Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([C@@H:13]([CH2:23][C@H:24]3[CH2:28][CH2:27][NH:26][CH2:25]3)[C:14]([NH:16][C:17]3[S:18][C:19]([F:22])=[CH:20][N:21]=3)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:36](Cl)(=[O:38])[CH3:37]>ClCCl>[C:36]([N:26]1[CH2:27][CH2:28][C@H:24]([CH2:23][C@H:13]([C:10]2[CH:9]=[CH:8][C:7]([S:4]([CH:1]3[CH2:3][CH2:2]3)(=[O:5])=[O:6])=[CH:12][CH:11]=2)[C:14]([NH:16][C:17]2[S:18][C:19]([F:22])=[CH:20][N:21]=2)=[O:15])[CH2:25]1)(=[O:38])[CH3:37]
Reactant: O=C(Nc1ncc(F)s1)[C@H](C[C@H]1CCNC1)c1ccc(S(=O)(=O)C2CC2)cc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CC[C@H](C[C@@H](C(=O)Nc2ncc(F)s2)c2ccc(S(=O)(=O)C3CC3)cc2)C1
Reaction time: 0.33 h
Yield: 76 %

Procedure:
The (R)-2-(4-(cyclopropylsulfonyl)phenyl)-N-(5-fluorothiazol-2-yl)-3-((S)-pyrrolidin-3-yl)propanamide (1.17 g, 2.77 mmol) obtained in Step 1 of Example 2 was dissolved in dichloromethane (27 mL), and thereafter, triethylamine (0.806 mL, 5.81 mmol) and acetyl chloride (0.207 mL, 2.91 mmol) were added to the above obtained solution under ice-cold condition. The obtained mixture was stirred for 20 minutes. Thereafter, the reaction solution was washed with a 1 M aqueous solution of hydrochloric acid and a saturated aqueous solution of sodium hydrogen carbonate. The resultant was dried over anhydrous sodium sulfate, and was then concentrated in vacuo. The obtained residue was purified by silica gel chromatography (chloroform/methanol=1%→15%) to obtain the captioned compound (980 mg, 76%) in the form of a white solid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:12]=[C:11](O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.P(Br)(Br)([Br:18])=O>>[F:1][C:2]([F:15])([F:14])[C:3]1[CH:12]=[C:11]([Br:18])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: O=P(Br)(Br)Br
Reactant: Oc1cc(C(F)(F)F)nc2ccccc12
Product: FC(F)(F)c1cc(Br)c2ccccc2n1

Procedure:
2-Trifluoromethyl cinchoninic acid, and substituted 2-trifluoromethyl cinchoninic acids, are known plant growth regulating materials. Such compounds can be prepared, as disclosed by B. M. Pinder and A. Burger (J. Med. Chem, 11, pp 267-269 (1968), by condensation of aniline, or a substituted aniline, with ethyl 4,4,4-trifluoroacetoacetate in the presence of polyphosphoric acid to produce a 2-trifluoromethyl-4-hydroxyquinoline from which the desired 2-trifluoromethyl cinchoninic acid can be obtained by two alternative procedures. In the first of such procedures, the 2-trifluoromethyl-4-hydroxyquinoline is brominated with phosphorus oxybromide to produce the corresponding 2-trifluoromethyl-4-bromoquinoline which is then reacted with n-butyllithium to produce a lithioquinoline which can in turn be treated with dry carbon dioxide to produce the desired 2-trifluoromethyl cinchoninic acid. In the second of such procedures, the 2-trifluoromethyl-4-hydroxyquinoline is chlorinated with phosphorus oxychloride and the resulting 2-trifluoromethyl-4-chloroquinoline is reacted with cuprous cyanide in N-methylpyrrolidone to convert it to the corresponding nitrile which is then hydrolyzed to the desired 2-trifluoromethyl cinchoninic acid. However, not only are both these procedures complex and involved, but they involve the use of corrosive materials such as phosphorus oxybromide and phosphorus oxychloride as well as air- and water-sensitive materials such as butyllithium and copper cyanide.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C@H:4]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:5][C:6](=[O:10])[C@H:7]([CH3:9])[NH2:8].C(N[C@H](C(O)=O)C)(OC(C)(C)C)=O.C[O:33][C:34](=O)[C@H:35]([CH2:37][C:38]1C=CC=C[CH:39]=1)N>CO.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:18])[C@H:4]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:5][C:6](=[O:10])[C@H:7]([CH3:9])[NH:8][C:34](=[O:33])[CH2:35][CH2:37][CH:38]=[CH2:39]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)N
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: CO
Solvent: ClCCl
Product: C=CCCC(=O)N[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC

Procedure:
Following General Procedure A and using N-(L-alaninyl)-L-phenylalanine methyl ester (prepared by coupling N-BOC-L-alanine (Sigma) and L-phenylalanine methyl ester (Sigma) using General Procedure A, followed by removal of the BOC-group using General Procedure Y) and pent-4-enoic acid (Aldrich), the title compound was prepared as a solid (mp=125.5-126.5° C.). The reaction was monitored by tlc (Rf=0.32 in 50% EtOAc/hexanes; 0.51 in 10% CH3OH/CH2Cl2) and the product was purified by flash chromatography using 10% CH3OH/CH2Cl2 as the eluent.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.CC([O-])(C)C.[K+].[F:18][C:19]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[C:21](F)[CH:20]=1>CS(C)=O.O>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:21]2[CH:22]=[C:23]([N+:25]([O-:27])=[O:26])[CH:24]=[C:19]([F:18])[CH:20]=2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1cc(F)cc(F)c1
Reactant: COC(=O)c1ccc(O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1ccc(Oc2cc(F)cc([N+](=O)[O-])c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-hydroxybenzoic acid methyl ester (3.00 g, 19.5 mmol) in DMSO (30 ml) was added t-BuOK (2.56 g, 21.5 mmol) at room temperature and the mixture was stirred at room temperature for 30 minutes under N2 flow. 1,3-Difluoro-5-nitrobenzene (2.34 ml, 20.5 mmol) was added dropwise at room temperature. The mixture was heated at 90° C. for 2 hours under N2 flow. The reaction mixture was cooled to room temperature, diluted with H2O, and then extracted with EtOAc. The extract washed with H2O and brine, dried over MgSO4, filtered and concentrated under vacuum giving the title compound as a dark brown oil, which was crystallized with i-Pr2O. The crystals were collected by filtration to give the desired product as pale yellow crystal (1.92 g, 40%). The filtrate gave additional product (1.46 g, 30%) as pale yellow crystal by silica gel column chromatography eluting with 4:1 EtOAc/hexane.
Reaction SMILES: [C:1]([O:6][CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17][CH2:18][C:19]1[N:20]=[CH:21][CH:22]=[C:23]2[CH:27]=[CH:26][S:25][C:24]=12)(=[O:5])[CH2:2][CH2:3][CH3:4].C1C=C(Cl)C=C(C(OO)=[O:36])C=1.C([O-])(O)=O.[Na+].S([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl.CCOCC.O>[C:1]([O:6][CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([CH2:18][C:19]1[N:20]=[CH:21][CH:22]=[C:23]2[CH:27]=[CH:26][S:25][C:24]=12)=[O:36])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)OCn1c(SCc2nccc3ccsc23)nc2ccccc21
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: CCCC(=O)OCn1c(S(=O)Cc2nccc3ccsc23)nc2ccccc21
Reaction time: 1 h

Procedure:
To a solution of 318.0 mg (0.800 mmol) of 1-butyryloxymethyl-2-[(thieno[2, 3-c]pyridin-7-yl)methylthio]benzimidazole (Ib-6) in 30 ml of CHCl3 was added 224.3 mg (1.04 mmol) of 80% m-CPBA at -10° to -15 ° C., and the mixture was stirred for 1 hr. To the solution were added 3 ml of saturated aqueous NaHCO3 and 0.6 ml of 10% aqueous sodium sulfite. After bringing back to room temperature, the solution was mixed with water and extracted with CHCl3. After drying CHCl3 layer over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, whereby brown viscous liquid was obtained. After silica gel column chromatography, the crystals were dispersed with ether, followed by filtration and washed with ether, whereby 169.8 mg (Yield : 51.3%) of the objective compound (Ic-12), 1-butyryloxymethyl-2-[(thieno[2, 3-c]pyridin7-yl)methylsulfinyl]benzimidazole was obtained as crystals.
Reaction SMILES: CC([O-])(C)C.[K+].[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[C:29]3[C:24](=[CH:25][C:26](F)=[C:27]([F:30])[CH:28]=3)[N:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].[CH3:32][N:33]1[CH2:38][CH2:37][N:36]([CH2:39][CH2:40][CH2:41][OH:42])[CH2:35][CH2:34]1>C1COCC1>[C:7]([O:11][C:12]([N:14]1[CH2:15][CH2:16][CH:17]([C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:42][CH2:41][CH2:40][CH2:39][N:36]4[CH2:35][CH2:34][N:33]([CH3:32])[CH2:38][CH2:37]4)=[C:27]([F:30])[CH:28]=3)[N:23]=[CH:22][N:21]=2)[CH2:18][CH2:19]1)=[O:13])([CH3:9])([CH3:8])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(F)c(F)cc23)CC1
Reactant: CN1CCN(CCCO)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN1CCN(CCCOc2cc3ncnc(C4CCN(C(=O)OC(C)(C)C)CC4)c3cc2F)CC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 61.3 %

Procedure:
A solution of 1.19M KOtBu in THF (128 μL, 152 μmol) was added dropwise with stirring over 2.5 min to a 0° C. homogeneous solution of 4-(6,7-Difluoro-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (38.1 mg, 109 μmol), as prepared in the previous step, and 3-(4-Methyl-piperazin-1-yl)-propan-1-ol (22.4 mg, 142 μmol) in THF (170 μL). The reaction was stirred at 0° C. for 1.5 hr, and was then partitioned with DCM (2 mL) and 1M NaCl (2 mL). The aq layer was back-extracted with DCM (1×2 mL), and the combined cloudy white organic layers were dried (Na2SO4) and concentrated. The residue was purified by silica flash chromatography (1:2 hex/EtOAc/3% DMEA eluent) to yield the title compound as an off-white foam (32.6 mg, 61%). NOe experiments support the assigned regioisomer. Select 1H-NMR resonances and nOes (300 MHz, CDCl3) δ 7.73 (d, J=11.4 Hz, 1H), 7.43 (d, J=8.1 Hz, 1H), 3.46 (tt, 1H). Irradiation of the diagnostic methine proton at δ 3.46 generates an nOe to the quinazoline C5 proton at δ 7.73, but not to the quinazoline C8 proton at δ 7.43. The C5 proton has a larger coupling constant than the C8 proton, indicating fluorine substitution at C6 of the quinazoline. LC/MS (ESI): calcd mass 487.3, found 488.3 (MH)+.
Reaction SMILES: N1CCCNC[CH2:2]1.N1CCNCC1.[N:14]1([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][C:22]=2[O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:20][CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.Cl>C=O.CO.C(O)=O>[CH3:2][N:17]1[CH2:18][CH2:19][CH2:20][N:14]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][C:22]=2[O:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:15][CH2:16]1
Reactant: C1CNCCNC1
Reactant: c1ccc(Oc2cnccc2N2CCCNCC2)cc1
Agent: C1CNCCN1
Agent: C=O
Agent: Cl
Solvent: O=CO
Solvent: CO
Product: CN1CCCN(c2ccncc2Oc2ccccc2)CC1
Temperature: 100 °C

Procedure:
By substituting 30 g of hexahydro-1H-1,4-diazepine for the piperazine in Example 1, the product is 4-(hexahydro-1H-1,4-diazepin-1-yl)-3-phenoxy pyridine, bp 143°-145° C./0.13 mm). Three and four tenths g of this material is dissolved in a mixture of 4.5 g 37% formalin and 2 ml of methanol and is treated with 6 g of 97-100% formic acid. The mixture is heated at 100° C. for 18 hours. The mixture is cooled, treated with an excess of dilute hydrochloric acid and concentrated in vacuo. The residue is shaken with 100 ml of toluene and excess dilute aqueous sodium hydroxide. The organic phase is dried, concentrated and distilled to give 4-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)-3-phenoxypyridine; bp 130°-131° C./0.1 mm.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[S:4][C:5]([C:9](O)=[O:10])=[C:6]([CH3:8])[N:7]=1.[Cl:14]C(OC(Cl)(Cl)Cl)=O>ClC1C=CC=CC=1.N1C=CC=CC=1>[F:1][C:2]([F:13])([F:12])[C:3]1[S:4][C:5]([C:9]([Cl:14])=[O:10])=[C:6]([CH3:8])[N:7]=1
Reactant: Cc1nc(C(F)(F)F)sc1C(=O)O
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: Clc1ccccc1
Product: Cc1nc(C(F)(F)F)sc1C(=O)Cl
Reaction time: 2 h
Yield: 98 %

Procedure:
In a similar apparatus to Example 1, 4.2 g (0.02 mole) of 2-trifluoromethyl-4-methylthiazole-5-carboxylic acid were suspended in 100 ml of chlorobenzene, followed by the addition of 0.04 g of pyridine. Under heating and reflux, 9.9 g (0.05 mole) of trichloromethyl chloroformate were added dropwise over 5 hours. After completion of the dropwise addition, stirring was continued for additional 2 hours. After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated to obtain 4.5 g of 2-trifluoromethyl-4-methylthiazole-5-carboxylic acid chloride. Its purity and yield were 98.7% and 98.0%, respectively.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH:6]([N:9]2[N:19]=[C:18]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=3)[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:10]2=[O:11])[CH2:5][CH2:4][CH2:3]1.[C:28]([OH:31])(=[O:30])[CH3:29]>>[CH3:1][N:2]1[CH2:8][CH2:7][CH:6]([N:9]2[N:19]=[C:18]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:10]2=[O:11])[CH2:5][CH2:4][CH2:3]1.[C:28]([O-:31])(=[O:30])[CH3:29]
Reactant: CC(=O)O
Agent: CN1CCCC(n2nc(Cc3ccc(Cl)cc3)c3ccccc3c2=O)CC1
Product: CC(=O)[O-]

Procedure:
The pH value of the solution so obtained is 5.5, the molar ratio azelastine : acetic acid is 1:1.1.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C1(C)C(C)=CC=CC=1.[C:15]([Si:19]([CH3:22])([CH3:21])Cl)([CH3:18])([CH3:17])[CH3:16].[OH-].[Na+]>C1(C)C=CC=CC=1>[Si:19]([N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:22])[CH3:21]
Reactant: C1CNCCN1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)N1CCNCC1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
A flask equipped with a stirrer, reflux condenser; dropping funnel and thermometer was charged with 1076.3 g (12.5 mol) of piperazine and 500 ml of xylene and heated at 110° C. Once the internal temperature became steady, 1507.0 g (5.0 mol) of a 50 wt % toluene solution of t-butyldimethylchlorosilane was added dropwise over 3 hours. Stirring was continued for 2 hours at the temperature. The reaction solution was cooled to room temperature, to which 2,500 g of a 10 wt % sodium hydroxide aqueous solution was added. The organic layer was separated. On distillation, 646.6 g of a fraction having a boiling point of 70-71° C./0.2 kPa was collected, which was 1-t-butyldimethylsilylpiperazine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[CH2:11]Br.[C-:14]#[N:15].[Na+]>CO>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[CH2:11][C:14]#[N:15]
Reactant: COC(=O)c1cccc(F)c1CBr
Reactant: [C-]#N
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cccc(F)c1CC#N
Temperature: 50 °C
Reaction time: 2 h

Procedure:
2-Bromomethyl-3-fluoro-benzoic acid methyl ester (5.1 g, 21 mmol) was dissolved in methanol (50 ml), and sodium cyanide aqueous solution (4.2 ml, 5 ml, 21 mmol) was added dropwise thereto. After completion of the dropwise addition, the mixture was stirred at 50° C. for 2 hours. The residue obtained by evaporating the solvent from the reaction solution under a reduced pressure was mixed with ethyl acetate, washed with water and saturated brine and then dried with anhydrous it magnesium sulfate. The solvent was removed by evaporation from the organic layer under a reduced pressure, and the thus obtained material was separated and purified by a silica gel column chromatography to obtain 3.3 g (17 mmol, 82% in yield) of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]([OH:8])[CH2:4][CH2:5][C:6]=1[CH3:7].[CH2:9]([Mg]Br)[CH3:10]>C1COCC1.[Ni](Cl)Cl.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:9]([C:2]1[CH:3]([OH:8])[CH2:4][CH2:5][C:6]=1[CH3:7])[CH3:10]
Reactant: CC1=C(Br)C(O)CC1
Reactant: CC[Mg]Br
Agent: Cl[Ni]Cl
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCC1=C(C)CCC1O
Temperature: 25 °C

Procedure:
The alcohol (Intermediate V2, 16 mmol) in THF (30 mL) at 0 EC was treated with ethyl magnesium bromide (40 mmol). The catalyst, 1,3-bis(diphenylphosphino)propane nickel (II) chloride (0.75 mmol) (NiCl2dppp) was added in one portion and the mixture was heated to reflux for 3 hours following the procedure of Organ et al. J. Org. Chem. 1997, 62, 1523, incorporated herein by reference.) The reaction mixture was cooled to rt and quenched with sat. NH4Cl solution. The mixture was filtered and partitioned between brine and diethyl ether. The organic layer was removed and dried over Na2SO4, filtered and concentrated under vacuum. The oil was purified by chromatography on SiO2 with 20% EtOAc:Hx to yield 2-ethyl-3-methyl-cyclopent-2-enol (Intermediate V3). Use of the alcohol (Intermediate V3) in the applicable steps of Method A and Method P produced 4-(2-ethyl-3-methyl-cyclopent-2-enylmethyl)-1,3-dihydro-imidazol-2-one (Compound 64). 1H NMR (300 MHz, CD3OD-d4): δ 6.03 (s, 1H), 2.88 (brs, 1H), 2.65-2.59 (m, 1H), 2.27-1.83 (series of m, 6H), 1.62 (s, 3H), 1.54-1.45 (m, 1H), 0.97 (t, J=6 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[C:10]2[S:9][C:8]([C:11]([OH:13])=O)=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:14]1([NH2:25])[C:19](F)=[C:18](F)[C:17](F)=[C:16](N)C=1F.[ClH:26].Cl.CN(C(O[N:36]1N=N[C:38]2C=CC=N[C:37]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[ClH:26].[N:25]12[CH2:16][CH2:17][CH:18]([CH2:19][CH2:14]1)[C@@H:37]([NH:36][C:11]([C:8]1[S:9][C:10]3[C:2]([Br:1])=[CH:3][CH:4]=[CH:5][C:6]=3[CH:7]=1)=[O:13])[CH2:38]2
Reactant: Nc1c(F)c(N)c(F)c(F)c1F
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1cc2cccc(Br)c2s1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(Br)c2s1

Procedure:
903.8 mg (3.52 mmol) of 7-bromo-1-benzothiophene-2-carboxylic acid, 700.0 mg (3.52 mmol) of R-aminoquinulidine dihydrochloride, 1604.0 mg (4.22 mmol) of HATU, 1635.7 mg (12.66 mmol) of N,N-diisopropylethylamine and 7.0 ml of DMF are reacted by general method B. The reaction mixture is purified by preparative HPLC. The product is dissolved in a 1:1 mixture of 4 M HCl in dioxane and 1 N hydrochloric acid and then concentrated and dried under high vacuum. 1087 mg (77% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][C:12]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[NH2:28])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:30]1[CH:35]=[CH:34][C:33]([CH:36]=O)=[CH:32][N:31]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[BH4-].[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl.CO>[C:1]([O:5][C:6]([N:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][C:12]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N:28]=[CH:36][C:33]3[CH:34]=[CH:35][N:30]=[N:31][CH:32]=3)=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1Cc2cc(NC(=O)c3ccccc3N)ccc2C(C)(C)C1
Reactant: O=Cc1ccnnc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1Cc2cc(NC(=O)c3ccccc3N=Cc3ccnnc3)ccc2C(C)(C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 7-(2-amino-benzoylamino)-4,4-dimethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (512 mg, 1.3 mmol), pyridazine-4-carbaldehyde (140 mg, 1.3 mmol) and p-toluenesulfonic acid (10 mg) was heated at reflux in toluene (5 mL) for 1 h. The mixture was cooled to RT and diluted with CH2Cl2. NaBH4 (50 mg, 1.3 mmol) was added to the mixture followed by MeOH (2 mL). The mixture was stirred for 1 h. The crude material was purified with flash chromatography (SiO2, 5% MeOH/CH2Cl2) to give a yellow solid. MS (ES+): 488.0 (M+H)+. Calc'd for C28H33N5O3: 487.59.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][S:6][C:7]1[CH:8]=[C:9]([O:29][C:30]2[C:31]([CH3:36])=[N:32][CH:33]=[CH:34][CH:35]=2)[C:10]([NH:13][C:14]2[S:18][N:17]=[C:16]([C@H:19]3[CH2:23][O:22]C4(CCCCC4)[O:20]3)[N:15]=2)=[N:11][CH:12]=1.[ClH:37].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.C(OCC)(=O)C>[ClH:37].[CH3:1][O:2][CH2:3][CH2:4][CH2:5][S:6][C:7]1[CH:8]=[C:9]([O:29][C:30]2[C:31]([CH3:36])=[N:32][CH:33]=[CH:34][CH:35]=2)[C:10]([NH:13][C:14]2[S:18][N:17]=[C:16]([C@H:19]([OH:20])[CH2:23][OH:22])[N:15]=2)=[N:11][CH:12]=1
Reactant: COCCCSc1cnc(Nc2nc([C@H]3COC4(CCCCC4)O3)ns2)c(Oc2cccnc2C)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COCCCSc1cnc(Nc2nc([C@H](O)CO)ns2)c(Oc2cccnc2C)c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
(S)-N-(5-(3-methoxypropylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decane-2-yl)-1,2,4-thiadiazol-5-amine (85 mg, 0.16 mmol) was dissolved in ethanol (5 ml) and 1M HCl (0.5 ml) was added. The mixture was heated to 70° C. and agitated 3 hours. Upon cooling, the reaction was diluted with ethyl acetate, basified with sodium carbonate solution and washed with water and brine, dried (MgSO4), filtered and evaporated. The resulting solid was dissolved in small amount of dichloromethane and treated with 1M HCl in ether. After evaporation, (S)-1-(5-(5-(3-methoxypropylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol hydrochloride (65 mg, 90% yield) was obtained as white solid. Mass Spectrum (apci) m/z=450.1 (M+H−HCl).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:33][CH2:34][CH3:35])=[C:9]([C:11]2[N:12]([C:30](Cl)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH:36]1[CH2:41][CH2:40][NH:39][CH2:38][C:37]1=[O:42]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:33][CH2:34][CH3:35])=[C:9]([C:11]2[N:12]([C:30]([N:39]3[CH2:40][CH2:41][NH:36][C:37](=[O:42])[CH2:38]3)=[O:31])[C@H:13]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CNCCN1
Reactant: CCOc1ccc(C(C)(C)C)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1ccc(C(C)(C)C)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCNC(=O)C1

Procedure:
4-[(4S,5R)-2-(5-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-one was prepared from (4S,5R)-2-(5-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12d) and 2-piperazinone (Avocado Organics) in an analogous manner as described in example 25. LR-MS: 593.3 [(M+H)+]