Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:10]([C:20]2[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][CH:21]=2)[N:9]=1.C(N(CC)CC)C.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>O1CCCC1>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:10]([C:20]2[CH:28]=[CH:27][C:23]([C:24]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[O:26])=[CH:22][CH:21]=2)[N:9]=1
Reactant: C1COCCN1
Reactant: O=C(O)c1ccc(-n2nc(-c3ccccc3O)nc2-c2ccccc2O)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(c1ccc(-n2nc(-c3ccccc3O)nc2-c2ccccc2O)cc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3.0 g of 4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid (Example 5) and 1.25 ml of chloro-N,N-2-trimethyl-1-propen-1-amine [CAS-Reg.-No. 26189-59-3] are stirred for 2 h in 50 ml of tetrahydrofuran. 2.2 ml of triethylamine and 0.8 ml of morpholine are added and the mixture is stirred at room temperature for 18 h. It is poured onto water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The residue is crystallized from isopropanol. After drying, {4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]-phenyl}morpholin-4-yl-methanone remains as colorless crystals of m.p. 157-160° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[CH:4][CH:3]=1.S(Cl)([Cl:13])=O>CN(C=O)C>[Cl:1][C:2]1[C:7]([C:8]([Cl:13])=[O:10])=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cnccc1Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cnccc1Cl

Procedure:
A mixture of 1.416 g (8.99 mmol) of 4-chloronicotinic acid, 15 ml of thionyl chloride and two droplets of DMF was heated under reflux for 2 hours. The reaction mixture was allowed to cool, and then concentrated under reduced pressure to obtain 4-chloronicotinoyl chloride. The compound thus obtained was then suspended in a mixture of 10 ml of acetone and 10 ml of THF. The suspension thus obtained was then added dropwise to a solution of 753 mg of ammonium thiocyanate in 15 ml of acetone with stirring in 5 minutes. After the termination of dropwise addition, the reaction mixture was heated to a temperature of 40° C. with stirring for 6 minutes to obtain a mixture containing 4-chloronicotinoyl isothiocyanate. To the mixture thus obtained was then added dropwise a solution of 1.55 g of 4-chloro-N-methylaniline in 10 ml of acetone with stirring in 5 minutes. The reaction mixture was stirred at room temperature for 17 hours, concentrated to half the initial volume under reduced pressure, and then poured into about 500 ml of ice-water. The resulting crystal was collected by filtration, washed with water, and then dried under reduced pressure. The resulting crude product was purified through silica gel column chromatography (eluant: CHCl3 +1 to 3% methanol), and then recrystallized from ethanol to obtain 717 mg of 2-[N-(4-chlorophenyl)-N-methylamino]-4H-pyrido[3,4-e]-1,3-thiazin-4-one.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[NH:11][CH2:10][CH2:9]2)([CH3:5])[C:3]#[N:4].[Br:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22](Br)[C:19]=1[CH:20]=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[Br:17][C:18]1[C:19]([CH:20]=[O:21])=[C:22]([N:11]2[CH2:10][CH2:9][C:8]3[C:13](=[CH:14][CH:15]=[C:6]([C:2]([CH3:1])([CH3:5])[C:3]#[N:4])[CH:7]=3)[C:12]2=[O:16])[CH:23]=[CH:24][CH:25]=1
Reactant: O=Cc1c(Br)cccc1Br
Reactant: CC(C)(C#N)c1ccc2c(c1)CCNC2=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(C)(C#N)c1ccc2c(c1)CCN(c1cccc(Br)c1C=O)C2=O
Temperature: 110 °C
Yield: 45.6 %

Procedure:
To 1.3 g (6.07 mmol) 2-methyl-2-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)-propionitrile dissolved in 20 ml degassed dioxane was added 6.40 g (24.27 mmol) 2,6-dibromobenzaldehyde, 3.96 g (12.14 mmol) cesium carbonate, 70 mg (0.121 mmol) Pd(dba)2, and 105 mg (0.182 mmol) xantphos. The mixture was heated to 110° C. for 3 h, cooled to room temperature, and filtered over Celite rinsing with dioxane. The mixture was then concentrated and purified by column chromatography, eluting with ethyl acetate/hexanes to provide 1.10 g (46%) 2-[2-(3-bromo-2-formylphenyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl]-2-methylpropionitrile.
Reaction SMILES: [N+:1]([C:4]1[C:14]([NH2:15])=[CH:13][C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:6]=2[CH:5]=1)([O-])=[O:2].[N:16]#[C:17][NH2:18].[CH]Cl.[OH-].[Na+]>O>[N+:1]1([O-:2])[C:4]2[CH:5]=[C:6]3[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:7]3=[CH:13][C:14]=2[N:15]=[C:17]([NH2:18])[N:16]=1
Reactant: N#CN
Reactant: Nc1cc2c(cc1[N+](=O)[O-])CCCCC2
Agent: [CH]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1nc2cc3c(cc2[n+]([O-])n1)CCCCC3
Temperature: 50 °C
Reaction time: 3 h
Yield: 10.3 %

Procedure:
A mixture of nitroaniline 185 (2.26 g, 11.0 mmol) and cyanamide (1.84 g, 43.8 mmol) were mixed together at 100° C., cooled to 50° C., cHCl (10 mL) added carefully and the mixture heated at 100° C. for 4 h. The mixture was cooled to 50° C., 7.5 M NaOH solution added until the mixture was strongly basic and the mixture stirred at 100° C. for 3 h. The mixture was cooled, diluted with water (100 mL), filtered, washed with water (3×20 mL), washed with ether (10 mL) and dried. The residue as purified by chromatography, eluting with 5% MeOH/DCM, to give amine 186 (0.26 g, 10%) as a yellow powder: mp (MeOH) 261-265° C.; 1H NMR [(CD3)2SO] δ 7.86 (s, 1H, H-11), 7.29 (s, 1H, H-5), 7.13 (br s, 2H, NH2), 2.84-2.90 (m, 4H, H-6, H-10), 1.74-1.80 (m, 2H, H-8), 1.58-1.67 (m, 4H, H-7, H-9); 13C NMR [(CD3)2SO] δ 160.2, 152.8, 147.8, 141.2, 127.9, 124.3, 117.8, 35.6, 35.1, 31.3, 29.3, 28.0. Anal. calcd for C12H14N4O: C, 62.6; H, 6.1; N, 24.3. Found: C, 62.9; H, 6.2; N, 24.6%.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]([CH2:11][NH:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[N:16][N:17]2[C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)([OH:10])[C:6]([F:9])([F:8])[F:7])[CH3:2].C(N(CC)C(C)C)(C)C.[CH3:38][C:39]1[CH:47]=[CH:46][CH:45]=[C:44]([CH3:48])[C:40]=1[C:41](Cl)=[O:42]>ClCCl>[CH2:1]([N:3]([CH2:4][C:5]([CH2:11][NH:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[N:16][N:17]2[C:22]1[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=1)([OH:10])[C:6]([F:8])([F:9])[F:7])[C:41](=[O:42])[C:40]1[C:44]([CH3:48])=[CH:45][CH:46]=[CH:47][C:39]=1[CH3:38])[CH3:2]
Reactant: CCNCC(O)(CNc1cccc2c1cnn2-c1ccc(F)cc1)C(F)(F)F
Reactant: Cc1cccc(C)c1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC(O)(CNc1cccc2c1cnn2-c1ccc(F)cc1)C(F)(F)F)C(=O)c1c(C)cccc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(Ethylamino)-1,1,1-trifluoro-2-({[1-(4-fluorophenyl)-1H-indazol-4-yl]amino}methyl)-2-propanol (25 mg, 0.063 mmol) was dissolved in anhydrous dichloromethane (0.15 ml). N,N-diisopropylethylamine (0.011 ml, 0.13 mmol) was then added followed by 2,6-dimethylbenzoyl chloride in DCM (10.6 mg, 0.065 mmol as a 100 μl aliquot of 80.8 mg in 0.76 ml DCM) and the mixture stirred at room temperature overnight. The mixture was diluted with dichloromethane, washed successively with aqueous sodium bicarbonate and water and then dried through a hydrophobic frit and evaporated and the crude product purified by mass directed autopreparation (System B). Product containing fractions were partitioned between dichloromethane and aqueous sodium bicarbonate. The aqueous layer was re-extracted with dichloromethane and the combined organic extracts were washed successively water and brine, dried through a hydrophobic frit and evaporated in vacuo to give the title compound (13.1 mg).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]1[CH2:15][CH2:14][N:13]([C:16]([C:18]2[CH:23]=[CH:22][C:21](Br)=[CH:20][N:19]=2)=[O:17])[CH2:12][CH2:11]1.[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])(O)=O.[Na+]>CO.O1CCOCC1>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]1[CH2:15][CH2:14][N:13]([C:16]([C:18]2[CH:23]=[CH:22][C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:20][N:19]=2)=[O:17])[CH2:12][CH2:11]1
Reactant: OB(O)c1ccccc1
Reactant: O=C(c1ccc(Br)cn1)N1CCC(c2nc3ccccc3[nH]2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: O=C(c1ccc(-c2ccccc2)cn1)N1CCC(c2nc3ccccc3[nH]2)CC1
Temperature: 100 °C
Yield: 80 %

Procedure:
To a stirred mixture of [4-(1H-benzimidazol-2-yl)piperidin-1-yl](5-bromopyridin-2-yl)methanone (39 mg, 0.10 mmol) and phenylboronic acid (20.1 mg, 0.17 mmol) in a mixture of MeOH (0.5 mL) and 1,4-dioxane (1.5 mL) is added 2M aqueous NaHCO3 (0.3 mL). The mixture is degassed with N2. 1,1′-bis(diphenylphosphino)ferrocene-palladium (II) dichloride dichloromethane complex (5 mol %) is added and the mixture is heated at 100° C. under microwave irradiation for 30 mins. The mixture is filtered through a pad of celite and the filtrate is concentrated under reduced pressure. Purification by column chromatography (Isolute column, eluent DCM, 5% MeOH) affords 30.6 mg of [4-(1H-benzimidazol-2-yl)piperidin-1-yl](5-phenylpyridin-2-yl)methanone.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[O:8][CH:9]=[CH:10][CH:11]=1.[CH3:12][C:13]1([CH:18]=[O:19])[CH2:17][CH2:16][CH2:15][O:14]1.[Cl-].[NH4+]>CCCCCC.O1CCCC1>[CH3:6][C:7]1[O:8][C:9]([CH:18]([C:13]2([CH3:12])[CH2:17][CH2:16][CH2:15][O:14]2)[OH:19])=[CH:10][CH:11]=1
Reactant: Cc1ccco1
Reactant: CC1(C=O)CCCO1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccc(C(O)C2(C)CCCO2)o1
Temperature: -70 °C
Reaction time: 2 h
Yield: 66.4 %

Procedure:
24 ml (60 mmol, 1.5 eq) of a 2.5 M solution of n-butyllithium in hexane were added dropwise to a solution of 5.0 g (60 mmol, 1.5 eq) of 2-methylfuran in 100 ml of tetrahydrofuran cooled to −70° C. The reaction medium was stirred and allowed to return to ambient temperature for 2 hours. The reaction medium was cooled to −70° C. and then 6.0 g (40 mmol, 1 eq) of 2-methyltetrahydrofuran-2-carbaldehyde at 77% were added. The reaction medium was stirred at ambient temperature for 3 hours. The reaction medium was treated with a saturated ammonium chloride solution and extracted with ethyl acetate. The organic phases were combined, washed with a saturated sodium chloride solution, filtered over magnesium sulfate and evaporated. 5.21 g of (5-methylfuran-2-yl)-(2-methyltetrahydrofuran-2-yl)methanol were obtained. Yield=66%. TLC/SiO2: heptane/EtOAc (60/40), developing with KMnO4.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([O:28][CH3:29])=[CH:11][C:12]([N+:25]([O-:27])=[O:26])=[C:13]([CH:24]=1)[C:14]([O:16]CC1C=CC=CC=1)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CCO.O>[CH2:1]([O:8][C:9]1[C:10]([O:28][CH3:29])=[CH:11][C:12]([N+:25]([O-:27])=[O:26])=[C:13]([CH:24]=1)[C:14]([OH:16])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc([N+](=O)[O-])c(C(=O)OCc2ccccc2)cc1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc([N+](=O)[O-])c(C(=O)O)cc1OCc1ccccc1
Reaction time: 8 h
Yield: 94.7 %

Procedure:
To a solution of benzyl 5-(benzyloxy)-4-methoxy-2-nitrobenzoate (1.4 g, 3.56 mmol) in EtOH (10 mL) was added 1N NaOH (4.27 mL, 4.27 mmol). The mixture was stirred at RT for 1 h, upon which an additional aliquot of NaOH (4.27 mL, 4.27 mmol) was added. Stirring was continued at RT overnight. The mixture was diluted with water (20 mL) and washed with CH2Cl2 (2×25 mL). The aqueous layer was acidified to pH=2 with 0.5 N HCl and extracted with EtOAc (3×50 mL). The combined organics were dried (Na2SO4), filtered and concentrated in vacuo to give 5-(benzyloxy)-4-methoxy-2-nitrobenzoic acid (1.02 g, 3.37 mmol, 94%).
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].C[Si](C)(C)N[Si](C)(C)C.[Cl:18][C:19]1[CH:20]=[C:21]([CH:40]=[CH:41][C:42]=1[Cl:43])[C:22]([NH:24][C:25]1[CH:26]=[N:27][C:28]([O:31][C:32]2[CH:37]=[CH:36][C:35]([CH2:38]Cl)=[CH:34][CH:33]=2)=[CH:29][CH:30]=1)=[O:23]>[Sn](Cl)(Cl)(Cl)Cl.CO>[Cl:18][C:19]1[CH:20]=[C:21]([CH:40]=[CH:41][C:42]=1[Cl:43])[C:22]([NH:24][C:25]1[CH:26]=[N:27][C:28]([O:31][C:32]2[CH:37]=[CH:36][C:35]([CH2:38][N:1]3[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]3=[O:3])=[CH:34][CH:33]=2)=[CH:29][CH:30]=1)=[O:23]
Reactant: O=c1cc[nH]c(=O)[nH]1
Reactant: O=C(Nc1ccc(Oc2ccc(CCl)cc2)nc1)c1ccc(Cl)c(Cl)c1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CO
Product: O=C(Nc1ccc(Oc2ccc(Cn3ccc(=O)[nH]c3=O)cc2)nc1)c1ccc(Cl)c(Cl)c1
Temperature: 150 °C
Reaction time: 5.5 h

Procedure:
To uracil (200 mg, 1.8 mmol) was added hexamethyldisilazane (5 mL), and the resulting solution was stirred for 5.5 hours at 150° C. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in a solution of acetonitrile (10 mL)-THF (5 mL), and to this solution were added 3,4-dichloro-N-[6-(4-chloromethylphenoxy)pyridin-3-yl]benzamide (500 mg, 1.2 mmol) and tin tetrachloride (3 drops). The resulting solution was refluxed for 2.5 hours. To this reaction solution was added methanol (1 mL), and the resulting solution was stirred for 30 minutes at room temperature. The resulting reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol:chloroform=1:99→3:97), to thereby yield 20 mg of the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[C:10]([O:17][CH:18]([CH3:20])[CH3:19])[N:9]=2)[CH2:4][CH2:3]1.C([O-])=O.[NH4+]>[Pd].CO>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:9]=[C:10]([O:17][CH:18]([CH3:19])[CH3:20])[C:11]([NH2:14])=[CH:12][CH:13]=2)[CH2:4][CH2:3]1
Reactant: CC(C)Oc1nc(N2CCN(C)CC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)Oc1nc(N2CCN(C)CC2)ccc1N
Temperature: 80 °C
Yield: 114.7 %

Procedure:
In a microwave tube, 500 mg of 1-methyl-4-[5-nitro-6-(propan-2-yloxy)pyridin-2-yl]piperazine are introduced into 15 ml of methanol. 675 mg of ammonium formate and 270 mg of Pd/C (10%) are added. The reaction medium is microwave-heated at 80° C. for 5 minutes. The mixture is filtered on Clarcel and the Clarcel is rinsed with methanol. The filtrate is concentrated under reduced pressure, so as to give 512 mg of 6-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)pyridin-3-amine in the form of a purple gum.
Reaction SMILES: [O:1]=[C:2]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][NH:8][CH2:7][C@@H:6]1[C:11]([O:13][CH3:14])=[O:12].[CH:27]1([S:34][CH2:35][CH2:36]Cl)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[O:1]=[C:2]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:36][CH2:35][S:34][CH:27]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:7][C@@H:6]1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)[C@H]1CNCC[C@H]1CCC(=O)c1ccnc2ccc(OC)cc12
Reactant: ClCCSC1CCCCCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)[C@H]1CN(CCSC2CCCCCC2)CC[C@H]1CCC(=O)c1ccnc2ccc(OC)cc12
Temperature: 72 °C
Reaction time: 24 h
Yield: 59.1 %

Procedure:
A mixture composed of 3.06 g of methyl (3R,4R)-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-carboxylate, 1.79 g of 2-chloroethyl cycloheptyl sulfide, 5.39 g of potassium carbonate, and 1.29 g of potassium iodide in 75 cm3 of acetonitrile was heated with stirring and under an inert atmosphere at a temperature in the region of 72° C. for 24 hours. After cooling to approximately 20° C., the reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue obtained was purified by chromatography at atmospheric pressure on a column of silica gel (particle size 20-45 μ; diameter 4 cm; mass 150 g), elution was carried out with an ethyl acetate/methanol (95/5 by volume) mixture, and 50-cm3 fractions were collected. The fractions comprising the desired product were combined and then concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 2.6 g of methyl (3R,4R)-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]-1-[2-(cycloheptylthio)ethyl]piperidine-3-carboxylate were obtained in the form of a viscous oil.
Reaction SMILES: OC(C)(C)C[C@@:4]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:9][C:8](=[O:10])[N:7]([C@H](C2C=CC(C3C=CN=C(OC)C=3)=CC=2)C)[CH2:6][CH2:5]1.C(=O)([O-])[O-].[K+].[K+].IC.Cl>C(#N)C>[C:27]1([CH:4]2[O:9][C:8](=[O:10])[NH:7][CH2:6][CH2:5]2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: COc1cc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)ccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: O=C1NCCC(c2ccccc2)O1
Temperature: 25 °C
Yield: 133.2 %

Procedure:
(S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(2-methoxypyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (28 mg, 0.061 mmol), potassium carbonate (17 mg, 2 equiv), and Iodomethane (40 μL, 10 equiv) were mixed with acetonitrile (2.5 mL) and heated at reflux for 4 h. After being cooled to rt, the mixture was acidified with 5% aq HCl and purified by prep HPLC to afford (S)-6-(2-hydroxy-2-methylpropyl)-3-(S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (14.4 mg. 52%). LC-MS and 1H NMR (CD3OD) were the same as those of product made by Method 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:21])=[C:16]([F:20])[C:17]=2[F:19])[C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10]1.[N+:26]([O-])([O-:28])=[O:27].[K+]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:26]([O-:28])=[O:27])=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:21])=[C:16]([F:20])[C:17]=2[F:19])[C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10]1
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2c(F)c(F)c(F)cc2c1=O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C(O)c1cn(-c2cc([N+](=O)[O-])c(F)cc2F)c2c(F)c(F)c(F)cc2c1=O
Temperature: 60 °C
Reaction time: 8 h
Yield: 88.8 %

Procedure:
To 10 ml of conc. sulfuric acid was added 1.7 g of 1-(2,4-difluorophenyl)-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. Potassium nitrate (1.5 g) was added in portions to the solution, which was heated at 60° C. and stirred overnight. The reaction solution was allowed to cool down, poured into ice water, and stirred overnight. The precipitated solid was collected by filtration and washed with water, ethanol and diethyl ether to give 1.7 g of the title compound.
Reaction SMILES: F[B-](F)(F)F.[O:6]=[N+:7]=[O:8].[CH3:9][N:10]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[N:12]=[C:11]1[N+:18]([O-:20])=[O:19]>C(Cl)Cl>[CH3:9][N:10]1[C:14]([N+:7]([O-:8])=[O:6])=[C:13]([N+:15]([O-:17])=[O:16])[N:12]=[C:11]1[N+:18]([O-:20])=[O:19]
Reactant: Cn1cc([N+](=O)[O-])nc1[N+](=O)[O-]
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: Cn1c([N+](=O)[O-])nc([N+](=O)[O-])c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 73.5 %

Procedure:
Nitronium tetrafluoroborate (NO2BF4, 5.0 g, 37.6 mmol) was added to the solid of 1-methyl-2,4-dinitroimidazole (4.0 g, 23.3 mmol) at room temperature. Then the reaction temperature was brought to 105° C. within 15 minutes. At that temperature, all solids melted. The reaction mixture was then stirred at that temperature for 1.5 hrs, then cooled to room temperature and diluted with methylene chloride before being poured onto ice/water. The product was extracted with methylene chloride (3×60 ml). The combined organic phase was washed successively with water (50 ml), 10% aq. NaHCO3 (30 ml), and water (50 ml) and dried over Na2SO4. The solvent was removed in vacuo and the residue was recrystallized with ethanol to give 3.72 g (74%) of 1-methyl-2,4,5-trinitroimidazole as pale yellow crystals, mp=84.0-85.0° C. (literature, mp=82° C.). The structure of the compound was confirmed by NMR spectroscopy.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](NC2N=CC(N3CCN(C(OC(C)(C)C)=O)CC3)=CC=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[NH2:30][C:31]1[N:36]=[CH:35][C:34]([N:37]2[C@@H:42]([CH3:43])[CH2:41][N:40]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C@H:39]([CH3:51])[CH2:38]2)=[CH:33][CH:32]=1.BrC1C(=O)N(C)C=C(Br)C=1>>[Br:1][C:2]1[CH:3]=[C:4]([NH:30][C:31]2[N:36]=[CH:35][C:34]([N:37]3[C@@H:42]([CH3:43])[CH2:41][N:40]([C:44]([O:46][C:47]([CH3:49])([CH3:48])[CH3:50])=[O:45])[C@H:39]([CH3:51])[CH2:38]3)=[CH:33][CH:32]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: C[C@@H]1CN(c2ccc(N)nc2)[C@@H](C)CN1C(=O)OC(C)(C)C
Reactant: Cn1cc(Br)cc(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cn2)c1=O
Agent: Cn1cc(Br)cc(Br)c1=O
Product: C[C@@H]1CN(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)[C@@H](C)CN1C(=O)OC(C)(C)C
Yield: 79 %

Procedure:
Following the procedures as described for compound 101i, reaction of 122b (766 mg, 2.50 mmol) and 3,5-dibromo-1-methylpyridin-2(1H)-one (668 mg, 2.50 mmol) afforded 122c as a yellow solid (978 mg, 79%). LCMS: [M+H]+ 492
Reaction SMILES: [BH4-].[Na+].[I-].[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2[CH2:15][C:16]1[CH:17]=[N+:18]([CH3:22])[CH:19]=[CH:20][CH:21]=1>CO>[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2[CH2:15][C:16]1[CH2:17][N:18]([CH3:22])[CH2:19][CH2:20][CH:21]=1
Reactant: COc1ccc2[nH]cc(Cc3ccc[n+](C)c3)c2c1
Agent: [BH4-]
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2[nH]cc(CC3=CCCN(C)C3)c2c1

Procedure:
Sodium borohydride in pellets (5.71 g; 0.0396 mol) was added to a cold (~0° C.) stirring mixture of compound of Description 7 [3-[(5-methoxy-1H-indol-3-yl)methyl]-1-methyl-pyridinium iodide] (7.45 g; 0.0196 mol) in methanol (150 ml). The reaction mixture was stirred at 0° C. for 2 hours. The reaction was then quenched with a saturated solution of aqueous sodium carbonate and the solvent (methanol) was evaporated under vacuum. The product was extracted with methylene chloride from the residual alkaline aqueous solution. The organic extract was dried (MgSO4) and evaporated under vacuum. Purification by Flash Chromatography of the crude product using silica gel and elution with methylene chloride/methanol/ammonia (90/10/1) yielded the desired compound. A solution of the desired compound in diethyl ether was saturated with gaseous hydrogen chloride. A white solid was precipitated. The title compound hydrochloride was collected by filtration, washed with diethyl ether and dried under vacuum (3.5 g).
Reaction SMILES: [CH3:1][CH:2]([NH2:7])[CH:3]([CH3:6])[CH2:4][CH3:5].[CH2:8]([O:11][C:12]1[C:20]([O:21][CH3:22])=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][C:13]=1[O:23][CH3:24])[C:9]#[CH:10]>>[CH3:1][CH:2]([NH:7][C:16](=[O:17])[C:15]1[CH:14]=[C:13]([O:23][CH3:24])[C:12]([O:11][CH2:8][C:9]#[CH:10])=[C:20]([O:21][CH3:22])[CH:19]=1)[CH:3]([CH3:6])[CH2:4][CH3:5]
Reactant: C#CCOc1c(OC)cc(C(=O)Cl)cc1OC
Reactant: CCC(C)C(C)N
Product: C#CCOc1c(OC)cc(C(=O)NC(C)C(C)CC)cc1OC

Procedure:
According to the same method as that of Production Example 1, 1,2-dimethylbutylamine was used in place of 2,2-dimethylpropylamine, 4-(2-propynyloxy)-3,5-dimethoxybenzoyl chloride was used in place of 4-(2-propynyloxy)-3-methoxybenzoyl chloride to obtain N-(1,2-dimethylbutyl)-4-(2-propynyloxy)-3,5-dimethoxybenzamide (hereinafter, described as the compound 22 of the present invention) represented by the formula: