Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[S:8][C:7]([CH3:9])=[N:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=1)([CH3:3])[CH3:2].Br(O)(=O)=O.[C-]#N.[Na+].B(F)(F)F>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)C.CS(C)=O.C(O)(=O)C>[CH:1]([C:4]1[S:8][C:7]([CH3:9])=[N:6][C:5]=1[C:10]1[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(-c2nc(C)sc2C(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: FB(F)F
Agent: [C-]#N
Solvent: CC(=O)O
Solvent: CS(C)=O
Solvent: CCOCC
Product: Cc1nc(-c2ccc(O)cc2)c(C(C)C)s1

Procedure:
In the fourth step, the compound (5) prepared in the third step is reacted with bromic acid and acetic acid, sodium cyanide and dimethylsulfoxide, or tetrabutylammonium iodide and boron trifluoride.diethylether, to afford 4-(5-isopropyl-2-methyl-1,3-thiazol-4-yl)-phenol (6). Conventionally, ethanethiol is used, whereby offensive odors occur and reagent handling is difficult to the extent of being unsuitable for use in mass production. However, in the present invention, the use of the compound (5) and the above materials reacting therewith, in particular, bromic acid and acetic acid result in decreased offensive odors, low price, simple reagent handling and a drastically increased preparation yield (yield: 84%).
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[NH:10][CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[Br:22][C:23]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26]>CN(C)C=O.O.ClCCl>[Br:22][C:23]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:24]=1[C:25]([N:10]1[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[NH:7][C:6]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:11]1)=[O:26]
Reactant: c1cnc2c(c1)CNc1ccccc1N2
Reactant: O=C(Cl)c1ccc(F)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: O=C(c1ccc(F)cc1Br)N1Cc2cccnc2Nc2ccccc21
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 59.5 %

Procedure:
To a solution of 6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine of Example 1, Step B (5.15 g, 26.1 mmol) in dimethylformamide (70 mL) under nitrogen was added potassium carbonate (7.95 g, 57.51 mmol). The mixture was cooled and treated dropwise with a solution of crude 2-bromo-4-fluorobenzoyl chloride of Step A (31.37 mmol) in dimethylformamide (30 mL). After stirring at room temperature for 75 minutes the mixture was diluted with water and extracted with dichloromethane. The organic extracts were dried over magnesium sulfate and evaporated to dryness to give a brown solid foam. The crude material was dissolved in dichloromethane and absorbed onto a silica Merck-60 flash column. Elution with a hexane-ethyl acetate gradient (from 95:5 to 75:25) provided the pure title compound (6.18 g) along with some impure material (1.2 g). The pure material was triturated with hexane to provide an off-white solid foam, which was used as such in the next step.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:10]([C:11](=O)[C:12]#[CH:13])=[C:6]2[CH:5]=[CH:4][CH:3]=1.Cl.[CH:23]1([NH:28][C:29]([NH2:31])=[NH:30])[CH2:27][CH2:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:10]([C:11]3[CH:12]=[CH:13][N:31]=[C:29]([NH:28][CH:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)[N:30]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: N=C(N)NC1CCCC1
Reactant: C#CC(=O)c1c(-c2ccc(F)cc2)nn2c(Cl)cccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Fc1ccc(-c2nn3c(Cl)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Yield: 43.8 %

Procedure:
In a similar manner as described in Example 7 1-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-2-propyn-1-one (210 mg, 0.70 mmol), cyclopentylguanidine hydrochloride (291 mg, 2.1 mmol), and potassium carbonate (345 mg, 2.1 mmol) were heated at 120° C. for 1.5 hours in 1-methyl-2-pyrrolidinone (8 mL) to form 4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine (125 mg, 44%) as a white foam. 1H NMR (CDCl3) δ 8.42 (d, 1H), 8.09 (d, 1H), 7.67 (dd, 2H), 7.30 (m, 1H), 7.17 (t, 2H), 7.06 (d, 1H), 6.33 (d, 1H), 5.30 (d, 1H), 4.35 (m, 1H), 2.18–2.05 (m, 2H), 1.84–1.52 (m, 6H); 19F NMR (CDCl3) δ −112.78; MS m/z 408 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][C:16](OS(C(F)(F)F)(=O)=O)=[CH:17][CH:18]=2)[C:13]1=[O:30].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:83][N:84]1[CH2:89][CH2:88][NH:87][CH2:86][CH2:85]1>C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][C:16]([N:87]3[CH2:88][CH2:89][N:84]([CH3:83])[CH2:85][CH2:86]3)=[CH:17][CH:18]=2)[C:13]1=[O:30]
Reactant: COC(=O)c1ccc(C)c(-n2ccc3ccc(OS(=O)(=O)C(F)(F)F)cc3c2=O)c1
Reactant: CN1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C)c(-n2ccc3ccc(N4CCN(C)CC4)cc3c2=O)c1
Temperature: 95 °C
Reaction time: 16 h

Procedure:
Methyl 4-methyl-3-[1-oxo-7-{[(trifluoromethyl)sulfonyl]oxy} isoquinolin-2(1H)-yl]benzoate (243 mg), palladium acetate (12 mg), BINAP (69 mg), and cesium carbonate (449 mg) were placed in a reaction tube under an atmosphere of argon. Toluene (2.5 ml) was added followed by N-methylpiperazine (0.183 ml) and the reaction mixture was stirred in a sealed tube at 95° C. for 16 hours. The reaction mixture was diluted with ethyl acetate and washed with water (2×), brine, dried (magnesium sulfate) and concentrated. Purification by column chromatography on an ion exchange column (isolute SCX column from International Sorbent Technology Limited, Henoed, Mid-Glamorgan, UK) using initially methanol and then a 99:1 mixture of methanol and aqueous ammonia solution gave methyl 4-methyl-3-[7-(4-methylpiperazin-1-yl)-1-oxoisoquinolin-2(1H)-yl]benzoate as a brown solid (189 mg); NMR Spectrum: (DMSOd6) 2.12 (s, 3H), 2.23 (s, 3H), 2.50 (m, 4H), 3.25 (m, 4H), 3.88 (s, 3H), 6.65 (d, 1H), 7.12 (d, 1H), 7.52-7.60 (m, 3H), 7.63 (d, 1H), 7.80 (s, 1H), 7.99 (d, 1H); Mass Spectrum: M+H+ 392.
Reaction SMILES: C(OC([NH:8][CH2:9][C@H:10]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH2:17][CH2:16]1)[C:11]([O:13][CH3:14])=[O:12])=O)(C)(C)C.[ClH:31].CO>C(O)(C)C>[ClH:31].[ClH:31].[NH2:8][CH2:9][CH:10]([N:15]1[CH2:16][CH2:17][N:18]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH2:19][CH2:20]1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)[C@H](CNC(=O)OC(C)(C)C)N1CCN(C(=O)OCc2ccccc2)CC1
Agent: Cl
Solvent: CO
Solvent: CC(C)O
Product: COC(=O)C(CN)N1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 40 °C
Yield: 90 %

Procedure:
A solution of 1.45 g (3.4 mmol) of benzyl 4-((S)-2-tert-butoxycarbonylamino-1-methoxycarbonylethyl)piperazine-1-carboxylate in 3.5 ml of a solution of hydrochloric acid in isopropanol, having a concentration 5-6N, and 10 ml of methanol is heated at 40° C. for 3 h and then evaporated. The residue is taken up in diethyl ether and filtered. 1.2 g (90%) of benzyl 4-(2-amino-1-methoxycarbonylethyl)piperazine-1-carboxylate dihydrochloride are obtained in the form of a solid.
Reaction SMILES: S(Cl)([Cl:3])=O.C1C=CC=CC=1.[Cl:11][C:12]1[C:20]([Br:21])=[CH:19][C:18]([N+:22]([O-:24])=[O:23])=[CH:17][C:13]=1[C:14](O)=[O:15]>CN(C=O)C>[Cl:11][C:12]1[C:20]([Br:21])=[CH:19][C:18]([N+:22]([O-:24])=[O:23])=[CH:17][C:13]=1[C:14]([Cl:3])=[O:15]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(Br)c1Cl
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: O=C(Cl)c1cc([N+](=O)[O-])cc(Br)c1Cl
Yield: 100.4 %

Procedure:
5.1 ml (69.9 mmol) of thionyl chloride and a solvent mixture comprising 50 ml of benzene and 0.2 ml of DMF were added to 14.07 g (50.2 mmol) of 2-chloro-3-bromo-5-nitrobenzoic acid. The obtained mixture was heated under reflux for 2 hours and distilled to remove the solvent. Benzene was added to the residue and the obtained mixture was distilled again to remove the solvent. Thus, 15.07 g of the title compound was obtained (yield: quantitative).
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][S:15]([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=3)(=[O:17])=[O:16])=[CH:11][CH:12]=2)[CH2:7][CH2:6]1)=[O:4].C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[CH2:38][P:39]([O:44][CH2:45][CH3:46])([O:41][CH2:42][CH3:43])=[O:40])(=O)=O.O>CN(C)C=O.C(OCC)(=O)C>[Cl:24][C:22]1[CH:23]=[C:18]([S:15]([N:14]([CH2:38][P:39](=[O:40])([O:44][CH2:45][CH3:46])[O:41][CH2:42][CH3:43])[C:10]2[CH:9]=[C:8]3[C:13](=[CH:12][CH:11]=2)[N:5]([C:3](=[O:4])[NH:2][CH3:1])[CH2:6][CH2:7]3)(=[O:17])=[O:16])[CH:19]=[C:20]([Cl:25])[CH:21]=1
Reactant: CNC(=O)N1CCc2cc(NS(=O)(=O)c3cc(Cl)cc(Cl)c3)ccc21
Reactant: CCOP(=O)(COS(=O)(=O)C(F)(F)F)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOP(=O)(CN(c1ccc2c(c1)CCN2C(=O)NC)S(=O)(=O)c1cc(Cl)cc(Cl)c1)OCC
Reaction time: 3 h

Procedure:
2.2 g 5-(3,5-dichloro-phenylsulphonylamino)-2,3-dihydro-indole-1-carboxylic acid-methylamide are dissolved in 15 ml dimethylformamide. To this are added 1.67 g potassium carbonate and 1.32 ml diethoxy-phosphorylmethyl trifluoro-methanesulphonate. The mixture is left for 3 hours at ambient temperature with stirring, the solvent is eliminated in vacuo and the residue is divided between water and ethyl acetate. The aqueous phase is extracted twice from ethyl acetate and the combined organic phases are dried on magnesium sulphate. The solvents are eliminated in vacuo and the residue is extracted from diisopropylether/ethyl acetate.
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][C:7]1[CH:8]=[C:9]([NH:15][C:16]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[N:17]=2)[C:10]([C:13]#[N:14])=[N:11][CH:12]=1.FC(F)(F)C(O)=O>ClCCl.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[NH2:6][C:7]1[CH:8]=[C:9]([NH:15][C:16]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[N:17]=2)[C:10]([C:13]#[N:14])=[N:11][CH:12]=1
Reactant: COc1ccc(CNc2cnc(C#N)c(Nc3cc(C)cc(C)n3)c2)c(OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)nc(Nc2cc(N)cnc2C#N)c1
Reaction time: 0.17 h

Procedure:
To a suspension of 5-[(2,4-dimethoxybenzyl)amino]-3-[(4,6-dimethylpyridin-2-yl)amino]pyridine-2-carbonitrile (240 mg, 0.62 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (0.96 mL, 12.5 mmol) dropwise, and the reaction mixture was stirred for 10 minutes. The reaction mixture was diluted with ethyl acetate and aqueous saturated sodium bicarbonate. The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-65% ethyl acetate/hexanes, linear gradient) to afford 5-amino-3-[(4,6-dimethylpyridin-2-yl)amino]pyridine-2-carbonitrile. MS ESI calc'd for C13H14N5 [M+H]+ 240. found 240. 1H NMR (500 MHz, DMSO-d6) δ 8.59 (s, 1H), 7.61 (d, J=2.3 Hz, 1H), 7.36 (d, J=2.2 Hz, 1H), 6.57 (s, 1H), 6.55 (s, 1H), 6.25 (s, 2H), 2.28 (s, 3H), 2.18 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[N:4][C:5]([C:18]([F:21])([F:20])[F:19])=[C:6]([CH:17]=1)[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[OH:16])=[O:8]>C(O)(C)C.CCCCCCC>[Br:1][C:2]1[C:3]([O:22][CH2:23][C:24]([F:25])([F:26])[F:27])=[N:4][C:5]([C:18]([F:21])([F:19])[F:20])=[C:6]([CH:17]=1)[C:7]([NH:9][C@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[OH:16])=[O:8]
Reactant: O=C(NC1CCCCC1O)c1cc(Br)c(OCC(F)(F)F)nc1C(F)(F)F
Solvent: CCCCCCC
Solvent: CC(C)O
Product: O=C(N[C@H]1CCCC[C@H]1O)c1cc(Br)c(OCC(F)(F)F)nc1C(F)(F)F

Procedure:
5-Bromo-N-((1RS,2SR)-2-hydroxy-cyclohexyl)-6-(2,2,2-trifluoro-ethoxy)-2-trifluoromethyl-nicotinamide (103 g) was subjected to chiral chromatography on ChiralPak AD with 5% isopropanol/n-heptane as eluent. The product eluted as first peak to give after evaporation of the solvent the title compound (42.4 g) as a white solid, MS (ISP) 465.0, 467.0 (M+H)+; [α]D20=−19.8°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2C(=O)O[CH:10]([C:14]([F:17])([F:16])[F:15])[N:9]=2)=[CH:4][CH:3]=1.FC(F)(F)S([C:23]([S:31]([C:34]([F:37])([F:36])[F:35])(=[O:33])=[O:32])=[CH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=O)=O.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10]([C:14]([F:15])([F:16])[F:17])=[C:24]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:23]=2[S:31]([C:34]([F:35])([F:36])[F:37])(=[O:32])=[O:33])=[CH:6][CH:7]=1
Reactant: O=C1OC(C(F)(F)F)N=C1c1ccc(Cl)cc1
Reactant: O=S(=O)(C(=Cc1ccccc1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=S(=O)(c1c(-c2ccc(Cl)cc2)[nH]c(C(F)(F)F)c1-c1ccccc1)C(F)(F)F

Procedure:
A solution of 4-(p-chlorophenyl)-2-(trifluoromethyl)-3-oxazolin-5-one (1.0 g, 3.8 mmol) and β,β-bis[(trifluoromethyl)sulfonyl]styrene (1.4 g, 3.8 mmol) in dimethylformamide is stirred for two hours at 110° C., treated with triethylamine (0.38 g, 3.8 mmol), stirred for several hours at reflux and diluted with an ethyl acetate/water mixture. The organic phase is separated, washed with water and dilute hydrochloric acid, dried over anhudrous magnesium sulfate and concentrated in vacuo to obtain a residue. Chromatography of the residue using silica gel and a 1:10 ethyl acetate/hexanes solution gives the title product as an amber oil which is identified by 1HNMR and 13CNMR spectral analyses.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:16]Br.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:9]([O:8][C:7]1[C:2]([NH2:1])=[N:3][CH:4]=[C:5]([Br:16])[CH:6]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Nc1ncccc1OCc1ccccc1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Nc1ncc(Br)cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
200 g (1 mol) of 2-amino-3-benzyloxypyridine were initially charged in 4 l of dichloromethane, and a solution of 62 ml (1.2 mol) of bromine in 620 ml of dichloromethane was added at 0° C. over a period of 30 min. After the addition had ended, the reaction solution was stirred at 0° C. for 60 min. About 4 l of saturated aqueous sodium bicarbonate solution were then added to the mixture. The organic phase was separated off and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate 6:4) and the product fractions were concentrated. This gave 214 g (77% of theory) of the title compound.
Reaction SMILES: [C:1]1([C:7]2[C:11]3[CH:12]([OH:29])[CH:13]([CH2:16][CH2:17]OS(C4C=CC(C)=CC=4)(=O)=O)[CH2:14][CH2:15][C:10]=3[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.Cl.[F:40][C:41]1[CH:54]=[CH:53][C:44]([C:45]([CH:47]2[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)=[O:46])=[CH:43][CH:42]=1>CN(C=O)C>[F:40][C:41]1[CH:42]=[CH:43][C:44]([C:45]([CH:47]2[CH2:52][CH2:51][N:50]([CH2:17][CH2:16][CH:13]3[CH:12]([OH:29])[C:11]4[C:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)=[N:8][O:9][C:10]=4[CH2:15][CH2:14]3)[CH2:49][CH2:48]2)=[O:46])=[CH:53][CH:54]=1
Reactant: Cc1ccc(S(=O)(=O)OCCC2CCc3onc(-c4ccccc4)c3C2O)cc1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1ccc(F)cc1)C1CCN(CCC2CCc3onc(-c4ccccc4)c3C2O)CC1
Temperature: 80 °C
Yield: 15 %

Procedure:
To a solution consisting of 3-phenyl-5-(2-tosyloxyethyl)-4-hydroxy-4,5,6,7-tetrahydro-1,2-benzisoxazole (8.0 g) and DMF (100 n-il) was added diisopropylethyl amine (6.7 ml) and 4-(4-fluorobenzoyl)piperidine hydrochloride (7.1 g) at room temperature with stirring. The flask was flushed with nitrogen and warmed to 80° C. for 4.5 hours. Upon cooling to room temperature, water and ethyl acetate were added to the reaction mixture. The layers were separated and the aqueous phase was extracted 3 times with ethyl acetate. The combined organic layers were washed with brine and dried (MgSO4). Filtration and concentration gave the crude product. Purification via flash column chromatography (silica gel, 2% triethylamine/ether) afforded 1.3 g of 5-[2-(4-(4-fluorobenzoyl)-1-piperidinyl)-ethyl]-3-phenyl-4-hydroxy-4,5,6,7-tetrahydro-1,2-benzisoxazole.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH3:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1O>>[C:1]1([C:13]2([CH3:12])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1CCCCC1O
Reactant: c1ccccc1
Agent: O=S(=O)(O)O
Product: CC1(c2ccccc2)CCCCC1
Reaction time: 2 h
Yield: 107.6 %

Procedure:
940 g (about 12.0 mole) of benzene was charged into a 3 L 4-necked flask and cooled to below 5° C. in an ice bath, followed by the addition of 1080 g (about 10.5 moles) of 95 concentrated sulfuric acid. The mixture was further cooled until the interior of the reaction vessel was cooled to below 5° C., followed by the addition of a mixture of 550 g (about 4.8 moles) of 2-methylcyclohexanol and 400 g (about 3.8 moles) of benzene in droplets over 5 hours. Thereafter, the reaction was continued for 2 hours. The reaction solution was transferred into a 5 L separatory funnel to separate the sulfuric acid phase. 1 L of pure water was then added to the solution 5 times so as to dissolve and remove the by-products and other impurities. The resulting solution was made alkali with 1% aqueous solution of sodium hydroxide, followed by the addition of 1 L of water until the aqueous phase was made neutral. After the separation of the aqueous phase, the remaining was dehydrated with sodium sulfate anhydride, followed by removal of the light fractions and the excess benzene under at a temperature of 100° C. and pressure of 0.4 kPa (3 mmHg) thereby obtaining about 900 g of crude 1-phenyl-1-methylcyclohexane. This was subjected to vacuum distillation thereby obtaining 800 g of a fraction having a boiling point of 119.7 to 120.5° C. at a pressure of 0.4 kPa (3 mmHg). The fraction was charged into a 2 L autoclave, followed by the addition of 8 g of a nickel-based hydrogenating catalyst. The reaction was carried out at a temperature of 150° C. and at a maximum pressure of 6.86×106 Pa (70 kg/cm2) until the absorption of hydrogen did not occurred. Thereafter, the catalyst was removed thereby obtaining about 820 g of the targeted product represented by the formula
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([CH2:12][CH2:13][Cl:14])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1.C(N(CC)CC)C.Cl[C:23](Cl)([O:25]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)(Cl)Cl>[Cl:1][CH2:2][CH2:3][N:4]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:23]=[O:25])=[CH:7][CH:6]=1)[CH2:12][CH2:13][Cl:14]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc(N(CCCl)CCCl)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C=Nc1ccc(N(CCCl)CCCl)cc1
Reaction time: 0.12 h

Procedure:
The known compound phenylisocyanate N-mustard 19 can be prepared by following the literature procedure35,36 with modification (Scheme 3). The commercially available 4-fluoronitrobenzene (15) is reacted with diethanolamine under refluxing to give 4-[N,N-bis(2-hydroxyethyl)amino]nitrobenzene (16), which is then converted to 4-[N,N-bis(2-chloroethyl)amino]nitrobenzene (17) by treating with thionyl chloride. Catalytic hydrogenation (10% Pd/C, H2) of compound 17 in ethyl acetate affords N,N-bis(2-chloroethyl)benzene-1,4-diamine (18), which is immediately treated with HCl in ethyl acetate to yield hydrochloride salt of 18. The hydrochloride salt 18 is suspended in CHCl3 and cooled in an ice-bath. To the suspension is added triethylamine and stirred in Argon atmosphere for 5 to 10 min. and then is added dropwise triphosgene solution in CHCl3 and continuously stirred for 20 min. The reaction mixture is evaporated under reduced pressure and the residue is the triturated with THF, filtered and the filtrate containing phenylisocyanate 19, which is used directly for the next reaction without purification. Compound 18 and 19 can be used for the synthesis of the newly invented compounds.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](O)(C)[CH2:16][C:17](O)=O.[C:22]([O:25]C(=O)C)(=[O:24])C>>[Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH:16]=[CH:17][C:22]([OH:25])=[O:24]
Reactant: CC(O)(CC(=O)O)c1ccccc1-c1ccc(Br)cc1Br
Reactant: CC(=O)OC(C)=O
Product: O=C(O)C=CCc1ccccc1-c1ccc(Br)cc1Br

Procedure:
1 g. of 3-(2',4'-dibromobiphenylyl)-3-hydroxybutyric acid and 10 ml. of acetic anhydride are heated under reflux for 2 hours and the mixture is poured onto ice and worked up in the customary manner to give 3-(2',4'-dibromo-4-biphenylyl-2-butenoic acid.
Reaction SMILES: [NH:1]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C@H:2]([C:12]([NH:14][C@H:15]([C:23]([NH:25][C@H:26]([C:30]([NH:32][CH:33](OC)[C:34]([OH:36])=[O:35])=[O:31])[CH:27]([CH3:29])[CH3:28])=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-].[Na+].CO>O1CCOCC1>[NH:1]([C:39]([O:41][C:42]([CH3:44])([CH3:43])[CH3:45])=[O:40])[C@H:2]([C:12]([NH:14][C@H:15]([C:23]([NH:25][C@H:26]([C:30]([NH:32][CH2:33][C:34]([OH:36])=[O:35])=[O:31])[CH:27]([CH3:29])[CH3:28])=[O:24])[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COC(NC(=O)[C@@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C)C(C)C)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Temperature: 25 °C

Procedure:
Mix Boc-Ser(OBn)-Phe-Val-Gly(OMe), SEQ ID NO:23, (3.95 g, 6.45 mmol), 1 N sodium hydroxide (39 mL, 39 mmol), methanol (100 mL) and dioxane (60 mL). Stir at room temperature under a nitrogen atmosphere until hydrolysis is complete. Evaporate the solvent in vacuo and purify by silica gel chromatography (chloroform) to give Boc-Ser(OBn)-Phe-Val-Gly, SEQ ID NO:25, (3.32 g, 85.4%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][O:16][CH3:17])[CH:6]=[CH:7][C:8](O)=O.[NH2:18][C:19]1[C:20](=[O:33])[N:21]([CH2:30][CH2:31][CH3:32])[C:22](=[O:29])[N:23]([CH2:26][CH2:27][CH3:28])[C:24]=1[NH2:25].[OH-].[Na+].Cl>O1CCOCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][O:16][CH3:17])/[CH:6]=[CH:7]/[C:8]1[NH:18][C:19]2[C:20](=[O:33])[N:21]([CH2:30][CH2:31][CH3:32])[C:22](=[O:29])[N:23]([CH2:26][CH2:27][CH3:28])[C:24]=2[N:25]=1
Reactant: COCOc1ccc(C=CC(=O)O)cc1OC
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCCn1c(=O)c2[nH]c(/C=C/c3ccc(OCOC)c(OC)c3)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.7 %

Procedure:
3-Methoxy-4-methoxymethoxy cinnamic acid (4.63 g, 19.4 mmol) and 3-(3-diethylaminopropyl)-1-ethylcarbodiimido hydrochloride (5.08 g) were added to a mixed solution of 4.00 g (17.7 mmol) of 5,6-diamino-1,3-dipropyluracil [J. Med. Chem., 28, 487 (1985)] in 50 ml of dioxane/25 ml of water. The solution was stirred at room temperature for 1 hour while adjusting to pH 5.5. The reaction mixture was cooled to room temperature, then 1.59 g of sodium hydroxide and 2N sodium hydroxide solution (50 ml) were added thereto. The mixture was heated under reflux for 1 hour, followed by cooling. The mixture was neutralized by adding 2N hydrochloric acid and the resulting precipitate was collected by filtration. The obtained crude product was recrystallized from dioxane/water to give 5.06 g (67% yield) of Compound c as pale yellow crystals.