ethyl acetate/2:1) to give N2-(3-acetoxymethyl-2,4,6-trimethylphenyl)-3-[N-(3,4-dimethylisoxazol-5-yl)-N-methoxymethylaminosulfonyl]-2-thiophenecarboxamide (0.79 g, 50%) as a yellow oil.
Reaction SMILES: [C:1]1(=[O:6])[O:5][CH2:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:9]=1[CH2:10]I>>[Cl:7][C:8]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:9]=1[CH2:10][CH:2]1[CH2:3][CH2:4][O:5][C:1]1=[O:6]
Reactant: O=C1CCCO1
Reactant: Clc1ccc(CI)c(Cl)c1
Product: O=C1OCCC1Cc1ccc(Cl)cc1Cl
Yield: 78.5 %

Procedure:
Using the procedure to synthesize Example 1 and using reagents γ-butyrolactone (1.1 g, 13 mmol), and 2,4-dichlorobenzyl iodide (5.6 g, 20 mmol) affords 2.5 g (78%) of the title compound as a tan solid. 1H NMR (CDCl3) δ 7.36 (d, 1H), 7.17 (m, 2H), 4.30 (m, 1H), 4.10 (m, 1H), 3.32 (dd, 1H), 2.87-2.78 (m, 2H), 2.20 (m, 1H), 1.95 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:17])[NH:10][C:11]1([C:14](=[O:16])[NH2:15])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].[CH2:23]([O:25][C:26](=[O:31])[C:27](=O)[CH2:28]Br)[CH3:24]>C1COCC1>[CH2:23]([O:25][C:26]([C:27]1[N:15]=[C:14]([C:11]2([NH:10][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:17])[CH2:12][CH2:13]2)[O:16][CH:28]=1)=[O:31])[CH3:24]
Reactant: CCOC(=O)C(=O)CBr
Reactant: NC(=O)C1(NC(=O)OCc2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1coc(C2(NC(=O)OCc3ccccc3)CC2)n1
Temperature: 70 °C
Reaction time: 24 h
Yield: 48.1 %

Procedure:
To a solution of (1-carbamoyl-cyclopropyl)-carbamic acid benzyl ester (3.0 g, 8.1 mmol) in THF (100 mL) was added NaHCO3 (9.7 g, 120 mmol) and 3-bromo-2-oxo-propionic acid ethyl ester (8.1 mL, 64.0 mmol). The reaction was heated at 70° C. for 15 h. The resulting orange suspension was filtered through celite and concentrated under reduced pressure. The resulting orange oil was dissolved in THF (10 mL) and to this was added trifluoroacetic anhydride (1 mL). The mixture was stirred at room temperature for 24 h. The reaction was quenched with satd NaHCO3 and extracted with EtOAc (3×50 mL). The combined extracts were washed with water, brine and dried with MgSO4. The mixture was filtered, concentrated and purified by reverse phase HPLC. The combined HPLC fractions were extracted with EtOAc (3×100 mL). The extracts were washed with water, brine and dried with MgSO4. The mixture was filtered and concentrated to give 2-(1-benzyloxycarbonylamino-cyclopropyl)-oxazole-4-carboxylic acid ethyl ester (1.3 g, 3.9 mmol) as a white solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[O:7][C:6]([C:8]([O:10]CC)=[O:9])=[N:5][N:4]=1.[OH-].[K+:14]>C(O)C>[CH3:1][S:2][C:3]1[O:7][C:6]([C:8]([O-:10])=[O:9])=[N:5][N:4]=1.[K+:14]
Reactant: CCOC(=O)c1nnc(SC)o1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CSc1nnc(C(=O)[O-])o1
Yield: 86 %

Procedure:
A solution of ethyl 5-methylthio-1,3,4-oxadiazole-2-carboxylate (4.31 g., 0.023 mole) in absolute ethanol (50 ml.) was treated dropwise with 2.87 g. (0.023 mole) of 45 wt.% potassium hydroxide solution. The resultant white precipitate was isolated by filtration, washed with ethanol and dried to yield 3.92 g. (86%) of the title compound; M.P. 176°-177° C. with decomposition after recrystallization from ethanol.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:22])[C:7]([C:19]([OH:21])=[O:20])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:4][C:3]=1[F:23].[N+:24]([O-])([O-:26])=[O:25].[K+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:22])[C:7]([C:19]([OH:21])=[O:20])=[CH:8][N:9]2[C:12]2[CH:13]=[CH:14][C:15]([F:18])=[C:16]([N+:24]([O-:26])=[O:25])[CH:17]=2)=[CH:4][C:3]=1[F:23]
Reactant: O=[N+]([O-])[O-]
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)c2nc(Cl)c(F)cc2c1=O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C(O)c1cn(-c2ccc(F)c([N+](=O)[O-])c2)c2nc(Cl)c(F)cc2c1=O
Temperature: 80 °C
Reaction time: 2 h
Yield: 64.7 %

Procedure:
To 10 ml of conc. sulfuric acid was added 1.5 g of 7-chloro-6-fluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid. Potassium nitrate (1.4 g) was added in portions to the solution, which was heated and stirred at 80° C. for 2 hours. The reaction solution was allowed to cool down, poured into ice water, and stirred overnight. The precipitated solid was collected by filtration and successively washed with water, ethanol, and diethyl ether to give 1.1 grams of the title compound.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([C:15]2[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=2[F:22])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5])C.[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[C:32]([F:35])([F:34])[F:33])[CH2:27][NH2:28]>>[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[C:32]([F:33])([F:34])[F:35])[CH2:27][NH:28][C:4]([C:6]1[N:7]=[C:8]([C:15]2[C:16]([F:22])=[CH:17][CH:18]=[CH:19][C:20]=2[F:21])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5]
Reactant: CCOC(=O)c1nc(-c2c(F)cccc2F)n(C)c(=O)c1O
Reactant: NCc1ccc(C(F)(F)F)c(F)c1
Product: Cn1c(-c2c(F)cccc2F)nc(C(=O)NCc2ccc(C(F)(F)F)c(F)c2)c(O)c1=O

Procedure:
Prepared according to the procedure described for example 2 from 2-(2,6-difluoro-phenyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (31 mg, 0.1 mmol) and 3-fluoro-4-trifluoromethylbenzylamine (97 mg, 0.5 mmol). The title product was obtained as an off-white solid (44.7 mg, 98% yield). 1HNMR (500 MHz, CDCl3) δ: 12.13 (1H, s), 7.88 (1H, br s), 7.57–7.47 (4H, m), 7.06 (2H, dd, J=8.54, 7.32 Hz), 4.59 (2H, d, J=6.41 Hz), 3.41 (3H, s). HRMS (ESI) calcd for C20H12F6N3O3 (M−H): 456.0782; found: 456.0788.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([N:19]([CH2:34][CH3:35])[CH2:20][CH2:21][NH:22][C:23]([C:25]1[C:29]([CH3:30])=[C:28]([CH:31]=O)[NH:27][C:26]=1[CH3:33])=[O:24])[CH3:18].N1CCCCC1>C(O)C>[CH2:34]([N:19]([CH2:17][CH3:18])[CH2:20][CH2:21][NH:22][C:23]([C:25]1[C:29]([CH3:30])=[C:28]([CH:31]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[CH:15][C:7]=3[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[NH:11][C:10]2=[O:16])[NH:27][C:26]=1[CH3:33])=[O:24])[CH3:35]
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Reactant: O=C1Cc2c(cccc2-c2ccccc2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(-c4ccccc4)c32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 55.9 %

Procedure:
To a solution of 4-phenyl-1,3-dihydro-indol-2-one (41.9 mg, 0.20 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (53.1 mg, 0.20 mmol) in ethanol (1 mL) was added piperidine (0.1 mL). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide 2,4-dimethyl-5-(2-oxo-4-phenyl-1,2-dihydro-indol-3-ylidenemethyl)-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (51 mg, 56%)