Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6](Br)[CH:7]=[C:8]2[C:12]=1[NH:11][N:10]=[C:9]2[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:3].[OH:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.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>[NH2:1][C:2]([C:4]1[CH:5]=[C:6]([C:32]2[CH:33]=[CH:34][C:29]([CH2:28][OH:27])=[CH:30][CH:31]=2)[CH:7]=[C:8]2[C:12]=1[NH:11][N:10]=[C:9]2[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:3]
Reactant: OCc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(-c4ccc(CO)cc4)cc23)CC1

Procedure:
Following the general procedure of Example 66, a mixture of 1,1-dimethylethyl 4-[7-(aminocarbonyl)-5-bromo-1H-indazol-3-yl]-1-piperidinecarboxylate (Intermediate 5) (30 mg, 0.07 mmols), [4-(hydroxymethyl)phenyl]boronic acid (32 mg, 0.21 mmols), cesium carbonate (150 mg), and Pd(PPh3)4 (10 mg) in dioxane/water (3/1, 4 mL) were reacted to give the title compound.
Reaction SMILES: [CH3:1][C@:2]12[CH2:10][CH2:9][C@@H:8]3[C:11]4[CH:12]=[CH:13][C:14]([OH:19])=[CH:15][C:16]=4[CH2:17][CH2:18][C@H:7]3[C@@H:6]1[CH2:5][CH2:4][C@H:3]2[OH:20].C(#N)C.C([O-])([O-])=O.[Na+].[Na+].[NH2:30][S:31](Cl)(=[O:33])=[O:32]>Cl>[S:31]([O:19][C:14]1[CH:13]=[CH:12][C:11]2[C@H:8]3[CH2:9][CH2:10][C@@:2]4([CH3:1])[C@H:6]([C@@H:7]3[CH2:18][CH2:17][C:16]=2[CH:15]=1)[CH2:5][CH2:4][C@H:3]4[O:20][S:31](=[O:33])(=[O:32])[NH2:30])(=[O:33])(=[O:32])[NH2:30]
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC[C@H]2O
Reactant: NS(=O)(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: C[C@]12CC[C@@H]3c4ccc(OS(N)(=O)=O)cc4CC[C@H]3[C@@H]1CC[C@H]2OS(N)(=O)=O
Reaction time: 9 h
Yield: 17.5 %

Procedure:
52 mg (0.19 mM) of 13β-methyl-1,3,5(10)-gonatrien-3,17α-diol are dissolved 10 ml acetonitrile accompanied by heat and 500 mg of (anhydrous) Na2CO3 are added. After the solution is cooled, 30 mg (0.26 mM) of H2NSO2Cl are added and the solution is stirred vigorously. At one-hour intervals, 9 portions of H2NSO2Cl are added for every 10 mg. After 9 hours, the solution is worked up by stirring in diluted hydrochloric acid solution and the steroid is extracted with ether. The residue remaining after the concentration of the extract is absorbed in 4 ml of an acetonitrile/ethanol mixture (3:1) and separated by preparative HPLC (ET 125/8/4 Nucleosil 120-5C18 Macherey-Nagel, RT7.0) using acetonitrile as eluent. After concentration of the fraction with the Rt=7.0 (Rt=0.2; gel benzene; acetone=4:1) or Rt=8.1 (Rf=0.22 gel, benzene/acetone 4:1), 28.9 mg of the 3,17α-disulfamate (35.4%) and 9.8 mg (14.6%) of the 3 monosulfamate are isolated in the form of white powder.
Reaction SMILES: C(OC([CH2:6][O:7][CH2:8][C@@H:9]([NH:17][C:18](=[O:24])OC(C)(C)C)[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)=O)C.FC(F)(F)C(O)=O>ClCCl>[F:16][C:12]1[CH:11]=[C:10]([C@@H:9]2[NH:17][C:18](=[O:24])[CH2:6][O:7][CH2:8]2)[CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)COC[C@@H](NC(=O)OC(C)(C)C)c1cccc(F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1COC[C@H](c2cccc(F)c2)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.8 %

Procedure:
In a 10 mL round bottom flask was added tert-butyl (S)-2-((ethoxycarbonyl)methoxy)-1-(3-fluorophenyl)ethylcarbamate (69 mg, 0.2 mmol), dichloromethane (1.5 mL), and trifluoroacetic acid (0.5 mL). The solution was stirred at room temperature overnight then concentrated to dryness. The residue was then dissolved in tetrahydrofuran (2 mL) and subsequently treated with DIEA (0.5 mL) and potassium carbonate (excess) and heated 50° C. for 1 h. Upon cooling to room temperature, the reaction solution was diluted with water (3 mL) and extracted with ethyl acetate. The combined organics were dried over magnesium sulfate, filtered and concentrated. Purification on silica gel (40% ethyl acetate/hexanes) gave (S)-5-(3-fluorophenyl)morpholin-3-one (37 mg, 95%) as a colorless oil. HPLC-MS calculated for C10H10FNO2 (M+H+) 196.2, found 196.1.
Reaction SMILES: [F:1][C:2]1([F:11])[CH2:7][CH2:6][CH:5]([C:8](O)=[O:9])[CH2:4][CH2:3]1.C[CH2:13][N:14](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.CNOC>C(Cl)Cl.O>[F:1][C:2]1([F:11])[CH2:7][CH2:6][CH:5]([C:8]([NH:14][CH3:13])=[O:9])[CH2:4][CH2:3]1
Reactant: O=C(O)C1CCC(F)(F)CC1
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNOC
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CNC(=O)C1CCC(F)(F)CC1
Reaction time: 0.5 h
Yield: 85.1 %

Procedure:
To a solution of 4,4-difluorocyclohexanecarboxylic acid (5 g, 30.49 mmol) in DCM (40 mL) were added DIPEA (11.8 g, 91.46 mmol) and HATU (17.38 g, 45.73 mmol). The mixture was stirred for 0.5 hr. The N,O-dimethylhydroxylamine hydrochloride (3.56 g, 36.58 mmol) was added to the mixture. The mixture was stirred at 28° C. for 12 hr. Water (20 mL) was added and the mixture was extracted by CH2Cl2 (30 mL*3). The organic layer was washed with brine and dried over sodium sulfate. The organic layer was concentrated to give the crude product, the crude product was purified by column chromatography on silica gel eluted with (petroleum ether/ethyl acetate 10:1→2:1) to gave 4,4-difluoro-N-methyl cyclohexanecarboxamide (4.6 g, 73.36%) for next step.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH2:18][CH2:17]1.[Cl:27][C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[C:30]([F:43])[C:29]=1[OH:44]>>[Cl:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH2:18][CH2:17]2)[CH:31]=[C:30]([F:43])[C:29]=1[OH:44]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](CCN(C)C)CC1
Product: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](CCN(C)C)CC1

Procedure:
Following general procedure M, 1-(6-bromo-4-((trans-4-(2-(dimethylamino)ethyl)cyclohexyl)amino)quinolin-3-yl)ethanone (63 mg, 0.15 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (61 mg, 0.225 mmol) to afford the desired product (37 mg, 51%) as a yellow solid. 1H NMR (500 MHz, DMSO) δ 10.65 (d, J=7.9 Hz, 1H), 8.93 (s, 1H), 8.31 (d, J=2.1 Hz, 1H), 8.03 (dd, J=8.7, 2.1 Hz, 1H), 7.85 (d, J=8.7 Hz, 1H), 7.61-7.54 (m, 2H), 4.20-4.11 (m, 1H), 2.66 (s, 3H), 2.28 (t, J=7.3 Hz, 2H), 2.22-2.15 (m, 2H), 2.15 (s, 6H), 1.84 (d, J=12.5 Hz, 2H), 1.51-1.31 (m, 5H), 1.21-1.09 (m, 2H). ESI MS m/z 484 [C27H31ClFN3O2+H]+; HPLC>99% (AUC), tR=11.13 min.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:16])[C:7]([C:13]([OH:15])=[O:14])=[CH:8][N:9]2[CH3:12])=[CH:4][CH:3]=1.O=S(Cl)Cl.[CH3:21][CH2:22]O>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:16])[C:7]([C:13]([O:15][CH2:21][CH3:22])=[O:14])=[CH:8][N:9]2[CH3:12])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)O)c(=O)c2ccc(Cl)cc21
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cn(C)c2cc(Cl)ccc2c1=O

Procedure:
A solution of 7-chloro-1-methyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (0.50 g, 2.10 mmol) and SOCl2 (2.0 mL) in EtOH (15.0 mL) was heated to 78° C. for 6 h. After the completion of reaction (TLC monitoring), EtOH was distilled off, added water and extracted with EtOAc (3×70 mL). The combined organics was washed with saturated NaHCO3 solution, dried (Na2SO4), filtered and concentrated to obtain the desired product in quantitative yields.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.[OH-].[Na+].Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].C1(C)C=CC=CC=1.Cl>O>[C:13]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1)([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]
Reactant: O=C(O)C1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 64 %

Procedure:
To a stirred solution of piperidine-4-carboxylic acid (5.0 g, 38.7 mmol) and NaOH (1.86 g, 46.5 mmol) in H2O (15 ml) was added dropwise a 50% solution of benzyl chloroformate in toluene (13.6 mL, 40.6 mmol) over a period of half an hour at 0° C. The reaction mixture was stirred at room temperature for 6 hours. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was acidified with dil. HCl (pH 3) and extracted with ethyl acetate (3×100 ml). The combined organic phases were dried over sodium sulfate and concentrated. The crude product was purified by flash column chromatography (silica gel, elution with 30% ethyl acetate/n-hexanes) to afford piperidine-1,4-dicarboxylic acid monobenzyl ester (VI) (6.5 g, 64%) as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]([C:13]1[O:14][C:15]2[C:20]([C:21](=[O:29])[C:22]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:19][C:18](Br)=[CH:17][CH:16]=2)[CH3:12].[H][H].ClCCl>CO.[Pd]>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]([C:13]1[O:14][C:15]2[C:20]([C:21](=[O:29])[C:22]=1[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:12]
Reactant: CC(c1oc2ccc(Br)cc2c(=O)c1-c1ccccc1)n1cnc2c(N)ncnc21
Reactant: [H][H]
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: CC(c1oc2ccccc2c(=O)c1-c1ccccc1)n1cnc2c(N)ncnc21
Yield: 37.7 %

Procedure:
To a solution of example 21 (0.080 g, 0.173 mmoles) in methanol (10 ml), palladium on carbon (10% 16 mg) was added and the solution was hydrogenated at RT under 5 kg/cm2 pressure of hydrogen for 24 h. The solution was filtered through celite and concentrated. The crude product was purified by column chromatography with methanol: dichloromethane to afford the title compound as light yellow solid (0.025 g, 38% yield). MP: 254-257° C. 1H-NMR (δ ppm, DMSO-D6, 400 MHz): δ 8.46(s, 1H), 8.03(s, 1H), 8.01(d, J=1.6 Hz, 1H), 7.83(dt, J=7.3,1.7 Hz, 1H), 7.65 (d, J=8.2 Hz, 1H), 7.50 (m, 4H), 7.37(dd, J=8.1,1.7 Hz, 1H),7.22(s, 2H), 5.67(q, J=7.3 Hz, 1H),1.89(d, J=7.2 Hz, 3H).). Mass: 384.19(M+1).
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].N[C@@H]1CCCC[C@H]1N.I[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27].[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][NH:39][C:38](=[O:42])[CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30]>[Cu](I)I>[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][N:39]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:38](=[O:42])[CH2:37]1)=[O:35])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)CCc1ccccc1I
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Product: CC(C)CCc1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1=O
Temperature: 120 °C
Reaction time: 8 h
Yield: 29.2 %

Procedure:
Charge in a pressure tube copper iodide (16 mg, 0.08 mmol), potassium phosphate (717 g, 3.4 mmol), trans-1,2-diaminocyclohexane (0.020 ml, 0.17 mmol), 1-Iodo-2-(3-methyl-butyl)-benzene (462 mg, 1.7 mmol) and 3-oxo-piperazine-1-carboxylic acid tert-butyl ester (405 g, 2.02 mmol). Purge with nitrogen and add 2 ml of dry 1,4-dioxane. Cap the tube and stir at 120° C. overnight. Filter through celite eluting with EtOAc and concentrate. Purify in a silica gel cartridge (10 g) eluting with hexane followed by EtOAc/hexane 1:1 to give the title compound as a yellow solid (172 mg, 29%).
Reaction SMILES: [CH:1]1([C:4]([N:6]2[C:15]3[C:10](=[C:11]([OH:21])[C:12]([N:16]4[N:20]=[CH:19][CH:18]=[N:17]4)=[CH:13][CH:14]=3)[CH2:9][CH2:8][C@@H:7]2[CH3:22])=[O:5])[CH2:3][CH2:2]1.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.N1C=CC=CC=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[CH:1]1([C:4]([N:6]2[C:15]3[C:10](=[C:11]([O:21][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:12]([N:16]4[N:17]=[CH:18][CH:19]=[N:20]4)=[CH:13][CH:14]=3)[CH2:9][CH2:8][C@@H:7]2[CH3:22])=[O:5])[CH2:2][CH2:3]1
Reactant: C[C@H]1CCc2c(ccc(-n3nccn3)c2O)N1C(=O)C1CC1
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@H]1CCc2c(ccc(-n3nccn3)c2Oc2ccccc2)N1C(=O)C1CC1
Temperature: 40 °C
Reaction time: 18 h

Procedure:
A 50-mL round-bottom flask equipped with balloon of air was charged with (S)-cyclopropyl(5-hydroxy-2-methyl-6-(2H-1,2,3-triazol-2-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone (0.150 g, 0.50 mmol), phenylboronic acid (0.185 g, 1.52 mmol), copper (II) acetate (0.228 g, 1.26 mmol), pyridine (0.12 mL, 1.49 mmol), triethyl amine (0.10 mL, 0.75 mmol), and dichloromethane (4 mL), and the resulting mixture stirred for 18 h at 40° C. The reaction mixture was cooled to room temperature and filtered, and the filtrate was concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 5% dichloromethane/methanol). The product was further purified by preparative-HPLC with the following conditions (Waters I): Column, SunFire Prep C18, 5 um, 19×100 mm; Mobile phase, water (0.05% ammonium bicarbonate) and acetonitrile (55% to 75% acetonitrile in 7 min, flow rate: 20 mL/min); Detector, UV 220&254 nm. This afforded (S)-cyclopropyl(2-methyl-5-phenoxy-6-(2H-1,2,3-triazol-2-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone (0.025 g, 14%) as a white solid. 1H NMR (300 MHz, CD3OD) δ ppm 0.76-0.84 (m, 1H), 0.91-1.06 (m, 2H), 1.15-1.23 (m, 4H), 1.43-1.52 (m, 1H), 1.94-2.04 (m, 1H), 2.21-2.49 (m, 2H), 2.75-2.88 (m, 1H), 4.75-4.83 (m, 1H), 6.65-6.74 (m, 2H), 6.92 (d, J=7.20 Hz, 1H), 7.17 (t, J=7.50 Hz, 2H), 7.52 (d, J=8.70 Hz, 1H), 7.62 (d, J=8.70 Hz, 1H), 7.75 (s, 2H). MS (ESI, pos. ion) m/z 375 [M+H]+.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15]O)=[N:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][CH:18]1[CH2:22][CH2:21][NH:20][C:19]1=[O:23]>>[CH3:17][CH:18]1[CH2:22][CH2:21][N:20]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([C:8]#[C:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:14][N:13]=2)[C:19]1=[O:23]
Reactant: OCc1ccc(C#Cc2ccccc2)cn1
Reactant: CC1CCNC1=O
Product: CC1CCN(Cc2ccc(C#Cc3ccccc3)cn2)C1=O

Procedure:
The title compound, light yellow oil, MS: m/e=291.1 (M+H+), can be prepared in accordance with the general method of example 31, step 2 from (5-phenylethynyl-pyridin-2-yl)-methanol (example 31, step 1) and rac-3-methyl-pyrrolidin-2-one.
Reaction SMILES: [CH2:1]([C:4]([NH:6][C:7]1[CH:15]=[C:14]2[C:10]([C:11]([C:18]([O:20][CH2:21][CH3:22])=[O:19])([CH3:17])[C:12](=[O:16])[NH:13]2)=[CH:9][C:8]=1[N+:23]([O-])=O)=O)[CH2:2][CH3:3].[H][H]>[Pd].C(O)C>[CH2:1]([C:4]1[NH:6][C:7]2[CH:15]=[C:14]3[NH:13][C:12](=[O:16])[C:11]([C:18]([O:20][CH2:21][CH3:22])=[O:19])([CH3:17])[C:10]3=[CH:9][C:8]=2[N:23]=1)[CH2:2][CH3:3]
Reactant: [H][H]
Reactant: CCCC(=O)Nc1cc2c(cc1[N+](=O)[O-])C(C)(C(=O)OCC)C(=O)N2
Agent: [Pd]
Solvent: CCO
Product: CCCc1nc2cc3c(cc2[nH]1)NC(=O)C3(C)C(=O)OCC
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Analogously to Example 5, 1.40 g. (4.0 mmole) 6-propylcarbonylamino-5-nitro-3-ethoxycarbonyl-3-methylindolin-2-one is suspended in 140 ml. ethanol and hydrogenated in the presence of 0.1 g. 10% palladium on charcoal at normal pressure and ambient temperature. After 270 ml. of hydrogen have been taken up, the catalyst is filtered off with suction and the filtrate is evaporated to dryness. The residue is stirred for 1 hour at 60° C. in 10 ml. glacial acetic acid, the glacial acetic acid is distilled off and the residue is taken up in water and neutralised with 2N aqueous sodium hydroxide solution. The mixture is shaken out three times with dichloromethane and the combined dichloromethane phases are dried over anhydrous sodium sulphate, filtered and the filtrate evaporated to dryness. After crystallisation of the residue from isopropanol, there is obtained 0.4 g. (33% of theory) of the title compound; m.p. 258°-261° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].CCN(C(C)C)C(C)C.Cl[C:22]([O:24][CH3:25])=[O:23]>C1COCC1>[F:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH:4][C:22](=[O:23])[O:24][CH3:25]
Reactant: COC(=O)Cl
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)Nc1cc([N+](=O)[O-])ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
A solution of 2-fluoro-5-nitroaniline (500 mg, 3.20 mmol) in THF (20 mL) was treated with DIEA (0.84 mL, 4.8 mmol) followed by methyl chloroformate (0.25 mL, 3.20 mmol). The reaction mixture was stirred at room temperature overnight and concentrated to dryness. The crude product was dissolved in a small amount of DCM and purified by flash chromatography (SiO2, 20% ethyl acetate/hexanes to 50% ethyl acetate/hexanes, 40 g column, 30 min. gradient) to afford Intermediate 59A (450 mg, 65.6%). HPLC: Rt=2.868 min. (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min. gradient, monitored at 220 nm). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.94 (1H, s), 8.72 (1H, dd, J=6.80, 2.77 Hz), 7.87-8.09 (1H, m), 7.52 (1H, t), 3.72 (3H, s).
Reaction SMILES: [Br-].[O:2]=[C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[O:4]1.O1CCCC1.CC(C)([O-])C.[K+].[Cl:42][C:43]1[CH:44]=[CH:45][C:46]([N+:51]([O-:53])=[O:52])=[C:47]([CH:50]=1)[CH:48]=O>O>[Cl:42][C:43]1[CH:44]=[CH:45][C:46]([N+:51]([O-:53])=[O:52])=[C:47]([CH:50]=1)[CH:48]=[C:5]1[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:3](=[O:2])[O:4]1
Reactant: O=Cc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: O=C1OC([P+](c2ccccc2)(c2ccccc2)c2ccccc2)c2ccccc21
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1OC(=Cc2cc(Cl)ccc2[N+](=O)[O-])c2ccccc21
Reaction time: 0.08 h
Yield: 49.7 %

Procedure:
To a mixture of (3-oxo-1,3-dihydro-2-benzofuran-1-yl)(triphenyl) phosphonium bromide (5.1 g) and tetrahydrofuran (50 mL) were added potassium tert-butoxide (1.3 g) and 5-chloro-2-nitro benzoaldehyde (1.0 g) at room temperature under an argon atmosphere, followed by stirring for 5 minutes. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 3-(5-chloro-2-nitrobenzylidene)-2-benzofuran-1(3H)-one (808 mg).
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=O.[C:11]([C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][N:15]=1)(=O)[CH3:12].CC([O-])(C)C.[K+]>C1COCC1>[Cl:10][C:6]1[CH:7]=[CH:8][N:9]=[C:2]2[C:3]=1[CH:4]=[CH:12][C:11]([C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][N:15]=1)=[N:1]2
Reactant: Nc1nccc(Cl)c1C=O
Reactant: CC(=O)c1ncccc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Clc1cccnc1-c1ccc2c(Cl)ccnc2n1
Temperature: -20 °C
Reaction time: 2 h

Procedure:
Dissolve 2-amino-4-chloronicotinaldehyde (312 mg, 2.0 mmol) and 2-acetyl-3-chloropyridine (310 mg, 2.0 mmol) in anhydrous THF (5.0 mL) and cool it to −20° C. under N2 atmosphere. Add in portion t-BuOK (448 mg, 4.0 mmol) to the reaction mixture and stir the mixture at 10° C. for 2 hours. Concentrate the reaction mixture under vacuum, dilute the residue with water (10 mL), filter the solid, wash the solid with water and dry under high vacuum to afford the title product as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:38]=[CH:37][C:7]([C:8]([O:10][C@@:11]([C:18]2[N:19]=[N:20][N:21]([CH2:23][C:24]3[CH:33]=[C:32]4[C:27]([C:28](Cl)=[CH:29][C:30]([C:34]#[N:35])=[N:31]4)=[CH:26][CH:25]=3)[CH:22]=2)([C:14]([F:17])([F:16])[F:15])[CH2:12][CH3:13])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C([Sn](CCCC)(CCCC)[C:44]([O:46][CH2:47][CH3:48])=[CH2:45])CCC.[Cl-].[Li+]>O1CCOCC1.C(OCC)(=O)C.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>[N+:1]([C:4]1[CH:38]=[CH:37][C:7]([C:8]([O:10][C@@:11]([C:18]2[N:19]=[N:20][N:21]([CH2:23][C:24]3[CH:33]=[C:32]4[C:27]([C:28]([C:44]([O:46][CH2:47][CH3:48])=[CH2:45])=[CH:29][C:30]([C:34]#[N:35])=[N:31]4)=[CH:26][CH:25]=3)[CH:22]=2)([C:14]([F:17])([F:16])[F:15])[CH2:12][CH3:13])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CC[C@](OC(=O)c1ccc([N+](=O)[O-])cc1)(c1cn(Cc2ccc3c(Cl)cc(C#N)nc3c2)nn1)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C=C(OCC)c1cc(C#N)nc2cc(Cn3cc([C@](CC)(OC(=O)c4ccc([N+](=O)[O-])cc4)C(F)(F)F)nn3)ccc12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-1-{1-[(4-chloro-2-cyanoquinolin-7-yl)methyl]-1H-1,2,3-triazol-4-yl}-1-(trifluoromethyl)propyl 4-nitrobenzoate (900 mg, 1.65 mmol), tributyl (1-ethoxyvinyl)tin (0.6 ml, 1.73 mmol) in dioxane (6 mL) was added lithium chloride (210 mg, 4.96 mmol) and Pd(PPh3)4 (95 mg, 0.083 mmol). The reaction mixture was stirred at 100° C. overnight then cooled to room temperature. The solution was then diluted with ethyl acetate, washed with sat. sol. of ammonium chloride, brine and dried over magnesium sulfate. The crude material was purified on silica gel (eluting solvent: 3% acetone in CH2Cl2) to afford the title compound. 1H NMR (400 MHz, acetone-d6): δ 8.52 (s, 1H), 8.42 (d, 2H), 8.39 (d, 1H), 8.30 (d, 2H), 8.05 (d, 1H), 7.95 (s, 1H), 7.75 (dd, 1H), 6.02 (s, 2H), 4.75 (dd, 2H), 4.12 (q, 2H), 3.05 (m, 1H), 2.85 (m, 1H), 1.40 (t, 3H), 1.15 (t, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][N:4]=[C:3]1SC.[CH3:9][NH:10][NH2:11]>>[CH3:9][N:10]([C:3]1[N:2]([CH3:1])[CH2:6][CH2:5][N:4]=1)[NH2:11]
Reactant: CSC1=NCCN1C
Reactant: CNN
Product: CN(N)C1=NCCN1C

Procedure:
N-Methyl-N-(1-methyl-4,5-dihydro-1 H-imidazol-2-yl)-hydrazine is prepared according to Step B of Example 25 using 1-methyl-2-methylsulfanyl-4,5-dihydro-1 H-imidazole and methyl hydrazine.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)=O.[Br:16][C:17]1[CH:24]=[C:21]([CH:22]=O)[C:20]([OH:25])=[CH:19][CH:18]=1>CC(C)=O>[Br:16][C:17]1[CH:18]=[CH:19][C:20]2[O:25][C:8]([CH2:9][C:11]3[S:12][CH:13]=[CH:14][CH:15]=3)=[CH:22][C:21]=2[CH:24]=1
Reactant: O=Cc1cc(Br)ccc1O
Reactant: O=C(CBr)c1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Brc1ccc2oc(Cc3cccs3)cc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Potassium carbonate (12.0 g, 0.087 mol) and subsequently 2-bromo-1-(thiophen-2-yl)ethanone (7.0 g, 0.034 mol; prepared as described in J. Med. Chem. 30, 1497 (1987)) were added to a stirred solution of 5-bromosalicylaldehyde (6.9 g, 0.034 mol) in acetone (150 mL). The mixture was stirred at ambient temperature for 30 min at first and then refluxed for 1 h. Solid mass was filtered off, washed with hot acetone (2×50 mL) and the filtrate was evaporated in vacuo. The residue (11.3 g) was crystallized from ethanol (15 mL) giving (5-bromo-benzo[b]furan-2-yl)-(thiophen-2-yl)methane. Yield: 8.0 g (77%). M.p. 84–86° C.