Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:11]=[C:12]([CH:16]=O)[CH:13]=[N:14][CH:15]=2)=[CH:4][CH:3]=1.[ClH:18].[O:19]([NH2:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+]>>[ClH:18].[CH3:20][O:19][N:21]=[CH:16][C:12]1[CH:13]=[N:14][CH:15]=[C:10]([C:9]#[C:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH:11]=1
Reactant: CON
Reactant: O=Cc1cncc(C#Cc2ccc(F)cc2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CON=Cc1cncc(C#Cc2ccc(F)cc2)c1
Yield: 64 %

Procedure:
Prepare essentially as described in EXAMPLE 6 using 5-(4-fluorophenylethynyl)-pyridine-3-carbaldehyde, (prepared essentially as described in EXAMPLE 99), (150 mg, 0.64 mmol), methoxylamine hydrochloride (430 mg, 5.15 mmol) and potassium carbonate to give the title compound (120 mg, 64%).
Reaction SMILES: [NH2:1][C@@H:2]([CH:5]([CH3:7])[CH3:6])[CH2:3][OH:4].[CH2:8]1[CH2:14][S:11](=[O:13])(=[O:12])[O:10][CH2:9]1>O1CCCC1.O>[OH:4][CH2:3][C@@H:2]([NH:1][CH2:9][CH2:8][CH2:14][S:11]([OH:13])(=[O:12])=[O:10])[CH:5]([CH3:7])[CH3:6]
Reactant: O=S1(=O)CCCO1
Reactant: CC(C)[C@H](N)CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[C@@H](CO)NCCCS(=O)(=O)O
Temperature: 25 °C

Procedure:
To a solution of (S)-(−)-2-amino-3-methyl-1-butanol (2.50 g, 24.2 mmol) in tetrahydrofuran (35 mL) was slowly added 1,3-propane sultone (2.89 g, 23.0 mmol). The mixture was stirred at reflux for 3 h. The reaction mixture was cooled to room temperature. The solid material was collected by filtration, washed with acetone (2×25 mL). The crude product was suspended in 80% acetone/ethanol (75 mL). The suspension was stirred at reflux for 30 secondes. The solid product was collected by filtration, and dried in a vacuum oven (50° C.), to afford compound EP (2.9 g, 56%). 1H NMR (D2O, 500 MHz) δ ppm 3.78 (dd, 1H), 3.62 (dd, 1H), 3.13 (m, 2H), 2.90 (m, 1H), 2.88 (t, 3H), 1.90 (m, 3H), 0.90 (d, 3H), 0.84 (d, 3H). 13C NMR (D2O, 125 MHz) δ ppm 64.74, 57.24, 48.20, 44.44, 26.98, 21.49, 18.53, 17.00. [OC]D=+4.1° (c=0.0017 in water), ES-MS 224 (M−1).
Reaction SMILES: [O:1]=[C:2]1[N:6](C(OCC)=O)[C:5]2[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=2[N:3]1[C:16]([O:18][CH2:19][CH3:20])=[O:17].OC1NC2C=CC=CC=2N=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[O:1]=[C:2]1[N:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:4]2[CH:15]=[CH:14][CH:13]=[CH:12][C:5]=2[NH:6]1
Reactant: CCOC(=O)n1c(=O)n(C(=O)OCC)c2ccccc21
Agent: O=C([O-])[O-]
Agent: Oc1nc2ccccc2[nH]1
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)n1c(=O)[nH]c2ccccc21
Reaction time: 2 h

Procedure:
A mixture of 11.0 g (39.5 mmol) of diethyl 2-oxobenzimidazole-1,3-dicarboxylate (III), 5.30 g (39.5 mmol) of 2-hydroxybenzimidazole and 6.55 g (47.4 mmol) of potassium carbonate in acetonitrile (200 ml) was heated under reflux with vigorous stirring for 2 h. Most of the solvent was then removed in vacuo, and the residue was mixed with 150 ml of 1N hydrochloric acid. The solid residue was filtered, washed with water, dried in vacuo and recrystallized from toluene.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][C@@H:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[NH:5][C:4]1=[O:15])[CH3:2].CC(C)([O-])C.[K+].[C:22]([S:30][CH2:31][C@H:32]([CH3:36])[C:33](Cl)=[O:34])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1>[CH2:1]([N:3]1[CH2:7][C@@H:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[N:5]([C:33](=[O:34])[C@H:32]([CH3:36])[CH2:31][S:30][C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:4]1=[O:15])[CH3:2]
Reactant: CCN1C[C@@H](C(=O)OC(C)(C)C)NC1=O
Reactant: C[C@@H](CSC(=O)c1ccccc1)C(=O)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCN1C[C@@H](C(=O)OC(C)(C)C)N(C(=O)[C@H](C)CSC(=O)c2ccccc2)C1=O
Yield: 75.8 %

Procedure:
3.0 g of tert.-butyl (4S)-1-ethyl-2-oxo-imidazolidine-4-carboxylate, 1.6 g of potassium tert.-butoxide, (2S)-3-benzoylthio-2-methylpropionyl chloride (prepared from 3.2 g of (2S)-3-benzoylthio-2-methylpropionic acid and 10 ml of thionyl chloride) and 40 ml of tetrahydrofuran are treated in the same manner as described in Example 2-(2). Then, the oily residue obtained is purified by silica gel chromatography (Solvent, toluene-ethyl acetate(20:1)). 4.2 g of tert.-butyl (4S)-1-ethyl-3-[(2S)-3-benzoylthio-2-methylpropionyl]-2-oxo-imidazolidine-4-carboxylate are obtained as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[C:4]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[N:3]=1.[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN=C=NCCCN(C)C.Cl.O>CN(C=O)C.CN(C)C1C=CN=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:23][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:10])[CH:5]=[C:4]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[N:3]=1
Reactant: Nc1nc(C(=O)O)cc(-c2ccco2)n1
Reactant: NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc(C(=O)NCc2ccccc2)cc(-c2ccco2)n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 35.3 %

Procedure:
A solution of 2-amino-6-(2-furyl)pyrimidine-4-carboxylic acid (103 mg, 0.5 mmol) in DMF (2 mL) was treated with benzylamine (59 mg, 0.55 mmol), EDCl (104 mg, 0.54 mmol) and 4-dimethylaminopyridine (66 mg, 0.54 mmol), stirred at room temperature for 17 h, poured into water (25 mL) and extracted with EtOAc (2×25 mL). The combined organic phase was washed with water (25 mL), dried (MgSO4), concentrated in vacuo and purified by chromatography [SiO2; isopropyl ether:EtOAc, (100:0-0:100)] to give the title compound (52 mg, 40%) as an off-white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[N:17]=[C:18]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[O:19][C:20]=3[C:21]([F:24])([F:23])[F:22])=[O:15])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[O:31]=[C:32]1[NH:36][C:35](=[O:37])[CH:34]([CH2:38][C:39](O)=[O:40])[S:33]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[O:31]=[C:32]1[NH:36][C:35](=[O:37])[CH:34]([CH2:38][C:39]([N:1]2[CH2:6][CH2:5][CH:4]([C:7]3[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]4[N:17]=[C:18]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[O:19][C:20]=4[C:21]([F:22])([F:23])[F:24])=[O:15])=[CH:11][CH:12]=3)[CH2:3][CH2:2]2)=[O:40])[S:33]1
Reactant: O=C(O)CC1SC(=O)NC1=O
Reactant: O=C(Nc1ccc(C2CCNCC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1NC(=O)C(CC(=O)N2CCC(c3ccc(NC(=O)c4nc(-c5ccccc5)oc4C(F)(F)F)cc3)CC2)S1
Yield: 90.1 %

Procedure:
2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-piperidin-4-yl-phenyl)-amide (60.1 mg, 0.149 mmol), (2,4-dioxo-thiazolidin-5-yl)-acetic acid (26.2 mg, 0.149 mmol), triethylamine (63 uL, 0.448 mmol) and BOP (63.2 mg, 0.149 mmol) in 1 mL DMF were reacted as above. The crude product was purified by flash chromatography to yield 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-{1-[2-(2,4-dioxo-thiazolidin-5-yl)-acetyl]-piperidin-4-yl}-phenyl)-amide as a white solid (76.9 mg, 90%). ES-MS calcd for C27H23F3N4O5S (m/e) 572.57, obsd 573 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.Cl[CH2:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:17][CH2:16]1)=[O:14]>C(OCC)C>[F:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][CH:18]2[CH2:19][CH2:20][N:15]([C:13](=[O:14])[CH2:12][NH:1][C:2]3[CH:3]=[C:4]4[C:8](=[CH:9][CH:10]=3)[NH:7][N:6]=[CH:5]4)[CH2:16][CH2:17]2)=[CH:23][CH:24]=1
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: O=C(CCl)N1CCC(Cc2ccc(F)cc2)CC1
Solvent: CCOCC
Product: O=C(CNc1ccc2[nH]ncc2c1)N1CCC(Cc2ccc(F)cc2)CC1

Procedure:
The title compound is prepared from 5-aminoindazol (Aldrich) and 2-chloro-1-[4-(4-fluoro-benzyl)-piperidin-1-yl]-ethanone (Example 197a) according to the method described in Example 142b. Melting Point: 113-114° C. (diethylether)
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.Cl[CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14].CO.CCOC(C)=O>C1COCC1>[CH3:14][Si:13]([CH3:16])([CH3:15])[CH2:12][CH2:11][O:10][CH2:9][N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: c1c[nH]cn1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccnc1
Temperature: 25 °C
Yield: 70 %

Procedure:
To a stirred suspension of NaH (60% dispersion in oil, 0.65 g, 16.2 mmol) at 0° C. was added imidazole (1 g, 14.7 mmol) in THF (14 mL). The mixture was warmed to room temperature over 30 min, then re-cooled to 0° C. followed by an addition of (2-(chloromethoxy)ethyl)trimethylsilane (2.73 ml, 15.4 mmol). The combined mixture was warmed to room temperature over 1 h, quenched with saturated aqueous ammonium chloride, concentrated to dryness and partitioned between water and EtOAc. Organic phase was collected, dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by column chromatography (eluents EtOAc, then MeOH/EtOAc 20:80), to afford the title compound (2.04 g, 70% yield) as a white solid. MS (m/z) 199.3 (M+H).
Reaction SMILES: C([O-])(=O)C.C([O:8][CH2:9][C:10]1[C:11]([N:42]2[CH2:54][CH2:53][N:45]3[C:46]4[CH2:47][CH2:48][CH2:49][CH2:50][C:51]=4[CH:52]=[C:44]3[C:43]2=[O:55])=[N:12][CH:13]=[CH:14][C:15]=1[C:16]1[CH:21]=[C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][N:32]([CH:35]4[CH2:38][O:37][CH2:36]4)[CH2:31][C@@H:30]3[CH3:39])=[CH:25][N:24]=2)[C:19](=[O:40])[N:18]([CH3:41])[CH:17]=1)(=O)C.O[Li].O>CC(O)C.C1COCC1.O>[OH:8][CH2:9][C:10]1[C:11]([N:42]2[CH2:54][CH2:53][N:45]3[C:46]4[CH2:47][CH2:48][CH2:49][CH2:50][C:51]=4[CH:52]=[C:44]3[C:43]2=[O:55])=[N:12][CH:13]=[CH:14][C:15]=1[C:16]1[CH:21]=[C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][N:32]([CH:35]4[CH2:38][O:37][CH2:36]4)[CH2:31][C@@H:30]3[CH3:39])=[CH:25][N:24]=2)[C:19](=[O:40])[N:18]([CH3:41])[CH:17]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C5COC5)C[C@@H]4C)cn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: CC(=O)[O-]
Agent: [Li]O
Solvent: O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(N4CCn5c(cc6c5CCCC6)C4=O)c3CO)cn(C)c2=O)nc1
Yield: 85 %

Procedure:
Following the procedures as described for 118, acetate hydrolysis of 119a with LiOH.H2O in iPrOH/THF (1:1) and H2O, gave 119 as a white solid (184 mg, 85%). LCMS: [M+H]+ 651. 1H NMR (500 MHz, CDCl3) δ 8.65 (d, J=2.5, 1H), 8.50 (d, J=5.0, 1H), 7.99 (s, 1H), 7.87 (s, 1H), 7.84 (d, J=2.0, 1H), 7.35 (d, J=5.0, 1H), 7.33 (d, J=7.0, 1H), 6.90 (s, 1H), 6.83 (d, J=9.0, 1H), 5.04-5.06 (m, 1H), 4.62-4.73 (m, 5H), 4.51 (s, 1H), 4.32 (s, 1H), 4.16 (s, 1H), 4.11 (s, 1H), 3.89 (s, 1H), 3.72 (s, 3H), 3.57 (t, J=6.0, 1H), 3.48 (s, 1H), 3.07-3.12 (m, 2H), 2.53-2.63 (m, 7H), 2.24 (m, 1H), 1.88-1.93 (m, 2H), 1.80 (s, 2H), 0.99 (d, J=6.5, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=NO)=[C:24]([CH:29]=[CH2:30])[N:23]=[C:22]3[O:31][CH2:32][CH2:33][CH3:34])=[C:16]([F:35])[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].S(=O)(=O)(O)[OH:37].C.O>CCOC(C)=O.[Pd]>[C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=[O:37])=[C:24]([CH:29]=[CH2:30])[N:23]=[C:22]3[O:31][CH2:32][CH2:33][CH3:34])=[C:16]([F:35])[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: O=S(=O)(O)O
Reactant: C=Cc1nc(OCCC)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2F)c1C=NO
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: O
Product: C=Cc1nc(OCCC)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2F)c1C=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Intermediate (18c) (7.4 g, 15.0 mmol) was dissolved in EtOAc (200 mL), followed by the addition of sulfuric acid (1.50 mL). 10% Pd/C, Degussa type, wet 50% (0.05:0.45:0.5, palladium:carbon black:water, 16.0 g) was then added and the mixture was degassed with nitrogen and then stirred at room temperature under hydrogen for 2 hours. The mixture was then degassed with nitrogen, the palladium was filtered off under nitrogen and the resulting material was concentrated to obtain the title compound as a pale yellow oil (6.5 g). Anal. HPLC retention time=3.2 minutes. Gradient conditions: 10% solvent B/90% solvent A to 90% solvent B/10% solvent A over 6 minutes. MS m/z: [M+H+] calcd for C27H34FN3O3, 468.27; found 468.4. 1H-NMR (DMSO-d6) 7.67 (1H, d), 7.54 (1H, t), 7.33 (1H, t) 7.10 (1H, d), 7.03 (2H, d), 6.87 (1H, s), 5.08 (1H, s), 4.12 (2H, m), 4.00 (2H, s), 3.99 (2H, s), 3.48 (2H, s), 2.32 (2H, m), 1.62 (3H, m), 1.14 (9H, s), 0.85 (3H, t).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[NH:15][C@H:14]2[CH3:19])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C[Si](C)(C)N[Si](C)(C)C.[Na].[Br:32][C:33]1[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][C:34]=1[CH2:35]Br.CCOC(C)=O>C1COCC1.O>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:35][C:34]3[CH:37]=[C:38]([C:41]([F:42])([F:44])[F:43])[CH:39]=[CH:40][C:33]=3[Br:32])[C@H:14]2[CH3:19])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: FC(F)(F)c1ccc(Br)c(CBr)c1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1Br
Reaction time: 0.25 h

Procedure:
To (4S,5R)-5-(3,5-bis-trifluoromethyl-phenyl)-4-methyl-oxazolidin-2-one (0.246 g, 0.79 mmol) in THF (10 mL) at mom temperature was added sodium hexamethyldisilazane (1M in THF; 1.02 mL, 1.02 mmol), and the reaction was stirred for 15 minutes. 2-Bromo-5-(trifluoromethyl)benzyl bromide (0.250 g, 0.79 mmol) was added, and the reaction was stirred overnight at room temperature. The mixture was worked-up with EtOAc and H2O, and the crude material was purified by silica gel chromatography to give the title compound.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:30])[C:8]([CH:19]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([O:22]CC)=[O:21])=[C:9]2[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[C:31]([CH:33]1[CH2:35][CH2:34]1)#[CH:32]>CC#N.O>[C:26]([O:25][CH:19]([C:8]1[C:7]([CH3:30])=[CH:6][C:5]2[C:10](=[CH:11][C:2]([C:32]#[C:31][CH:33]3[CH2:35][CH2:34]3)=[CH:3][CH:4]=2)[C:9]=1[C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=1)[C:20]([OH:22])=[O:21])([CH3:28])([CH3:29])[CH3:27]
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2ccc(Br)cc2c1-c1ccc(Cl)cc1
Reactant: C#CC1CC1
Solvent: O
Solvent: CC#N
Product: Cc1cc2ccc(C#CC3CC3)cc2c(-c2ccc(Cl)cc2)c1C(OC(C)(C)C)C(=O)O

Procedure:
2-tert-Butoxy-2-(1-(4-chlorophenyl)-7-(cyclopropylethynyl)-3-methylnaphthalen-2-yl)acetic acid (75) was prepared by the method of Example 67 from ethyl 2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate using ethynylcyclopropane. 1H-NMR: 400 MHz, (CD3OD) δ: 7.69 (m, 2H), 7.57 (m, 3H), 7.32 (m, 2H), 7.18 (s, 1H), 5.16 (s, 1H), 2.59 (s, 3H), 1.42 (br m, 1H), 0.97 (s, 9H), 0.83 (br m, 2H), 0.68 (br m, 2H). HPLC (Kinetex 2.6u, 50×4.6 mm, 2-100% MeCN/H2O+0.05% HOAc, 5 min run): tR (min)=3.78.
Reaction SMILES: CO[C:3](=[O:38])[CH2:4][NH:5][C:6](=[O:37])[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:21]([N:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH:33]3[CH2:35][CH2:34]3)[CH2:25][CH2:24]2)=[O:22])=[CH:9][C:8]=1[Cl:36].[OH:39][CH2:40][CH2:41]NCCO>>[Cl:36][C:8]1[CH:9]=[C:10]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:21]([N:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH:33]3[CH2:34][CH2:35]3)[CH2:25][CH2:24]2)=[O:22])[C:11]([Cl:13])=[CH:12][C:7]=1[C:6]([N:5]([CH2:41][CH2:40][OH:39])[CH2:4][CH2:3][OH:38])=[O:37]
Reactant: OCCNCCO
Reactant: COC(=O)CNC(=O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Product: O=C(c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl)N(CCO)CCO
Yield: 71 %

Procedure:
The title compound was prepared in analogy to Example 1, from 2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoic acid (Example 29, intermediate) and 2-(2-hydroxy-ethylamino)-ethanol (commercially available, CAS RN 111-42-2). The product was purified on a preparative HPLC system (Phenomenex Gemini column) using a gradient of acetonitrile:water (containing 0.05% formic acid) (10:90 to 98:2) to give the desired compound as a light brown solid (71%). MS (ESI): m/z=571.150 [M+H]+.
Reaction SMILES: Cl.[O:2]1[CH:6]=[CH:5][C:4]([C:7]([CH2:9][NH2:10])=[O:8])=[CH:3]1.C(=O)(O)[O-].[Na+].[F:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH:10][CH2:9][C:7]([C:4]2[CH:5]=[CH:6][O:2][CH:3]=2)=[O:8])=[O:22])=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: NCC(=O)c1ccoc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(CNC(=O)c1ccc(F)cc1)c1ccoc1
Yield: 92.6 %

Procedure:
6.0 g of (3-furylcarbonyl)methylamine hydrochloride, 7.8 g of sodium bicarbonate and 6.4 g of 4-fluorobenzoyl chloride are treated in the same manner as described in Preparation 1-(1). 8.5 g of N-(4-fluorobenzoyl)-(3-furylcarbonyl)methylamine are thereby obtained. Yield: 92.4%
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:11]2[NH:10][C:9](=[O:14])[C:8]3[NH:15][CH:16]=[CH:17][C:7]=3[C:6]=2[CH:5]=1)([O-])=O.[CH2:18]([C:20]([O-:22])=[O:21])[CH3:19]>C(O)(=O)C.[Fe]>[C:20]([NH:1][C:4]1[CH:13]=[CH:12][C:11]2[NH:10][C:9](=[O:14])[C:8]3[NH:15][CH:16]=[CH:17][C:7]=3[C:6]=2[CH:5]=1)(=[O:21])[CH3:18].[CH2:18]([C:20]([O-:22])=[O:21])[CH3:19]
Reactant: O=c1[nH]c2ccc([N+](=O)[O-])cc2c2cc[nH]c12
Agent: [Fe]
Agent: CCC(=O)[O-]
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Yield: 10.6 %

Procedure:
134 mg (2.4 mmol) of iron is added to 72 mg (0.24 mmol) of 8-nitro-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate (synthesis 66) dissolved in 4 mL of acetic acid. The mixture is refluxed for 1 h. The solution is filtered while hot and the solid is rinsed with a minimum of hot acetic acid. The filtrate is evaporated, then the residue (mixture of 8-acetylamino-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate and 8-amino-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate 85/15) is purified by preparative LCMS to give 4 mg (5%) of 8-acetylamino-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in the form of a gray solid.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:15]=[C:14]([NH2:16])[O:13][N:12]=3)[CH:9]=2)[N:4]([S:17]([C:20]2[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH:3]=1.[CH:27]([O:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([Sn](CCCC)(CCCC)CCCC)[N:32]=1)([CH3:29])[CH3:28]>CN(C=O)C.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:27]([O:30][C:31]1[N:32]=[C:33]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]4[N:15]=[C:14]([NH2:16])[O:13][N:12]=4)[CH:9]=3)[N:4]([S:17]([C:20]3[CH:21]=[CH:22][C:23]([CH3:24])=[CH:25][CH:26]=3)(=[O:19])=[O:18])[CH:3]=2)[CH:34]=[CH:35][CH:36]=1)([CH3:29])[CH3:28]
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4noc(N)n4)ccc32)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(OC(C)C)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cccc(OC(C)C)n3)c3cc(-c4noc(N)n4)ccc32)cc1
Temperature: 90 °C
Yield: 61.6 %

Procedure:
Argon gas was bubbled through a solution of 3-(3-iodo-1-tosyl-1H-indol-5-yl)-1,2,4-oxadiazol-5-amine (350 mg, 0.73 mmol) and 2-isopropoxy-6-(tributylstannyl)pyridine (374 mg, 0.87 mmol) in dry DMF (3.5 mL) for 15 min. To the mixture was added CuI (139 mg, 0.73 mmol) and Pd(PPh3)4 (84 mg, 0.073 mmol) and argon gas was further bubbled for additional 15 min. The reaction was heated at 90° C. for 1 h then cooled to RT. The reaction was quenched with ice cold water. The resulting suspension was filtered and washed with water. The solid was purified with basic alumina column chromatography (eluent: 20% EtOAc in petroleum ether) to give 3-(3-(6-isopropoxypyridin-2-yl)-1-tosyl-1H-indol-5-yl)-1,2,4-oxadiazol-5-amine (220 mg, 61.5%). MS (ESI, pos. ion) m/z: 490.1 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([NH:7][C:8](=[O:15])[C:9](=[O:14])[N:10]2[OH:13])=[CH:5][C:4]=1[C:16]([F:19])([F:18])[F:17])#[N:2].C(N(CC)CC)C.[CH:27]1(Br)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>C(O)C>[C:1]([C:3]1[CH:12]=[C:11]2[C:6]([NH:7][C:8](=[O:15])[C:9](=[O:14])[N:10]2[O:13][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:5][C:4]=1[C:16]([F:19])([F:17])[F:18])#[N:2]
Reactant: N#Cc1cc2c(cc1C(F)(F)F)[nH]c(=O)c(=O)n2O
Reactant: BrC1CCCCC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: N#Cc1cc2c(cc1C(F)(F)F)[nH]c(=O)c(=O)n2OC1CCCCC1

Procedure:
To a solution of 0.3 g (1.1 mmol) 7-cyano-1-hydroxy-6-trifluoromethylquinoxaline -2,3(1H,4H)-dione in 30 ml ethanol was added 0.7 ml triethylamine and 1.5 ml (12 mmol) cyclohexylbromide. The reaction mixture was refluxed for 7 days and then evaporated in vacuo. The residue was stirred with water to give a precipitate (0.25 g. Recrystallization (dimethylformamide-water) gave 0.17 g (44%) of 7-cyano-1-cyclohexyloxy-6-trifluoromethylquinoxaline-2,3(1H,4H)-dione). M.p. 259° C. decomp. 1H-NMR (DMSO-d6): 8.0 (1H, s), 7.6 (1H, s), 4.3 (1H, m), 1.4 (8H, m).
Reaction SMILES: I[CH3:2].[OH-].[Na+].[C:5]([O:9][C:10]([N:12]1[CH2:23][CH2:22][C:15]2([NH:19][C:18](=[S:20])[NH:17][C:16]2=[O:21])[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].O>CO>[C:5]([O:9][C:10]([N:12]1[CH2:13][CH2:14][C:15]2([N:19]=[C:18]([S:20][CH3:2])[NH:17][C:16]2=[O:21])[CH2:22][CH2:23]1)=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)NC(=S)NC2=O
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CSC1=NC2(CCN(C(=O)OC(C)(C)C)CC2)C(=O)N1
Reaction time: 8 h
Yield: 77.1 %

Procedure:
Iodomethane (0.329 ml, 5.28 mmol) and a 1 N aqueous NaOH solution (3.3 ml, 3.3 mmol) were sequentially added to a solution of 4-oxo-2-thioxo-1,3,8-triaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (944 mg, 3.3 mmol) in methanol (33 ml) at room temperature, and the mixture was stirred at the same temperature overnight. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layers were combined and dried over magnesium sulfate, and the solvent was then distilled off. The residue was purified by silica gel column chromatography to give 2-methylsulfanyl-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-carboxylic acid tert-butyl ester (762 mg, 77%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:41])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([S:28]([CH2:31][CH3:32])(=[O:30])=[O:29])[CH:25]=[C:24](Br)[CH:23]=2)[C:10]=1[CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH3:2].[C:42](=[O:45])([O-])[O-:43].[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([O:3][C:4](=[O:41])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([S:28]([CH2:31][CH3:32])(=[O:30])=[O:29])[CH:25]=[C:24]([C:9]3[CH:14]=[CH:13][C:12]4[O:43][CH2:42][O:45][C:11]=4[CH:10]=3)[CH:23]=2)[C:10]=1[CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(S(=O)(=O)CC)c2)c1CCC(=O)OCC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cs+]
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(-c3ccc4c(c3)OCO4)cc(S(=O)(=O)CC)c2)c1CCC(=O)OCC
Yield: 196.3 %

Procedure:
A similar procedure as described in Example 41, step 1 was used, starting from 4-[3-[6-(3-bromo-5-ethanesulfonyl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (200 mg, 0.31 mmol), 3,4-(methylenedioxyphenyl)boronic acid (101 mg, 0.62 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (37 mg, 0.05 mmol), and cesium carbonate (199 mg, 0.62 mmol) to afford 4-[3-[6-(3-benzo[1,3]dioxol-5-yl-5-ethanesulfonyl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (212 mg, 99%) as a colorless viscous oil: ES(+)-HRMS m/e calcd for C38H48O10S (M+Na)+ 719.2860, found 719.2865.