Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][N:6]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].C([N-]C(C)C)(C)C.[Li+].[C:30]1([CH2:36][CH:37]=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:21])[CH:5]([N:6]([CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:37]([OH:38])[CH2:36][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:2]
Reactant: O=CCc1ccccc1
Reactant: CCOC(=O)CN(Cc1ccccc1)Cc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(C(O)Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 20 g (70.6 mmol) dibenzylamino-acetic acid ethyl ester in 240 ml tetrahydrofuran was stirred at −78° C. with 38.8 ml (77.6 mmol) lithium diisopropylamide (2M in heptane) for 30 minutes. 17.4 ml (77.6 mmol) phenylacetaldehyde were added and stirring was continued overnight. The mixture was allowed to warm to room temperature, water was added and most of the organic solvent was removed by distillation. About 20 g citric acid were dissolved in the aqueous residue. Extraction with ethylacetate and chromatography on silicagel with ethylacetate/heptane 1/5 yielded as first eluting fraction 5.4 g (19%) racemic (2S,3R and 2R,3S)-2-dibenzylamino-3-hydroxy-4-phenyl-butyric acid ethyl ester, MS m/e (%): 404.3 (M+H+, 100) and as second eluting fraction 4.1 g (15%) racemic (2R,3R and 2S,3S)-2-dibenzylamino-3-hydroxy-4-phenyl-butyric acid ethyl ester, MS m/e (%): 404.3 (M+H+, 100).
Reaction SMILES: C([O:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1)(=O)C1C=CC=CC=1.C[O-].[Na+].O>CO>[OH:9][N:10]1[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCN(OC(=O)c2ccccc2)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(O)CC1
Reaction time: 2 h

Procedure:
A solution of 3.8 g (0.012 mole) 1-benzoyloxy-4-[1,1-dimethylethoxycarbonyl]piperazine in 25 ml methanol-ether (1:1) was added dropwise to a stirred suspension of 0.95 g (0.017 mole) sodium methoxide in 25 ml methanol at room temperature. The mixture was stirred for 2 hours, treated with 50 ml H2O, and evaporated in vacuo. The residue was thoroughly extracted with ether and the extracts were dried (MgSO4), filtered, diluted with hexane, and evaporated to a lower volume to yield 1.9 white, crystalline solid, m.p. 95°-97° C. Calc. for C9H18N2O3 (202.25): C, 53.45; H, 8.97; N, 13.85; O, 23.73. Found: C, 53.26; H, 8.74; N, 13.98; O, 23.96.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[C:8]([CH3:10])[NH:7][C:6](=[O:11])[C:5]=1[CH2:12][NH:13][C:14]([C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]([CH:25]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH3:26])[C:17]=1[CH3:33])=[O:15].[O:34]1[CH2:36][CH2:35]1>C(Cl)Cl>[OH:34][CH2:35][CH2:36][N:30]1[CH2:29][CH2:28][CH:27]([CH:25]([N:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:16]([C:14]([NH:13][CH2:12][C:5]3[C:6](=[O:11])[NH:7][C:8]([CH3:10])=[CH:9][C:4]=3[O:3][CH3:2])=[O:15])=[C:17]2[CH3:33])[CH3:26])[CH2:32][CH2:31]1
Reactant: C1CO1
Reactant: COc1cc(C)[nH]c(=O)c1CNC(=O)c1c(C)n(C(C)C2CCNCC2)c2ccccc12
Agent: Cl
Solvent: ClCCl
Product: COc1cc(C)[nH]c(=O)c1CNC(=O)c1c(C)n(C(C)C2CCN(CCO)CC2)c2ccccc12
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a sealed tube charged with a magnetic stir bar was added (R or S)-N-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(piperidin-4-yl)ethyl)-1H-indole-3-carboxamide (Compound 326) (0.1 g, 0.229 mmol) was added DCM (3 mL) and the reaction cooled to 0° C. To the cooled reaction mixture was added oxirane which was condensed into the reaction vial (˜1 mL). The reaction was allowed to stir to rt over 4 h and was then conc. in vacuo to afford the crude material which was purified via silica gel chromatography (12 g) using ethyl acetate/MeOH (4:1) as eluent to afford the title compound as a white solid (50 mg). LCMS 481 (M+1)+; 1H NMR (DMSO-d6, 400 MHz) δ) δ 11.58 (s, 1 H), 7.77-7.65 (m, 2 H), 7.59 (d, J=7.8 Hz, 1 H), 7.11-6.99 (m, 2 H), 6.14 (s, 1 H), 4.54-4.44 (m, 1 H), 4.31 (d, J=5.1 Hz, 3 H), 4.13 (dd, J=7.1, 10.3 Hz, 1 H), 3.83 (s, 3H), 3.42 (q, J=6.0 Hz, 2 H), 2.93 (br. s., 1 H), 2.71-2.56 (m, 4 H), 2.31 (br. s., 2 H), 2.19 (s, 3 H), 2.03-1.83 (m, 2 H), 1.64 (br. s., 1 H), 1.53 (d, J=6.9 Hz, 3 H), 1.32 (d, J=11.1 Hz, 1 H), 1.02 (d, J=10.3 Hz, 1 H), 0.65 (d, J=11.8 Hz, 1 H).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:10]=[CH:9][N:8]=[N:7][CH:6]=1)[NH2:4].[F:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[F:21])[C:15](Cl)=O.N>>[F:11][C:12]1[CH:13]=[C:14]([C:15]2[O:1][N:2]=[C:3]([C:5]3[CH:10]=[CH:9][N:8]=[N:7][CH:6]=3)[N:4]=2)[CH:18]=[CH:19][C:20]=1[F:21]
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Reactant: NC(=NO)c1ccnnc1
Agent: N
Product: Fc1ccc(-c2nc(-c3ccnnc3)no2)cc1F

Procedure:
The titled compound was prepared according to the procedure of Method D using the product of Example 83D and 3,4-difluorobenzoyl chloride (Aldrich). 1H NMR (300 MHz, DMSO-d6) δ 7.80 (dt, J=10.5, 8.3 Hz, 1 H), 8.08-8.19 (m, 1 H), 8.29 (dd, J=5.4, 2.4 Hz, 1 H), 8.31-8.38 (m, 1 H), 9.55 (dd, J=5.4, 1.4 Hz, 1 H), 9.82 (dd, J=2.2, 1.2 Hz, 1 H) ppm; MS (DCI/NH3) m/z 261 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[C:21]1([NH:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:30][CH:29]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(OCC)(=O)C>CCCCCC>[C:21]1([N:27]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[CH:30][CH:29]=2)[C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:15]4[C:16]([C:13]=3[CH:14]=2)=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: c1ccc(Nc2ccc(-c3ccccc3)cc2)cc1
Reactant: Brc1ccc2c(c1)c1ccccc1n2-c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: c1ccc(-c2ccc(N(c3ccccc3)c3ccc4c(c3)c3ccccc3n4-c3ccccc3)cc2)cc1

Procedure:
The Rf values of the objective substance, 3-bromo-9-phenyl-9H-carbazole, and N-phenyl-N-(4-phenylphenyl)amine were respectively 0.65, 0.73, and 0.54, which were obtained by silica gel thin layer chromatography (TLC) (with a developing solvent containing ethyl acetate and hexane in a 1:5 ratio).
Reaction SMILES: [N:1]([CH:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[NH:6][C:5]1=[O:15])=[N+:2]=[N-:3].Cl[C:17](=[CH2:20])[C:18]#[N:19]>O>[C:18]([C:17]1[N:3]=[N:2][N:1]([CH:4]2[CH2:10][CH2:9][C:8]3[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=3[NH:6][C:5]2=[O:15])[CH:20]=1)#[N:19]
Reactant: C=C(Cl)C#N
Reactant: [N-]=[N+]=NC1CCc2ccccc2NC1=O
Solvent: O
Product: N#Cc1cn(C2CCc3ccccc3NC2=O)nn1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A mixture of 3-azido-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine (1.01 g) and 2-chloroacrylonitrile (0.95 g) in water (5 ml) is stirred at about 80° C. for 18 hours. Excess 2-chloroacrylonitrile is distilled off in vacuo, and the precipitated product is filtered off, washed with water and dried (yield 1.1 g; 87% of theory), m.p. 214-216° C. (recrystallization from ethyl acetate/toluene).
Reaction SMILES: O[C@@:2]([C@@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([C:21]([NH:23][C@@H:24]([CH2:37][CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[CH2:25][N:26]([CH3:36])[C:27](=[O:35])[O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])=[O:22])[CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH3:8].C(O)C>[Ni].O>[CH3:8][O:7][CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]([C@@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([C:21]([NH:23][C@@H:24]([CH2:37][CH:38]2[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]2)[CH2:25][N:26]([CH3:36])[C:27](=[O:35])[O:28][CH2:29][CH2:30][Si:31]([CH3:32])([CH3:33])[CH3:34])=[O:22])[CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COCCCC[C@@](O)(c1ccccc1)[C@@H]1CCCN(C(=O)N[C@@H](CC2CCCCC2)CN(C)C(=O)OCC[Si](C)(C)C)C1
Agent: [Ni]
Solvent: CCO
Solvent: O
Product: COCCCC[C@@H](c1ccccc1)[C@@H]1CCCN(C(=O)N[C@@H](CC2CCCCC2)CN(C)C(=O)OCC[Si](C)(C)C)C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
A 100-mL round bottom flask was charged with of 2-(trimethylsilyl)ethyl (S)-2-((R)-3-((S)-1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carboxamido)-3-cyclohexylpropyl-methylcarbamate (0.9806 g, 1.59 mol, 1.0 equiv), absolute ethanol (6 mL), and Raney nickel (2.15 g, ca. 20 equiv) (Aldrich Raney® 2800 nickel, slurry in water, washed with distilled water prior to use until the washings were neutral, then washed three times with absolute ethanol and stored under ethanol until needed.) The reaction mixture was heated to 100° C. for 3 h and then stirred at rt overnight. LC-MS showed about 60% conversion. The ethanolic solution was decanted from the catalyst. The catalyst was washed with absolute ethanol three times, the solvent being removed by decanting in each case. The organic solutions were combined and concentrated in vacuo. The residue was purified by reversed-phase HPLC (Phenomenex® Luna 5μ C18(2) 100 A, 250×21.20 mm, 5 micron, 70%→90% CH3CN/H2O, 0.1% CF3COOH over 8 min and then 90% CH3CN/H2O, 0.1% CF3COOH over 16 min, flow rate 25 mL/min) to give of 2-(trimethylsilyl)ethyl (S)-2-((S)-3-((R)-5-methoxy-1-phenylpentyl)-piperidine-1-carboxamido)-3-cyclohexylpropylmethylcarbamate (0.5422 g, 57%). LC-MS (3 min) tR=2.61 min, m/z 624 (M+Na+), 602 (M+H+). 1H NMR (400 MHz, CDCl3) δ 8.28 (br s, 2H), 7.29-7.25 (m, 2H), 7.21-7.17 (m, 1H), 7.09-7.06 (m, 2H), 5.46 (m, 1H), 4.21-4.06 (m, 4H), 3.68-3.59 (m, 2H), 3.33-3.27 (m, 2H), 3.28 (s, 3H), 2.92 (s, 3H), 2.68-2.63 (m, 1H), 2.43-2.29 (m, 2H), 1.80-0.83 (m, 25H), 0.02 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 158.5, 158.0, 142.8, 128.4, 128.2, 126.2, 72.7, 64.3, 58.3, 52.8, 49.4, 49.1, 47.9, 45.1, 41.2, 41.1, 34.7, 34.3, 33.4, 33.3, 32.4, 29.2, 28.7, 26.4, 26.2, 26.1, 25.1, 24.1, 17.7, −1.5.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[CH2:3][CH2:4][CH:5]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[OH:6].O[C:14]1[C:22]2[O:21][CH2:20][O:19][C:18]=2[CH:17]=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:12][N:2]([CH2:3][CH2:4][CH:5]([O:6][C:14]1[C:22]2[O:21][CH2:20][O:19][C:18]=2[CH:17]=[CH:16][CH:15]=1)[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[CH3:1]
Reactant: CN(C)CCC(O)c1cccs1
Reactant: Oc1cccc2c1OCO2
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(C)CCC(Oc1cccc2c1OCO2)c1cccs1
Reaction time: 24 h
Yield: 35 %

Procedure:
3-Dimethylamino-1-(thiophen-2-yl)-1-propanol (1.85 g, 0.01 mol), 4-hydroxyl-benzo[1,3]dioxolane (1.38 g, 0.01 mol) and triphenylphosphine (3.93 g, 0.015 mol) were dissolved in 80 ml of anhydrous tetrahydrofuran. The mixture was slowly added dropwise with the solution of diethyl azodicarboxylate (2.61 g, 0.015 mol) in 20 ml anhydrous tetrahydrofuran, the reaction temperature was controlled to be lower than −5° C. in an ice-salt bath. After completion of the addition, the ice-salt bath was removed, and the reaction was performed at room temperature for 24 h. After the end of reaction, tetrahydrofuran was distilled out under a reduced pressure, the resultant oily liquid was dissolved in 100 ml of ethyl acetate, washed with diluted sodium hydroxide aqueous solution and saturated sodium chloride aqueous solution separately once, dried over anhydrous sodium sulfate, and separated by silica gel column chromatography to obtain 1.07 g of N,N-dimethyl-3-[(benzo[1,3]dioxolan-4-yl)-oxy]-3-(thiophen-2-yl)-propylamine as a pale yellow oily liquid, which was dissolved in 30 ml of ethyl acetate, added with oxalic acid (0.32 g, 0.035 mol) to generate a pale yellow solid. The mixture was heated to reflux, cooled to room temperature, frozen for 2 h and filtrated. The filter cake was washed with cold ethyl acetate to obtain 1.31 g of the target compound as a pale yellow powdery solid in a yield of 33.2% and a melting point of 85-88° C. MS (m/e): 306.5 (M+1+); 1H-NMR δ (ppm, DMSO-d6): 7.46-7.48 (d, 1H, 5′-H); 7.11-7.12 (d, 1H, 3′-H); 6.95-6.97 (dd, 1H, 4′-H); 6.66-6.70 (t, 1H, 6-H); 6.53-6.59 (dd, 2H, 5,7-H); 5.97-5.98 (d, 2H, 2-H); 5.71-5.75 (t, 1H, CHO); 2.27-2.30 (t, 2H, CH2N); 2.19-2.21 (m, 1H, CH2CH2N); 2.11 (s, 6H, N(CH3)2); 2.06-2.08 (m, 1H, CH2CH2N).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10](=[O:20])[CH2:11][CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.[NH2:23][OH:24].C[O-].[Na+]>CO>[OH:24][NH:23][C:3](=[O:2])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10](=[O:20])[CH2:11]/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NO
Reactant: COC(=O)CCCCCNC(=O)CC=Cc1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C(CCCCCNC(=O)C/C=C/c1ccccc1)NO
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
(Method J7) To a mixture of 6-(4-phenyl-but-3-enoylamino)-hexanoic acid methyl ester (3/57) (100 mg, 0.35 mmol) and hydroxylamine hydrochloride (96 mg, 1.38 mmol) in methanol (1 ml) the 3.43 N solution of sodium methylate (0.61 ml, 2.1 mmol) in methanol was added. The mixture was stirred for 1 hour at room temperature, diluted with saturated NaH2PO4 (10 ml), and extracted with ethyl acetate (2×20 ml). The organic extracts were combined, washed with brine, and dried (Na2SO4). The solvent was evaporated and the residue was crystallized from ethyl acetate to give the title product, yield 66%. M.p. 127-128° C. (from ethyl acetate). 1H NMR (DMSO-d6, HMDSO), δ: 1.07-1.68 (m, 6H); 1.78-2.06 (m, 2H); 2.03 (t, 2H, J=6.6 Hz); 2.85-3.18 (m, 4H); 6.30 (dd, 1H, J=16.1 and 6.0 Hz); 6.48 (d, 1H, J=16.1 Hz); 7.14-7.53 (m, 5H); 7.85 (t, 1H, J=5.8 Hz); 8.63 (br s, 1H); 10.32 (br s, 1H). HPLC analysis on Zorbax SB-C18 column: impurities 2% (column size 4.6×150 mm; mobile phase 0.1% H3PO4, gradient from 50:50 to 90:10; detector UV 254 nm; sample concentration 0.75 mg/ml, flow rate 1.5 ml/min). Anal. Calcd for C16H22N2O3: C, 66.19; H, 7.64; N, 9.65. Found: C, 66.19; H, 7.69; N, 9.67.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:18])[NH:5][C:6](=[O:17])[N:7]([CH:16]=1)[C@@H:8]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[CH2:9]1)[CH3:2].[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>N1C=CC=CC=1>[CH2:1]([C:3]1[C:4](=[O:18])[NH:5][C:6](=[O:17])[N:7]([CH:16]=1)[C@@H:8]1[O:15][C@H:12]([CH2:13][O:14][S:25]([C:22]2[CH:23]=[CH:24][C:19]([CH3:29])=[CH:20][CH:21]=2)(=[O:27])=[O:26])[C@@H:10]([OH:11])[CH2:9]1)[CH3:2]
Reactant: CCc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CCc1cn([C@H]2C[C@H](O)[C@@H](COS(=O)(=O)c3ccc(C)cc3)O2)c(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 42 h
Yield: 39.4 %

Procedure:
To an ice-cooled solution of 5-ethyl-2'-deoxyuridine (1.0 g, 3.9 mmole) in dry pyridine (10 ml), is added p-toluenesulfonyl chloride (0.83 g, 4.4 mmole) and the reaction is kept at 0° C. for 42 hours. Tlc indicates that the starting material remains. Additional p-toluenesulfonyl chloride (180 mg) is added, and the solution is stirred at ca. 0° C. for 5 hours. The mixture is then evacuated in vacuo to a syrup, which is chromatographed on a short vacuum silica gel column using chloroform-methanol (15:1) to yield a white amorphous powder (630 mg, 39%), m.p. 173°-175° C.
Reaction SMILES: CC(C)([O-])C.[K+].C([Li])CCC.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20].[C:21](=[O:23])=[O:22]>O.O1CCCC1>[F:12][C:13]1[C:14]([O:19][CH3:20])=[CH:15][CH:16]=[CH:17][C:18]=1[C:21]([OH:23])=[O:22]
Reactant: COc1ccccc1F
Reactant: O=C=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(C(=O)O)c1F
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 51 %

Procedure:
A mixture of potassium tert-butoxide (30.80 g, 274 mmol) and anhydrous tetrahydrofuran (300 mL) was cooled to -78° C. and treated with a 1.6M solution of n-butyllithium (172 mL, 275 mmol) in hexanes. After stirring for 15 minutes, 2-fluoroanisole (31.35 g, 248 mmol) was added and the reaction was stirred an additional 1.8 hours. The reaction was poured into a 2 L Erlenmeyer flask containing dry ice and warmed to room temperature. Water (250 mL) was added and after extracting with ether (160 mL), the aqueous layer was acidified with concentrated hydrochloric acid, and filtered to give 2-fluoro-3-methoxybenzoic acid (21.43 g, 51%) as a yellow solid: mp 155°-160° C.; 1H NMR (acetone-d6) 300 MHz 7.46 (ddd, J=6.0 Hz J=1.8 Hz J=1.4 Hz, 1H) 7.36 (dt, J=1.6 Hz J=8.1 Hz, 1H) 7.20 (dt, J=1.4 Hz J=8.1 Hz, 1H) 3.92 (s, 3H); 19F NMR (acetone-d6) 300 MHz -134.04(m). Mass spectrum: M+H=171.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[O:7].Cl[C:9]1[N:14]=[CH:13][CH:12]=[CH:11][N:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN1CCCC1=O>O>[N:10]1[CH:11]=[CH:12][CH:13]=[N:14][C:9]=1[N:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[O:7]
Reactant: O=Cc1ccc[nH]1
Reactant: Clc1ncccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=Cc1cccn1-c1ncccn1
Temperature: 130 °C
Reaction time: 13 h
Yield: 27.2 %

Procedure:
A mixture of 1.9 g of 2-pyrrolecarbaldehyde, 2.3 g of 2-chloropyrimidine, 7.8 g of cesium carbonate and 20 ml of N-methylpyrrolidone was stirred at 130° C. for 13 hours, and then allowed to cool to room temperature. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate two times. The organic layers were combined, washed successively with water and an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel chromatography to obtain 0.94 g of 1-(2-pyrimidinyl)-1H-pyrrole-2-carbaldehyde of the formula:
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([C:18]3[O:22][C:21]([C:23]#[N:24])=[CH:20][CH:19]=3)=[CH:7][CH:8]=2)[N:3]=1.[F:25][C:26]1[CH:27]=[C:28]([NH:41][C:42](=[O:55])[NH:43][C:44]2[CH:54]=[CH:53][C:47]([C:48]([N:50]([CH3:52])[CH3:51])=[O:49])=[CH:46][CH:45]=2)[CH:29]=[CH:30][C:31]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[C:23]([C:21]1[O:22][C:18]([C:6]2[CH:5]=[C:4]3[C:9]([C:10]([N:12]4[CH2:17][CH2:16][O:15][CH2:14][CH2:13]4)=[N:11][C:2]([C:31]4[CH:30]=[CH:29][C:28]([NH:41][C:42](=[O:55])[NH:43][C:44]5[CH:54]=[CH:53][C:47]([C:48]([N:50]([CH3:52])[CH3:51])=[O:49])=[CH:46][CH:45]=5)=[CH:27][C:26]=4[F:25])=[N:3]3)=[CH:8][CH:7]=2)=[CH:19][CH:20]=1)#[N:24]
Reactant: N#Cc1ccc(-c2ccc3c(N4CCOCC4)nc(Cl)nc3c2)o1
Reactant: CN(C)C(=O)c1ccc(NC(=O)Nc2ccc(B3OC(C)(C)C(C)(C)O3)c(F)c2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=O)c1ccc(NC(=O)Nc2ccc(-c3nc(N4CCOCC4)c4ccc(-c5ccc(C#N)o5)cc4n3)c(F)c2)cc1
Temperature: 95 °C
Reaction time: 2 h
Yield: 6.1 %

Procedure:
To a 50 mL round bottom flask, 5-(2-chloro-4-morpholino-quinazolin-7-yl)furan-2-carbonitrile (0.12 g, 0.00035 mol), 4-(3-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide (0.144 g, 0.00053 mol), cesium carbonate (0.228 g, 0.0007 mol), DMF (3 mL) and water (3 mL) were added. The reaction mixture was degassed with nitrogen for 5-10 min. To the same reaction flask, Pd(PPh3)2Cl2 (0.013 g, 0.0000175 mol) was added and again degassed with nitrogen for 5-10 min. The reaction mixture was stirred at 95° C. for 2 h. To the cooled reaction mixture, water was added and extracted with ethyl acetate. The organic layer was separated, washed with water, brine and dried over anhydrous sodium sulfate. The organic layer was evaporated under reduced pressure to afford the crude product. The crude product was purified by column chromatography using 60-120 silica gel and 2-5% MeOH in chloroform to obtain the title compound [0.013 g, 6%]. 1H NMR (400 MHz, DMSO-d6): δ 9.21 (s, 1H), 9.04 (s, 1H), 8.27 (d, J=2.0 Hz, 1H), 8.19-8.13 (m, 2H), 7.93 (dd, J′=1.6, J″=8.4 Hz, 1H), 7.82 (d, J=4.0 Hz, 1H), 7.64 (d, J=3.6 Hz, 2H), 7.61 (d, J=2.0 Hz, 1H), 7.54 (d, J=8.4 Hz, 2H), 7.28 (dd, J′=8.8 Hz, J″=2.0 Hz, 2H), 3.83 (s, 8H), 2.96 (s, 6H). LC-MS (ESI): Calculated mass: 605.2; Observed mass: 606.2 (RT: 1.17 min).
Reaction SMILES: O[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH:11][C:12](=[O:30])[CH2:13][CH2:14][NH:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:21][CH:20]=1)(=[O:18])=[O:17])[C:5]([OH:7])=[O:6]>C(O)(=O)C>[CH2:25]([C:22]1[CH:21]=[CH:20][C:19]([S:16]([NH:15][CH2:14][CH2:13][C:12]2[O:30][C:9]3[CH:8]=[C:4]([C:5]([OH:7])=[O:6])[CH:3]=[CH:2][C:10]=3[N:11]=2)(=[O:18])=[O:17])=[CH:24][CH:23]=1)[CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCc1ccc(S(=O)(=O)NCCC(=O)Nc2ccc(C(=O)O)cc2O)cc1
Solvent: CC(=O)O
Product: CCCCCc1ccc(S(=O)(=O)NCCc2nc3ccc(C(=O)O)cc3o2)cc1
Yield: 9.7 %

Procedure:
A solution of the product of Step 2 (337 mg, 1.29 mmol) in glacial acetic acid (4 mL) in a sealed tube was heated at 120° C. for 60 h. The solvent was evaporated under reduced pressure, and the resulting residue purified by preparative HPLC to give the product (52 mg). MS m/e 417; HPLC retention time 3.44 min.
Reaction SMILES: [OH-].[K+].[N+:3]([C:6]1[C:7]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]([O:20]CC)=[O:19])[CH2:14][CH2:13]2)=[N:8][CH:9]=[CH:10][CH:11]=1)([O-:5])=[O:4].Cl>CO.O>[N+:3]([C:6]1[C:7]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]([OH:20])=[O:19])[CH2:14][CH2:13]2)=[N:8][CH:9]=[CH:10][CH:11]=1)([O-:5])=[O:4]
Reactant: CCOC(=O)C1CCN(c2ncccc2[N+](=O)[O-])CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C1CCN(c2ncccc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 134.6 %

Procedure:
To a solution of KOH (0.46 g, 8.16 mmol) in methanol (30 mL) and water (30 mL) was added Compound 258a (1.14 g, 4.08 mmol). The solution was stirred at r.t. for 1.5 hours, poured into water, acidified with 2M HCl and extracted with EtOAc. The combined organic layers were washed with brine, dried on Na2SO4 and evaporated to dryness in vacuo to afford the title product (1.38 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([CH3:9])[CH:8]=1)[NH2:5].[NH:10]([C:17]1[C:30]2[C:29](=[O:31])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22](=[O:32])[C:21]=2[C:20](S(C2C=CC(C)=CC=2)(=O)=O)=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[NH:10]([C:17]1[C:30]2[C:29](=[O:31])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22](=[O:32])[C:21]=2[C:20]([NH:5][C:4]2[CH:6]=[C:7]([CH3:9])[CH:8]=[C:2]([CH3:1])[CH:3]=2)=[CH:19][CH:18]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)c2ccc(Nc3ccccc3)c3c2C(=O)c2ccccc2C3=O)cc1
Reactant: Cc1cc(C)cc(N)c1
Product: Cc1cc(C)cc(Nc2ccc(Nc3ccccc3)c3c2C(=O)c2ccccc2C3=O)c1
Yield: 56 %

Procedure:
1-anilino-4-(3,5-dimethylanilino)anthraquinone was prepared by reaction of 3,5-dimethylaniline with 1-(anilino)-4-tosylanthraquinone. The isolated and purified reaction product has the structure illustrated below. ##STR16## The yield was 56% and m.p. 219.5°-220.5° C. Mass spectrum, m/e 418 (M+); H-NMR (CD2Cl2)δ12.20 (br s, 2H), 8.41-8.30 (m, 2H) 7.80-7.69 (m, 2H), 7.52-7.34 (m, 7H), 6.90 (br s, 3H), 2.32 (s, 6H); UV/VIS max (Xylenes) 404 nm (ε6 600), 600 (13 400), 641 (14 400).
Reaction SMILES: [OH:1][C:2]1[C:7]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[S:5](=[O:16])(=[O:15])[N:4]([CH3:17])[C:3]=1[C:18](OC)=[O:19].[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[N:24]=1>>[OH:1][C:2]1[C:7]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[S:5](=[O:16])(=[O:15])[N:4]([CH3:17])[C:3]=1[C:18]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[N:24]=1)=[O:19]
Reactant: COC(=O)C1=C(O)c2sc3ccccc3c2S(=O)(=O)N1C
Reactant: Cc1cccc(N)n1
Product: Cc1cccc(NC(=O)C2=C(O)c3sc4ccccc4c3S(=O)(=O)N2C)n1
Yield: 33 %

Procedure:
Prepared analogous to Example 1 from methyl 4-hydroxy-2-methyl-2H-[1]-benzothieno[2,3-e]-1,2-thiazine-3-carboxylate-1,1-dioxide and 2-amino-6-methyl-pyridine with a yield of 33% of theory.