Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[Cl:20][C:21]1[CH:22]=[C:23]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:24]=[CH:25][CH:26]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:30]1[CH2:29][CH2:28][N:27]([C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([Cl:20])[CH:22]=3)[CH2:32][CH2:31]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: CCOC(=O)Nc1nc2ccc(Cl)cc2nc1OC
Product: COc1nc2cc(Cl)ccc2nc1NC(=O)N1CCN(c2cccc(Cl)c2)CC1
Yield: 86 %

Procedure:
Ethyl N-(6-chloro-3-methoxyquinoxalin-2-yl)carbamate and 1-(3-chlorophenyl)piperazine were reacted by the same way with the example 106 to obtain the titled compound (yield, 86%). 1H NMR (300 MHz, CDCl3): δ 3.30 (s, 4H), 3.76 (s, 4H), 4.15 (s, 3H), 6.79-6.90 (m, 3H), 7.15-7.45 (m, 3H), 7.62-7.75 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=O)=[CH:4][CH:3]=1.[C:17]1(=O)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>O1CCCC1.[Zn].Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=C1CCCCC1
Reactant: O=C(c1ccc(O)cc1)c1ccc(Br)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: Oc1ccc(C(=C2CCCCC2)c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
To a 3-neck round-bottomed flask were added zinc powder (1.96 g, 30 mmol) followed by anhydrous THF (40 mL). To the stirred suspension was slowly added, via syringe, TiCl4 (1.6 mL, 2.77 g, 14.6 mmol) at room temperature. The reaction mixture was heated at reflux with stirring under a nitrogen atmosphere for 2 h. To the refluxing reaction mixture was added a solution of (4-bromophenyl)(4-hydroxyphenyl)methanone (2) (1.1 g, 3.61 mmol) and cyclohexanone (1.1 mL, 1.04 g, 10.6 mmol) in anhydrous tetrahydrofuran (40 mL). The stirred reaction mixture was heated at reflux under a nitrogen atmosphere for 2 h. The oil bath was removed and the reaction mixture was allowed to cool to room temperature. To the reaction mixture was slowly added water (24 mL) followed by 10% aqueous K2CO3 (24 mL). The reaction mixture was filtered through a pad of Celite and the pad washed with EtOAc. The filtrate was transferred to a separatory funnel with the aid of water and EtOAc and the layers were separated. The organic phase washed with brine, dried over MgSO4, filtered, and the filtrate was concentrated in vacuo to give the crude product. The crude product was purified by flash chromatography on silica gel with hexanes:EtOAc (100:0 to 60:40) to give 1.17 g (95%) of compound 6 as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 1.52 (m, 6 H), 2.12 (m, 4 H), 6.65 (d, J=8.4 Hz, 2 H), 6.82 (d, J=8.4 Hz, 2 H), 6.97 (d, J=8.3 Hz, 2 H), 7.44 (d, J=8.3 Hz, 2 H), 9.32 (s, 1 H). HRMS (EI) Calcd for C19H19BrO: 342.0619 (M+). Found: 342.0627.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5](N)[C:6](=[CH:10][CH:11]=1)[C:7]([OH:9])=[O:8].C(O)(=O)C.N([O-])=O.[Na+].[BrH:23]>O>[Br:23][C:5]1[CH:4]=[C:3]([C:2]([F:14])([F:13])[F:1])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: Br
Reactant: Nc1cc(C(F)(F)F)ccc1C(=O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1ccc(C(F)(F)F)cc1Br
Temperature: -10 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
205 g (1 mol) of 4-(trifluoromethyl)anthranilic acid, 600 ml of glacial acetic acid and 400 ml of 47% hydrobromic acid are introduced successively into a three-liter round-bottomed flask. After dissolution, the reaction mixture is cooled to -10° C., diluted with 400 ml of water and then treated dropwise with a solution of 69 g (1 mol) of sodium nitrite in 200 ml of water while maintaining the temperature below 0° C. When the addition is finished, the reaction mixture is stirred at 0° C. for 2 hours. This solution is run in dropwise into a six-liter reactor containing 143.5 g (1 mol) of cuprous bromide in 500 ml of 47% hydrobromic acid maintained at 60° C. When the addition is finished, the reaction mixture is stirred at 60° C. for one hour, cooled to room temperature and then poured into two liters of ice-cold water. The precipitate which forms is filtered on sintered glass, washed with water and then dried under a stream of air. There is thus obtained 216 g (yield: 80%) of 2-bromo-4-(trifluoromethyl)benzoic acid in the form of a solid melting at 118.5° C.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:15]([CH2:25][O:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[O:14][C@@H:11]([O:12][CH3:13])[C@@H:10]1[OH:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:36](OC(=O)C)(=[O:38])[CH3:37]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:36]([O:35][C@@H:10]1[C@@H:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:15]([CH2:25][O:26][CH2:27][C:28]2[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=2)[O:14][C@H:11]1[O:12][CH3:13])(=[O:38])[CH3:37]
Reactant: CO[C@@H]1O[C@H](COCc2ccc(Cl)cc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CO[C@@H]1O[C@H](COCc2ccc(Cl)cc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
Methyl 3,4-di-O-benzyl-6-O-(4-chlorobenzyl)-β-D-glucopyranoside (0.233 g, 0.467 mmol) was dissolved in 5 mL CH2Cl2. Acetic anhydride (53 μL, 0.560 mmol) and DMAP (0.114 g, 0.934 mmol) were added and the reaction mixture was stirred at room temperature for 1 h. The solution was filtered through silica, eluted with EtOAc and concentrated. Purification by flash column chromatography on silica gel (30% EtOAc/Hexanes) gave 224 mg (89%) of 20 as a colorless oil. [α]24D: −0.5° (c 0.79, CH2Cl2); IR (thin film). 2867, 1747, 1233, 1087, 1060 cm−1; 1H-NMR (CDCl3) δ 7.35–7.27 (m, 12H), 7.20–7.18 (m, 2H), 5.00 (dd, J=7.9, 8.8 Hz, 1H), 4.81 (d, J=10.7 Hz, 1H), 4.80 (d, J=11.6 Hz, 1H), 4.68 (d, J=11.3 Hz, 1H), 4.59 (d, J=12.5 Hz, 1H), 4.56 (d, J=10.7 Hz, 1H), 4.52 (d, J=12.2 Hz, 1H), 4.30 (d, J=7.9 Hz, 1H), 3.74–3.67 (m, 4H), 3.51–3.37 (m, 4H), 1.99 (s, 3H); C-NMR (CDCl3) δ 169.8, 138.2, 138.0, 136.8, 129.2, 128.7, 128.6, 128.2, 128.1, 128.0, 102.0, 83.2, 78.1, 75.3, 75.2, 73.2, 72.9, 68.9, 56.9, 21.2; FAB MS m/z (M+Na)+: calcd 563.1813, obsd 563.1817.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:11])=[CH:9][C:4]=2[CH:3]=[CH:2]1.[CH3:18][Mg]Br.C(OCC)C>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)([OH:11])[CH3:18])=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: C[Mg]Br
Reactant: O=C(c1ccccc1)c1ccc2occc2c1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(O)(c1ccccc1)c1ccc2occc2c1
Temperature: 25 °C

Procedure:
To a solution of benzofuran-5-yl(phenyl)methanone (1.0 g, 4.5 mmol) in 20 mL THF under nitrogen at 0° C. was added methylmagnesium bromide 3.0M in diethyl ether (2.2 mL, 6.7 mmol) dropwise via syringe. The reaction was allowed to warm to ambient temperature slowly. The reaction was quenched with sat'd aq. NH4Cl and DCM. The aqueous layer was extracted 2×DCM, and the combined organics were dried over anhyd sodium sulfate, filtered, and concentrated in vacuo to give 1-(benzofuran-5-yl)-1-phenylethanol as an oil, which was used without further purification. MS (ESI) m/z: Calculated: 238.1; Observed: 238.8 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7](I)=[CH:6][CH:5]=1.[C:12]1([SH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([S:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(I)cc1
Reactant: Sc1ccccc1
Product: COC(=O)c1ccc(Sc2ccccc2)cc1

Procedure:
The general procedure was used to convert Methyl-4-iodobenzoate and thiophenol to the title product. Purification by flash chromatography (hexane/ethyl acetate [6:1] as the eluent) gave the analytically pure product as a white solid (411 mg, 84% yield). 1H NMR (300 MHz, CDCl3) δ 7.88 (dt, J=8.67, 2H; Hb, Hb′), 7.51–7.47 (m, 2H; Hc, Hc′), 7.39–7.37 (m, 3H; Hd, Hd′, He), 7.21 (dt, J=8.67, 2H; Ha, Ha′), 3.89 (s, 3H; methyl protons). 13C NMR (75 MHz, CDCl3) δ 166.60 (C13), 144.33 (C1), 133.63 (C4), 132.29 (C8, C12), 130.03 (C7), 129.58 (C9, C11), 128.60 (C3, C5), 127.47 (C10), 127.39 (C2, C6), 52.02 (C14). Anal. Calcd. for C14H12O2S: C, 68.83; H, 4.95; S, 13.13; Found C, 68.87; H, 4.95; S, 12.96. mp found: 70–71° C.
Reaction SMILES: [O:1]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:5][NH:4][C:3](=[O:12])[CH2:2]1.[CH:13]1([N:18]2[C:22]3[N:23]=[C:24]([NH:27][C:28]4[N:33]=[N:32][C:31](Cl)=[CH:30][CH:29]=4)[N:25]=[CH:26][C:21]=3[C:20]3[CH:35]=[CH:36][N:37]=[CH:38][C:19]2=3)[CH2:17][CH2:16][CH2:15][CH2:14]1.C(N(CC)C(C)C)(C)C>CN1CCCC1=O>[CH:13]1([N:18]2[C:22]3[N:23]=[C:24]([NH:27][C:28]4[N:33]=[N:32][C:31]([N:9]5[CH2:8][CH2:7][C:6]6([O:1][CH2:2][C:3](=[O:12])[NH:4][CH2:5]6)[CH2:11][CH2:10]5)=[CH:30][CH:29]=4)[N:25]=[CH:26][C:21]=3[C:20]3[CH:35]=[CH:36][N:37]=[CH:38][C:19]2=3)[CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: Clc1ccc(Nc2ncc3c4ccncc4n(C4CCCC4)c3n2)nn1
Reactant: O=C1COC2(CCNCC2)CN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: O=C1COC2(CCN(c3ccc(Nc4ncc5c6ccncc6n(C6CCCC6)c5n4)nn3)CC2)CN1
Temperature: 160 °C
Yield: 4.6 %

Procedure:
To a mixture of compound 400 (110.0 mg, 646 μmol) and compound 140 (40.0 mg, 109 μmol) in N-methylpyrrolidinone (1.50 mL) was added N,N-diisopropylethylamine (DIEA) (0.100 mL, 575 μmol). The resulting mixture was heated at 160° C. under microwave irradiation for 6 h. The crude material was purified by reverse phase HPLC (acetonitrile/H2O containing 0.1% TFA each, 25 min from 10 to 40%). The isolated material was further purified by prep-TLC (10% methanol in DCM with 1% NH4OH) to give compound 396 as a yellow solid (2.5 mg, 5%). 1H NMR (500 MHz, CD3OD) δ 9.21 (s, 1 H) 8.91 (s, 1 H) 8.37-8.46 (m, 2 H) 8.08 (d, J=5.38 Hz, 1 H) 7.46 (d, J=10.03 Hz, 1 H) 5.43 (quin, 1 H) 4.21 (s, 2 H) 4.06 (ddd, J=13.27, 3.48, 3.30 Hz, 2 H) 3.37-3.42 (m, 4 H) 2.44 (dd, J=12.96, 8.31 Hz, 2 H) 2.08-2.24 (m, 4 H) 2.03 (d, J=13.45 Hz, 2 H) 1.84-1.93 (m, 2 H) 1.74-1.83 (m, 2 H) ppm; LCMS-ESI (POS), M/Z, M+1: Found 500.2, Calculated 500.2.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][S:24](=[O:27])[CH2:23][CH2:22]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[C:6]=2[N:7]=1.[CH:28]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=[O:29]>ClC1N=C(N2CCS(=O)CC2)C2N=CN=C(Cl)C=2N=1>[F:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][S:12][C:8]2[C:6]3[N:7]=[C:2]([N:33]4[CH2:34][CH2:35][N:30]([CH:28]=[O:29])[CH2:31][CH2:32]4)[N:3]=[C:4]([N:21]4[CH2:26][CH2:25][S:24](=[O:27])[CH2:23][CH2:22]4)[C:5]=3[N:11]=[CH:10][N:9]=2)=[CH:15][CH:16]=1
Reactant: O=CN1CCNCC1
Reactant: O=S1CCN(c2nc(Cl)nc3c(SCc4ccc(F)cc4)ncnc23)CC1
Agent: O=S1CCN(c2nc(Cl)nc3c(Cl)ncnc23)CC1
Product: O=CN1CCN(c2nc(N3CCS(=O)CC3)c3ncnc(SCc4ccc(F)cc4)c3n2)CC1

Procedure:
This compound was prepared analogous to Example 93 from 2-chloro-8-(4-fluorobenzyl-thio)-4-(1-oxido-thiomorpholino)-pyrimido-[5,4-d]-pyrimidine (m.p.: 192°-194° C.) and N-formyl-piperazine in dioxane.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[CH2:5]([N:9]=[C:10]=[O:11])[CH2:6][CH2:7][CH3:8]>C1(C)C=CC=CC=1>[CH2:1]([NH:4][C:10]([NH:9][CH2:5][CH2:6][CH2:7][CH3:8])=[O:11])[CH2:2][CH3:3]
Reactant: CCCCN=C=O
Reactant: CCCN
Solvent: Cc1ccccc1
Product: CCCCNC(=O)NCCC
Yield: 96.1 %

Procedure:
205.76 Grams (3.48 moles) of n-propylamine were charged to a 1--1., round bottom flask equipped with stirrer, thermometer, reflux condenser and addition funnel. 313.7 Grams (3.16 moles) of butyl isocyanate were charged to the addition funnel and added to the flask with stirring at a rate which maintained the contents at about 60°-65° C. Toluene was added to dissolve the solid product for transfer to a stripping vessel. The crude product solution was about 92 area % ureas on a solvent-free basis by gas chromatography. The crude product solution was freed of most of the solvent and lights under vacuum with a rotary evaporator leaving 480.6 g of pale yellow solid melting from 68°-70° C. Infrared analysis showed a clean spectrum in agreement with the proposed structure's functionality. The gas chromatograph showed three, major peaks in a 1:2:1 ratio indicating possible `scrambling` of alkyl groups and a statistically determined ratio of products.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:10]2[C:5](=[CH:6][C:7]([CH3:11])=[CH:8][CH:9]=2)[C:4]([CH3:15])([CH:12]([CH3:14])[CH3:13])[CH2:3]1.[CH3:17][O:18]C(Cl)Cl>[Ti](Cl)(Cl)(Cl)Cl.C(Cl)Cl>[CH:17]([C:8]1[CH:9]=[C:10]2[C:5]([C:4]([CH3:15])([CH:12]([CH3:13])[CH3:14])[CH2:3][C:2]2([CH3:16])[CH3:1])=[CH:6][C:7]=1[CH3:11])=[O:18]
Reactant: COC(Cl)Cl
Reactant: Cc1ccc2c(c1)C(C)(C(C)C)CC2(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1cc2c(cc1C=O)C(C)(C)CC2(C)C(C)C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Next, 1,1,3,5-tetramethyl-3-isopropylindane (12.96 g) is placed in a 1 liter three-necked round bottom flask equipped with a reflux condenser, a stirrer and a dropping funnel. In accordance with the general procedures described in Organic Syntheses, Collective Vol. 5, pp. 49-50, by A. Rieche, H. Gross, and E. Hoft, edited by H.E. Baumgarten, John Wiley and Sons (New York, N.Y. 1973), methylene chloride (37.5 ml) is added to the flask. The solution is then cooled in an ice bath, and titanium tetrachloride (19.0 g) is added over a period of about 3 minutes. While the solution is stirred and cooled, α,α-dichloromethyl methyl ether (5.75 g) is added dropwise over a 25 minute period. After the addition is complete, the mixture is stirred for about 5 minutes in the ice bath, for about 30 minutes without cooling, and for about 15 minutes at about 35° C. The reaction mixture is then poured into a separatory funnel containing about 50 g of crushed ice and is shaken thoroughly. The organic layer is separated, and the aqueous solution is extracted with two 10 ml portions of methylene chloride. The combined organic solution is washed three times with 10 ml portions of water. A crystal of hydroquinone is added to the methylene chloride solution, which is then dried over anhydrous sodium sulfate. After evaporation of the solvent, the residue is distilled to yield as a crude product, 6-formyl-1,1,3,5-tetramethyl-3-isopropylindane. The 6 formyl-1,1,3,5 tetramethyl-3-isopropylindane is then further purified using standard fractional distillation techniques.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[CH3:19])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:20].[CH3:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[O:28][C:27]([C:32](O)=[O:33])=[CH:26][C:25]2=[O:35]>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[CH3:19])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:20][C:32]([C:27]1[O:28][C:29]2[C:24]([C:25](=[O:35])[CH:26]=1)=[CH:23][C:22]([CH3:21])=[CH:31][CH:30]=2)=[O:33]
Reactant: Cc1cc(N2CCC(CN3CCCC3C)C2)ccc1N
Reactant: Cc1ccc2oc(C(=O)O)cc(=O)c2c1
Product: Cc1ccc2oc(C(=O)Nc3ccc(N4CCC(CN5CCCC5C)C4)cc3C)cc(=O)c2c1

Procedure:
The title compound was prepared in a manner substantially the same as Example 1 by coupling 2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenylamine with 6-methyl-4-oxo-4H-chromene-2-carboxylic acid. MS: 460.3 (M+H).
Reaction SMILES: [N:1]([N:3]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)S(C1C=CC(C)=CC=1)(=O)=O)=O.C[O-].[Na+]>COC(C)(C)C.CO>[C:15]1([CH:14]=[N+:3]=[N-:1])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)N(Cc2ccccc2)N=O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: COC(C)(C)C
Product: [N-]=[N+]=Cc1ccccc1
Yield: 30 %

Procedure:
N-Nitroso-N-benzyl-p-toluene sulphonamide (966 mg, 3.33 mmol) was added in small portions to a solution of sodium methoxide (2.0 ml of 2M solution in methanol) in t-butyl methyl ether (12 ml) and methanol (2 ml) at room temperature. After the addition was finished the reaction mixture was refluxed for 15-30 min. The reaction mixture was cooled and washed with water (3×6 ml). The ethereal solution of phenyl diazomethane was dried over sodium sulphate for 30 minutes. The solvent was removed in vacuo and the residue distilled under reduce pressure to give phenyl diazomethane as a dark red oil (30% yield, b.p. 20° C. at 1 mmHg) which was immediately dissolved in t-butyl methyl ether (6 ml).
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[CH3:11][C@@:12]12[C:28](=[O:29])[CH2:27][CH2:26][C@H:25]1[C@H:24]1[C@@H:15]([C:16]3[CH:17]=[CH:18][C:19]([OH:30])=[CH:20][C:21]=3[CH2:22][CH2:23]1)[CH2:14][CH2:13]2>N1C=CC=CC=1>[C:2]([O:30][C:19]1[CH:18]=[CH:17][C:16]2[C@@H:15]3[C@H:24]([C@H:25]4[C@@:12]([CH2:13][CH2:14]3)([CH3:11])[C:28](=[O:29])[CH2:27][CH2:26]4)[CH2:23][CH2:22][C:21]=2[CH:20]=1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Agent: Cl
Solvent: c1ccncc1
Product: C[C@]12CC[C@@H]3c4ccc(OC(=O)c5cccnc5)cc4CC[C@H]3[C@@H]1CCC2=O
Temperature: 0 °C

Procedure:
To nicotinoyl chloride hydrochloride (2.65 g, 0.015 mol) in pyridine (20 ml) at 0° C. was added estrone (2 g, 0.0074 mol). The mixture was refluxed for one hour and then poured over 100 ml of ice cold water, filtered, and dried over P2O5 under vacuum. Yield 72% (2.0076 g), m.p. 207°-210° C. NMR (CDCl3) δ9.3-9.1 (br s, 1H, C2 pyridinium proton), 8.8-8.6 (br d, 1H, C6 pyridinium proton, 8.4-8.2 (br d, 1H, C4 pyridinium proton), 7.5-7.1 (m, 2-H, C5 pyridinium proton+C1 estrone proton), 7.0-6.7 (m, 2H, C2,4 estrone protons), 3.2-1.3 (estrone skeletal protons, 15), 1.0-0.9 (s, 3H, C18 estrone protons). IR (KBr) 1750-1730 cm-1 (broad C=O stretching). Anal. calculated for C24H25NO3 ; C, 76.76; H, 6.72; N, 3.73. Found: C, 76.37; H, 6.96; N, 3.67. The product is further characterized by the structural formula: ##STR1549##
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH2:24]>>[CH3:17][O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:8](=[O:9])[CH:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: COCCCCCN
Product: COCCCCCNC(=O)C(c1ccccc1)c1ccccc1

Procedure:
The title compound, white solid, m.p. 74.2-75.0° C. and MS: m/e=312 (M+H+) was prepared in accordance with the general method of example 1 from diphenylacetyl chloride and 5-methoxy-pentylamine.
Reaction SMILES: [ClH:1].[N:2]([C:4]1[CH:8]=[N:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[C:5]=1[NH2:16])=O.[H][H]>C(O)C.[Pd]>[ClH:1].[ClH:1].[ClH:1].[N:13]1[CH:14]=[CH:15][C:10]([CH2:9][N:6]2[C:5]([NH2:16])=[C:4]([NH2:2])[CH:8]=[N:7]2)=[CH:11][CH:12]=1
Reactant: [H][H]
Reactant: Nc1c(N=O)cnn1Cc1ccncc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Nc1cnn(Cc2ccncc2)c1N

Procedure:
In an autoclave, 38.1 g (158 mmol) of the crude product from Step 2.2 was suspended in 800 mL of ethanol and hydrogenated at 9 bar of hydrogen pressure for 2 hours using 3.8 g of Pd/C (10%). The catalyst was then filtered off through diatomaceous earth, to the filtrate was added 200 mL of 3M ethanolic hydrochloric acid, and the solution was concentrated to incipient crystallization in a rotary evaporator at 40° C. To complete the crystallization, the mixture was cooled in an ice bath, after which the solid was filtered off. The product was then washed with a small amount of ethyl acetate and dried at 40° C. under vacuum. This gave 19.5 g (41% of the theoretical) of a slightly pink-colored powder.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[C:4]#[N:5].[S:11](N)([NH2:14])(=[O:13])=[O:12]>O1CCOCC1>[C:4]([C:3]1[C:6]([CH3:10])=[CH:7][CH:8]=[CH:9][C:2]=1[NH:1][S:11]([NH2:14])(=[O:13])=[O:12])#[N:5]
Reactant: NS(N)(=O)=O
Reactant: Cc1cccc(N)c1C#N
Solvent: C1COCCO1
Product: Cc1cccc(NS(N)(=O)=O)c1C#N
Temperature: 25 °C

Procedure:
A solution of 2-amino-6-methylbenzonitrile (1.32 g, 10 mmol) and sulfamide (4.81 g, 50 mmol) in dry 1,4-dioxane (50 mL) was refluxed under nitrogen for 3 days. After the reaction mixture was cooled down to room temperature, the precipitate was filtered and washed with dioxane. The filtrate was concentrated under reduced pressure, and the residue was purified by chromatography on silica gel eluting with EtOAc/hexanes (3:7) to give the title compound as a pale-white solid. 1H NMR (400 MHz, DMSO-d6) δ 2.44 (s, 3H), 7.19-7.21 (m, 3H), 7.39-7.41 (d, J=8.4 Hz, 1H), 7.53 (t, J=8.0 Hz, 1H), 9.41 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[OH:39])[C:5]([N:7]([CH:33]([CH3:35])[CH3:34])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[C@@H:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([O:26]C(=O)C(C)(C)C)[CH:20]=[CH:19][C:18]=2[CH2:17]1)=O.Cl[CH2:41][C:42]([N:44]([CH2:46][CH3:47])[CH3:45])=O>>[CH2:46]([N:44]([CH3:45])[CH2:42][CH2:41][O:39][C:38]1[CH:37]=[CH:36][C:4]([CH2:5][N:7]([CH:33]([CH3:35])[CH3:34])[C:8]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=2[C@@H:16]2[CH2:25][CH2:24][C:23]3[CH:22]=[C:21]([OH:26])[CH:20]=[CH:19][C:18]=3[CH2:17]2)=[CH:3][C:2]=1[F:1])[CH3:47]
Reactant: CCN(C)C(=O)CCl
Reactant: COc1ccc([C@@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)c(F)c2)C(C)C)c1
Product: CCN(C)CCOc1ccc(CN(c2cc(OC)ccc2[C@@H]2CCc3cc(O)ccc3C2)C(C)C)cc1F
Yield: 45.8 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[(3-fluoro-4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and 2-chloro-N-ethyl-N-methylacetamide (9.5 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (8.5 mg) was obtained.
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][O:8][CH:9]1[CH2:12][NH:11][CH2:10]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.Cl.[O:44]=[C:45]1[NH:58][C:48]2=[N:49][CH:50]=[C:51](/[CH:53]=[CH:54]/[C:55](O)=[O:56])[CH:52]=[C:47]2[NH:46]1>CN(C)C=O>[O:56]=[C:55]([N:11]1[CH2:12][CH:9]([O:8][CH2:7][C:3]2[S:2][CH:6]=[CH:5][CH:4]=2)[CH2:10]1)/[CH:54]=[CH:53]/[C:51]1[CH:52]=[C:47]2[NH:46][C:45](=[O:44])[NH:58][C:48]2=[N:49][CH:50]=1
Reactant: c1csc(COC2CNC2)c1
Reactant: O=C(O)/C=C/c1cnc2[nH]c(=O)[nH]c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(/C=C/c1cnc2[nH]c(=O)[nH]c2c1)N1CC(OCc2cccs2)C1
Reaction time: 8 h
Yield: 14.4 %

Procedure:
3-(Thiophen-2-ylmethoxy)-azetidine hydrochloride (127 mg, 0.62 mmol), EDCI (120 mg, 0.62 mmol), HOBt (86 mg, 0.62 mmol) and diisopropylethylamine (180 μL, 1.03 mmol) were successively added to a solution of (E)-3-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)acrylic acid hydrochloride (100 mg, 0.41 mmol) in dimethylformamide (10 mL) at room temperature. The reaction mixture was stirred overnight then partitioned between ethyl acetate (20 mL) and water (30 mL). The aqueous layer was separated and successively extracted with ethyl acetate (2×20 mL) and dichloromethane (2×20 mL). The combined organic phases were washed with a saturated solution of sodium chloride (3×30 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by chromatography on silica gel using dichloromethane/methanol (98:2 to 93:7) as eluent. The residue was triturated in pentane to afford the title product as a pale orange solid (21 mg, 14%).