Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][C:12]([CH3:19])([CH2:17][NH2:18])[CH2:13][N:14]([CH3:16])[CH3:15].CCN(C(C)C)C(C)C>CS(C)=O>[CH3:15][N:14]([CH3:16])[CH2:13][C:12]([CH3:19])([CH3:11])[CH2:17][NH:18][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: CN(C)CC(C)(C)CN
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CN(C)CC(C)(C)CNc1ccccc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 101.1 %

Procedure:
To a solution of 1-fluoro-2-nitrobenzene (353 mg, 2.5 mmol) in DMSO (5 mL) is added 2,2,N*1*,N*1*-Tetramethyl-propane-1,3-diamine (391 mg, 3 mmol), followed by Hunig's base (0.65 mL, 3.8 mmol). The reaction flask is sealed and heated to 80° C. for 16 h. The reaction is cooled to room temperature, is poured over ice water and is extracted with CH2Cl2. The organic layer is washed with water, brine, is dried (Na2SO4) and concentrated to afford the title crude compound (635 mg, crude) as an orange oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][C:6]([CH:8]1[CH2:10][CH2:9]1)=[O:7])[CH3:2].[Cl-].[Mg+2].[Cl-].N1C=CC=CC=1.Cl.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:11])[CH:5]([C:22]([C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)=[O:29])[C:6]([CH:8]1[CH2:10][CH2:9]1)=[O:7])[CH3:2]
Reactant: O=C(Cl)c1ccncc1
Reactant: CCOC(=O)CC(=O)C1CC1
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C(C(=O)c1ccncc1)C(=O)C1CC1
Temperature: 0 °C
Reaction time: 18 h
Yield: 79.7 %

Procedure:
7.5 g (48 mmol) of 3-cyclopropyl-3-oxo-propionic acid ethyl ester were dissolved in 250 ml of CH2Cl2, the solution was cooled at 0° C. and successively were added 4.71 g (49.5 mmol) of anhydrous magnesium chloride, 8.1 ml (100 mmol) of pyridine and 12.8 g (72 mmol) of isonicotinoyl chloride.hydrochloride. The yellow suspension was stirred 1 h under ice cooling and 18 h at room temperature. The reaction mixture was poured into crashed ice and extracted twice with CH2Cl2. The organic phases were washed with brine, dried over magnesium sulfate, and evaporated. The residual product was purified by column chromatography (n-heptane:EtOAc 1:1) to afford the title compound as light yellow oil (10 g, 79%). MS: 262.1 (MH+).
Reaction SMILES: F[C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([C:11]#[N:12])[C:5]2=[CH:4][CH:3]=1.[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.O>CN1CCCC1=O>[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:2]2[N:7]=[C:6]3[NH:8][N:9]=[C:10]([C:11]#[N:12])[C:5]3=[CH:4][CH:3]=2)[CH2:16][CH2:15]1
Reactant: N#Cc1n[nH]c2nc(F)ccc12
Reactant: CN1CCNCC1
Solvent: O
Solvent: CN1CCCC1=O
Product: CN1CCN(c2ccc3c(C#N)n[nH]c3n2)CC1

Procedure:
6-Fluoro-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile (1.62 g, 10.0 mmole) was dissolved in 20 mL of N-methylpyrrolidone. N-methylpiperazine (3.0 g, 30.0 mmole) was added and the reaction mixture was warmed for 2 hours at 80°. It was poured into H2O and then the product was filtered off and recrystallized from MeOH-H2H2O to give 1.41 g (58%) of analytically pure product, mp 255°(dec).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]2[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17]O)[CH2:12][CH2:11]2)[CH:5]=[C:6]([F:9])[C:7]=1[F:8].[BrH:19]>O>[F:1][C:2]1[CH:3]=[C:4]([CH:10]2[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][Br:19])[CH2:12][CH2:11]2)[CH:5]=[C:6]([F:9])[C:7]=1[F:8]
Reactant: Br
Reactant: OCCC1CCC(c2cc(F)c(F)c(F)c2)CC1
Solvent: O
Product: Fc1cc(C2CCC(CCBr)CC2)cc(F)c1F

Procedure:
4-(3',4',5'-Trifluorophenyl)-1-(2'-hydroxyethyl)cyclohexane (10.4 g) was added to an aqueous solution of 47% HBr (15 ml), followed by stirring the mixture under reflux for 2 hours, adding the reaction solution to water (50 ml), extracting with ethyl acetate (100 ml), washing the organic layer with water, drying over anhydrous MgSO4, and concentrating the solvent under reduced pressure, to obtain 4-(3',4',5'-trifluorophenyl)-1 -(2'-bromoethyl)cyclohexane (10.4g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15](O)=[O:16])=[C:13]([CH3:18])[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[C:11](=[O:29])[NH:10]2)=[C:5]([S:30][CH3:31])[CH:4]=1)#[N:2].C1C[N:35]([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[Cl-].[NH4+].Cl>C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]([NH2:35])=[O:16])=[C:13]([CH3:18])[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:27])([F:28])[F:26])[CH:20]=3)[C:11](=[O:29])[NH:10]2)=[C:5]([S:30][CH3:31])[CH:4]=1)#[N:2]
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: CSc1cc(C#N)ccc1[C@H]1NC(=O)N(c2cccc(C(F)(F)F)c2)C(C)=C1C(=O)O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CSc1cc(C#N)ccc1[C@H]1NC(=O)N(c2cccc(C(F)(F)F)c2)C(C)=C1C(N)=O
Temperature: 0 °C

Procedure:
The reaction was carried out under argon. (4S)-4-[4-Cyano-2-(methylsulfanyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (240 mg, 0.536 mmol) was dissolved in THF (5 ml), and PyBOP (419 mg, 0.805 mmol) and triethylamine (380 mg, 3.76 mmol) were added. After brief stirring the mixture was cooled to 0° C., and ammonium chloride (143 mg, 2.68 mmol) was added. The reaction mixture was stirred at RT overnight and the content of the flask was then added to 1 N hydrochloric acid. The mixture was extracted twice with ethyl acetate, and the combined organic phases were washed with 1 N hydrochloric acid and with saturated sodium chloride solution, dried and concentrated. The residue was purified by preparative HPLC. This gave 161 mg (67% of theory) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[NH:4][C:5]([CH3:23])=[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[N:8]=1.C(N(CC)CC)C.[C:31]1([S:37](Cl)(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>ClCCl>[CH3:23][C:5]1[NH:4][CH:3]([O:2][CH3:1])[N:8]([S:37]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)(=[O:39])=[O:38])[CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[C:6]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)C1=C(C)NC(OC)=NC1c1cccc([N+](=O)[O-])c1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1=C(C)NC(OC)N(S(=O)(=O)c2ccccc2)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.7 %

Procedure:
A solution of 1, 4-dihydro-2-methoxy-6-methyl-4-(3-nitrophenyl) -5-pyrimidinecarboxylic acid, ethyl ester (3.19 g, 10.0 mmole; see Example 5A) and distilled triethylamine (4.18 ml, 30.0 mmol) in distilled dichloromethane (20 ml) in an ice bath under argon was treated dropwise via syringe with benzenesulfonyl chloride (1.53 ml, 12.0 mmol). The reaction was then stirred at room temperature overnight; and then over the weekend. The mixture was partitioned between ethyl acetate and water. The organic phase was washed with saturated sodium chloride and flash chromatographed to give the title compound as a light brown oil (2.94 g).
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[N:5][CH:4]=[N:3]1.[Cl:7][C:8]1[CH:24]=[CH:23][C:11]([O:12][CH2:13][C:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=O)=[CH:10][CH:9]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([O:12][CH2:13][C:14](=[N:1][N:2]2[CH:6]=[N:5][CH:4]=[N:3]2)[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:23][CH:24]=1
Reactant: Nn1cncn1
Reactant: O=C(COc1ccc(Cl)cc1)c1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Fc1ccc(C(COc2ccc(Cl)cc2)=Nn2cncn2)cc1

Procedure:
To a stirred solution of 1-amino-1H-1,2,4-triazole (75% purity, 5.6 g, 0.05 mmol) and 2-(4-chlorophenoxy)-4'-fluoroacetophenone (13.2 g, 0.05 mmol) in 100 mL dry toluene is added a catalytic amount (1.0 g) p-toluene sulfonic acid. The mixture is heated at reflux with azeotropic removal of water for 4 days. Solvent is evaporated and the residue taken up in 200 mL ethyl acetate. The organic solution is washed with 2×100 mL 10% aqueous Na2CO3 and 1×100 mL brine. The dried (MgSO4) solution is filtered and concentrated to give the desired product which can be purified by chromatography or crystallization from an appropriate solvent.
Reaction SMILES: NC1N2N=CC(C3C=NC4C(C=3)=CC=CC=4)=C2N=C(C2CCN([C:27]([C:29]3[S:30][CH:31]=[CH:32][CH:33]=3)=[O:28])CC=2)C=1Br.[Cl:35][C:36]1[C:37]([N:56]2[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]2)=[N:38][C:39]2[N:40]([N:43]=[CH:44][C:45]=2[C:46]2[CH:47]=[N:48][C:49]3[C:54]([CH:55]=2)=[CH:53][CH:52]=[CH:51][CH:50]=3)[C:41]=1[NH2:42].BrC1C(C2CCNCC=2)=NC2N(N=CC=2C2C=NC3C(C=2)=CC=CC=3)C=1N>>[NH2:42][C:41]1[N:40]2[N:43]=[CH:44][C:45]([C:46]3[CH:47]=[N:48][C:49]4[C:54]([CH:55]=3)=[CH:53][CH:52]=[CH:51][CH:50]=4)=[C:39]2[N:38]=[C:37]([N:56]2[CH2:57][CH2:58][N:59]([C:27]([C:29]3[S:30][CH:31]=[CH:32][CH:33]=3)=[O:28])[CH2:60][CH2:61]2)[C:36]=1[Cl:35]
Reactant: Nc1c(Cl)c(N2CCNCC2)nc2c(-c3cnc4ccccc4c3)cnn12
Reactant: Nc1c(Br)c(C2=CCN(C(=O)c3cccs3)CC2)nc2c(-c3cnc4ccccc4c3)cnn12
Agent: Nc1c(Br)c(C2=CCNCC2)nc2c(-c3cnc4ccccc4c3)cnn12
Product: Nc1c(Cl)c(N2CCN(C(=O)c3cccs3)CC2)nc2c(-c3cnc4ccccc4c3)cnn12

Procedure:
(4-(7-Amino-6-chloro-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperazin-1-yl)(thiophen-2-yl)methanone was synthesized in a manner similar to the synthesis of (4-(7-amino-6-bromo-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-5,6-dihydropyridin-1(2H)-yl)(thiophen-2-yl)methanone, but with 6-chloro-5-(piperazin-1-yl)-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-7-amine substituted for 6-bromo-3-(quinolin-3-yl)-5-(1,2,3,6-tetrahydropyridin-4-yl)pyrazolo[1,5-a]pyrimidin-7-amine. The reaction was purified via reverse-phase preparatory HPLC to yield (4-(7-amino-6-chloro-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperazin-1-yl)(thiophen-2-yl)methanone as yellow solid. (M+H=490.19, retention time=3.75 min).
Reaction SMILES: Br[C:2](=[CH2:10])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9].C(=O)([O-])[O-].[Na+].[Na+].[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Sn](CCCC)(CCCC)CCCC)[CH:18]=1.B([O-])(OC)OC.[Li].B(OC)(OC)OC>C(O)C.C1C=CC=CC=1>[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:2](=[CH2:10])[CH2:3][N:4]2[CH2:8][CH2:7][CH2:6][C:5]2=[O:9])[CH:18]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Reactant: C=C(Br)CN1CCCC1=O
Agent: COB(OC)OC
Agent: COB([O-])OC
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: c1ccccc1
Product: C=C(CN1CCCC1=O)c1cccnc1
Yield: 82 %

Procedure:
To a suspension of 5.0 g (40.6 mmol) of pyrrolidinone potassium salt prepared from Example 1 in 40 mL of toluene, solution of 5.24 mL (2 equiv.) of 2,3-dibromopropene in 10 mL of toluene was added dropwise for 1 hour in water bath and the reaction mixture was reacted at 60˜70° C. for 2 hours. Upon completion of the reaction, the mixture was cooled to 0° C. and filtered to remove solid. It was then concentrated under reduced pressure and purified by separation with silica gel column chromatography (ethyl acetate/n-hexane (1:1)) to obtain 5.30 g (64% yield) of 1-(2-bromoallyl)-pyrrolidin-2-one. To degassed solution of 1.0 g (4.90 mmol) of 1-(2-bromoallyl)-pyrrolidin-2-one prepared in the above in 50 mL of ethanol/benzene (1:1), 5 mol% (172 mg) of ditriphenylphosphine palladium dichloride, degassed solution of 7.35 mL of 2N sodium carbonate and 3-pyridyl-tributyltin, dimethyl borate, trimethyl borate lithium salt, boronic acid propanediol ring ester (2 equiv.), etc. were added. The mixture was reacted for 15 minutes at room temperature, followed by heating at reflux for 18 hours. After concentrating under reduced pressure, it was extracted with ethyl acetate for three times and washed with brine for two times. The concentrated solution was purified by separation with silica gel column chromatography (ethyl acetate followed by methylene chloride/methanol (20:1)) to obtain 810 mg (82% yield) of 1-(2-pyridin-3-yl-allyl)-pyrrolidin-2-one. Ozones were added to solution of 100 mg (0.494 mmol) of 1-(2-pyridin-3-yl-allyl)-pyrrolidin-2-one at −78° C. to obtain 1-(2-oxo-2-pyridin-3-yl-ethyl)-pyrrolidin-2-one, which was the same as synthesized in Example 20.
Reaction SMILES: OO.[C:3]([O:7][C:8](=[O:36])[N:9]([CH2:16][CH:17]1[C:26]2[C:21](=[C:22]([O:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][N:29]=3)[CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH2:18]1)[CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])([CH3:6])([CH3:5])[CH3:4].C([O-])([O-])=[O:38].[K+].[K+].CS(C)=O>O>[C:3]([O:7][C:8](=[O:36])[N:9]([CH2:16][CH:17]1[C:26]2[C:21](=[C:22]([O:27][C:28]3[CH:33]=[CH:32][C:31]([C:34](=[O:38])[NH2:35])=[CH:30][N:29]=3)[CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH2:18]1)[CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])([CH3:5])([CH3:6])[CH3:4]
Reactant: CC(C)CCCN(CC1CCCc2c(Oc3ccc(C#N)cn3)cccc21)C(=O)OC(C)(C)C
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)CCCN(CC1CCCc2c(Oc3ccc(C(N)=O)cn3)cccc21)C(=O)OC(C)(C)C
Reaction time: 1.5 h
Yield: 197.2 %

Procedure:
Add 30% aq. H2O2 (239 uL) to a suspension of [5-(5-cyano-pyridin-2-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-(4-methyl-pentyl)-carbamic acid tert-butyl ester (111 mg, 0.239 mmol), K2CO3 (16 mg, 0.120 mmol) and DMSO (3 ml) stirring in an ice/water bath. After 1.5 hours, pour the reaction mixture into water and extract with EtOAc. Wash the extract with water and brine before drying (MgSO4) and concentrating to give [5-(5-Carbamoyl-pyridin-2-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-(4 methyl-pentyl)-carbamic acid tert-butyl ester (114 mg) as a white foam. Use this material without further purification.
Reaction SMILES: C(O[CH:5]1[CH:9]2[O:10][C:11](=[O:13])[CH2:12][CH:8]2[CH:7]([CH2:14][O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:6]1)(=O)C.[C:24]1([SH:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.B(F)(F)F.CCOCC.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CCCCCC.CCOCC.CCOC(C)=O.ClCCl.C1(C)C=CC=CC=1>[C:16]([O:15][CH2:14][CH:7]1[CH:8]2[CH:9]([O:10][C:11](=[O:13])[CH2:12]2)[CH:5]([S:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:6]1)(=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Sc1ccccc1
Reactant: CC(=O)OC1OC(COC(=O)c2ccccc2)C2CC(=O)OC12
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOCC
Product: O=C1CC2C(COC(=O)c3ccccc3)OC(Sc3ccccc3)C2O1
Temperature: -78 °C
Reaction time: 6.5 h
Yield: 72.6 %

Procedure:
To a suspension of 7 (35.7 g, 0.11 mol) and thiophenol (14.8 mL, 0.13 mol) in 220 mL of a 4:1 mixture of anhydrous toluene and dichloromethane at room temperature, boron trifluoride etherate (6.9 mL, 0.05 mol) was added dropwise. The resulting mixture was stirred at the same temperature for 6.5 h and then carefully poured into a biphasic mixture of 1000 mL of EtOAc and 100 mL of a saturated aqueous solution of NaHCO3 (sat. NaHCO3). The layers were separated and the organic layer was washed with 2×100 mL of saturated NaHCO3, 100 mL of water and 100 mL of brine. The organic layer was dried over anhydrous MgSO4, filtered and concentrated to afford a yellow liquid. This material was dissolved in 50 mL of CHCl3, and to it was added 200 mL of ether and 50 mL of hexane. The resulting solution was briefly cooled to −78° C. to induce crystallization. White powdery solid formed which was filtered off and washed with cold ether to afford 29.6 g of 8 (72% yield) as a mixture of two diastereomers: Rƒ0.70 and 0.53 (minor and major isomers, respectively, 60% EtOAc/hexane); 1H-NMR (CDCl3) δ (for major isomer only) 8.01 (m, 2H), 7.42-7.70 (m, 5H), 7.27 (m, 3H), 5.89 (d, 1H, J=5.2 Hz), 5.29 (dd, 1H, J=7.7, 5.2 Hz), 4.55 (m, 2H), 4.48 (m, 1H), 2.60-3.12 (m, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH3:15][CH:16]1[CH2:18][O:17]1>CN(C)C=O.O>[N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:15][CH:16]([OH:17])[CH3:18])[N:5]=1)([O-:3])=[O:2]
Reactant: CC1CO1
Reactant: O=[N+]([O-])c1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(O)Cn1ccc([N+](=O)[O-])n1
Temperature: 100 °C
Yield: 54.8 %

Procedure:
A solution of 3-nitro-1H-pyrazole (prepared in Example 3, 400 mg, 3.54 mmol) in N,N-dimethylformamide (5 mL) was treated with solid potassium carbonate (734 mg, 5.31 mmol) and 2-methyl-oxirane (500 μL, 3.54 mmol) and placed in a sealed tube and heated at 100° C. for 1 h in an oil bath. After this time the reaction was cooled to 25° C. and diluted with water (30 mL) and extracted with ethyl acetate (3×20 mL). The organic layers were then combined and washed with saturated aqueous brine solution (2×20 mL) and then dried over sodium sulfate, filtered and concentrated in vacuo with silica gel (2 g) and purified by Biotage Flash Chromatography (40S column, Silica gel, 60% ethyl acetate/hexanes) to afford 1-(3-nitro-pyrazol-1-yl)-propan-2-ol (332 mg, 55%) as a clear colorless oil: ES-HRMS m/e calcd for C6H9N3O3 (M+H)+ 172.0717, observed 172.0716; 36730-255 1H NMR (300 MHz, CDCl3) δ ppm 1.28 (d, J=6.3 Hz, 3H, CH3), 2.15 (br. s., 1H, OH), 4.03-4.13 (m, 1H, CH of CH2), 4.23-4.38 (m, 2H, OCH and CH of CH2), 6.91 (d, J=2.4 Hz, 1H, Ar), 7.56 (d, J=2.4 Hz, 1H, Ar).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]([CH3:15])=[CH2:14])=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Pd].[Pt].CCO>[C:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH3:15])[CH3:14])=[CH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=C(C)c1ccc(-c2ccccc2)nc1
Agent: [Pd]
Agent: [Pt]
Solvent: CCO
Product: CC(C)c1ccc(-c2ccccc2)nc1
Reaction time: 1.5 h
Yield: 54 %

Procedure:
2-Phenyl-5-(prop-1-en-2-yl)pyridine (11 g, 56.3 mmol) was added to a hydrogenator bottle containing EtOH (150 mL). The reaction mixture was degassed by bubbling N2 for 10 min. Pd/C (0.60 g, 5.63 mmol) and Pt/C (0.55 g, 2.82 mmol) were added to the reaction mixture. The reaction mixture was placed on the Parr hydrogenator for 1.5 h. The reaction mixture was filtered on a tightly packed Celite® bed and washed with dichloromethane. The solvent was removed on rotoevaporator and GC/MS confirmed complete conversion. The crude product was adsorbed on Celite® for column chromatography. The crude product was chromatographed on silica gel with 10% EtOAc in hexane to yield 6 g (54%) of 2-phenyl-5-isopropylpyridine (HPLC purity: 100%). The product was confirmed by GC/MS.
Reaction SMILES: [CH3:1][C:2]1([CH2:7][C:8]2[S:12][C:11]([C:13](=O)[CH2:14][CH2:15][C:16]([OH:18])=O)=[CH:10][CH:9]=2)[N:6]=[CH:5][CH:4]=[N:3]1.O.[NH2:21][NH2:22]>O>[CH3:1][C:2]1([CH2:7][C:8]2[S:12][C:11]([C:13]3[CH2:14][CH2:15][C:16](=[O:18])[NH:21][N:22]=3)=[CH:10][CH:9]=2)[N:6]=[CH:5][CH:4]=[N:3]1
Reactant: NN
Reactant: CC1(Cc2ccc(C(=O)CCC(=O)O)s2)N=CC=N1
Solvent: O
Product: CC1(Cc2ccc(C3=NNC(=O)CC3)s2)N=CC=N1
Temperature: 100 °C

Procedure:
A mixture of 3 g of 4-[5-(2-methyl-1-imidazolyl-methyl)-thien-2-yl]-4-oxobutyric acid, 0.54 ml of hydrazine hydrate and 50 ml water was heated for 2 hours at 100° C. After cooling the precipitated solid was filtered off, washed with water and dried.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]3[N:19]([C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:31][CH2:32][N:33]5[CH2:38][CH2:37][O:36][CH2:35][CH2:34]5)[CH:25]=4)=[N:22][N:23]=3)[CH:20]=2)[CH2:10][CH2:9]1)(C)(C)C.C(Cl)Cl.[C:43]([OH:49])([C:45]([F:48])([F:47])[F:46])=[O:44]>>[F:46][C:45]([F:48])([F:47])[C:43]([OH:49])=[O:44].[N:33]1([CH2:32][CH2:31][O:30][C:26]2[CH:25]=[C:24]([C:21]3[N:19]4[CH:20]=[C:15]([O:14][C@H:11]5[CH2:12][CH2:13][C@H:8]([NH2:7])[CH2:9][CH2:10]5)[CH:16]=[CH:17][C:18]4=[N:23][N:22]=3)[CH:29]=[CH:28][CH:27]=2)[CH2:34][CH2:35][O:36][CH2:37][CH2:38]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Oc2ccc3nnc(-c4cccc(OCCN5CCOCC5)c4)n3c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H]1CC[C@H](Oc2ccc3nnc(-c4cccc(OCCN5CCOCC5)c4)n3c2)CC1

Procedure:
A solution of Example 14 step a (196 mg, 0.178 mmol) in TFA (2 mL) and DCM (10 mL) was stirred at RT for 0.5 H, then concentrated in vacuo to give the title compound (quantitative yield). LCMS (Method 2): Rt 0.38 min, m/z 438 [M-CF3CO2+].
Reaction SMILES: O1[CH2:6][CH2:5][N:4]([C:7]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]3)=[O:8])[CH2:3][CH2:2]1.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:21]1([N:20]2[CH2:6][CH2:5][N:4]([C:7]([C:9]3[CH:10]=[C:11]4[C:16](=[CH:17][CH:18]=3)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]4)=[O:8])[CH2:3][CH2:2]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1ccccc1
Reactant: O=C1CCc2cc(C(=O)N3CCOCC3)ccc2N1
Product: O=C1CCc2cc(C(=O)N3CCN(c4ccccc4)CC3)ccc2N1

Procedure:
2.62 Grams of 6-morpholinocarbonyl-3,4-dihydrocarbostyril and 10 g of aniline were placed in a sealed tube and heated at 170°-200° C. for 5 hours. Excess aniline was removed by evaporation under reduced pressure, then the residue thus obtained was purified by means of silica gel column chromatography. Recrystallized from isopropanol to obtain 0.32 g of 6-(4-phenyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyril. Colorless needle-like crystals. Melting point: 200°-201° C.
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[C:10]3[N:11]([C:15]([C:19]([OH:21])=O)=[C:16]([CH3:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:34]([O:37][CH2:38][CH2:39][CH2:40][S:41]([NH2:44])(=[O:43])=[O:42])(=[O:36])[CH3:35].C1CCN2C(=NCCC2)CC1>C1COCC1.C(OCC)(=O)C.O>[C:34]([O:37][CH2:38][CH2:39][CH2:40][S:41]([NH:44][C:19]([C:15]1[N:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[C:10]2=[N:17][C:16]=1[CH3:18])=[O:21])(=[O:42])=[O:43])(=[O:36])[CH3:35]
Reactant: Cc1nc2c(OCC3CCCCC3)cccn2c1C(=O)O
Reactant: CC(=O)OCCCS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(=O)OCCCS(=O)(=O)NC(=O)c1c(C)nc2c(OCC3CCCCC3)cccn12
Temperature: 60 °C
Reaction time: 1 h
Yield: 31.7 %

Procedure:
To a suspension of 300 mg of 8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid in 5 ml of THF was added 253 mg of 1,1′-carbonyldiimidazole, followed by stirring at 60° C. for 1 hour. Subsequently, 283 mg of 3-(aminosulfonyl)propyl acetate and 389 μl of 1,8-diazabicyclo[5.4.0]-7-undecene were added thereto under ice-cooling, followed by stirring at room temperature overnight. To the reaction mixture were added water and ethyl acetate to carry out a layer separation operation. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography. Since the reaction was not completed, to the obtained purified product were added again 57 mg of 3-(aminosulfonyl)propyl acetate, 60 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride, 38 mg of 4-(dimethylamino)pyridine, and 2 ml of DMF, followed by stirring at room temperature overnight. To the reaction mixture were added a saturated aqueous ammonium chloride solution and chloroform to carry out a layer separation operation. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography. To the obtained product were added ethyl acetate and ethanol, followed by stirring. The resulting solid was collected by filtration and dried to obtain 149 mg of 3-[({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)sulfonyl]propyl acetate.