Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:3])[CH3:2].[CH:12]([P:15](Cl)(Cl)=[O:16])([CH3:14])[CH3:13]>>[CH:12]([P:15]1(=[O:16])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][N:4]1[CH:1]([CH3:3])[CH3:2])([CH3:14])[CH3:13]
Reactant: CC(C)NCc1ccccc1
Reactant: CC(C)P(=O)(Cl)Cl
Product: CC(C)N1Cc2ccccc2P1(=O)C(C)C
Yield: 16 %

Procedure:
The procedure of Example 30 was employed utilizing N-isopropyl-N-benzylamine and isopropyl phosphonic dichloride. The reaction of the dilithio compound and the isopropyl phosphonic dichloride was conducted at -70° C. The crude product produced as a result of the chromatographic separation was distilled at 130° C. and 0.1 mm to yield a colorless oil. This oil was slurried in petroleum ether to yield 1,2-diisopropyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (2.28 g, 16% yield) as a pale yellow oil having the following analysis:
Reaction SMILES: [CH2:1]([O:3][C@H:4]1[CH2:21][C@@:20]2([CH3:22])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[C:18](=O)[CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]2=[CH2:24])[CH2:6][C@@H:5]1[OH:25])[CH3:2].Cl.[NH2:27][OH:28]>C(O)C.[OH-].[Na+]>[CH2:1]([O:3][C@H:4]1[CH2:21][C@@:20]2([CH3:22])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[C:18](=[N:27][OH:28])[CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]2=[CH2:24])[CH2:6][C@@H:5]1[OH:25])[CH3:2]
Reactant: NO
Reactant: C=C1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](OCC)C[C@]4(C)[C@H]3C(=O)C[C@]12C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C=C1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](OCC)C[C@]4(C)[C@H]3C(=NO)C[C@]12C
Yield: 76.7 %

Procedure:
A solution of 2β-ethoxy-3α-hydroxy-17-methylene-5α-androstan-11-one (1.75 g) in ethanol (50 ml) was added to a mixture of hydroxylamine hydrochloride (3.6 g) in 50% sodium hydroxide solution (14 ml) and the resulting suspension was stirred and refluxed for 35 hours. Most of the solvent was evaporated in vacuo and the residue was partitioned between ethyl acetate and water. Evaporation of the washed organic layer and crystallization of the residue from ethyl acetate afford the title compound (1.4 g), m.p. 97°-99°, [α]D +44.1°.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1)[CH:6]=[CH:5]2.[NH2:20][OH:21].Cl>CCO>[OH:21][NH:20][C:16](=[NH:17])[C:15]1[CH:14]=[CH:13][C:12]([C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([OH:1])[CH:3]=3)[N:8]=2)=[CH:19][CH:18]=1
Reactant: NO
Reactant: N#Cc1ccc(-c2ccc3cc(O)ccc3n2)cc1
Agent: Cl
Solvent: CCO
Product: N=C(NO)c1ccc(-c2ccc3cc(O)ccc3n2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 77.8 %

Procedure:
See Scheme 4, route B. 4-(6-hydroxyquinolin-2-yl)benzonitrile (900 mg, 3.68 mmol) was dissolved in 25 mL of EtOH and to it was added NH2OH.HCl (500 mg, 7.36 mmol) and TEA (1.5 mL). The mixture was stirred at 80° C. for 2 hours followed by concentration in vacuo. The crude solids were then suspended in 25 mL of H2O and stirred for 1 hour. Filtration and drying of the solids yielded desired product (800 mg, 78% yield).
Reaction SMILES: S(C1C=CC(C)=CC=1)(O[CH:5]1[CH2:10][CH2:9][C:8]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)(=O)=O.[Cl:32][C:33]1[CH:34]=[C:35]([N:40]2[C:44]3([CH2:49][CH2:48][NH:47][CH2:46][CH2:45]3)[C:43](=[O:50])[NH:42][CH2:41]2)[CH:36]=[CH:37][C:38]=1[F:39].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.CN(C)C=O>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2([C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)[CH2:7][CH2:6][CH:5]([N:47]3[CH2:46][CH2:45][C:44]4([N:40]([C:35]5[CH:36]=[CH:37][C:38]([F:39])=[C:33]([Cl:32])[CH:34]=5)[CH2:41][NH:42][C:43]4=[O:50])[CH2:49][CH2:48]3)[CH2:10][CH2:9]2)=[CH:12][CH:13]=1
Reactant: O=C1NCN(c2ccc(F)c(Cl)c2)C12CCNCC2
Reactant: Cc1ccc(S(=O)(=O)OC2CCC(c3ccc(F)cc3)(c3ccc(F)cc3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1NCN(c2ccc(F)c(Cl)c2)C12CCN(C1CCC(c3ccc(F)cc3)(c3ccc(F)cc3)CC1)CC2
Reaction time: 5 h

Procedure:
A mixture of 10.6 g of 4,4-bis(p-fluorophenyl)cyclohexyl tosylate, 5.7 g of 1-(3-chloro-4-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one (m.p. 194.5°-196.5° C), 3.3 g of potassium carbonate, 4 g of potassium iodide and 50 ml of dimethylformamide is stirred at 75°-80° C for 5 hours. The reaction mixture is poured into water, and the precipitated crystals are collected by filtration, dried in a desiccator and dissolved in a mixture of chloroform and methanol (9:1). The solution is concentrated to some degree and cooled. The precipitated crystals are collected by filtration and purified in the same manner to give 8-[4,4-bis(p-fluorophenyl)cyclohexyl]-1-(3-chloro-4-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one as white crystals, melting at 201°-203° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](Cl)=[O:15])[CH2:10][CH2:9]1)(=[O:7])[CH3:6].[C:17]1([S:23][CH3:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCl>[C:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:15])[C:20]2[CH:21]=[CH:22][C:17]([S:23][CH3:24])=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)(=[O:7])[CH3:6]
Reactant: CSc1ccccc1
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CSc1ccc(C(=O)C2CCN(C(C)=O)CC2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82.4 %

Procedure:
To a stirred suspension of aluminum chloride (16.66 g, 125 mmol) in dichloromethane (100 mL) was added 1-acetyl-4-piperidinecarbonyl chloride (12.33 g, 65.0 mmol) at −10° C. Thioanisole (6.21 g, 50.0 mmol) was added dropwise at −10° C., the reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was poured into ice water (80 g), the organic layer was separated and the aqueous layer was extracted with dichloromethane (40 mL) The combined organic layers were washed with 1N aqueous sodium hydroxide (2×40 mL), brine (40 mL), dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure. Ethyl acetate and diethyl ether was added to the residue, the resulting precipitate was collected by filtration, washed with diethyl ether, and dried under reduced pressure to afford the title compound (11.43 g, 41.2 mmol, 82%) as a white solid.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].[I-].[CH2:8]([O:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([C:19](=[O:46])[C@@H:20]([NH:30][C:31]([C:33]2[CH:38]=[C:37](Cl)[N:36]=[C:35]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[N:34]=2)=[O:32])[CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:15][CH2:14]1)=[O:12])[CH3:9].[NH4+].[Cl-]>CN(C=O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCN(CC)CC>[CH2:8]([O:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([C:19](=[O:46])[C@@H:20]([NH:30][C:31]([C:33]2[CH:38]=[C:37]([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[N:36]=[C:35]([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[N:34]=2)=[O:32])[CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:15][CH2:14]1)=[O:12])[CH3:9]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(Cl)nc(-c3ccccc3)n2)CC1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cl-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(C#C[Si](C)(C)C)nc(-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
NEt3 (0.249 ml) and trimethylsilylacetylene (0.254 ml) in DMF (4.5 ml) were syringed into a flask containing cupper iodide (8.9 mg), bis-(triphenylphosphine) palladium(II)-dichloride (22.5 mg) and 4-{(S)-4-tert-butoxycarbonyl-2-[(6-chloro-2-phenyl-pyrimidine-4-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester (500 mg) under argon. The mixture was allowed to stir at RT overnight. A saturated NH4Cl solution was added and the resulting mixture was extracted with EA. The org. phases were dried (Na2SO4) and evaporated off. Column chromatography (EA/Hept 1/2 to 1/1.5) afforded 339 mg of the desired compound.
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][C:10]3[C:15]([C:6]=2[S:5](=[O:17])(=[O:16])[N:4]([CH3:18])[C:3]=1[C:19]([NH:21][C:22]1C=C(C)O[N:23]=1)=[O:20])=[CH:14][CH:13]=[CH:12][CH:11]=3.CN1C(C(Cl)=O)=C(N2CCCC2)[C:32]2C=CC3C([C:31]=2[S:30]1(=O)=O)=CC=CC=3.NC1C=C(C)ON=1>>[OH:1][C:2]1[C:7]2[CH:8]=[CH:9][C:10]3[C:15]([C:6]=2[S:5](=[O:17])(=[O:16])[N:4]([CH3:18])[C:3]=1[C:19]([NH:21][C:22]1[S:30][CH:31]=[CH:32][N:23]=1)=[O:20])=[CH:14][CH:13]=[CH:12][CH:11]=3
Reactant: Cc1cc(NC(=O)C2=C(O)c3ccc4ccccc4c3S(=O)(=O)N2C)no1
Reactant: CN1C(C(=O)Cl)=C(N2CCCC2)c2ccc3ccccc3c2S1(=O)=O
Agent: Cc1cc(N)no1
Product: CN1C(C(=O)Nc2nccs2)=C(O)c2ccc3ccccc3c2S1(=O)=O

Procedure:
4-Hydroxy-2-methyl-N-(5-methyl-3-isoxazolyl)-2H-naphtho [2,1-e]-1,2-thiazine-3-carboxamide-1,1-dioxide, m.p. 235° C, from 2-methyl-4-(1-pyrrolidyl)-2H-naphtho[2,1-e]-1,2-thiazine- 3-carboxylic acid chloride-1,1-dioxide and 3-amino-5-methylisoxazole.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.CCN(C(C)C)C(C)C.[NH2:26][C@@H:27]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:28]([NH:30][CH3:31])=[O:29]>CN(C=O)C>[CH3:33][C:32]([CH3:35])([CH3:34])[C@H:27]([NH:26][C:8]([C:5]1[CH:4]=[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])[C:28](=[O:29])[NH:30][CH3:31]
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(Cl)cn1
Reactant: CNC(=O)[C@@H](N)C(C)(C)C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)[C@@H](NC(=O)c1cc(OCC(F)(F)F)c(Cl)cn1)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-Chloro-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 24c, 72 mg, 282 μmol) in DMF (1 mL) was added 4-(4,6-dimethoxyl-1,3,5-triazin-2-yl)-4-methylmorpholininium chloride (CAN 3945-69-5, 82 mg, 296 μmol) and DIEA (34.5 μL, 296 μmol). The reaction mixture was then stirred at room temperature for 30 min, followed by addition of (S)-2-amino-N,3,3-trimethylbutanamide (CAN 89226-12-0, 43 mg, 296 μmol). The reaction mixture was stirred for 3 h. The crude reaction mixture was directly purified by preparative HPLC to deliver the desired compound (65 mg, 60%) as white solid. MS (ESI, m/z): 382.4 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:24]=[CH:23][C:11]([O:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][CH2:19][C@H:18]([CH3:22])[CH2:17]3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[BH4-].[Na+].C([O-])(=O)C([O-])=O.C(O)(=O)C(O)=O>CO.C(O)C.C(OCC)C>[OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]2[CH:24]=[CH:23][C:11]([O:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][CH2:19][C@H:18]([CH3:22])[CH2:17]3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: C[C@H]1CCCN(CCCOc2ccc(C3CCC(=O)CC3)cc2)C1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])C(=O)[O-]
Agent: [BH4-]
Solvent: CCOCC
Solvent: CCO
Solvent: CO
Product: C[C@H]1CCCN(CCCOc2ccc([C@H]3CC[C@H](O)CC3)cc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A To a solution of (3S)-1-{3-[4-(4-oxocyclohexyl)phenoxy]propyl}-3-methylpiperidine (170 mg) in methanol (5 mL) is added sodium borohydride (20 mg). The mixture is stirred for one hour at room temperature, and then concentrated under reduced pressure. The residue is partitioned between water (5 mL) and ethyl acetate (10 mL). The aqueous phase is extracted twice with ethyl acetate. The organic extracts are pooled, dried over magnesium sulfate, concentrated under reduced pressure to give 129 mg of crude base which is converted to the oxalate with oxalic acid (35 mg) in a mixture of ethanol and diethyl ether, giving 33 mg of (3S)-1-{3-[trans-4-(4-hydroxycyclohexyl)phenoxy]propyl}-3-methylpiperidine, oxalate as a white powder.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.BrBr.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH2:21][CH2:22][N:23]2[C:27](=[O:28])[C:26]3=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]3[C:24]2=[O:33])[CH:18]=[CH:19][CH:20]=1.C(=O)(O)[O-].[Na+]>C(OCC)C>[OH:33][C:24]1([C:3]2[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=2)[C:25]2[C:26](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27](=[O:28])[N:23]1[CH2:22][CH2:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([O:14][CH3:13])[CH:16]=1
Reactant: COc1ccc(Br)cc1
Reactant: COc1cccc(CCN2C(=O)c3ccccc3C2=O)c1
Agent: BrBr
Agent: O=C([O-])O
Agent: [Mg]
Solvent: CCOCC
Product: COc1ccc(C2(O)c3ccccc3C(=O)N2CCc2cccc(OC)c2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
104 mg (4.28 mmol) of magnesium turnings in 10 ml of absolute diethyl ether were admixed with 0.79 g (4.27 mmol) of 4-bromoanisole. The reaction was started by addition of a drop of bromine. After about 2 h, the magnesium had completely dissolved. The mixture was cooled to 0° C. and 0.3 g (1.07 mmol) of N-(2-(3-methoxyphenyl)ethyl)phthalimide was added. The reaction mixture was allowed to warm to room temperature and, after 2 h, admixed with 5 ml of saturated sodium bicarbonate solution. The aqueous phase was extracted twice with diethyl ether. The combined organic phases were dried and evaporated to dryness using a rotary evaporator. The resulting oil was purified by chromatography. Elution was carried out using a dichloromethanelmethanol gradient (0 to 2% methanol). The product, obtained as a colorless oils was foamed by coevaporation with diethyl ether. Yield: 0.32 g. M.p.: 119° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:8][NH2:9])=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[F:17][C:18]([F:34])([F:33])[C:19]([C:29](F)(F)[F:30])=[C:20](F)[C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23]>C(#N)C>[Cl:1][C:2]1[C:3]([N:8]2[C:29]([F:30])=[C:19]([C:18]([F:34])([F:33])[F:17])[C:20]([C:21]([F:26])([F:27])[C:22]([F:23])([F:24])[F:25])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: NNc1ncccc1Cl
Reactant: FC(=C(C(F)(F)F)C(F)(F)F)C(F)(F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Fc1c(C(F)(F)F)c(C(F)(F)C(F)(F)F)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 60 h

Procedure:
1.0 g (7.0 mmol) of 3-chloro-2-hydrazinopyridine is suspended in 2.9 ml (21 mmol) of triethylamine and 40.0 ml of acetonitrile and, at −65° C., added to 2.1 g (7 mmol) of (1,1,1,3,4,4,5,5,5-nonafluoro-2-(trifluoromethyl)pent-2-ene. The reaction mixture is slowly heated to room temperature and then stirred at room temperature for 60 hours. The solid is filtered off and afterwashed with diethyl ether. The solvent is removed under reduced pressure on a rotary evaporator. The product is extracted from the residue three times with cyclohexane. The organic phases are combined and the solvent is removed under reduced pressure on a rotary evaporator. This gives 1.95 g of 3-chloro-2-[5-fluoro-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazol-1-yl]pyridine (73%) as an orange oil.
Reaction SMILES: [F:1][C:2]([F:23])([C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]#[N:15])=[CH:8][CH:7]=1)=[O:4].[N-:24]=[N+:25]=[N-:26].[Na+].[Cl-].[NH4+].CN(C)C=O>O>[F:1][C:2]([F:23])([C:16]([F:21])([F:22])[C:17]([F:19])([F:20])[F:18])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]2[NH:26][N:25]=[N:24][N:15]=2)=[CH:8][CH:7]=1)=[O:4]
Reactant: N#CCCc1ccc(NC(=O)C(F)(F)C(F)(F)C(F)(F)F)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(CCc2nnn[nH]2)cc1)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 130 °C
Yield: 43.3 %

Procedure:
A mixture of 2,2,3,3,4,4,4-heptafluoro-N-[4-(2-cyanoethyl)phenyl]butanamide (3.9 g), sodium azide (3.7 g), ammonium chloride (3 g) and dimethylformamide (60 mL) was stirred under a nitrogen atmosphere and heated in a 130° C. oil bath for 48 hours. Water (300 mL) was added to the hot mixture to dissolve all suspended salts and the solution was allowed to cool to room temperature. More water was added and the precipitate was collected by filtration. The tan solid was dried at 65° C. in vacuo overnight and recrystallized from a hexane/tetrahydrofuran mixture to give 1.9 g (43% yield) of the title compound as a tan solid, m.p. 161°-162° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:11]([CH3:22])[C:12](=[O:21])[C:13]([CH3:20])=[CH:14][C:15]=1[C:16]([O:18]C)=[O:17].C1COCC1.[Li+].[OH-]>O>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:11]([CH3:22])[C:12](=[O:21])[C:13]([CH3:20])=[CH:14][C:15]=1[C:16]([OH:18])=[O:17]
Reactant: COC(=O)c1cc(C)c(=O)n(C)c1Nc1ccc(I)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C(=O)O)c(Nc2ccc(I)cc2F)n(C)c1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 78.4 %

Procedure:
A 100 mL round-bottom flask was charged with methyl 2-(2-fluoro-4-iodophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylate (2.38 g, 6.72 mmol) and THF (80 mL). To the mixture was added LiOH (20 mmol) previously dissolved in 30 mL of H2O and the reaction was stirred at room temperature for 72 hours. The organic solvent was removed under reduced pressure and the resulting aqueous layer was acidified with 1N aq. HCl. The precipitate was filtered and dried under vacuum to afford the title compound as a white solid (2.12 g, 92%).
Reaction SMILES: [CH2:1]([O:3][P:4]([N:9]1[CH2:22][CH2:21][N:20](S(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][N:12]([S:35]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[N+:44]([O-:46])=[O:45])(=[O:37])=[O:36])[CH2:11][CH2:10]1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].C1(S)C=CC=CC=1>CN(C=O)C>[CH2:7]([O:6][P:4]([N:9]1[CH2:10][CH2:11][N:12]([S:35]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[N+:44]([O-:46])=[O:45])(=[O:37])=[O:36])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][CH2:21][CH2:22]1)([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOP(=O)(OCC)N1CCN(S(=O)(=O)c2ccccc2[N+](=O)[O-])CCCCCCCN(S(=O)(=O)c2ccccc2[N+](=O)[O-])CC1
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)N1CCNCCCCCCCN(S(=O)(=O)c2ccccc2[N+](=O)[O-])CC1
Reaction time: 3 h
Yield: 18.3 %

Procedure:
To a stirred solution of 4-diethoxyphosphoryl-1,7-bis(2-nitrobenzenesulfonyl)-1,4,7-triazacyclotetradecane (1.32 g, 1.87 mmol) and K2CO3 (654 mg, 4.73 mmol) in DMF (11 mL) under nitrogen was added dropwise a solution of thiophenol (0.15 mL, 1.46 mmol) in DMF (8 mL) over 1 h. The mixture was stirred for an additional 3 h and then concentrated in vacuo. The residue was partitioned between CHCl3 (50 mL) and H2O (25 mL). The aqueous phase was separated and extracted with CHCl3 (3×20 mL) and the combined organic extracts were dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography on basic alumina (CHCl3 then 3% MeOH/CHCl3) to give the title compound as a yellow oil (178 mg, 23%): 1H NMR (CDCl3) δ1.31 (t, 6H, J=7.0 Hz), 1.40-1.67 (m, 10H), 2.65 (m, 2H), 2.78 (m, 2H), 3.12 (m, 2H), 3.26-3.37 (m, 4H), 3.48 (m, 2H), 3.97-4.09 (m, 4H), 7.61 (m, 1H), 7.68 (m, 2H), 8.06 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]([CH:17]([O:25][CH2:26][CH2:27][N:28]3[CH:32]=[CH:31][N:30]=[CH:29]3)[C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH:14]=[CH:13][C:9]=2[C:10](O)=[O:11])=[CH:4][CH:3]=1.[NH2:33][C@@H:34]([CH2:45][CH2:46][S:47][CH3:48])[C:35]([O:37][CH:38]1[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]1)=[O:36]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]([CH:17]([O:25][CH2:26][CH2:27][N:28]3[CH:32]=[CH:31][N:30]=[CH:29]3)[C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH:14]=[CH:13][C:9]=2[C:10]([NH:33][C@@H:34]([CH2:45][CH2:46][S:47][CH3:48])[C:35]([O:37][CH:38]2[CH2:39][CH2:40][N:41]([CH3:44])[CH2:42][CH2:43]2)=[O:36])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(C(OCCn2ccnc2)c2ccc(F)cc2)cc1-c1ccc(F)cc1
Reactant: CSCC[C@H](N)C(=O)OC1CCN(C)CC1
Product: CSCC[C@H](NC(=O)c1ccc(C(OCCn2ccnc2)c2ccc(F)cc2)cc1-c1ccc(F)cc1)C(=O)OC1CCN(C)CC1
Yield: 72.5 %

Procedure:
The title compound was prepared from 2-(4-fluorophenyl)-4-[1-(4-fluorophenyl)-2-(imidazol-1-yl)ethoxymethyl]benzoic acid by a similar method to that used for Example 1 but using N-methylpiperidin-4-yl (2S)-2-amino-4-(methylsulfanyl)butanoate (L-methionine (N-methylpiperidin-4-yl)ester) in place of L-methionine methyl ester.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([SH:7])=[N:4][N:3]=1.[OH-].[Li+].[I-].[Na+].[C:12]([C:16]1[N:21]=[C:20]([N:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][CH2:30]Cl)[CH2:24][CH2:23]2)[CH:19]=[C:18]([CH:32]2[CH2:34][CH2:33]2)[N:17]=1)([CH3:15])([CH3:14])[CH3:13]>CN(C)C=O>[C:12]([C:16]1[N:17]=[C:18]([CH:32]2[CH2:33][CH2:34]2)[CH:19]=[C:20]([N:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][CH2:30][S:7][C:5]3[S:6][C:2]([CH3:1])=[N:3][N:4]=3)[CH2:24][CH2:23]2)[N:21]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)c1nc(C2CC2)cc(N2CCN(CCCCl)CC2)n1
Reactant: Cc1nnc(S)s1
Agent: [I-]
Agent: [Li+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nnc(SCCCN2CCN(c3cc(C4CC4)nc(C(C)(C)C)n3)CC2)s1
Temperature: 70 °C
Yield: 90.1 %

Procedure:
0.23 g of 5-methyl-[1,3,4]thiadiazol-2-thiol (1.77 mmol) were dissolved in 20 ml of dimethylformamide. After addition of 0.04 g of lithium hydroxide (1.77 mmol) and 0.13 g of sodium iodide (0.88 mmol), the reaction mixture was stirred at 70° C. and 0.6 g of 2-tert-butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-cyclopropyl-pyrimidine (1.77 mmol), dissolved in 5 ml of dimethylformamide, added dropwise over 2 h. The mixture was stirred at 80° C. for 2 h. The dimethylformamide was then evaporated. The residue was partitioned between 40 ml of ethyl acetate and 15 ml of saturated aqueous sodium chloride solution and 15 ml of water. The aqueous phase was re-extracted twice with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated to dryness, to yield 0.69 g of the title compound as an oily residue. 0.8 g of the crude product were treated with 10 ml of n-hexane, the precipitate was collected by filtration and dried to yield 0.56 g of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]([O:18]C)=O)=[CH:13][CH:12]=2)=[O:10])=[CH:5][CH:4]=[N:3]1.O.[NH2:21][NH2:22]>CO>[CH3:1][N:2]1[C:6]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]([NH:21][NH2:22])=[O:18])=[CH:13][CH:12]=2)=[O:10])=[CH:5][CH:4]=[N:3]1
Reactant: NN
Reactant: COC(=O)c1ccc(C(=O)NCc2ccnn2C)s1
Solvent: CO
Solvent: O
Product: Cn1nccc1CNC(=O)c1ccc(C(=O)NN)s1
Yield: 49 %

Procedure:
Methyl 5-(1-methyl-1H-pyrazol-5-ylmethylcarbamoyl)thiophene-2-carboxylate (0.25 g, 0.90 mmol) in methanol (2.5 mL) was stirred with hydrazine monohydrate (0.17 mL, 3.6 mmol) at 70° C. for 3.5 hours. The precipitated solid was recovered by filtration, washed with chloroform and dried to give the desired product, 5-hydrazinocarbonylthiophene-2-carboxylic acid (1-methyl-1H-pyrazol-5-ylmethyl)amide (yield 49%).
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][O:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH2:8][CH2:7]1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([N:3]([CH3:2])[CH2:4][CH2:5][C@H:6]2[CH2:11][CH2:10][C@H:9]([CH2:12][O:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH2:8][CH2:7]2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: CNCC[C@H]1CC[C@H](COS(C)(=O)=O)CC1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: Cl
Product: CN(CC[C@H]1CC[C@H](COS(C)(=O)=O)CC1)S(=O)(=O)c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described in example 11.15, trans-methanesulfonic acid 4-(2-methylamino-ethyl)-cyclohexylmethyl ester HCl salt was reacted with 4-chloro-benzene sulphonyl chloride to yield trans-methanesulfonic acid 4-{2-[(4-chloro-benzenesulfonyl)-methyl-amino]-ethyl}-cyclohexylmethyl ester as colorless viscous oil, MS: 424 (MH+, 1Cl).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1I>>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[S:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: Fc1ccc(Br)c(I)c1
Reactant: COc1ccc(S)cc1
Product: COc1ccc(Sc2cc(F)ccc2Br)cc1

Procedure:
Prepared from 4-methoxy-benzenethiol and 1-bromo-4-fluoro-2-iodo-benzene.