Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH:6]([OH:7])[CH2:5][C:4]([CH2:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH2:8][CH3:9])[O:3]1.[H-].[Na+].[N:22]1[CH:27]=[CH:26][CH:25]=[N:24][C:23]=1Cl>C1(C)C=CC=CC=1.[Cl-].[Na+].O>[CH3:19][C:2]1([CH3:1])[CH:6]([O:7][C:23]2[N:24]=[CH:25][CH:26]=[CH:27][N:22]=2)[CH2:5][C:4]([CH2:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH2:8][CH3:9])[O:3]1
Reactant: Clc1ncccn1
Reactant: CCC1(COCc2ccccc2)CC(O)C(C)(C)O1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCC1(COCc2ccccc2)CC(Oc2ncccn2)C(C)(C)O1
Yield: 96.5 %

Procedure:
1 g of the alcohol of Example 3 was added to 220 mg of a 50% suspension of sodium hydride in oil dissolved in toluene (15 ml) and the mixture was stirred under reflux for 1 hour. 2-pyrimidinyl chloride (625 mg) in 10 ml toluene was added over 30 minutes. The mixture was stirred at reflux temperature for 16 hours. The mixture was then poured into brine and extracted with diethyl ether. The ether extract was dried over magnesium sulphate and evaporated to yield a residue which was purified on a silica gel column using 8% acetone in petrol as eluant to give 1.25 g (97%) of the desired product.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[C:6]([CH3:8])([CH3:7])[O:5][BH:4][O:3]1.Br[C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[C:14]([C:20]#[N:21])[NH:15]2.C(N(CC)CC)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>O1CCOCC1.C(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][C:2]1([CH3:9])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH:13]=[C:14]([C:20]#[N:21])[NH:15]3)[O:3]1
Reactant: CC1(C)OBOC1(C)C
Reactant: N#Cc1cc2c(Br)cccc2[nH]1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC1(C)OB(c2cccc3[nH]c(C#N)cc23)OC1(C)C
Temperature: 80 °C
Reaction time: 5 h
Yield: 65.6 %

Procedure:
4,4,5,5-Tetramethyl-[1,3,2]dioxaborolane (2.1 mL, 14.5 mmol) was added drop-wise to a mixture of 4-bromo-1H-indole-2-carbonitrile (1.27 g, 5.8 mmol), palladium acetate (33 mg, 0.145 mmol), triethylamine (1.21 mL, 8.7 mmol) and 2-(dicyclohexylphosphino)biphenyl (203 mg, 0.58 mmol) in dioxane at 80° C. The reaction mixture was stirred at 80° C. for 5 h then allowed to stand at RT overnight. The reaction mixture was diluted with DCM and washed with water, then the organic layer was isolated, dried (MgSO4) then concentrated in vacuo. The resultant crude material was purified by column chromatography to afford the title compound as a brown solid (1.02 g, 66%).
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].O.[C:7]([C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([O:20][CH2:21][CH3:22])=[N:12][CH:11]=1)([OH:9])=[O:8]>S(=O)(=O)(O)O>[C:7]([C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][C:18]=2[N+:1]([O-:4])=[O:2])[C:13]([O:20][CH2:21][CH3:22])=[N:12][CH:11]=1)([OH:9])=[O:8]
Reactant: O=[N+]([O-])[O-]
Reactant: CCOc1ncc(C(=O)O)c2ccccc12
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: CCOc1ncc(C(=O)O)c2c([N+](=O)[O-])cccc12
Temperature: 0 °C
Reaction time: 16 h
Yield: 100.7 %

Procedure:
A solution of potassium nitrate (34.9 g) in sulphuric acid (density 1.83; 280 cc) is added dropwise to a solution, stirred and cooled by iced water, of 4-carboxy-1-ethoxyisoquinoline (69.5 g) in sulphuric acid (density 1.83; 420 cc), whilst keeping the temperature below 20° C. The reactants are kept in contact for 16 hours at a temperature of about 20° C. and the reaction solution is then poured onto crushed ice (7 kg). The fine yellow crystals which precipitate are filtered off and then washed with water until a neutral filtrate is obtained. After drying, crude 4-carboxy-1-ethoxy-5-nitroisoquinoline (84.5 g) is obtained.
Reaction SMILES: [OH:1][C@H:2]1[C@@H:7]2[O:8][C:9]([CH3:13])([CH3:12])[O:10][CH2:11][C@H:6]2[O:5][C@@H:4]2[CH:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C@H:3]12.[H-].[Na+].[S:22](Cl)(=[O:25])(=[O:24])[NH2:23]>CN(C=O)C>[CH3:12][C:9]1([CH3:13])[O:8][C@H:7]2[C@H:2]([O:1][S:22](=[O:25])(=[O:24])[NH2:23])[C@H:3]3[CH:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C@H:4]3[O:5][C@@H:6]2[CH2:11][O:10]1
Reactant: NS(=O)(=O)Cl
Reactant: CCOC(=O)C1[C@@H]2[C@@H](O)[C@@H]3OC(C)(C)OC[C@H]3O[C@H]12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1[C@@H]2[C@@H](OS(N)(=O)=O)[C@@H]3OC(C)(C)OC[C@H]3O[C@H]12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
Compound 6a (0.28 g, 1.0 mmol) was added to a dry 3-neck flask containing NaH (60% dispersion in mineral oil, 0.12 g, 3.1 mmol) in DMF (10 mL) at 0° C. After 30 min at 0° C., sulfamoyl chloride (0.36 g, 3.1 mmol) was added in portions, and the reaction was stirred for an additional 1 hour at 0° C. The reaction mixture was quenched with H2O at 0° C. and diluted with ice cold H2O (20 mL) and dichloromethane (50 mL). The aqueous layer was removed, and the organic layer was washed with ice cold water (2×20 mL) and brine (1×20 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. Column chromatography (SiO2, a gradient of pure hexanes to a 2:3 ratio of ethyl acetate in hexanes) followed by preparative TLC (SiO2, 7:13 ratio of ethyl acetate in hexanes) on the crude mixture afforded a yellow glass (0.28 g, 0.80 mmol) 77% yield. 1H NMR (500 MHz, CDCl3): δ 4.98 (s, 2H), 4.75 (d, 1H, J=8.5 Hz), 4.15 (q, 2H, J=7.5 Hz), 3.99 (dd, 1H, J=8.0, 3.0 Hz), 3.88-3.82 (m, 2H), 3.69 (dd, 1H, J=11.0, 10.0 Hz), 3.22 (ddd, 1H, J=10.0, 10.0, 5.5 Hz), 2.18 (dd, 1H, J=5.0, 3.0 Hz), 1.96-1.94 (m, 1H), 1.50 (s, 3H), 1.40 (s, 3H) 1.27 (t, 3H, J=7.5 Hz) (FIG. 19). 13C NMR (500 MHz, CDCl3): δ 100.2, 77.9, 71.2, 63.3, 61.9, 61.3, 58.8, 31.0, 29.0, 22.6, 20.8, 19.2, 14.2 (FIG. 20). HRMS (m/z): [M+H]+ calculated for C13H22NO8S, 352.1061. found 352.1061. Anal. calculated for C13H21NO8S: C, 44.44; H, 6.02. Found C, 44.54; H, 5.80.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[C:11]2[S:10][C:9](S)=[N:8][C:7]=2[CH:6]=[CH:5][CH:4]=1>C(O)(=O)C.[Fe]>[F:14][C:2]([F:1])([F:13])[C:3]1[C:11]2[S:10][CH:9]=[N:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: FC(F)(F)c1cccc2nc(S)sc12
Agent: [Fe]
Solvent: CC(=O)O
Product: FC(F)(F)c1cccc2ncsc12
Yield: 80.7 %

Procedure:
Following the same procedure as in step 2 of Example 337 using 7-(trifluoromethyl)-1,3-benzothiazole-2-thiol (300 mg, 1.28 mmol, 1.00 equiv) and iron powder (710 mg, 10.00 equiv) in acetic acid (12.0 mL). 210 mg of the title compound was obtained as a crude product as a gray-white solid, which was used directly for next step without further purification.
Reaction SMILES: [C:1](O)(=O)[CH2:2][C:3]([OH:5])=[O:4].[Br:8][C:9]1[S:13][C:12](C=O)=[CH:11][CH:10]=1.N1CCCCC1>N1C=CC=CC=1>[Br:8][C:9]1[S:13][C:12](/[CH:1]=[CH:2]/[C:3]([OH:5])=[O:4])=[CH:11][CH:10]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccc(Br)s1
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)/C=C/c1ccc(Br)s1
Temperature: 100 °C

Procedure:
Malonic acid (44.40 g, 426.7 mmol) was added to a mixture of 5-bromothiophene-2-carbaldehyde (50 g, 261.7 mmol), piperidine (2.84 mL) and pyridine (150 mL). The mixture was refluxed for 1 h at 80° C. and than at 100° C. over night. The volatiles were evaporated and the residue was dissolved in water and acidified with hydrochloric acid (pH 2). The crude product was crystallized in ethanol. Yield: 55.24 g (90.5%). 1H NMR (270 MHz, CH3OH-d4) δ ppm 6.14 (d, J=15.83 Hz, 1H) 7.11-7.16 (m, 2H) 7.68 (d, J=16.36 Hz, 1H); MS 233.1 (M−H)+; Purity (HPLC) 94%.
Reaction SMILES: [NH:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[S:2]1(=[O:14])=[O:13].[H-].[Na+].Br[CH2:18][CH2:19][CH2:20][Cl:21]>CN(C)C=O.O.C(OCC)(=O)C>[Cl:21][CH2:20][CH2:19][CH2:18][N:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[S:2]1(=[O:13])=[O:14]
Reactant: ClCCCBr
Reactant: O=S1(=O)Nc2cccc3c2N1CCC3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=S1(=O)N(CCCCl)c2cccc3c2N1CCC3
Reaction time: 0.5 h
Yield: 77 %

Procedure:
1-(3-Chloropropyl)-5,6-dihydro(1H,4H)-1,2,5-thiadiazolo[4,3,2-ij]quinoline 2,2-dioxide can be obtained as follows: a solution of 5,6-dihydro-(1H,4H)-1,2,5-thiadiazolo[4,3,2-ij]quinoline 2,2-dioxide (4 g) in dry N,N-dimethylformamide (30 cc) is added dropwise to a suspension of sodium hydride (0.69 g, 80% suspension in oil) in N,N-dimethylformamide (20 cc). After 30 minutes' stirring, a solution of 1-bromo-3-chloropropane (3.25 g) in N,N-dimethylformamdide (20 cc) is added. The reaction mixture is stirred at 25° C. for 2 hours and is then diluted in a mixture of water (300 cc) and ethyl acetate (300 cc). The organic phase is washed with water (3×200 cc), is dried over magnesium sulphate and is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (0.2-0.063-mm particle size, 4-cm diameter, 50-cm height), and eluted at a pressure of 0.7 bars of nitrogen with a mixture of cyclohexane and ethyl acetate (80-20 by volume), 125-cc fractions being collected. Fractions 4 to 12 are combined and concentrated to dryness under reduced pressure (2.7 kPa) to give 1-(3-chloropropyl)-5,6-dihydro-(1H,4H)-1,2,5-thiadiazolo[4,3,2-ij]quinoline 2,2-dioxide (4.2 g) in the form of a yellow oil.
Reaction SMILES: [CH3:1][CH2:2][Mg+].[Br-].[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:14](=O)[CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]>C1COCC1.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[C:5]([O:9][C:10]([N:12]1[CH2:13][C:14]2([CH2:2][CH2:1]2)[N:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:16][CH2:17]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)C(=O)C1
Reactant: CC[Mg+]
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)C2(CC2)C1
Temperature: 5 °C
Reaction time: 16 h
Yield: 58 %

Procedure:
To EtMgBr (344 mL) in THF cooled to −78° C. was added Ti(OiPr)4 (39 g, 137.93 mmol), followed by commercially available 4-benzyl-3-oxo-piperazine-1-carboxylic acid tert-butyl ester (40 g, 137.93 mmol) and the resultant reaction mixture was heated to reflux for 1 h. After cooling the reaction mixture to 5° C., another portion of EtMgBr (344 ml) and Ti(OiPr)4 (39 g, 137.93 mmol) was added. The mixture was stirred for 16 h at RT. The reaction mixture was quenched with NH4Cl solution and stirred for 15 min and filtered through a celite bed and washed with EtOAc. The aqueous layer was again extracted with EtOAc (3×). The combined EtOAc layers were washed with water and dried over Na2SO4 and concentrated under reduced pressure. Purification by column chromatography to afforded the title compound as a solid (24 g, 58%).
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:3]2([CH2:8][CH2:7][N:6]([CH2:9][C:10]#[N:11])[CH2:5][CH2:4]2)[O:2]1.N>[Ni]>[NH2:11][CH2:10][CH2:9][N:6]1[CH2:5][CH2:4][C:3]2([O:12][CH2:13][CH2:1][O:2]2)[CH2:8][CH2:7]1
Reactant: N#CCN1CCC2(CC1)OCCO2
Agent: [Ni]
Agent: N
Product: NCCN1CCC2(CC1)OCCO2
Reaction time: 20 h
Yield: 77.8 %

Procedure:
A suspension of 12.7 g of 4,4-ethylenedioxy-1-piperidineacetonitrile, 1.3 ml of Raney nickel and 113 ml of 2% methanolic solution of ammonia was catalytically hydrogenated at room temperature under 50 atm for 20 hours. After the reaction, the catalyst was filtered off, and the filtrate was concentrated. The resulting pale green liquid was purified by alumina column chromatography [eluting solvent: ethyl acetate→ethyl acetate—methanol (10:1)] to give 10.1 g of a colorless liquid.
Reaction SMILES: [C:1]([CH:5]=[C:6]([Cl:8])[F:7])([F:4])([F:3])[F:2].[C:9]([O:14]F)([O:12]F)([F:11])[F:10]>>[Cl:8][C:6]1([F:7])[CH:5]([C:1]([F:4])([F:3])[F:2])[O:14][C:9]([F:11])([F:10])[O:12]1
Reactant: FC(Cl)=CC(F)(F)F
Reactant: FOC(F)(F)OF
Product: FC1(F)OC(C(F)(F)F)C(F)(Cl)O1

Procedure:
In a 200 ml 5 necked reactor, equipped with a mechanical stirrer, thermocouple, bubbling inlet for introducing the reacting gaseous mixture and an inert gas, 51.3 g (0.346 moles) of CF3—CH═CFCl are introduced. The reactor is then brought, by a cryostat, to the temperature of −70° C. At this point, under strong stirring, a mixture of CF2(OF)2 (BDM) (1 nl/h) and He (3 nl/h) for 3h 52′ (equivalent to 0.173 moles of BDM) is added in a continuous way.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:11]([NH2:12])=[C:10]([C:13]([O:15]C)=[O:14])[S:9][N:8]=2)[CH:2]=1.C(O)C.[OH-].[Na+].Cl>O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:11]([NH2:12])=[C:10]([C:13]([OH:15])=[O:14])[S:9][N:8]=2)[CH:2]=1
Reactant: COC(=O)c1snc(-c2cccnc2)c1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1c(-c2cccnc2)nsc1C(=O)O
Temperature: 0 °C

Procedure:
A solution of 1.8 g. of methyl 3-(3-pyridyl)-4-amino-5-isothiazolecarboxylate in 20 ml. of ethanol and 20 ml. of water containing three pellets of sodium hydroxide was heated at reflux for ninety minutes. The reaction mixture was then added to 50 ml. of ice water, and the aqueous mixture was acidified by the addition of 1N aqueous hydrochloric acid. The solid precipitate was collected by filtration and recrystallized from acetic acid and water to provide 3-(3-pyridyl)-4-amino-5-isothiazolecarboxylic acid. M.P. 235°-236° C.
Reaction SMILES: Cl.C[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20]C)[CH:16]=3)[C:11]=2[C:22]2[CH:23]=[C:24]([O:28][CH2:29][CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)[CH:25]=[CH:26][CH:27]=2)=[CH:6][CH:5]=1.B(Br)(Br)Br>>[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([OH:20])[CH:16]=3)[C:11]=2[C:22]2[CH:23]=[C:24]([O:28][CH2:29][CH2:30][CH2:31][N:32]3[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]3)[CH:25]=[CH:26][CH:27]=2)=[CH:6][CH:5]=1
Reactant: COc1ccc(-c2ccc3cc(OC)ccc3c2-c2cccc(OCCCN3CCCCC3)c2)cc1
Agent: BrB(Br)Br
Agent: Cl
Product: Oc1ccc(-c2ccc3cc(O)ccc3c2-c2cccc(OCCCN3CCCCC3)c2)cc1
Yield: 91.2 %

Procedure:
In a manner similar to that used in Example 3, 0.75 g (1.45 mmol) of 1-[3-[3-[2-(4-methoxyphenyl)-6-methoxynaphth-1-yl]phenyloxy]propyl]piperidine hydrochloride and 0.34 mL (3.62 mmol) of BBr3 were converted to 0.6 g of the title compound, isolated a tan amorphous powder.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:3]=1[CH2:4][NH:5][C@H:6]1[CH2:10][CH2:9][NH:8][CH2:7]1.Cl[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][N:18]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:3]=1[CH2:4][NH:5][C@H:6]1[CH2:10][CH2:9][N:8]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][N:18]=2)[CH2:7]1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: Clc1ccc(CN[C@H]2CCNC2)c(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1ccc(N2CC[C@H](NCc3ccc(Cl)cc3Cl)C2)nc1

Procedure:
Stir a mixture of (S)-(2,4-dichlorobenzyl)-pyrrolidin-3-ylamine (200 mg, 0.82 mmol), 6-chloronicotinonitrile (75 mg, 0.54 mmol) and diisopropylethylamine (140 μl, 0.82 mmol) in DMF (5 mL) at room temperature overnight. Concentrate and chromatograph on silica gel to give the title compound. Form the hydrochloride by essentially the procedure in Example 1 to give 1H NMR (300 MHz, MeOH-d4) δ 8.44 (1H, d, J=1.51 Hz), 7.95 (1H, dd, J=9.23, 2.07 Hz), 7.56-7.68 (2H, m), 7.40 (1H, dd, J=8.38, 2.17 Hz), 6.97 (1H, d, J=9.42 Hz), 4.42 (2H, d, J=3.01 Hz), 4.16-4.25 (1H, m), 4.04-4.13 (1H, m), 3.82-3.96 (2H, m), 3.63-3.77 (1H, m), 2.56-2.69 (1H, m), 2.43 (1H, m), MS (ES): 347 [M+].
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]1[O:19][CH:14]([O:15][CH2:16][CH:17]=[CH2:18])[C@H:13]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@@H:12]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@@H:11]1[O:36][C@@H:37]1[O:66][C@H:65]([CH2:67][O:68][Si](C(C)(C)C)(C)C)[C@@H:56]([O:57][CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[C@H:47]([O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C@H:38]1[O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH2:21]([O:20][C@@H:13]1[C@@H:12]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@H:11]([O:36][C@@H:37]2[O:66][C@H:65]([CH2:67][OH:68])[C@@H:56]([O:57][CH2:58][C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)[C@H:47]([O:48][CH2:49][C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=3)[C@H:38]2[O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C@@H:10]([CH2:9][OH:8])[O:19][CH:14]1[O:15][CH2:16][CH:17]=[CH2:18])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: C=CCOC1O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O[C@@H]2O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=CCOC1O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 61.6 %

Procedure:
The compound (8.67 g, 8.17 mmol) synthesized in Example 5 (5a) was dissolved in tetrahydrofuran (150 mL) and a solution of 1.0 M tetrabutyl ammonium fluoride in THF (20 mL, 20 mmol) was added thereto, followed by stirring of the mixture at room temperature for 5 hours. After the solvent was distilled off under reduced pressure, the residue was purified using silica gel flash column chromatography (methylene chloride:methanol, 50:1, V/V) to obtain the desired title compound (4.19 g, yield 62%) as a colorless oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][OH:10])[CH2:3][CH2:2]1.[CH:11]([NH:14][C:15]([C@H:17]1[CH2:22][CH2:21][C@@H:20]([NH:23][C:24]2[C:29]([N+:30]([O-:32])=[O:31])=[CH:28][N:27]=[C:26](OCCOC)[CH:25]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])[CH3:12]>>[CH:11]([NH:14][C:15]([C@H:17]1[CH2:18][CH2:19][C@@H:20]([NH:23][C:24]2[C:29]([N+:30]([O-:32])=[O:31])=[CH:28][N:27]=[C:26]([O:10][CH2:9][CH2:8][CH2:7][N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[CH:25]=2)[CH2:21][CH2:22]1)=[O:16])([CH3:13])[CH3:12]
Reactant: OCCCN1CCOCC1
Reactant: COCCOc1cc(N[C@H]2CC[C@@H](C(=O)NC(C)C)CC2)c([N+](=O)[O-])cn1
Product: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(OCCCN3CCOCC3)ncc2[N+](=O)[O-])CC1

Procedure:
Intermediate cis-N-isopropyl-4-(2-(3-morpholinopropoxy)-5-nitropyridin-4-ylamino)cyclohexanecarboxamide was prepared with 3-morpholinopropan-1-ol using a 2 step procedure analogous to that used to prepare cis-N-isopropyl-4-(2-(2-methoxyethoxy)-5-nitropyridin-4-ylamino)cyclohexanecarboxamide (200 mg).
Reaction SMILES: [CH:1]([C:4]1[N:8]2[CH:9]=[C:10]([S:13][C:14]3[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=3[CH2:16][NH2:17])[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1)([CH3:3])[CH3:2].[CH2:22]([N:24]=[C:25]=[O:26])[CH3:23]>ClCCl>[CH2:22]([NH:24][C:25]([NH:17][CH2:16][C:15]1[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=1[S:13][C:10]1[CH:11]=[CH:12][C:7]2[N:8]([C:4]([CH:1]([CH3:3])[CH3:2])=[N:5][N:6]=2)[CH:9]=1)=[O:26])[CH3:23]
Reactant: CC(C)c1nnc2ccc(Sc3ccccc3CN)cn12
Reactant: CCN=C=O
Solvent: ClCCl
Product: CCNC(=O)NCc1ccccc1Sc1ccc2nnc(C(C)C)n2c1
Reaction time: 0.33 h
Yield: 93.3 %

Procedure:
To a solution of 2-(3-Isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-ylsulfanyl)-benzylamine (200.0 mg, 0.671 mmol) in dichloromethane (6.71 mL) under nitrogen at ambient temperature was added ethyl isocyanate (53.0 μL, 0.67 mmol). The reaction was stirred for 20 minutes, then the solvent was removed in vacuo. The residue was recrystallized from ethyl acetate to give the title compound (231 mg, 94%). MS (M+1)=370.5.
Reaction SMILES: O[C:2]1[C:7]([C:8]2[CH:13]=CC=C[CH:9]=2)=[N:6][C:5]([Br:14])=[CH:4][N:3]=1.OC1C(C(C)C)=NC([Br:25])=CN=1>>[Br:25][C:2]1[C:7]([CH:8]([CH3:13])[CH3:9])=[N:6][C:5]([Br:14])=[CH:4][N:3]=1
Reactant: CC(C)c1nc(Br)cnc1O
Reactant: Oc1ncc(Br)nc1-c1ccccc1
Product: CC(C)c1nc(Br)cnc1Br

Procedure:
This compound is prepared by replacing the 2-hydroxy-3-phenyl-5-bromopyrazine used in Step A of Preparation 87 by an equivalent quantity of 2-hydroxy-3-isopropyl-5-bromopyrazine.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]2[N:14]=[C:15]([CH2:17][O:18][C:19]3[C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[F:34])=[C:26]4[N:21]([C:22]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=5[F:41])=[N:23][N:24]=[CH:25]4)[N:20]=3)[N:16]=[C:10]2[CH2:9]1)=O)(C)(C)C.[ClH:42]>C(OCC)(=O)C>[ClH:42].[F:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[C:27]1[C:19]([O:18][CH2:17][C:15]2[N:16]=[C:10]3[CH2:9][NH:8][CH2:13][CH2:12][N:11]3[N:14]=2)=[N:20][N:21]2[C:26]=1[CH:25]=[N:24][N:23]=[C:22]2[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[F:41]
Reactant: CC(C)(C)OC(=O)N1CCn2nc(COc3nn4c(-c5ccccc5F)nncc4c3-c3ccccc3F)nc2C1
Agent: Cl
Solvent: CCOC(C)=O
Product: Fc1ccccc1-c1c(OCc2nc3n(n2)CCNC3)nn2c(-c3ccccc3F)nncc12

Procedure:
To 2-[3,7-bis(2-Fluorophenyl)pyrazolo[1,5-d][1,2,4]triazin-2-yloxymethyl]-5,6-dihydro-8H-[1,2,4]triazolo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (100 mg, 0.18 mmol) in ethyl acetate (3 ml) was added a saturated solution of hydrogen chloride in: ethyl acetate (2 ml), and the resultant mixture was stirred at room temperature for 5.5 h. 2-[3,7-Bis(2-fluorophenyl)pyrazolo[1,5-d][1,2,4]triazin-2-yloxymethyl]-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine hydrochloride was precipitated as a pale yellow solid, and was separated by filtration, washed thoroughly with ethyl acetate and dried (71 mg). Data for the title compound: 1H NMR (360 MHz, DMSO) δ 3.67 (2H, m), 4.37 (2H, t, J=5.8 Hz), 4.48 (2H, s), 5.39 (2H, s), 7.33-7.55 (5H, m), 7.69 (1H, td, J=7.6, 1.7 Hz), 7.77 (1H, m), 7.92 (1H, td, J=7.3, 1.7 Hz), 9.44 (1H, s), 10.07 (2H, br s); MS (ES+) m/e 461 [MH]+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[CH3:15][C:16]1[N:17]=[CH:18][O:19][C:20]=1[C:21](Cl)=[O:22].C(N(CC)CC)C.C(OCC)(=O)C>ClCCl>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:21]([C:20]1[O:19][CH:18]=[N:17][C:16]=1[CH3:15])=[O:22]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: Cc1ncoc1C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1ncoc1C(=O)NCCc1c[nH]c2ccc(Cl)cc12
Yield: 78.1 %

Procedure:
This compound was obtained following Method B starting from 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.0456 g, 0.193 mmol), 4-methyloxazole-5-carbonyl chloride (0.029 g; 0.193 mmol), and triethylamine (0.068 mL; 0.483 mmol) in dichloromethane (3 mL). Flash chromatography on silica gel eluting with 4 to 30% of ethyl acetate in dichloromethane gave 0.0458 g (78%) of N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-4-methyloxazole-5-carboxamide as a solid.
Reaction SMILES: CC(CC)C(O)=[O:4].[CH3:8][CH:9]([CH2:24][CH3:25])[C:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)=[O:11].O.C(=O)([O-])O.[Na+]>CO>[OH:4][C:21]1[CH:22]=[CH:23][C:18]([C:15]2[CH:16]=[CH:17][C:12]([C:10](=[O:11])[CH:9]([CH3:8])[CH2:24][CH3:25])=[CH:13][CH:14]=2)=[CH:19][CH:20]=1
Reactant: CCC(C)C(=O)c1ccc(-c2ccccc2)cc1
Reactant: CCC(C)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCC(C)C(=O)c1ccc(-c2ccc(O)cc2)cc1
Yield: 87.9 %

Procedure:
0.67 g of the above 2-methylbutanoic acid-4-(2-methylbutanoyl) biphenyl was mixed with 95 ml of methyl alcohol and 5 ml of water and added with 1.14 g (13.6 mmol) of sodium hydrogen carbonate with stirring, which was subjected to hydrolysis reaction at room temperature for 40 hours. After the completion of the reaction, methanol was distilled off and 1 normal hydrochloric acid was added to adjust pH to not more than 1, and the extraction with dichloromethane was performed. The extracted liquid was washed with water, dried on anhydrous sodium sulfate and purified by a column chromatography of silica gel after the removal of the solvent to obtain 0.44 g (yield 88%) of (+)-4-hydroxy-4'-(2-methylbutanoyl) biphenyl at a light yellow crystal having the aforementioned properties.