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)[NH:8][CH2:7][N:6]([CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)[C:5]2=[O:20].[H-].[Na+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1(C)C=CC=CC=1.CS(C)=O>[CH2:23]([N:8]1[C:9]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:11][CH:10]=2)[C:5](=[O:20])[N:6]([CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH2:7]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: O=C1c2cc(Cl)ccc2NCN1CCN1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: O=C1c2cc(Cl)ccc2N(Cc2ccccc2)CN1CCN1CCOCC1
Reaction time: 0.5 h

Procedure:
3.50 Grammes (11.8 mmoles) of 6-chloro-2,3-dihydro-3-[2-(4morpholinyl)ethyl]-4(1H)-quinazolinone are dissolved in 20 ml of a mixture of toluene and dimethylsulfoxide in a ratio 5:1. The solution is dripped into a suspension containing 340 mg (14.2 mmoles) of 95% sodium hydride in 30 ml of dimethylsulfoxide and the reaction mixture is kept at 40° C. for 30 minutes. Afterwards a mixture containing 2.11 ml (17.7 mmoles) of benzylbromide and 60 ml of toluene is dripped into the solution and the suspension is kept at 40° C. for 4 hours.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]O)=[CH:4][CH:3]=1.CI.[H-].[Na+].[CH2:14]1[CH2:18][O:17][CH2:16][CH2:15]1>>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][CH2:16][O:17][CH2:18][CH2:14][C:15]2[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][CH:4]=2)=[CH:4][CH:3]=1
Reactant: OCc1ccc(Br)cc1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: Brc1ccc(CCOCCc2ccc(Br)cc2)cc1
Temperature: 25 °C

Procedure:
4-Bromobenzylalcohol (5.0 g, 26.7 mmol) was dissolved in THF (130 ml) and methyl iodide added (6.7 ml, 107.0 mmol). Sodium hydride (1.20 g of 80% dispersion in oil, 40.1 mmol) was added in two portions while stirring at room temperature under nitrogen. After stirring for 2 hours, the solvents were removed in vacuo and the residue partitioned between water and ether. The water was reextracted with ether and the combined organic fractions were then washed with water and brine before drying (Na2SO4) and evaporating in vacuo to give 4-bromobenzylmethyl ether as an orange liquid (5.3 g, 26.4 mmol). δH (250 MHz, CDCl3) 3.39 (3H, s, CH3), 4.40 (2H, s, CH2), 7.21 (2H, d, J 7.5 Hz, Ar-H), 7.48 (2H, d, J 7.5 Hz, Ar-H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.C(=O)([O-])[O-:18].[Ca+2]>O1CCOCC1.O>[OH:18][CH2:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1
Reactant: O=C(c1ccccc1)c1ccc(CBr)cc1
Reactant: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: C1COCCO1
Product: O=C(c1ccccc1)c1ccc(CO)cc1
Yield: 87.8 %

Procedure:
To a suspension of 2 (6.0 g, 22 mmol) in a mixture of 1,4 dioxane (60 ml) and water (60 ml) was added calcium carbonate (10.8 g, 110 mmol). The mixture was heated to reflux for 18 h, concentrated in vacuo and the residue portioned between DCM and water. The organic layer was collected, dried over MgSO4, concentrated in vacuo then recrystalised from diethyl ether to furnish 3 (4.1 g, 89%) as a white solid; M.P. 59-61° C. (Lit 61-64° C.); δH (CDCl3) 3.14 (s, 1H, CH2OH), 4.75 (s, 2H, CH2OH), 7.41-7.49 (m, 4H, 3-, 3′-, 5-, 5′-H), 7.54-7.58 (m, 1H, 4′-H), 7.72-7.76 (m, 4H, 2-, 2′-, 6-, 6′-H) ppm; δC (CDCl3) 64.4 (CH2OH), 126.4 (3′-, 5′-C), 128.3 (3-, 5-C), 130.0, 130.4 (2-, 2′-, 6-, 6′-C), 132.5 (4′-C), 136.4, 137.5 (1-, 1′-C), 140.0 (4-C), 196.9 (Ar2C═O) ppm; νmax (thin film) 3406, 3058, 2921, 1655, 1279 cm−1; m/z (ES) 211 ([M−H]− 100%), 183 (45%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10](Br)[CH:9]=2)=[O:4].[CH3:18][Sn](C)(C)C>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>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([CH3:18])[CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(O)c2ccc(Br)cc2sc1=O
Reactant: C[Sn](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)c1c(O)c2ccc(C)cc2sc1=O
Temperature: 122.5 °C
Yield: 68.3 %

Procedure:
To a mixture of 7-bromo-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester (Example 5e) (150 mg, 0.48 mmol) in DMF was added tetramethyltin (254 mg, 1.43 mmol) and PdCl2(PPh3)2 (17 mg, 0.024 mmol). The resulting mixture was purged with nitrogen gas for 20 seconds and heated in a 120-125° C. oil bath for 1 h. The reaction mixture was diluted with water (15 mL) and the suspended black solid was filtered off. The clear filtrate was acidified to pH 4 using 1 N HCl and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The crude product was triturated with MeOH (1 mL) and the solid collected to provide 4-hydroxy-7-methyl-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester (82 mg). 1H NMR (200 MHz, CDCl3): δ (ppm)=15.20 (s, 1H), 8.23 (d, J=8.5 Hz, 1H), 7.17 (m, 2H), 4.00 (s, 3H), 2.44 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH2:11][CH:12]3[NH:17][CH:16]([C:5]2=1)[CH2:15][CH2:14][CH2:13]3.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[CH2:26])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][N:7]2[C:8]3[C:4](=[CH:3][C:2]([CH3:1])=[CH:10][CH:9]=3)[C:5]3[C@@H:16]4[NH:17][C@H:12]([CH2:11][C:6]2=3)[CH2:13][CH2:14][CH2:15]4)=[CH:21][CH:20]=1
Reactant: Cc1ccc2[nH]c3c(c2c1)C1CCCC(C3)N1
Reactant: C=Cc1ccc(Cl)cc1
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(Cl)cc2)C[C@@H]2CCC[C@H]1N2

Procedure:
The coupling of 2-methyl-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole (226 mg, 1.0 mmol; Example 118A) and 1-chloro-4-vinylbenzene (277 mg, 1.99 mmol; Aldrich) was performed according to the procedure described in Example 114B to afford the title compound as a racemic mixture. Individual enantiomers were obtained by preparative chiral supercritical fluid chromatography (ChiralPak® OD-H 5 μm column, 21×250 mm, 35° C., 10-50% gradient of CH3OH—CO2 containing 0.1% diethylamine, 20 minute) to afford the title compound as the second-eluting enantiomer: 1H NMR (300 MHz, methanol-d4) δ ppm 1.04-1.20 (m, 1H), 1.29-1.44 (m, 2H), 1.66 (dd, J=13, 2 Hz, 1H), 1.78-2.04 (m, 3H), 2.40 (s, 3H), 2.92 (dd, J=17, 7 Hz, 1H), 2.98-3.17 (m, 2H), 3.50-3.57 (m, 1H), 4.21 (ddd, J=15, 9, 6 Hz, 1H), 4.32-4.42 (m, 1H), 4.43-4.47 (m, 1H), 6.92-7.00 (m, 3H), 7.14-7.21 (m, 3H), 7.27 (d, J=8 Hz, 1H); MS (DCI/NH3) m/z 365 367 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[CH:5]=[C:4]([CH3:15])[N:3]=1.[Cl:16][C:17]1[CH:22]=[C:21](B(O)O)[CH:20]=[CH:19][N:18]=1>>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[C:4]([CH3:15])[N:3]=[C:2]([C:21]3[CH:20]=[CH:19][N:18]=[C:17]([Cl:16])[CH:22]=3)[N:7]=2)=[CH:9][CH:10]=1
Reactant: OB(O)c1ccnc(Cl)c1
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc(Cl)n1
Product: Cc1cc(-c2ccc(Cl)cc2)nc(-c2ccnc(Cl)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-(4-chloro-phenyl)-6-methyl-pyrimidine (example A.11) (0.24 g, 1.0 mmol) and commercially available 2-chloro-pyridine-4-boronic acid (0.21 g, 1.3 mmol) according to the general procedure IVb. Obtained as a light yellow solid (0.23 g, 73%). MS (ISP) 316.1 [(M+H)+]; mp 175° C.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].Br[CH:6]([C:10]1[CH:15]=[C:14]([CH3:16])[N:13]=[C:12]([S:17][CH3:18])[N:11]=1)[C:7](=O)[CH3:8]>C(O)C>[CH3:8][C:7]1[N:1]=[C:2]([NH2:4])[S:3][C:6]=1[C:10]1[CH:15]=[C:14]([CH3:16])[N:13]=[C:12]([S:17][CH3:18])[N:11]=1
Reactant: CSc1nc(C)cc(C(Br)C(C)=O)n1
Reactant: NC(N)=S
Solvent: CCO
Product: CSc1nc(C)cc(-c2sc(N)nc2C)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Thiourea (2.7 g, 35 mmol) is added to a stirred solution of 1-bromo-1-(6-methyl-2-methylsulfanyl-pyrimidin-4-yl)-propan-2-one (AC3) in ethanol (100 ml) at 60° C. After 30 minutes the reaction is allowed to cool to room temperature. After standing for 18 hours the hydrobromide salt of the titled compound is removed by filtration and washed with diethyl ether. The product is dissolved in water and 2M sodium hydroxide is added to precipitate the titled compound as the free base.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:17][CH3:18])[C:10]([C:19]([NH:21][OH:22])=[NH:20])=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].CO[C:27](=O)[CH2:28][N:29]([CH3:31])[CH3:30].[ClH:33]>O1CCCC1.C(O)(C)C>[ClH:33].[CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:17][CH3:18])[C:10]([C:19]3[N:20]=[C:27]([CH2:28][N:29]([CH3:31])[CH3:30])[O:22][N:21]=3)=[CH:9]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cccc2c(C(=N)NO)cn(CC3CCCCC3)c12
Reactant: COC(=O)CN(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: COc1cccc2c(-c3noc(CN(C)C)n3)cn(CC3CCCCC3)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Molecular sieves (4 Å, powdered, 200 mg) were added to a suspension of 1-(cyclohexyl)methyl-N-hydroxy-7-methoxy-1H-indole-3-carboxamidine (250 mg, 0.829 mmol) in tetrahydrofuran (6 ml) under nitrogen, and the mixture was stirred at room temperature for 30 min. Sodium hydride (60% suspension in oil, 36 mg, 0.900 mmol) was added, then the resulting mixture was stirred at 60° C. for 20 min. The reaction mixture was cooled to room temperature and N,N-dimethylglycine methyl ester (194 mg, 1.66 mmol) was added to the mixture. The resulting mixture was stirred at reflux temperature for 2 h and then concentrated in vacuo. The obtained residue was mixed with dichloromethane (200 ml), washed with 5% aqueous sodium carbonate, dried over magnesium sulfate and concentrated in vacuo. The obtained oil was purified by flash column chromatography eluting with 0.6% (v/v) methanol in dichloromethane to afford an oil. This oil was dissolved in isopropanol (3 ml), then hydrogen chloride (1M solution in diethyl ether; 3 ml) was added to the solution. The resulting mixture was concentrated in vacuo to afford the title compound (1:1 hydrochloride salt) (66 mg).
Reaction SMILES: [C:1]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH3:16][C:17]([O-])([CH3:19])[CH3:18].[K+].[I-].[Na+]>C(O)(C)(C)C>[CH2:16]([O:4][CH2:3][CH2:2][CH:2]([C:3]([O:5][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:4])[C:1]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:17]1[CH:19]=[CH:8][CH:6]=[CH:7][CH:18]=1
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)C(CCOCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 48 h

Procedure:
Di(tert-butyl) malonate (151.4 g, 686 mmol) was added dropwise at 50° C. to a suspension of potassium tert-butylate (77 g, 686 mmol) in 500 ml of tert-butanol. Sodium iodide (10.33 g) was then added, followed by dropwise addition of Intermediate 5C (117.1 g, 686 mmol) at 40-50° C. The resulting thick suspension was stirred at 70° C. for two days. During this time, two further portions of potassium tert-butylate (15.4 g each, 70 mmol) were added. The mixture was then poured into ice-water and extracted three times with diethyl ether. The organic layers were dried over Na2SO4, filtered and evaporated. The crude product was finally purified by column chromatography using a cyclohexane/ethyl acetate gradient (70:1→15:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[C:11]([O:15][CH3:16])[CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([CH2:17][C:18](=[CH:21]NC1C=CC=CC=1)[C:19]#[N:20])=[CH:8]2.[ClH:29].[NH2:30][C:31]([NH2:33])=[NH:32].C[O-].[Na+]>C(O)C>[ClH:29].[NH2:32][C:31]1[N:33]=[C:19]([NH2:20])[C:18]([CH2:17][C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][C:11]([O:15][CH3:16])=[C:12]([O:13][CH3:14])[C:3]=3[O:2][CH3:1])[CH:8]=2)=[CH:21][N:30]=1
Reactant: N=C(N)N
Reactant: COc1cc2cc(CC(C#N)=CNc3ccccc3)ccc2c(OC)c1OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COc1cc2cc(Cc3cnc(N)nc3N)ccc2c(OC)c1OC
Yield: 27 %

Procedure:
The aldehyde from above was converted to 2-(5,6,7-trimethoxy-2-naphthylmethyl)-3-anilinoacrylonitrile on a 8 mmol scale in the same manner as Example 5-A. The crude product from this reaction was cyclised with guanidine hydrochloride and sodium methylate in ethanol as in Example 5-B to give the title compound as the free base, 0.74 g (27% yield). This was recrystallised from ethanol plus an equivalent of hydrochloric acid, 0.26 g, mp 252°-254°. Anal. Calcd. for C18H20N4O3HCl: C 57.37; H, 5.62; N, 14.87; Cl, 9.41. Found: C, 57.11; H, 5.67; N, 14.79; Cl, 9.31.
Reaction SMILES: [I:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[CH3:7].C(N(CC)C(C)C)(C)C.Cl[CH2:18][O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:20]([O:19][CH2:18][N:6]1[C:2]([I:1])=[C:3]([CH3:7])[CH:4]=[N:5]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1cn[nH]c1I
Reactant: ClCOCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cnn(COCc2ccccc2)c1I
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-iodo-4-methyl-1H-pyrazole (0.5 g, 2.4 mmol, CAS RN 24086-18-8) in CH2Cl2 (5 mL) was added N,N-diisopropylethylamine (342 mg, 450 μL, 2.64 mmol) and benzyl chloromethyl ether (460 mg, 407 μL, 2.64 mmol, CAS RN 3587-60-8) at 0° C. The reaction mixture was stirred at room temperature for 30 minutes and then poured on 30 mL 10% aqueous NaHCO3 solution and 30 mL CH2Cl2. The layers were separated and the aqueous layer was extracted a second time with 30 mL CH2Cl2. The organic layers were washed with 30 mL brine, dried with MgSO4, filtered and concentrated under vacuum. The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 70:30). Colorless oil (610 mg, 77%). MS (ESI): m/z=329.014 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][S:9]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16](=[O:21])[CH2:15]3)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH2:22]([N:24]([CH2:39][CH3:40])[CH2:25][CH2:26][NH:27][C:28]([C:30]1[C:34]([CH3:35])=[C:33]([CH:36]=O)[NH:32][C:31]=1[CH3:38])=[O:29])[CH3:23]>>[CH2:39]([N:24]([CH2:22][CH3:23])[CH2:25][CH2:26][NH:27][C:28]([C:30]1[C:34]([CH3:35])=[C:33]([CH:36]=[C:15]2[C:14]3[C:18](=[CH:19][CH:20]=[C:12]([S:9](=[O:11])(=[O:10])[NH:8][C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[CH:13]=3)[NH:17][C:16]2=[O:21])[NH:32][C:31]=1[CH3:38])=[O:29])[CH3:40]
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Reactant: O=C1Cc2cc(S(=O)(=O)Nc3cccc(Cl)c3)ccc2N1
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3ccc(S(=O)(=O)Nc4cccc(Cl)c4)cc32)c1C
Yield: 37.2 %

Procedure:
2-Oxo-2,3-dihydro-1H-indole-5-sulfonic acid (3-chloro-phenyl)amide (120 mg, 3.8 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide (100 mg) to give 80 mg (37%) of the title compound as a yellow solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[N:7]1.[C:15]1([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[N:6]1([CH2:5][CH2:4][CH2:3][CH2:2][N:28]2[CH2:29][CH2:30][CH:25]([C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=[CH:17][CH:16]=3)[CH2:26][CH2:27]2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[N:7]1
Reactant: ClCCCCn1nnc2ccccc21
Reactant: c1ccc2c(C3CCNCC3)cccc2c1
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc2c(C3CCN(CCCCn4nnc5ccccc54)CC3)cccc2c1
Temperature: 25 °C
Yield: 59.8 %

Procedure:
1-(4-chlorobutyl)-1H-benzotriazole (7.55 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, 4-(1-naphthyl)piperidine (6.4 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred and mixed, then heated and refluxed to react for 20 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3 and purified, eluted with dichloromethane to produce 6.9 g compound (I-156) with a yield of 60.1%. ESI-MS [M+H]+: m/z 385.3.
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH:22]1([NH2:27])[CH2:26][CH2:25][CH2:24][CH2:23]1>CCCCO>[CH:22]1([NH:27][C:2]2[C:3]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=3)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: NC1CCCC1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Solvent: CCCCO
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(NC3CCCC3)nc2c1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
Into an 8-mL sealed tube, was placed methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (200 mg, 0.58 mmol, 1.00 equiv), cyclopentanamine (246.8 mg, 2.90 mmol, 5.00 equiv), and n-BuOH (2 mL). The resulting solution was stirred for 4 hrs at 100° C. in an oil bath. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:50) resulting in 214.1 mg (crude) of methyl 3-(cyclopentylamino)-2-phenylquinoxaline-6-carboxylate as a yellow oil.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][C:11]([CH3:14])([OH:13])[CH3:12]>C(Cl)(Cl)Cl.C(Cl)Cl>[CH3:12][C:11]1([CH3:14])[CH2:10][CH2:9][CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[O:13]1
Reactant: CC(C)(O)CCCc1ccccc1O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC1(C)CCCc2ccccc2O1
Temperature: 80 °C

Procedure:
To a solution of 100 mg (0.52 mmol) 5-(o-hydroxyphenyl)-2-methyl-2-pentanol in 2 ml chloroform is added 25 mg (25 wt %) of p-tosic acid in one portion. The resulting solution is then heated at 80° C. for 2 hours. The reaction mixture is then diluted with methylene chloride and washed with a sat. solution of sodium bicarbonate. The organic layer is dried (MgSO4), filtered and concentrated to obtain 2,2-dimethyl-2,3,4,5-tetrahydro-1-benzoxepin which is used directly in the next step.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[Cl:14][C:15]1[N:24]=[C:23](Cl)[C:22]2[C:17](=[CH:18][C:19]([O:28][CH3:29])=[C:20]([O:26][CH3:27])[CH:21]=2)[N:16]=1.O>O1CCOCC1>[Cl:14][C:15]1[N:24]=[C:23]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])[C:22]2[C:17](=[CH:18][C:19]([O:28][CH3:29])=[C:20]([O:26][CH3:27])[CH:21]=2)[N:16]=1
Reactant: COc1cc2nc(Cl)nc(Cl)c2cc1OC
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)C(C(=O)OCC)c1nc(Cl)nc2cc(OC)c(OC)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Diethyl malonate (0.76 mL) was dissolved in dioxane (25 mL), sodium hydride (200 mg) was added, and the mixture was stirred at room temperature for 30 min. Then, 2,4-dichloro-6,7-dimethoxyquinazoline (1.3 g) was added, and the mixture was heated under reflux for 3.5 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was recrystallized from a mixed solvent of ethyl acetate and hexane to give the title compound (840 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([O:14][CH3:15])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+](=[CH2:18])=[N-]>CO>[CH3:18][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([O:14][CH3:15])[CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:2]=1[NH2:1]
Reactant: COc1cc(C(=O)O)c(N)c([N+](=O)[O-])c1
Reactant: C=[N+]=[N-]
Solvent: CO
Product: COC(=O)c1cc(OC)cc([N+](=O)[O-])c1N

Procedure:
To a solution of 2-amino-5-methoxy-3-nitro-benzoic acid (2 g, 9.4 mmol) in methanol (100 mL) was added slowly a saturated ethereal solution of diazomethane gas until the starting material was completely consumed (25 mL). Ether was removed under vacuum and the resulting residue was purified by column chromatography using 5% ethyl acetate in hexane to obtain the title compound as a yellow solid which was used directly for the next reaction.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([S:9]([OH:12])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.N([O-])=O.[Na+].[CH3:18][S:19]SC>O>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([S:9]([OH:12])(=[O:11])=[O:10])=[CH:3][C:2]=1[S:19][CH3:18]
Reactant: CSSC
Reactant: Nc1cc(S(=O)(=O)O)ccc1Cl
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CSc1cc(S(=O)(=O)O)ccc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 291.5 %

Procedure:
To a solution of 3-amino-4-chloro-benzenesulfonic acid (5.00 g, 24 mmol) in distilled water (38 mL) and concentrated HCl (6 mL, 72 mmol) at 0° C. was added sodium nitrite (1.99 g, 28.9 mmol) in H2O (10 mL). After 1.5 h, the mixture was allowed to warm to 25° C. and stirred for 1.5 h. Methyl disulfide (10.7 mL, 120 mmol) was added and the mixture heated to 70° C. for 18 h. The solvent was removed, in vacuo, to give an orange solid (16.7 g) that was used as is in the next reaction.
Reaction SMILES: [CH2:1](Br)[C:2]#C.[CH2:5]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([S:25](=[O:28])(=[O:27])[NH2:26])[C:17]=1[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:12]([OH:14])=[O:13])[CH:6]=[CH2:7]>>[CH2:1]([O:13][C:12](=[O:14])[C:11]1[CH:15]=[C:16]([S:25](=[O:28])(=[O:27])[NH2:26])[C:17]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:9]([NH:8][CH2:5][C:6]#[CH:7])[CH:10]=1)[CH3:2]
Reactant: C=CCNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1
Reactant: C#CCBr
Product: C#CCNc1cc(C(=O)OCC)cc(S(N)(=O)=O)c1Oc1ccccc1

Procedure:
By substituting propargyl bromide (4.8 g) for the allyl bromide of Example 58 A and extending the reaction time to 48 hours, ethyl-4-phenoxy-3-propargylamino-5-sulphamyl-benzoate was obtained with a melting point of 189°-190° C.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].Cl[SiH:5]1[N:9]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:8]=[CH:7][N:6]1[C:14]([CH3:17])([CH3:16])[CH3:15]>CCCCCC>[C:14]([N:6]1[CH:7]=[CH:8][N:9]([C:10]([CH3:13])([CH3:12])[CH3:11])[SiH:5]1[NH:3][CH2:1][CH3:2])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)N1C=CN(C(C)(C)C)[SiH]1Cl
Reactant: CCN
Solvent: CCCCCC
Product: CCN[SiH]1N(C(C)(C)C)C=CN1C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
In an argon atmosphere, 3.40 g (75.5 mmol) of ethylamine was dissolved in 30 mL of hexane, and a solution obtained by dissolving 5.78 g (24.8 mmol) of Si(tBuNCHCHNtBu)(H)Cl in 5 mL of hexane was added thereto at −20° C. After stirring at room temperature for 2 hours, insoluble matters produced were separated by filtration, and the solvent was removed by distillation from the filtrate under atmospheric pressure. The obtained residue was distilled under reduced pressure (distillation temperature: 86° C./4.1×102 Pa) to obtain 1,3-di-tert-butyl-2-ethylamino-1,3-diaza-2-silacyclopent-4-ene (Si(tBuNCHCHNtBu)(H)NHEt) as a pale yellow liquid (yielded amount: 5.77 g, yield: 96%).