Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([CH3:11])[N:3]=1.NC1C=CC([N+:19]([O-:21])=[O:20])=C(C)N=1.[N+]([O-])(O)=O>OS(O)(=O)=O>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:19]([O-:21])=[O:20])=[C:4]([CH3:11])[N:3]=1
Reactant: Cc1ccc([N+](=O)[O-])c(N)n1
Reactant: Cc1nc(N)ccc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: O=[N+]([O-])O
Product: Cc1nc(N)c([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 50 °C

Procedure:
8.5 g of this mixture of 2-amino-6-methyl-3-nitropyridine and 2-amino-6-methyl-5-nitropyridine was dissolved in H2SO4 (100 mL) at 0° C. and HNO3 (2.74 mL, d=1.49) was added drop-wise over 10 min. After complete addition, the mixture was warmed to 50° C. for 90 min., cooled, then poured onto 200 g of ice. The residue was collected by filtration and washed with cold H2O (2×50 mL) to give 2-amino-6-methyl-3,5-dinitropyridine as a yellow solid.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:12]=2)[CH:10]=1)=[O:5].Br[C:26]1[N:31]=[CH:30][CH:29]=[CH:28][N:27]=1>>[F:23][C:18]1[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:26]4[N:31]=[CH:30][CH:29]=[CH:28][N:27]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3cccnc3F)c2)cn1
Reactant: Brc1ncccn1
Product: O=C(c1cn(-c2cccc(-c3cccnc3F)c2)cn1)c1ncccn1

Procedure:
This compound is prepared by method C using compound 12i and 2-bromopyrimidine
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][N:10]=2)[CH2:5][CH2:4]1)[CH3:2].[H][H]>CO.[Pd]>[CH2:1]([N:3]1[CH2:4][CH2:5][N:6]([C:9]2[N:10]=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: [H][H]
Reactant: CCN1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Agent: [Pd]
Solvent: CO
Product: CCN1CCN(c2ccc(N)cn2)CC1
Yield: 102.8 %

Procedure:
A mixture of 2.47 g (10 mmol) 1-ethyl-4-(5-nitro-pyridin-2-yl)-piperazine and 0.247 g Pd/C (10%) in 25 ml methanol was treated with 1 bar hydrogen at room temperature for 2 h. After filtration the mixture was evaporated to dryness to yield 2.12 g (98%) of the title compound as colorless solid. (m/e): 207.3 (MH+; 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH:10]([CH3:17])[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.Cl.[NH2:20][OH:21].N1C=CC=CC=1>C(O)C.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[N:20][OH:21])[CH:10]([CH3:17])[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: NO
Reactant: CC(C(=O)c1ccc(Cl)cc1Cl)c1cccnc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CCO
Product: CC(C(=NO)c1ccc(Cl)cc1Cl)c1cccnc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A solution of 3.6 g of 2',4'-dichloro-2-methyl-2-(3-pyridyl)acetophenone in 15 ml of ethanol and 4 ml of water is treated with 1.4 g of hydroxylamine hydrochloride, 3 ml of pyridine and 90 mg of 4-N,N-dimethylaminopyridine and the reaction mixture is heated to reflux temperature. After 16 hours, it is poured into ice-water and extracted with ethyl acetate. The organic phase is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crystalline crude product is recrystallised from methylene chloride/n-hexane. 2',4'-Dichloro-2-methyl-2-(3-pyridyl)acetophenone oxime is obtained as an E/Z isomer mixture in the form of beige crystals, m.p. 163°-165° C.
Reaction SMILES: C1(S(CC2C(C(OCC)=O)=C(O)C(Br)=CC=2)(=O)=O)C=CC=CC=1.[Br:24][C:25]1[C:26]([O:37]C)=[C:27]([C:32]([CH2:35][Br:36])=[CH:33][CH:34]=1)[C:28]([O:30][CH3:31])=[O:29]>>[Br:24][C:25]1[C:26]([OH:37])=[C:27]([C:32]([CH2:35][Br:36])=[CH:33][CH:34]=1)[C:28]([O:30][CH3:31])=[O:29]
Reactant: COC(=O)c1c(CBr)ccc(Br)c1OC
Agent: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(Br)c1O
Product: COC(=O)c1c(CBr)ccc(Br)c1O

Procedure:
Prepared by proceeding in a similar manner to Intermediate 52, starting from methyl 3-bromo-6-bromomethyl-2-methoxybenzoate (Intermediate 89).
Reaction SMILES: C([O:3][C:4](=[O:15])[CH:5]([CH3:14])[C:6]([NH:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[O:7])C.[OH-].[Li+]>O1CCCC1.O>[CH3:14][CH:5]([C:6]([NH:8][CH2:9][C:10]([F:11])([F:12])[F:13])=[O:7])[C:4]([OH:15])=[O:3]
Reactant: CCOC(=O)C(C)C(=O)NCC(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C(=O)O)C(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a solution of 1.48 g (6.52 mmol) 2-Methyl-N-(2,2,2-trifluoro-ethyl)-malonamic acid ethyl ester in 40 ml of tetrahydrofurane, 20 ml of water and 1.09 g (26 mmol) of lithium hydroxide were added and the mixture was stirred overnight at room temperature. After concentration in vacuo water (50 ml) was added and the mixture was extracted with dichloromethane (three times 30 ml). The aqueous phase was acidified with 8 N hydrochloric acid and extracted with dichloromethane (four times 30 ml). The combined organic layers from the second extraction were dried (MgSO4) and evaporated in vacuo to give 1.09 g (84%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][N:7]1[CH2:12][CH2:11][CH2:10][CH:9]([OH:13])[C:8]1=[O:14]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][S:2]([O:13][CH:9]1[CH2:10][CH2:11][CH2:12][N:7]([CH3:6])[C:8]1=[O:14])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CN1CCCC(O)C1=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CN1CCCC(OS(C)(=O)=O)C1=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 86.9 %

Procedure:
Methanesulfonyl chloride (0.8 ml., 0.01 mole) was added dropwise to a stirred solution of 1-methyl-2-oxo-3-piperidinol (1.29 g, 0.01 mole) and 4-dimethylaminopyridine (2.44 g., 0.02 mole), in 50 ml. methylene chloride at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 15 min. and at 25° C. for 2.5 hours. The reaction mixture was then washed with 50 ml. saturated aqueous sodium chloride solution containing 6.8 ml. of 6N aqueous hydrochloric acid solution, dried over anhydrous sodium sulfate and concentrated in vacuo to a thick oil of the title compound (1.8 g., 87% yield). NMR (CDCl3): 1.6-2.37 (c, 4H); 2.96 (s, 3H); 3.1-3.4 (c) and 3.24 (s) (total 5H); and 4.9 (m, 1H)ppm.
Reaction SMILES: [NH2:1][C:2]([NH2:7])=[CH:3][N+:4]([O-:6])=[O:5].[C:8]([CH2:11][C:12](=O)[CH3:13])(=O)[CH3:9]>>[NH2:1][C:2]1[C:3]([N+:4]([O-:6])=[O:5])=[C:12]([CH3:13])[CH:11]=[C:8]([CH3:9])[N:7]=1
Reactant: CC(=O)CC(C)=O
Reactant: NC(N)=C[N+](=O)[O-]
Product: Cc1cc(C)c([N+](=O)[O-])c(N)n1
Yield: 52 %

Procedure:
For the example of the reaction of 1,1-diamino-2-nitroethene with acetylacetone to give 2-amino-3-nitro-4,6-dimethylpyridine, this reaction is described by Troschutz et al., in Arch. Pharm., 325 (1992), 785-789. A yield of 52 percent is described.
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[CH2:12][CH2:11][C:10](=[O:13])[NH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].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>>[C:1]([O:5][C:6]([C@@H:8]1[CH2:12][CH2:11][C:10](=[O:13])[N:9]1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCC(=O)N1
Reactant: Fc1ccc(Br)nc1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(C)(C)OC(=O)[C@@H]1CCC(=O)N1c1ccc(F)cn1
Temperature: 120 °C
Yield: 5.9 %

Procedure:
To a pressure tube containing (S)-5-oxo-pyrrolidine-2-carboxylic acid tert-butyl ester (0.5 g, 2.699 mmol), 2-bromo-5-fluoropyridine (0.57 g, 3.239 mmol), cesium carbonate (1.231 g, 3.779 mmol), Xantphos (0.156 g, 0.27 mmol), and tris (dibenzylideneacetone)palladium (0) (0.247 g, 0.27 mmol) is added 13.5 mL degassed anhydrous 1,4-dioxane. The mixture is heated at 120° C. under an atmosphere of Argon overnight. The solution is cooled to room temperature, filtered through Celite®, and concentrated under reduced pressure. The crude material is purified by flash chromatography eluting product with 305 ethyl acetate/heptanes. The product fractions are pooled and concentrated under reduced pressure to afford 45 mg of title compound. Yield 6%. ESI m/z 225=MH+
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:16]2[CH:17]=[N:18][C:19](F)=[CH:20][CH:21]=2)[C:8]([NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C[S:24](C)=O>>[CH:1]1([CH2:6][CH:7]([C:16]2[CH:17]=[N:18][C:19]([SH:24])=[CH:20][CH:21]=2)[C:8]([NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(C)=O
Reactant: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(F)nc1
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(S)nc1
Temperature: 160 °C
Reaction time: 1 h

Procedure:
A solution of 3-cyclopentyl-2-(6-fluoropyridin-3-yl)-N-thiazol-2-ylpropionamide (EXAMPLE 14, 350 mg, 1.1 mmol) and NaSMe (1.53 g, 22.0 mmol) in anhydrous, degassed DMSO (4 mL) was stirred at 160° C. (bath) for 1 h. On cooling, the mixture was partitioned between EtOAc (50 mL) and 1M HCl (50 mL). The organic layer was washed with H2O (20 mL) and brine (50 mL). The solvent was evaporated and the residue recrystallised (EtOAc-1H) to give the title compound: RTA=3.24 min; m/z (ES+)=334.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.C([Mg]Cl)C=C.C(OCC)C.[C:19]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[O:30][C:31](=[O:39])[C:32]3[CH:38]=[N:37][CH:36]=[CH:35][C:33]=3[N:34]=2)=[C:25]([O:40][CH:41]2[CH2:46][CH2:45][N:44]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:43][CH2:42]2)[CH:24]=1)([CH3:22])([CH3:21])[CH3:20]>C1COCC1.C(OCC)(=O)C>[C:19]([C:23]1[CH:28]=[CH:27][C:26]([C:29]([NH:34][C:33]2[CH:35]=[CH:36][N:37]=[CH:38][C:32]=2[C:31]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=2)=[O:39])=[O:30])=[C:25]([O:40][CH:41]2[CH2:42][CH2:43][N:44]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:45][CH2:46]2)[CH:24]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(C(C)(C)C)ccc2-c2nc3ccncc3c(=O)o2)CC1
Reactant: Nc1ccc(Cl)cn1
Agent: C=CC[Mg]Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(C(C)(C)C)ccc2C(=O)Nc2ccncc2C(=O)Nc2ccc(Cl)cn2)CC1
Yield: 72.4 %

Procedure:
To a stirring solution of 2-amino-5-chloropyridine (0.055 g, 0.42 mmol) in THF (5 mL) at 0° C., was added a 1.0 M solution of allylmagnesium chloride in diethyl ether (0.4 mL, 0.4 mmol). To this solution was then added a solution of 2-[4-tert-butyl-2-(1-Boc-piperidin-4-yloxy)-phenyl]-4H-pyrido[4,3-d][1,3]oxazin-4-one (0.12 g, 0.25 mmol) in THF (3 mL). After several hours, the solution was diluted with ethyl acetate and washed twice with brine. The organic phase was then dried with MgSO4, filtered and concentrated in vacuo to give a white solid which was washed with diethyl ether and dried in vacuo to give the title compound (0.11 g, 70%).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:17])=[C:4]([NH:9]C(=O)OC(C)(C)C)[CH:5]=[C:6]([CH3:8])[CH:7]=1.Cl.[OH-].[Na+]>C(O)(C)C.O>[Br:1][C:2]1[C:3]([F:17])=[C:4]([CH:5]=[C:6]([CH3:8])[CH:7]=1)[NH2:9]
Reactant: Cc1cc(Br)c(F)c(NC(=O)OC(C)(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: Cc1cc(N)c(F)c(Br)c1
Temperature: 60 °C
Yield: 89.8 %

Procedure:
To a solution of tert-butyl 3-bromo-2-fluoro-5-methylphenylcarbamate (985 mg, 3.24 mmol) in isopropyl alcohol (10 mL) was added concentrated aqueous HCl (˜12 M, 2.6 mL, 32.4 mmol) and the reaction mixture was warmed to 60° C. for 2 hours, allowed to cool to room temperature, and then concentrated in vacuo to afford a white solid. The solid was dissolved in water and the resulting aqueous solution was neutralized with aqueous 1.0 M NaOH solution, and extracted with Et2O. The organic phase was washed with brine, dried (MgSO4) and concentrated to afford 3-bromo-2-fluoro-5-methylaniline (594 mg, 2.91 mmol, 90%) which was carried forward without further purification: 1H NMR (300 MHz, CDCl3) δ 2.21 (s, 3H) 3.71 (br s, 2H) 6.51 (d, J=7.9 Hz, 1H) 6.70 (d, J=4.7 Hz, 1H).
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:9])[O:6][CH2:7][CH3:8])[C:2]#[CH:3].[OH-].[K+].Cl[CH2:13][C:14]1[N:19]=[CH:18][CH:17]=[CH:16][N:15]=1>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.C1(C)C=CC=CC=1>[CH2:7]([O:6][C:5]([N:4]([CH2:13][C:14]1[N:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[CH2:1][C:2]#[CH:3])=[O:9])[CH3:8]
Reactant: C#CCNC(=O)OCC
Reactant: ClCc1ncccn1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: C#CCN(Cc1ncccn1)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
11.5 g (91 mmol) of ethyl N-propargylcarbamate are introduced into 90 ml of toluene, 20.3 g of KOH powder and 0.5 g of triethylbenzylammonium chloride are added, and 13.5 g (104 mmol) of 2-chloromethyl-pyrimidine (German Offenlegungsschrift 2,932,643) are added dropwise at room temperature. The mixture is stirred overnight at room temperature, the salts are filtered off with suction, the filtrate is washed using saturated sodium chloride solution, dried over magnesium sulphate and concentrated, and the concentrate is distilled.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]([NH2:11])=[O:10])[CH:6]=[CH:5][CH:4]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH:2]([C:3]1[N:8]=[C:7]([C:9]([NH2:11])=[O:10])[CH:6]=[CH:5][CH:4]=1)=[O:1]
Reactant: NC(=O)c1cccc(CO)n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: NC(=O)c1cccc(C=O)n1
Yield: 61.3 %

Procedure:
A mixture of 6-hydroxymethyl-2-pyridinecarboxamide (100 g) and manganese dioxide (500 g) in chloroform (2 l) was heated under reflux for 48 hours. Manganese dioxide was removed by filtration and the filtrate was evaporated in vacuo to give 6-formyl-2-pyridinecarboxamide (60.46 g).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1.[N+:16]([CH3:19])([O-:18])=[O:17].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][C:8]1[CH:15]=[CH:14][C:11](/[CH:12]=[CH:19]/[N+:16]([O-:18])=[O:17])=[CH:10][CH:9]=1
Reactant: O=Cc1ccc(CCc2ccco2)cc1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=[N+]([O-])/C=C/c1ccc(CCc2ccco2)cc1
Temperature: 120 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
To an acetic acid (5 mL) solution of 4-(2-furan-2-yl-ethyl)-benzaldehyde (480 mg, 2.4 mmol) described in Manufacturing Example 80-1-4 were added nitromethane (732 mg, 12 mmol) and ammonium acetate (370 mg, 4.8 mmol) under nitrogen atmosphere at room temperature, which was stirred for 2 hours at 120° C. The reaction mixture was partitioned into water and ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure to obtain the title compound (554 mg, 95%) as a crude product.
Reaction SMILES: [CH3:1][CH2:2][C@@:3]12[O:22][C@@H:21]1[C@@H:19]1[CH2:20][N:5]([CH2:6][CH2:7][C:8]3[C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=4[NH:15][C:16]=3[C@@:17]([C:56]([O:58][CH3:59])=[O:57])([C:23]3[CH:24]=[C:25]4[C@:33]56[C@@H:37]7[C@:38]([CH2:53][CH3:54])([C@@H:42]([O:49][C:50]([CH3:52])=[O:51])[C@:43]([OH:48])([C:44]([O:46][CH3:47])=[O:45])[C@@H:32]5[N:31]([CH3:55])[C:26]4=[CH:27][C:28]=3[O:29][CH3:30])[CH:39]=[CH:40][CH2:41][N:36]7[CH2:35][CH2:34]6)[CH2:18]1)[CH2:4]2.OS(O)(=O)=O>O>[CH3:1][CH2:2][C@@:3]12[O:22][C@@H:21]1[C@H:19]1[CH2:20][N:5]([CH2:6][CH2:7][C:8]3[C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=4[NH:15][C:16]=3[C@@:17]([C:56]([O:58][CH3:59])=[O:57])([C:23]3[CH:24]=[C:25]4[C@:33]56[C@@H:37]7[C@:38]([CH2:53][CH3:54])([C@@H:42]([O:49][C:50]([CH3:52])=[O:51])[C@:43]([OH:48])([C:44]([O:46][CH3:47])=[O:45])[C@@H:32]5[N:31]([CH3:55])[C:26]4=[CH:27][C:28]=3[O:29][CH3:30])[CH:39]=[CH:40][CH2:41][N:36]7[CH2:35][CH2:34]6)[CH2:18]1)[CH2:4]2
Reactant: CC[C@]12CN3CCc4c([nH]c5ccccc45)[C@@](C(=O)OC)(c4cc5c(cc4OC)N(C)[C@H]4[C@@](O)(C(=O)OC)[C@H](OC(C)=O)[C@]6(CC)C=CCN7CC[C@]54[C@@H]76)C[C@@H](C3)[C@H]1O2
Agent: O=S(=O)(O)O
Solvent: O
Product: CC[C@]12CN3CCc4c([nH]c5ccccc45)[C@@](C(=O)OC)(c4cc5c(cc4OC)N(C)[C@H]4[C@@](O)(C(=O)OC)[C@H](OC(C)=O)[C@]6(CC)C=CCN7CC[C@]54[C@@H]76)C[C@H](C3)[C@H]1O2

Procedure:
About 0.25 g. of leurosine sulfate were converted to the free base by dissolving the salt in water and making the resulting solution alkaline. The free base was insoluble in the aqueous alkaline layer and was extracted with chloroform. Evaporation of the chloroform yielded leurosine free base as a residue.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:13]=[C:12]([OH:14])[NH:11][N:10]=1.S(OC)(O[CH3:19])(=O)=O.C(=O)([O-])[O-].[K+].[K+].N.Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:13]=[C:12]([OH:14])[N:11]([CH3:19])[N:10]=1
Reactant: COS(=O)(=O)OC
Reactant: Oc1cc(-c2ccc(Cl)cc2Cl)n[nH]1
Agent: Cl
Agent: N
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Cn1nc(-c2ccc(Cl)cc2Cl)cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.2 %

Procedure:
30 g of 3-(2,4-dichlorophenyl)-5-hydroxy-1H-pyrazole from Example 3.1 were initially charged in 750 ml of toluene. 23.1 g of dimethyl sulfate and 7.5 g of potassium carbonate were added, and the mixture was heated at reflux for 2 h. After cooling to room temperature, the mixture was made alkaline using ammonia and stirred overnight. The mixture was acidified by addition of hydrochloric acid (pH about 1) and cooled to room temperature, and the precipitated solid was filtered off. Drying gave 21.4 g of 3-(2,4-dichlorophenyl)-5-hydroxy-1-methyl-1H-pyrazole (purity according to GC 99.2%, yield 66.8%). M.p.: 128° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:13](OC(=O)C)(=[O:15])[CH3:14]>N1C=CC=CC=1>[C:13]([O:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1ccc(C)cc1O
Solvent: c1ccncc1
Product: COC(=O)c1ccc(C)cc1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of methyl 2-hydroxy-4-methylbenzoate (19.7 g, 0.119 mole) in pyridine (15 ml) was treated with acetic anhydride (15 ml, 16.23 g, 0.158 mol). The reaction was stirred at ambient temperature overnight and then the solvent evaporated. The residue was dissolved in CH2Cl2 and the solution washed with 2N aqueous HCl, water, saturated aqueous NaHCO3 solution, dried (MgSO4) and evaporated to give methyl 2-acetoxy-4-methylbenzoate which was used without further purification (24.58 g, 99%).
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@@H:11]([N:13]=[N+]=[N-])[CH2:10][C@H:9]1[C:16]([N:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1)=[O:17])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CP(C)C>C1COCC1>[C:1]([N:8]1[CH2:12][C@@H:11]([NH2:13])[CH2:10][C@H:9]1[C:16]([N:18]1[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]1)=[O:17])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CN1CCN(C(=O)[C@@H]2C[C@H](N=[N+]=[N-])CN2C(=O)OC(C)(C)C)CC1
Agent: CP(C)C
Solvent: C1CCOC1
Product: CN1CCN(C(=O)[C@@H]2C[C@H](N)CN2C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(2S,4S)-1-Boc-4-azido-2-[(4-methylpiperazin-1-yl)carbonyl]pyrrolidine (11.67 g, 34.48 mmol) obtained in Step B was dissolved in THF (30 mL). Trimethyl phosphine (3.40 mL, 38.37 mmol) was added dropwise thereto at 0˜5° C. The reaction solution was stirred for 2 hours at room temperature, concentrated in vacuo and basified with saturated NaHCO3 aqueous solution. The solution was extracted with EtOAc two times and concentrated in vacuo to give the title compound in oil form (10.61 g, 98.5%).
Reaction SMILES: C(O[C:6](=O)[NH:7][C@H:8]1[CH2:11][C@H:10]([N:12]2[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[C:14]([CH3:22])([CH3:21])[C:13]2=[O:23])[CH2:9]1)(C)(C)C.BrC1[S:27][CH:28]=[C:29]([CH3:31])[N:30]=1>>[CH3:22][C:14]1([CH3:21])[C:15]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[N:12]([C@H:10]2[CH2:9][C@H:8]([NH:7][C:6]3[S:27][CH:28]=[C:29]([CH3:31])[N:30]=3)[CH2:11]2)[C:13]1=[O:23]
Reactant: Cc1csc(Br)n1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](N2C(=O)C(C)(C)c3cccnc32)C1
Product: Cc1csc(N[C@H]2C[C@H](N3C(=O)C(C)(C)c4cccnc43)C2)n1

Procedure:
3,3-Dimethyl-1-(trans-3-((4-methylthiazol-2-yl)amino)cyclobutyl)-1 h-pyrrolo[2,3-b]pyridin-2(3h)-one was prepared by Method B7 using starting materials 1-(trans-3-aminocyclobutyl)-3,3-dimethyl-1H-pyrrolo[2,3-b]pyridin-2(3H)-one hydrochloride (intermediate 26, 0.100 g, 0.329 mmol) and 2-bromo-4-methylthiazole (0.0585 g, 0.329 mmol) at 120° C. for 96 h. M+1: 329.1. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.38 (s, 6 H) 2.25 (s, 3 H) 2.33-2.42 (m, 2 H) 3.38-3.49 (m, 2 H) 4.35 (br. s., 1 H) 5.27 (quin, J=8.56 Hz, 1 H) 5.60 (br. s., 1 H) 6.09 (s, 1 H) 6.96 (t, J=6.16 Hz, 1 H) 7.43 (d, J=6.85 Hz, 1 H) 8.17 (d, J=5.30 Hz, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.[CH:12]1([C:15](=[N:17]O)[NH2:16])[CH2:14][CH2:13]1>C(O)C>[NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]1[O:6][N:17]=[C:15]([CH:12]2[CH2:14][CH2:13]2)[N:16]=1
Reactant: COC(=O)c1ccccc1N
Reactant: NC(=NO)C1CC1
Solvent: CCO
Product: Nc1ccccc1-c1nc(C2CC2)no1

Procedure:
Methyl 2-amino-benzoate (6 g, 40 mmol) and cyclopropylcarboxamid oxime (5 g, 50 mmol) was refluxed for 10 h in dry ethanol containing 0.25 g sodium and 2 g molecular sieves. The mixture was filtered while hot, and cooled precipitating 2.8 g of the desired product as white needles. Upon additionof water to the flitrate, a further amount of 3.2 g white crystals could beisolated. M.p. 84.4°-84.9° C.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[O:8][C:7]([CH2:9][OH:10])=[CH:6][CH:5]=1.[CH3:11]I>CN(C=O)C>[Br:3][C:4]1[O:8][C:7]([CH2:9][O:10][CH3:11])=[CH:6][CH:5]=1
Reactant: OCc1ccc(Br)o1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1ccc(Br)o1
Reaction time: 0.08 h
Yield: 20.9 %

Procedure:
Sodium hydride (95%, 28 mg, 1.12 mmol) was diluted in dry DMF (1 mL) and cooled to 0° C. (5-bromo-2-furanyl)methanol (177 mg, 1 mmol) in DMF (2 mL) was added, and the mixture was stirred for 5 minutes. Methyl iodide (0.07 mL, 1.12 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was quenched by the careful addition of water, then extracted with ethyl acetate (20 mL), followed by dichloromethane (20 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography, eluting with EtOAc/hexanes. The desired fractions were combined and concentrated, giving 40 mg (21%) of the title compound.
Reaction SMILES: [SH:1][C:2]1[S:6][C:5]([S:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:4][N:3]=1.[Br:14][CH2:15][CH2:16][CH2:17]Br.C(=O)([O-])[O-].[K+].[K+].C(C(C)=O)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[Br:14][CH2:15][CH2:16][CH2:17][S:1][C:2]1[S:6][C:5]([S:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:4][N:3]=1
Reactant: CCOC(=O)CSc1nnc(S)s1
Reactant: BrCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CCC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)CSc1nnc(SCCCBr)s1
Temperature: 60 °C
Reaction time: 3 h
Yield: 29.8 %

Procedure:
A mixture of 3 g of ethyl [(5-mercapto-1,3,4-thiadiazol-2-yl)thio]acetate, 9 g of 1,3-dibromopropane, 2.02 g of anhydrous potassium carbonate, 0.01 g of tetra-n-butylammonium bromide, and 20 ml of methyl ethyl ketone was vigorously stirred for 3 hour at 60° C. Toluene was added to the reaction mixture and the resultant mixture was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue thus formed was applied to silica gel column chromatography and eluted with a mixture of toluene and ethyl acetate (9:1) to provide 1.35 g of ethyl [[5-(3-bromopropyl)thio-1,3,4-thiadiazol-2-yl]thio]acetate.