Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([SH:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[C@:11]([OH:17])([CH3:16])[C:12]([F:15])([F:14])[F:13].I[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N+:26]([O-:28])=[O:27].C[O-].[Na+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[C:6]([S:8][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N+:26]([O-:28])=[O:27])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[C@:11]([OH:17])([CH3:16])[C:12]([F:15])([F:13])[F:14]
Reactant: C[C@@](O)(C(=O)Nc1ccc(S)cc1Cl)C(F)(F)F
Reactant: O=[N+]([O-])c1ccccc1I
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@](O)(C(=O)Nc1ccc(Sc2ccccc2[N+](=O)[O-])cc1Cl)C(F)(F)F
Temperature: 135 °C
Yield: 60.5 %

Procedure:
A mixture of (R)-N-(2-chloro-4-mercaptophenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (0.1 g), 1-iodo-2-nitrobenzene (0.086 g), sodium methoxide (0.021 g), and cuprous chloride (0.014 g) in DMF (1 ml) was stirred and heated to 135° C. for 2.5 hours then allowed to cool to room temperature. The reaction mixture was diluted with water (5 ml) and poured onto a Varian Chem Elut column. When the liquid had been adsorbed the column was eluted with ethyl acetate and the eluate was concentrated by evaporation. The residue was purified on a silica gel Mega Bond Elut column, eluting with 5-40% ethyl acetate/hexane to give the title compound (0.085 g) as a glass. MS: 419 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:12][CH3:13])=[S:11].C[O:15][CH2:16][CH2:17][O:18]C.C(C=O)=O.NC(N)=S>C(N(CC)CC)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:16]([OH:15])[CH:17]([OH:18])[N:12]([CH3:13])[C:10]1=[S:11]
Reactant: COCCOC
Reactant: CNC(=S)Nc1ccc(C)cc1C
Agent: NC(N)=S
Agent: O=CC=O
Solvent: CCN(CC)CC
Product: Cc1ccc(N2C(=S)N(C)C(O)C2O)c(C)c1
Reaction time: 1 h

Procedure:
30.0 g of N-(2,4-dimethylphenyl)-N'-methyl-thiourea were stirred with 150 ml of 1,2-dimethoxy-ethane and 10 ml of triethylamine, and 36.0 g of a 30% strength aqueous solution of glyoxal was added. After stirring for a short time, the thiourea slowly dissolved, the reaction being exothermic. The temperature was allowed to rise to 50° C. and the solution was kept at this temperature for a further 1 hour. Thereafter, the solvent was distilled off in vacuo and the oily residue was stirred with water, with the addition of a little acetic acid. The reaction product, which solidified in the crystalline form, was filtered off, washed with water and dried. The yield was 37 g. For purification, the product could be recrystallised from isopropyl alcohol.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH3:7][N:8]1[CH2:15][CH:14]2[C:16](=O)[CH:10]([CH2:11][CH2:12][CH2:13]2)[CH2:9]1.CCOCC>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[CH3:7][N:8]1[CH2:15][CH:14]2[C:16](=[CH2:1])[CH:10]([CH2:11][CH2:12][CH2:13]2)[CH2:9]1
Reactant: CN1CC2CCCC(C1)C2=O
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: C=C1C2CCCC1CN(C)C2
Reaction time: 0.5 h
Yield: 104.7 %

Procedure:
To a solution of 6.9 g of methyltriphenyl phosphonium bromide in toluene (30 ml) was added 2.2 g of potassium tert-butoxide at 0° C. and the resulting mixture was stirred for 30 minutes. Next, 3.0 g of 3-methyl-3-azabicyclo[3.3.1]nonan-9-one was added thereto and the mixture was reacted for 1 hour. After adding ether, the reaction mixture was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After filtering and concentrating, the residue was purified by silica gel column chromatography (eluted with ether/n-hexane) to thereby give 3.1 g of the title compound as a yellow oily substance.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:16]2[C:15]3[N:14]=[C:13]([NH:17][C:18]4[CH:23]=[C:22]([N:24]5[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]5)[CH:21]=[CH:20][C:19]=4[O:31][C:32]([F:35])([F:34])[F:33])[N:12]=[CH:11][C:10]=3[CH2:9][CH2:8][C:7]=2[C:6]([C:36]([O-:38])=O)=[N:5]1.[K+].[N:40]1(C([O-])=O)C2C=CC=CC=2N=N1.[NH4+]>CC(N(C)C)=O.O>[OH:1][CH2:2][CH2:3][N:4]1[C:16]2[C:15]3[N:14]=[C:13]([NH:17][C:18]4[CH:23]=[C:22]([N:24]5[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]5)[CH:21]=[CH:20][C:19]=4[O:31][C:32]([F:33])([F:35])[F:34])[N:12]=[CH:11][C:10]=3[CH2:9][CH2:8][C:7]=2[C:6]([C:36]([NH2:40])=[O:38])=[N:5]1
Reactant: CN1CCN(c2ccc(OC(F)(F)F)c(Nc3ncc4c(n3)-c3c(c(C(=O)[O-])nn3CCO)CC4)c2)CC1
Reactant: O=C([O-])n1nnc2ccccc21
Agent: [K+]
Agent: [NH4+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CN1CCN(c2ccc(OC(F)(F)F)c(Nc3ncc4c(n3)-c3c(c(C(N)=O)nn3CCO)CC4)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
A suspension of potassium 1-(2-hydroxy-ethyl)-8-[5-(4-methyl-piperazin-1-yl)-2-trifluoromethoxy-phenylamino]-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate (1.54 g, 2.69 mmol) in anhydrous DMA (40 mL) was treated with N-ethyl-N′,N′-diisopropyl carbodiimide hydrochloride (EDCI) (1.03 g, 5.38 mmol) and with ammonium 1H-1,2,3-benzotriazol-1-ate (0.819 g, 5.38 mmol). The reaction was stirred at room temperature overnight. The reaction was diluted with water and the resulting precipitate was collected by filtration to afford the title compound (1.32 g, 88% yield).
Reaction SMILES: Br[C:2]1[N:3](C(OC(C)(C)C)=O)[C:4]([C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=3)[CH:10]=[C:9]([O:24][C@@H:25]([CH3:29])[CH2:26][O:27][CH3:28])[CH:8]=2)=[CH:5][CH:6]=1.[NH:37]1[CH:41]=[CH:40][C:39](B(O)O)=[N:38]1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O>[CH3:28][O:27][CH2:26][C@H:25]([CH3:29])[O:24][C:9]1[CH:8]=[C:7]([C:4]2[NH:3][C:2]([C:41]3[CH:40]=[CH:39][NH:38][N:37]=3)=[CH:6][CH:5]=2)[CH:12]=[C:11]([O:13][C:14]2[CH:15]=[CH:16][C:17]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:18][CH:19]=2)[CH:10]=1
Reactant: OB(O)c1cc[nH]n1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(Br)n2C(=O)OC(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(-c3cc[nH]n3)[nH]2)c1
Temperature: 25 °C
Reaction time: 168 h
Yield: 50.8 %

Procedure:
t-Butyl 2-bromo-5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrole-1-carboxylate (375 mg, 0.446 mmol) synthesized in Example (13c) and commercially available 1H-pyrazol-3-ylboronic acid (120 mg, 1.00 mmol) were dissolved in a mixed solvent of 1,2-dimethoxyethane (20 mL) and water (5 mL), [1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloride dichloromethane complex (28 mg, 0.034 mmol) and an aqueous potassium carbonate solution (3M, 0.65 mL, 1.95 mmol) were added, and stirring was carried out at 100° C. for 7 days under nitrogen atmosphere. After the reaction solution was cooled to room temperature, water (10 mL) was added, and extraction was carried out with ethyl acetate (20 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=20%-80%) to afford the desired compound (106 mg, yield 35%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:12][CH2:13][CH:14]([OH:23])[CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.ClC1C(NCC(=O)CC(C)C)=NC2C(N=1)=CC=CC=2.CS(C)=O.N(C)(C)C>CCN(CC)CC>[Cl:1][C:2]1[C:3]([NH:12][CH2:13][C:14](=[O:23])[CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: OC(CCc1ccccc1)CNc1nc2ccccc2nc1Cl
Agent: CC(C)CC(=O)CNc1nc2ccccc2nc1Cl
Agent: CN(C)C
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C(CCc1ccccc1)CNc1nc2ccccc2nc1Cl

Procedure:
3b is prepared from 2b according to the protocol described for 3a; 2b (4.7 g, 14.4 mmol), 14.4 ml DMSO, 14.4 ml Et3N, and Me3N.SO3 (4 g, 28.8 mmol). The product is purified by chromatography on a silica column, eluent: C6H12/Et2O (80:20) to give a yellow solid (4.51 g, 96%); 1H NMR (100 MHz, CDCl3) δ: 2.82-3.01 (m, 4H), 4.38 (d, J=5 Hz, 2H), 6.4 (m, 1H), 7.23-7.84 (m, 9H). Analysis calculated for C18H16N3OCl: C, 66.36; H, 4.95; N, 12.90. Experimental: C, 66.53; H, 5.23; N, 12.78.
Reaction SMILES: COC1C=CC([C:9]2[C:10]([N+]([O-])=O)=[C:11]([O:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19](C4C=CC(OC)=CC=4)[C:18]=3[N+:32]([O-])=O)[CH:12]=[CH:13][C:14]=2Cl)=CC=1.C[C:39](C)=[O:40].S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][C:11]2[CH:10]=[CH:9][C:14]([O:40][CH3:39])=[CH:13][CH:12]=2)=[C:18]([CH:19]=1)[NH2:32]
Reactant: CC(C)=O
Reactant: COc1ccc(-c2c(Cl)ccc(Oc3ccc(Cl)c(-c4ccc(OC)cc4)c3[N+](=O)[O-])c2[N+](=O)[O-])cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(Oc2ccc(Cl)cc2N)cc1

Procedure:
An 80.0 g. portion of the above nitro derivative in 800 ml. of acetone is added to 320.0 g. of sodium hydrosulfite in 800 ml. of water. The mixture is heated to reflux on a steam bath for one hour, cooled and extracted with benzene. The benzene extract is washed with water, dried over anhydrous sodium sulfate, and evaporated in vacuo to a yellow oil. Treatment in hexane, with cooling produces crystals of 5-chloro-2-(p-methoxyphenoxy)-aniline.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][CH:3]=1.[C:13](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH3:13])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(F)c2ccccc12
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COc1ccc(F)c2ccccc12
Reaction time: 72 h
Yield: 48.4 %

Procedure:
21.7 g of 4-Fluoro-naphthalen-1-ol were dissolved in 250 ml acetone. 39.0 g of potassium carbonate and 14.6 ml dimethyl sulfate were added at room temperature. The reaction was placed under nitrogen and stirred for 72 h. The mixture was filtrated, the solid washed with acetone, and the filtrate was concentrated to a viscous oil, which was taken up in ethyl acetate. This was washed with water and with brine, dried over sodium sulfate, filtered through celite and concentrated. The resulting oil was distilled using a Kugelrohr-apparatus, yielding 11.4 g of 4-fluoro-1-methoxynaphthalene.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15](OS(C(F)(F)F)(=O)=O)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:25]([OH:29])[CH2:26][C:27]#[CH:28]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:28]#[C:27][CH2:26][CH2:25][OH:29])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: C#CCCO
Reactant: O=S(=O)(Oc1ccc2c(-c3ccc(Cl)cc3)nsc2c1)C(F)(F)F
Product: OCCC#Cc1ccc2c(-c3ccc(Cl)cc3)nsc2c1

Procedure:
In analogy to example 14.1, Trifluoro-methanesulfonic acid 3-(4-chloro-phenyl)-benzo[d]isothiazol-6-yl ester and 3-butyn-1-ol were converted to yield 4-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-but-3-yn-1-ol as yellow solid, mp: 128–129° C., MS: 313 (M, 1 Cl).
Reaction SMILES: [CH:1]([C:3]([Cl:11])(Cl)[CH2:4][C:5]([CH3:9])(Cl)[C:6]#[N:7])=O.[ClH:12]>>[Cl:12][C:6]1[C:5]([CH3:9])=[CH:4][C:3]([Cl:11])=[CH:1][N:7]=1
Reactant: Cl
Reactant: CC(Cl)(C#N)CC(Cl)(Cl)C=O
Product: Cc1cc(Cl)cnc1Cl
Temperature: 145 °C

Procedure:
21.4 g of the 4-formyl-2-methyl-2,4,4-trichlorobutyronitrile obtained in (a) are heated for 4 to 5 hours to 145° C. while introducing a weak stream of dry HCl gas. After it has cooled, the dark melt is subjected to steam distillation, affording 9.9 g of 2,5-dichloro-3-methylpyridine in the form of colourless crystals (recrystallised from CH3OH/H2O in the volume ratio of 4:1).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([Cl:11])=[N:8][CH:7]=[N:6][C:5]=2[NH:4][CH:3]=1.C([Li])CCC.[CH3:17][S:18]SC>C1COCC1.[NH4+].[Cl-]>[Cl:11][C:9]1[C:10]2[C:2]([S:18][CH3:17])=[CH:3][NH:4][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: CSSC
Reactant: Clc1ncnc2[nH]cc(Br)c12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CSc1c[nH]c2ncnc(Cl)c12
Reaction time: 1 h
Yield: 97.6 %

Procedure:
To 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0.18 g, 0.77 mmol) in dry THF (2 ml), cooled in a dry ice-acetone bath, was added dropwise n-butyllithium (0.77 ml, 1.9 mmol, 2.5 M in hexanes). The mixture was stirred for 1 hour, then dimethyldisulfide (0.077 mL, 0.77 mmol) suspended in dry THF (1 ml) was added. The solution was stirred for 2.5 hours at −78° C. and then diluted with aqueous NH4Cl. The phases were separated and the water extracted 2 times with ethyl acetate. The combined organic phases were dried over Na2SO4, and concentrated in vacuo to afford 4-chloro-5-methylsulfanyl-7H-pyrrolo[2,3-d]pyrimidine as an orange solid (150 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([N:12]1[CH2:17][CH2:16][C:15]2[S:18][CH:19]=[CH:20][C:14]=2[CH2:13]1)[C:9](N)=[O:10].[CH3:21][OH:22]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([N:12]1[CH2:17][CH2:16][C:15]2[S:18][CH:19]=[CH:20][C:14]=2[CH2:13]1)[C:9]([O:22][CH3:21])=[O:10]
Reactant: NC(=O)C(c1ccccc1Cl)N1CCc2sccc2C1
Reactant: CO
Product: COC(=O)C(c1ccccc1Cl)N1CCc2sccc2C1
Temperature: 85 °C
Reaction time: 6 h

Procedure:
1 g (0.00326 mol) (±)-(2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetamide was dissolved in 20 mL methanol and refluxed at 85° C. During the reflux 10 mL polyphosphoric acid was added dropwise over a period of 1 hr and refluxing was continued for 6 hour. The excess of solvent was removed under reduced pressure. To the residue, 50 mL ethyl acetate was added at 0° C. and the reaction mixture was made basic with aq. NaHCO3, up to pH 9. Out of the two phases separated, the organic layer was isolated, dried over anhydrous Na2SO4 and concentrated. The residue obtained was purified by column chromatography using hexane:ethyl acetate (9:1) as eluent. The product obtained was stored under nitrogen atmosphere and kept in refrigerator before converting into salt. The yield of titled product was 310 mg (30%).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH2:6][C:5]2=[CH:9][S:10][CH:11]=[C:4]2[S:3]1(=[O:13])=[O:12].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1.C(N(CC)CC)C.Cl>CS(C)=O>[OH:8][C:7]1[N:2]([CH3:1])[S:3](=[O:13])(=[O:12])[C:4]2[C:5](=[CH:9][S:10][CH:11]=2)[C:6]=1[C:22](=[O:23])[NH:21][C:18]1[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CN1C(=O)Cc2cscc2S1(=O)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CN1C(O)=C(C(=O)Nc2ccc(Cl)cc2)c2cscc2S1(=O)=O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
1 g (4.6 mmol) of 3,4-dihydro-2-methyl-3-oxo-2H-thieno[3,4-e]-1,2-thiazine 1,1-dioxide are stirred at room temperature under nitrogen for 3 hours with 0.71 g (4.6 mmol) of p-chlorophenylisocyanate and 0.47 g (4.6 mmol) of triethylamine in 10 ml of absolute dimethylsulfoxide. Thereafter, the mixture is poured into 40 ml of 2-N hydrochloric acid and 25 g of ice and stirred for 20 minutes. The separated precipitate is filtered off under suction and washed neutral with water. The precipitate is dissolved in 200 ml of methylene chloride, the turbid solution is dried over sodium sulfate, stirred with 0.3 g of active carbon and filtered. The filtrate is extracted with five 100 ml portions of saturated sodium carbonate solution, each of the aqueous phases being re-extracted with a small amount of methylene chloride. The combined aqueous phases are acidified to pH 1 with concentrated hydrochloric acid. The precipitated product is extracted with two 150 ml portions of methylene chloride. The combined organic phases are dried over sodium sulfate. The solvent is distilled off, whereby the product crystallizes out. For purification, the product is recrystallized from ca 30 ml of methanol. There is obtained 3-hydroxy-2-methyl-4-(4-chlorophenylcarbamoyl)-2H-thieno[3,4-e]-1,2-thiazine 1,1-dioxide of melting point 154°-156° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][NH:7][N:6]=1)=[O:4].[C:13]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH3:1][O:2][C:3]([C:5]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][N:7]([CH3:13])[N:6]=1)=[O:4]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1n[nH]cc1[N+](=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)c1nn(C)cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 53.7 %

Procedure:
To a solution of 4-nitro-1H-pyrazole-3-carboxylic acid methyl ester (3.1 g, 18.1 mmol) in dry acetone (2 ml) was added K2CO3 (5 g, 36.2 mmol) at 25° C. The reaction mixture was cooled to 0° C., and methyl iodide (2.2 ml, 36.3 mmol) was added. The temperature was again raised to 25° C., and then heated to 70° C. for 2 hrs. The solvent was removed in vacuo The residue was diluted with EtOA and washed with water and with brine, dried (Na2SO4), filtered, and concentrated. The crude product was purified by column chromatography over silica gel. Elution with 20% EtOAc/hexane) gave the undesired isomer 2-methyl-4-nitro-2H-pyrazole-3-carboxylic acid methyl ester (1 g, 30%), subsequent elution with 40% EtOAc/hexane provided the desired isomer 1-methyl-4-nitro-1H-pyrazole-3-carboxylic acid methyl ester (1.8 g, 54%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1Cl)[N:8]([CH2:13][CH3:14])[CH:7]=[C:6]([C:15]([OH:17])=[O:16])[C:5]2=[O:18].[CH2:19]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CS(C)=O>[CH2:19]([N:26]1[CH2:31][CH2:30][N:29]([C:11]2[CH:10]=[C:9]3[C:4]([C:5](=[O:18])[C:6]([C:15]([OH:17])=[O:16])=[CH:7][N:8]3[CH2:13][CH3:14])=[CH:3][C:2]=2[Cl:1])[CH2:28][CH2:27]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(Cl)c(Cl)cc21
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: CS(C)=O
Product: CCn1cc(C(=O)O)c(=O)c2cc(Cl)c(N3CCN(Cc4ccccc4)CC3)cc21
Temperature: 110 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
A solution of 4.3 g of 6,7-dichloro-1-ethyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid and 10.5 g of 1-benzylpiperazine in 45 cm3 of DMSO was stirred and heated to 110° C. After 2 hours, the amount of Cl- ions in the reaction mixture corresponded to 94% of the amount calculated for the removal of one halogen atom. After evaporation of the solvent, the reaction product was isolated as in the preceding example; it was purified by recrystallisation from methyl cellosolve. 3.2 g of 7-(4-benzylpiperazinyl)-6-chloro-1-ethyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid, m.p. 228° C., were obtained.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([NH:18]CC3C=CC(OC)=CC=3)[C:12]3[N:13]([CH:15]=[CH:16][N:17]=3)[N:14]=2)[CH2:4][CH2:3]1.C(O)(C(F)(F)F)=O>ClCCl>[NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([NH2:18])[C:12]3[N:13]([CH:15]=[CH:16][N:17]=3)[N:14]=2)[CH2:4][CH2:3]1
Reactant: COc1ccc(CNc2cc(N[C@H]3CC[C@H](N)CC3)nn3ccnc23)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cc(N[C@H]2CC[C@H](N)CC2)nn2ccnc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To N6-(trans-4-aminocyclohexyl)-N8-(4-methoxybenzyl)imidazo[1,2-b]pyridazine-6,8-diamine from 1b in dichloromethane (5 mL) was added TFA (2 mL). After stirring at RT for 2 hours, the reaction solution was concentrated in vacuo To provide crude N6-(trans-4-aminocyclohexyl)imidazo[1,2-b]pyridazine-6,8-diamine that was used without further purification. LC/MS, m/e 247.16 (M+1). HPLC Rt, 0.73 min. Waters Sunfire C18 column (4.6×50 mm). 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% B 1 min, flow rate 4 mL/min.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][N:7]([CH3:13])[C:8]([CH3:12])([CH3:11])[C:9]#[N:10].[OH-:14].[Ba+2].[OH-]>>[CH3:6][N:7]([CH3:13])[C:8]([CH3:12])([CH3:11])[C:9]([NH2:10])=[O:14]
Reactant: CN(C)C(C)(C)C#N
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Ba+2]
Product: CN(C)C(C)(C)C(N)=O
Temperature: 90 °C
Reaction time: 0.08 h
Yield: 43.1 %

Procedure:
Conc. Sulphuric acid (8 ml.) was added to 2-dimethylamino-2-methyl-propionitrile (2 g.), and was heated to 90°C and allowed to stand for five mins. The reaction mixture was added to ice cold water (100 ml.), barium hydroxide (32 g.) was added to neutralise the acid and the mixture was filtered (hyflo). The filtrate was evaporated under reduced pressure to give a solid residue which was crystallised from light petroleum (80°-100°C) to give 2-dimethylamino-2-methylpropionamide (1 g. 45%) m.p. 109°-111°C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][CH:17]([NH:20]C(=O)OC(C)(C)C)[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH2:19][CH2:18][CH:17]([NH2:20])[CH2:16][CH2:15]2)[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(C2CCN(Cc3ccccc3)CC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CCN(C2CCN(Cc3ccccc3)CC2)CC1

Procedure:
A solution of 7.0 g (18.7 mmol) tert-butyl (1′-benzyl-[1,4′]bipiperidinyl-4-yl)-carbamate and 14.3 mL (185 mmol) TFA in 80 mL DCM was refluxed overnight. The mixture was evaporated down i. vac., the residue was combined with 200 mL 30% K2CO3 solution and extracted three times with 100 mL EtOAc, discarding the first 100 mL of extract. The combined organic phases were dried over Na2SO4, filtered and evaporated down. The product was reacted further without purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].[NH:13]1[CH:17]=[CH:16][CH:15]=[CH:14]1>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([C:14]1[NH:13][CH:17]=[CH:16][CH:15]=1)=[O:8])([O-:3])=[O:2]
Reactant: c1cc[nH]c1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: Cc1ccccc1
Product: O=C(c1cccc([N+](=O)[O-])c1)c1ccc[nH]1

Procedure:
Alternatively, about 0.5 to 2 molar equivalents of m-nitrobenzoyl chloride (Formula ;b 7 where Z is chloro) (available from Aldrich) is added to pyrrole or an optionally substituted pyrrole (represented by Formula 8, prepared, e.g., as described in Reaction Schemes 1 and 2) dissolved in an inert organic solvent (preferably toluene) and heated, preferably to the reflux temperature of the solvent used, in an inert atmosphere (e.g., under nitrogen). The reaction takes place over a period of about 1 to 30 hours, preferably 10 to 25 hours, and most preferably about 18 hours. The 2-(3'-nitrobenzoyl)pyrrole intermediate of Formula 9 is isolated and purified in the usual manner.
Reaction SMILES: [F:1][C:2]1[C:3]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][CH2:15]2)=[C:4]([C:7]([F:13])=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)[CH2:5]Cl.B.[Na].Cl>CS(C)=O>[CH2:23]([O:22][C:20]([N:17]1[CH2:18][CH2:19][N:14]([C:3]2[C:2]([F:1])=[CH:9][C:8]([N+:10]([O-:12])=[O:11])=[C:7]([F:13])[C:4]=2[CH3:5])[CH2:15][CH2:16]1)=[O:21])[CH3:24]
Reactant: CCOC(=O)N1CCN(c2c(F)cc([N+](=O)[O-])c(F)c2CCl)CC1
Agent: B
Agent: Cl
Agent: [Na]
Solvent: CS(C)=O
Product: CCOC(=O)N1CCN(c2c(F)cc([N+](=O)[O-])c(F)c2C)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
To a solution of 3,6-difluoro-2-(4-ethoxycarbonyl-1-piperazinyl)-5-nitrobenzyl chloride (8.1 g) in dimethylsulfoxide (90 ml) is added gradually sodium boron hydride (1.8 g) at below 30° C. The mixture is stirred at the same temperature for one hour, and the reaction mixture is poured into ice water, and then acidified with conc. hydrochloric acid and extracted with diethyl ether. The solvent is distilled off to give 2-(4-ethoxycarbonyl-1-piperazinyl)-3,6-difluoro-5-nitrotoluene (7.1 g).