Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[OH:8][C:9]1([C:15]2[CH:16]=[C:17]([S:21]([C:24]3[CH:25]=[C:26]([C:31]([NH2:33])=[NH:32])[S:27][C:28]=3[S:29][CH3:30])(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=2)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.[H-].[Na+].IC>CN(C=O)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:2][O:8][C:9]1([C:15]2[CH:16]=[C:17]([S:21]([C:24]3[CH:25]=[C:26]([C:31]([NH2:33])=[NH:32])[S:27][C:28]=3[S:29][CH3:30])(=[O:22])=[O:23])[CH:18]=[CH:19][CH:20]=2)[CH2:10][CH2:11][O:12][CH2:13][CH2:14]1
Reactant: CSc1sc(C(=N)N)cc1S(=O)(=O)c1cccc(C2(O)CCOCC2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CI
Product: COC1(c2cccc(S(=O)(=O)c3cc(C(=N)N)sc3SC)c2)CCOCC1
Reaction time: 0.33 h

Procedure:
To a solution of the BOC-protected amidine (46 mg, 0.09 mmol) (prepared in example 149) in 0.2 mL of DMF at 25° C. was added NaH (60% oil dispersion, 5.7 mg, 0.14 mmol). The reaction was allowed to stir for 20 mins then iodomethane (6 uL, 0.09 mmol) was added and the reaction stirred for additional 12 hrs. The solvent was evaporated and the crude material purified by flash chromatography to give the title compound as a BOC protected amidine, which was deprotected in 2 mL of 50% TFA/DCM (25° C., 1 hr) to give the title compound (11.5 mg, 20%) as a yellow solid: 1H NMR (400 MHz, CD3OD) δ 8.34 (s, 1H), 8.14 (m, 1H), 7.92 (m, 1H), 7.80 (m, 1H), 7.66 (m, 1H), 3.89 (m, 4H), 3.00 (s, 3H), 2.74 (s, 3H), 2.02 (m, 4H). Mass spectrum (ESI, m/z) calcd. for C18H22N2O4S3 426.1, found 427.1 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]([CH3:28])([CH2:22][CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:9]([CH:11](C(OCC)=O)[C:12](OCC)=[O:13])=[O:10])=[CH:4][CH:3]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O.Cl>CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O1CCCC1>[CH3:26][C:24]([CH3:25])([CH3:27])[CH2:23][CH2:22][C@@:8]1([CH3:28])[C:5]2[C:4](=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:12]([OH:13])=[CH:11][C:9]1=[O:10]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)[C@@](C)(CCC(C)(C)C)c1ccc(F)cc1
Agent: CS(=O)(=O)O
Agent: Cl
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)CC[C@]1(C)C(=O)C=C(O)c2cc(F)ccc21
Temperature: 70 °C
Yield: 50.2 %

Procedure:
The compound of Example 25D (1.68 g, 4.25 mmol) was dissolved in Eaton's reagent (15 mL, 1:10 (w/w) phosphorus pentoxide in methanesulfonic acid, cf. P. E. Eaton, et al. J. Am. Chem. Soc. 1973, 38, 4071) and warmed at 70° C. for 18 h. The solution was cooled to 25° C. and added to a mixture of ice and water. The mixture was extracted with dichloromethane (3×) and the combined organic layers dried (Na2SO4) and concentrated in vacuo. The oil obtained was dissolved in tetrahydrofuran (30 mL) and treated with 1 N HCl solution, followed by warming at reflux for 18 h. The mixture was cooled and extracted with ethyl acetate (2×). The combined organic layers were extracted with water (2×) and saturated NaCl solution. Drying (Na2SO4) and concentration in vacuo afforded a brown solid, which was triturated with ether-hexane and the resulting solid collected by filtration. These procedures afforded the title compound (590 mg, 50%) as an off-white solid. 1H NMR (300 MHz, DMSO-d6): δ 0.32 (m, 1 H) 0.71 (m, 10 H) 1.43 (s, 3 H) 1.91 (s, 1 H) 2.05 (m, 1 H) 5.73 (s, 1 H) 7.43 (m, 1 H) 7.57 (dd, J=9.56, 2.57 Hz, 1 H) 7.71 (s, 1 H) 11.79 (s, 1 H). Specific rotation: [α]D −27.7°(c 2.11, EtOH).
Reaction SMILES: Cl[CH2:2][C:3](=[O:25])[C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([C:19](=[O:23])[CH2:20]2)[C@:16]2([CH3:17])[C@H:11]([CH2:12][C:13](=[O:24])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>O1CCCC1.O>[O:29]1[CH2:30][CH2:31][N:26]([CH2:2][C:3](=[O:25])[C@@H:4]2[C@:21]3([CH3:22])[C@H:7]([C@H:8]4[C@H:18]([C:19](=[O:23])[CH2:20]3)[C@:16]3([CH3:17])[C@H:11]([CH2:12][C:13](=[O:24])[CH2:14][CH2:15]3)[CH2:10][CH2:9]4)[CH2:6][CH2:5]2)[CH2:27][CH2:28]1
Reactant: C[C@]12CCC(=O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CCl)[C@@]3(C)CC(=O)[C@@H]12
Reactant: C1COCCN1
Solvent: C1CCOC1
Solvent: O
Product: C[C@]12CCC(=O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CN4CCOCC4)[C@@]3(C)CC(=O)[C@@H]12
Reaction time: 72 h

Procedure:
21-Chloro-5α-pregnane-3,11,20-trione (200 mg.) in dry tetrahydrofuran (4 ml.) was treated with morpholine (0.20 ml.), and the solution was refluxed for 21/2 hours, and then left at room temperature for 3 days. The solution was diluted with water and extracted with chloroform. The organic solution was washed with water, dried over sodium sulphate and evaporated to a white foam (210 mg.), which was purified by preparative TLC in ethyl acetate to give 21-morpholino-5α-pregnane-3,11,20-trione (88 mg.) as a white foam, [α]D + 99°, (c 0.59). Treatment of this product in similar manner to that described in Example 50 gave title compound.
Reaction SMILES: S([O-])([O-])=O.[Na+:5].[Na+].C(=O)(O)[O-].[Na+].O.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=1[S:23](Cl)(=[O:25])=[O:24]>C1(C)C=CC=CC=1>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=1[S:23]([O-:25])=[O:24].[Na+:5]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(Cl)c(S(=O)[O-])c1
Reaction time: 2 h

Procedure:
321 ml. (4.7 moles) of chlorosulfonic acid and 79 g. (0.5 moles) of 4-chloro-nitrobenzene are stirred at 130° C. for 6 hours. The reaction mixture is then cooled to a temperature below 10° C. and is poured onto 750 ml. of icy water. The mixture is filtered at room temperature and the substance collected on the filter is washed acid-free with about 2 liters of water. The crude 2-chloro-5-nitrobenzene sulfonyl chloride obtained is subjected to the subsequent reaction steps without purification. 118 g. (0.935 moles) of anhydrous sodium sulfite and 20 g. of sodium bicarbonate are dissolved in 250 ml. of water, and to the solution obtained a mixture of the crude 2-chloro-5-nitrobenzene sulfonyl chloride and 20 g. of sodium bicarbonate is added at a temperature of 23° to 25° C., in one hour. The reaction mixture is stirred for two hours at a temperature of 23° to 25° C., and, after the addition of 200 ml. of toluene, for further 15 minutes. The mixture is stirred at 25° C. and the substance filtered off is washed with 100 ml. of toluene. The sodium 2-chloro-5-nitrobenzene sulfinate obtained is dissolved in 400 ml. of water at 40° C., and the solution is admixed with 200 ml. of toluene. The insoluble part is filtered off and the toluene phase is separated from the filtrate. The aqueous phase is cooled to 10° C., acidified with 100 ml. of concentrated aqueous hydrochloric acid solution and the precipitated crystals are stirred, filtered off at 10° C. and dried. 61 g. of 2-chloro-5-nitrobenzene sulfinic acid are obtained. Yield: 55% of theoretical related to 4-chloro-nitrobenzene.
Reaction SMILES: N(OC(C)(C)C)=O.N[C:9]1[N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:12]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:11][C:10]=1[C:22]#[N:23].C(Br)(Br)[Br:25]>>[Br:25][C:9]1[N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:12]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:11][C:10]=1[C:22]#[N:23]
Reactant: CCCCc1nc(C#N)c(N)n1CC(C)C
Reactant: BrC(Br)Br
Agent: CC(C)(C)ON=O
Product: CCCCc1nc(C#N)c(Br)n1CC(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 39 %

Procedure:
tert-Butyl nitrite (6.2 g, 0.060 mol) was added over a period of five minutes to solution of 5-amino-2-butyl-1-(2-methylpropyl)-1H-imidazole-4-carbonitrile (6.60 g, 30.0 mmol) in bromoform (50 mL). After about ten minutes, an exotherm occurred, and the reaction was poured into ice water. The reaction temperature peaked at 55° C. The reaction was stirred at room temperature for 45 minutes and then concentrated under reduced pressure while heating at about 55° C. The crude product (20 g) was purified by column chromatography on silica gel (eluting sequentially with dichloromethane and 5% ethyl acetate in dichloromethane) to provide 3.37 g (39%) of 5-bromo-2-butyl-1-(2-methylpropyl)-1H-imidazole-4-carbonitrile as an orange oil.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:31][CH2:32][CH3:33])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH2:26][C:27](O)=[O:28])([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)=[O:17])[C:7]1=[O:30])[CH3:2].Cl.C(N=C=NCCCN(C)C)C.[NH2:46][C:47]1[CH:52]=[CH:51][C:50]([CH3:53])=[CH:49][CH:48]=1>ClCCl.CN(C)C1C=CN=CC=1>[CH2:32]([O:31][CH:4]([O:3][CH2:1][CH3:2])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH2:26][C:27]([NH:46][C:47]2[CH:52]=[CH:51][C:50]([CH3:53])=[CH:49][CH:48]=2)=[O:28])([NH:15][C:16]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=2)=[O:17])[C:7]1=[O:30])[CH3:33]
Reactant: CCOC(CN1C(=O)C(CC(=O)O)(NC(=O)Nc2ccc(C)cc2)c2ccccc21)OCC
Reactant: Cc1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCOC(CN1C(=O)C(CC(=O)Nc2ccc(C)cc2)(NC(=O)Nc2ccc(C)cc2)c2ccccc21)OCC
Reaction time: 18 h
Yield: 116.5 %

Procedure:
In 100 ml of dichloromethane was dissolved 2.8 g of (+)-1-(2,2-diethoxyethyl)-3-hydroxycarbonylmethyl-3-(N'-(4-methylphenyl)ureido)indolin-2-one, and 1.20 g of 4-dimethylaminopyridine, 1.90 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, and 1.10 g of p-toluidine were successively added thereto. The mixture was stirred for 18 hours and concentrated. The concentrate was diluted with ethyl acetate, washed successively with dilute hydrochloric acid and saturated aqueous sodium hydrogencarbonate. The organic layer was dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to yield 3.90 g (81%) of the title compound as a white powder. The resulting compound was found to be optically pure as analyzed by high performance liquid chromatography using an optically active column (CHIRALCEL OD, produced by Daicel Chemical Industries, Ltd.).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=O)[CH2:7][CH2:8][C:2]1=2.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]=[C:18]=S)=[CH:13][CH:12]=1.C[Si](C)(C)[Si](C)(C)C.[Li].O.[NH2:30][NH2:31]>C1COCC1.O.C(O)(=O)C>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[C:7]3[CH2:8][C:2]4[S:1][CH:5]=[CH:4][C:3]=4[C:6]=3[NH:31][N:30]=2)=[CH:13][CH:12]=1
Reactant: O=C1CCc2sccc21
Reactant: S=C=Nc1ccc(Br)cc1
Reactant: NN
Agent: C[Si](C)(C)[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: Brc1ccc(Nc2n[nH]c3c2Cc2sccc2-3)cc1
Reaction time: 8 h
Yield: 32 %

Procedure:
A mixture of 5,6-Dihydro-cyclopenta[b]thiophen-4-one (1.0 g, 7.4 mmol) and 1-Bromo-4-isothiocyanato-benzene (1.5 g, 7.2 mmol) in THF (2.0 mL) was added to lithium hexamethyl disilane (7.0 mL, 7.2 mmol) dropwise at room temperature. The reaction mixture was stirred for 8 hr. Hydrazine monohydrate (0.4 mL, 7.9 mmol) and glacial acetic acid (0.5 mL) were added to the reaction mixture, which was then heated at the reflux temperature for 24 hr. The resulting mixture was added to water (30 mL) and then extracted with ethyl acetate. The target product was purified by gravity column chromatography (50% EtOAc in hexane) to give (4-Bromo-phenyl)-(4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-amine as brown solid in 32% yield.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=1.[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Cl:34])[C:18]=1[NH:19][C:20]1[C:29]2[C:24](=[C:25]([OH:32])[C:26]([O:30][CH3:31])=[CH:27][CH:28]=2)[O:23][C:22](=[O:33])[CH:21]=1>>[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Cl:34])[C:18]=1[NH:19][C:20]1[C:29]2[C:24](=[C:25]([O:32][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=3)[C:26]([O:30][CH3:31])=[CH:27][CH:28]=2)[O:23][C:22](=[O:33])[CH:21]=1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1O
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCc1cccc([N+](=O)[O-])c1

Procedure:
The title compound was prepared from 1-(bromomethyl)-3-nitrobenzene and 4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxy-2H-chromen-2-one (Example 29) following the procedure outlined in Example 25. 1H NMR (400 MHz, DMSO-d6): δ 9.55 (s, 1H), 8.81 (s, 2H), 8.40 (s, 1H), 8.19 (ddd, 1H), 7.99 (d, 1H), 7.95 (d, 1H), 7.68 (t, 1H), 7.24 (d, 1H), 5.20 (s, 2H), 4.65 (s, 1H), 3.94 (s, 3H); MS (ESI): 487.8.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][CH:14]([O:17][CH2:18][C:19]([OH:21])=O)[CH2:13][CH2:12]2)=[CH:6][C:5]=1[C:22]([F:25])([F:24])[F:23])([O-:3])=[O:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:59][C:60]1[CH:61]=[C:62]2[C:67](=[CH:68][CH:69]=1)[CH:66]=[C:65]([N:70]1[CH2:75][CH2:74][NH:73][CH2:72][CH2:71]1)[CH:64]=[CH:63]2>ClCCl>[F:59][C:60]1[CH:61]=[C:62]2[C:67](=[CH:68][CH:69]=1)[CH:66]=[C:65]([N:70]1[CH2:71][CH2:72][N:73]([C:19](=[O:21])[CH2:18][O:17][CH:14]3[CH2:15][CH2:16][CH:11]([NH:10][C:7]4[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([C:22]([F:24])([F:23])[F:25])[CH:6]=4)[CH2:12][CH2:13]3)[CH2:74][CH2:75]1)[CH:64]=[CH:63]2
Reactant: O=C(O)COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Reactant: Fc1ccc2cc(N3CCNCC3)ccc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1)N1CCN(c2ccc3cc(F)ccc3c2)CC1
Reaction time: 8 h
Yield: 11.3 %

Procedure:
To a solution of 2-[(4-[4-nitro-3-(trifluoromethyl)phenyl]aminocyclohexyl)-oxy]acetic acid (173 mg, 0.48 mmol, 1 eq) in dichloromethane (50 ml) was added DIEA (61.8 mg, 0.48 mmol, 1 eq), HATU (182 mg, 0.48 mmol, 1 eq) and 1-(6-fluoronaphthalen-2-yl)piperazine (110 mg, 0.48 mmol, 1 eq) at room temperature under an inert atmosphere of nitrogen. The resulting solution was stirred overnight. The reaction was then quenched by the addition of water (100 ml) and extracted with dichloromethane (3×50 ml) and the organic layers were combined and then dried over anhydrous sodium sulfate. The solids were filtered off. The resulting mixture was concentrated under vacuum to give a residue, which was applied onto a silica gel column and eluted with 2% methanol in dichloromethane. The product-containing fractions were combined and concentrated under vacuum to afford 1-[4-(6-fluoronaphthalen-2-yl)piperazin-1-yl]-2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]ethan-1-one as a yellow solid (31.1 mg, 11%); (ES, m/z): [M−H]− 573.2; 1H NMR (300 MHz, DMSO/D2O): δ 8.05 (d, J=6.9 Hz, 1H), 7.77-7.82 (m, 2H), 7.53-7.56 (dd, J=1.8, 7.5 Hz, 1H), 7.43-7.46 (dd, J=1.5, 6.9 Hz, 1H), 7.28-7.33 (m, 1H), 7.25 (d, J=1.2 Hz, 1H), 7.06 (s, 1H), 6.83-6.86 (dd, J=1.8, 6.9 Hz, 1H), 4.21 (s, 2H), 3.63 (broad s, 4H), 3.37-3.52 (m, 2H), 3.21-3.26 (m, 4H), 1.94-2.05 (m, 4H), 1.34-1.39 (m, 2H), 1.23-1.29 (m, 2H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH2:12][CH:11]([N:16]([CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1)[CH3:17])[CH2:10]2>N1C=CC=CC=1.C(Cl)Cl>[CH3:1][S:2]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH2:12][CH:11]([N:16]([CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([NH:26][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:24][CH:25]=1)[CH3:17])[CH2:10]2)(=[O:4])=[O:3]
Reactant: CN(CCc1ccc(N)cc1)C1Cc2ccc(N)cc2C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(CCc1ccc(NS(C)(=O)=O)cc1)C1Cc2ccc(NS(C)(=O)=O)cc2C1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Methanesulphonyl chloride (0.155 ml) was added to a solution of 5-amino-2-[N-(4-aminophenethyl)-N-methylamino]indane (0.28 g) in pyridine (30 ml) and the reaction mixture was stirred at room temperature for 17 hours. The solvent was then removed by evaporation in vacuo to give a gum which was dissolved in methylene chloride, washed with aqueous sodium bicarbonate and brine, dried (MgSO4) and evaporated in vacuo. The residue was purified by column chromatography on silica eluting with methylene chloride containing methanol (0% up to 2%) and the product-containing fractions were combined and evaporated to dryness in vacuo to afford the title compound as a foam, yield 0.27 g.
Reaction SMILES: [C:1]([C:4]1[S:8][CH:7]=[C:6]([C:9]([NH2:11])=[O:10])[CH:5]=1)(=[O:3])[CH3:2].[BrH:12].BrBr>C(Cl)(Cl)Cl.C(O)(=O)C>[Br:12][CH2:2][C:1]([C:4]1[S:8][CH:7]=[C:6]([C:9]([NH2:11])=[O:10])[CH:5]=1)=[O:3]
Reactant: CC(=O)c1cc(C(N)=O)cs1
Reactant: Br
Agent: BrBr
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: NC(=O)c1csc(C(=O)CBr)c1

Procedure:
A solution of 5-acetylthiophene-3-carboxamide (0.5 g) in chloroform at 50° was treated with hydrogen bromide in acetic acid (4 drops) and then bromine (0.15 ml) in chloroform (10 ml) dropwise over 30 min. The resulting pale yellow solution was washed with water (2×100 ml), dried and evaporated to small volume to deposit the title compound as a white solid (0.55 g) which recrystallised from water, m.p. 150°-157° (d).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH:7]([OH:9])[CH3:8])[O:4][N:3]=1.C1COCC1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.F[C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[N+:33]([O-:35])=[O:34]>O.CCOC(C)=O>[F:32][C:30]1[CH:29]=[CH:28][C:27]([N+:33]([O-:35])=[O:34])=[C:26]([CH:31]=1)[O:9][CH:7]([C:5]1[O:4][N:3]=[C:2]([CH3:1])[CH:6]=1)[CH3:8]
Reactant: Cc1cc(C(C)O)on1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(C(C)Oc2cc(F)ccc2[N+](=O)[O-])on1

Procedure:
To a solution of 4.15 g (32.64 mmol) 1-(3-Methylisoxazol-5-yl)ethanol in THF 32.64 mL (1 M in THF; 32.64 mmol) LiHMDS is added drop wise. After 30 minutes of stirring 5.19 g (32.64 mmol) 2,4-difluoro-1-nitro-benzene is added. The mixture is stirred over night. The mixture is diluted with water and EtOAc. The organic layer is separated, washed with water, dried and evaporated. The residue is purified by FC giving rise to 5-[1-(5-fluoro-2-nitro-phenoxy)ethyl]-3-methyl-isoxazole.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[CH2:13][CH2:12][CH2:11][NH:10][C:9](=S)[C:8]=2[CH:15]=1)([O-:3])=[O:2].CO[CH:18](OC)[CH2:19][NH2:20].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1.[Hg](OC(C)=O)OC(C)=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[CH2:13][CH2:12][CH2:11][N:10]3[C:9](=[N:20][CH:19]=[CH:18]3)[C:8]=2[CH:15]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2c(c1)C(=S)NCCC2
Reactant: COC(CN)OC
Agent: CC(=O)O[Hg]OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2c(c1)-c1nccn1CCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 14.4 %

Procedure:
A solution of 8-nitro-2,3,4,5-tetrahydro-benzo[c]azepine-1-thione (2 g, 9 mmol) and 2,2-dimethoxy-ethylamine (4.7 g, 45 mmol, 5.0 eq.) in THF (100 mL) was treated with Hg(OAc)2 (4.3 g, 13.5 mmol, 1.5 eq.) at 5° C. The mixture was warmed to 25° C. and stirred for 2 hours, then concentrated. The residue was dissolved in toluene/water (11:1, 150 mL) and treated with p-toluenesulfonic acid (0.76 g, 4 mmol). This mixture was then heated at 65° C. for 24 h and subsequently concentrated under vacuum. The resulting residue was dissolved in methanol/HCl solution (2:1, 100 mL) and heated at 90° C. for 12 hours. Solvent evaporation and purification with silica gel chromatography (DCM/MeOH (9:1)) gave 9-nitro-5,6-dihydro-4H-1,3a-diaza-benzo[e]azulene (300 mg, 1.3 mmol, 15%). 1H NMR (300 MHz, CD3OD) δ 8.50 (d, 1H), 8.23 (dd, 1H), 7.61 (d, 1H), 7.32 (d, 1H), 7.12 (d, 1H), 4.05 (t, 2H), 2.85 (t, 2H), 2.42 (pent, 2H); MS (m/e) 230 (M+1).
Reaction SMILES: [F:1][CH:2]([F:41])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][CH:23]([N:26]([CH2:31][CH2:32]CO)[S:27]([CH3:30])(=[O:29])=[O:28])[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:35]=[CH:36][CH:37]=[C:38]([O:39][CH3:40])[C:5]=2[N:4]=1.[CH3:42]S(Cl)(=O)=O.[NH:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1>>[F:41][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][CH:23]([N:26]([CH2:31][CH2:32][CH2:42][N:47]4[CH2:52][CH2:51][O:50][CH2:49][CH2:48]4)[S:27]([CH3:30])(=[O:28])=[O:29])[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:35]=[CH:36][CH:37]=[C:38]([O:39][CH3:40])[C:5]=2[N:4]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCC(N(CCCO)S(C)(=O)=O)CC2)n1
Reactant: CS(=O)(=O)Cl
Reactant: C1COCCN1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCC(N(CCCN3CCOCC3)S(C)(=O)=O)CC2)n1
Yield: 58 %

Procedure:
Reaction of N-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}-N-(3-hydroxypropyl)methanesulfonamide with methanesulfonyl chloride as in Example 53, followed by reaction with morpholine for 10 days at room temperature, gave N-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}-N-[3-(4-morpholinyl)propyl]methanesulfonamide in 58% yield. Hydrochloride: mp (MeOH) 229-231° C.; 1H NMR (DMSO-d6) δ10.23 (br s, 1H), 7.89 (d, J=8.0 Hz, 1H), 7.70 (t, JHF=52.9 Hz, 1H), 7.41 (t, J=8.2 Hz, 1H), 6.95 (d, J=7.8 Hz, 1H), 4.84-4.74 (m, 2H), 3.98 (s, 3H), 3.95-3.85 (m, 3H), 3.80 (m, 4H), 3.73-3.67 (m, 6H), 3.39-3.29 (m, 2H), 3.17 (t, J=7.2 Hz, 2H), 3.11-2.99 (m, 9H), 1.94-1.84 (m, 4H), 1.72-1.70 (m, 2H); Anal. Calcd. for C29H42ClF2N9O5S.0.75H2O: C, 48.7; H, 6.1; N, 17.6; Cl, 5.0. Found: C, 48.7; H, 6.2; N, 17.6; Cl, 4.9%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([OH:13])=[CH:8][CH:7]=2)#[N:2].Br[CH:15]([CH2:25][CH3:26])[C:16]([NH:18][C:19]([CH3:24])([CH3:23])[C:20]#[C:21][CH3:22])=[O:17]>>[C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:13][CH:15]([CH2:25][CH3:26])[C:16]([NH:18][C:19]([CH3:24])([CH3:23])[C:20]#[C:21][CH3:22])=[O:17])=[CH:8][CH:7]=2)#[N:2]
Reactant: CC#CC(C)(C)NC(=O)C(Br)CC
Reactant: N#Cc1cnc2ccc(O)cc2c1
Product: CC#CC(C)(C)NC(=O)C(CC)Oc1ccc2ncc(C#N)cc2c1

Procedure:
In a similar procedure to Example 6 Stage 2, 3-cyano-6-hydroxyquinoline was reacted with 2-bromo-N-(4-methylpent-2-yn-4-yl) butyramide to give 2-(3-cyano-6-quinolinyloxy)-N-(4-methylpent-2-yn-4-yl) butyramide as a pale yellow solid, m.p. 116-118° C., 1H NMR (CDCl3) δ: 1.08(3H, t); 1.61(3H, s); 1.63(3H, s); 1.80(3H, s); 2.07-2.13(2H, m); 4.72(1H, t); 6.46(1H, s); 7.50 (1H, m); 7.57(1H, dd); 7.71(1H, d); 8.17(1H,d); 8.92(1H, d).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=[O:18].[K+].[K+].Br[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2(C=O)C=CC=CC2)=[CH:30][C:29]=1[O:42][CH3:43]>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][CH2:25][CH2:26][O:27][C:28]4[CH:33]=[CH:32][C:31]([CH:34]=[O:18])=[CH:30][C:29]=4[O:42][CH3:43])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: O=C([O-])[O-]
Reactant: COc1cc(C2(C=O)C=CC=CC2)ccc1OCCCBr
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C=O)ccc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 102.8 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.2 g, 10 mmol), K2CO3 (2.3 g) and 1-[4-(3-bromopropoxy)-3-methoxyphenyl]phenylmethanone (3.47 g, 10 mmol) in acetonitrile (100 ml) was heated at reflux for 3 hours. At the end of reaction, the acetonitrile was concentrated and the mixture was extracted into dichloromethane (200 ml). The insolubles were filtered off and the solvent was evaporated to an oil. Purification was carried out by flash chromatography over a silica gel column (SiO2, 50 g; eluted with dichloromethane, 600 ml; 1% methanol:dichloromethane, 600 ml; 2% methanol: 98% dichloromethane, 600 ml). The fractions containing the pure product were combined and concentrated to give 4.24 g (87%) of an off-white solid. Recrystallization from ethanol (75 ml) gave 3.9 g of 1-[4-[3-[4-(6-fluoro-1,2-benziosoxazol-3-yl)-1-piperidinyl]-propoxy]-3methoxyphenyl]phenylmethanone as off-white crystals, m.p.=128°-130° C.