Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([CH3:12])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)=O.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C(O)C.C(=O)([O-])O.[Na+]>O>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:13]=[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]3[C:2]=2[CH3:12])=[CH:6][CH:7]=1
Reactant: Nc1ccccn1
Reactant: CC(Br)C(=O)c1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1c(-c2ccc(Br)cc2)nc2ccccn12
Yield: 37.1 %

Procedure:
Dissolving 4.3 g (16 mmol) of 2,4′-dibromopropiophenon obtained and 1.4 g (15 mmol) of 2-aminopyridine into 50 milliliter of ethanol, adding 1.9 g of sodium hydrogen carbonate, the resultant suspension was refluxed under heating for 6 hours. After completion of the reaction, adding water and an extraction was carried out using dichloro-methane. Washing the organic layer with water, it was dried with the use of sodium sulfate. The solvent was removed by distillation and the resultant syrup was refined by silica gel column chromatography thereby obtaining 1.6 g of 2-(4-bromo-phenyl)-3-methyl-imidazo [1,2-a] pyridine (yield: 37%).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][N:7]([CH3:9])[CH2:6][N:5]([C:10]2[S:11][C:12]3[C:18]([CH2:19][C:20]#[N:21])=[C:17]([N+:22]([O-])=[O:23])[CH:16]=[CH:15][C:13]=3[N:14]=2)[C:4]1=[O:25])[CH3:2].C(N(CC)CC)C.C[Si](Cl)(C)C>CN(C)C=O>[CH2:1]([N:3]1[CH2:8][N:7]([CH3:9])[CH2:6][N:5]([C:10]2[S:11][C:12]3[C:18]4[C:17](=[N:22][O:23][C:19]=4[C:20]#[N:21])[CH:16]=[CH:15][C:13]=3[N:14]=2)[C:4]1=[O:25])[CH3:2]
Reactant: CCN1CN(C)CN(c2nc3ccc([N+](=O)[O-])c(CC#N)c3s2)C1=O
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN1CN(C)CN(c2nc3ccc4noc(C#N)c4c3s2)C1=O
Temperature: 25 °C

Procedure:
0.2 g of [2-(3-ethyl-5-methyl-2-oxo-1,3,5-triazinan-1-yl)-6-nitro-1,3-benzothiazol-7-yl]methyl cyanide was charged into about 2 ml dimethylformamide. About 15 equivalents of triethylamine were then added followed by about 15 equivalents of trimethylsilyl chloride. The solution was stirred at room temperature for about 4–20 hours. The reaction was quenched by pouring into dilute aqueous hydrochloric acid then extracted well with ethyl acetate. The combined organics were back extracted with dilute sodium bicarbonate then dried over magnesium sulfate and concentrated. The dark oil was further purified by preparative HPLC to yield 2-(3-ethyl-5-methyl-2-oxo-1,3,5-triazinan-1-yl) [1,3]thiazolo[5′,4′: 3,4]benzo[c]isoxazol-8-yl cyanide.
Reaction SMILES: [Br:1][C:2](=[CH2:6])[CH2:3][CH2:4][OH:5].N1C=CN=C1.[Si:12](Cl)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Br:1][C:2](=[CH2:6])[CH2:3][CH2:4][O:5][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=C(Br)CCO
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: C=C(Br)CCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
To a solution of 3-bromobut-3-en-1-ol (ACROS, 15.18 g, 100.53 mmol) in DCM (300 mL) at room temperature was added imidazole (8.90 g, 130.69 mmol), 4-dimethylaminopyridine (2.456 g, 20.11 mmol) and tert-butyldimethylsilyl chloride (16.67 g, 110.58 mmol). The reaction mixture was stirred at room temperature for 3 hours, then filtered to remove solids and washed with brine. The organics were dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0%-15% ethyl acetate/hexanes) afforded the title compound (24.67 g, 93%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[N:3]=1.O.[NH2:24][NH2:25]>>[NH:24]([C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[N:3]=1)[NH2:25]
Reactant: Cn1cnc2c(Nc3ccc(C(F)(F)F)cc3)nc(Cl)nc21
Reactant: NN
Solvent: O
Product: Cn1cnc2c(Nc3ccc(C(F)(F)F)cc3)nc(NN)nc21

Procedure:
Was prepared according to Example 8 from (2-chloro-9-methyl-9H-purin-6-yl)-(4-trifluoromethyl-phenyl)-amine and hydrazine monohydrate.
Reaction SMILES: C[O-].[Na+].[CH2:4]([N:6]1[C:11](=[O:12])[C:10]2=[N:13][O:14][C:15]([CH3:16])=[C:9]2[C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:7]1)[CH3:5].[CH:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CO>[CH2:4]([N:6]1[C:11](=[O:12])[C:10]2=[N:13][O:14][C:15]([CH:16]=[CH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:9]2[C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:7]1)[CH3:5]
Reactant: O=Cc1ccccc1
Reactant: CCn1nc(-c2ccccc2)c2c(C)onc2c1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCn1nc(-c2ccccc2)c2c(C=Cc3ccccc3)onc2c1=O

Procedure:
To a freshly prepared solution of sodium methoxide (108 mg, 1.96 mmol) in methanol (2 ml), a solution of 6-ethyl-3-methyl-4-phenyl-6H-isoxazolo[3,4-d]pyridazin-7-one (500 mg, 1.96 mmol) (Dal Piaz, V.; Giovannoni, M. P.; Castellana, C.; et al, J. Med. Chem. 1997, 40, 1417-1421) in of dry methanol (2 ml) was added and the mixture was stirred for a while. Then, benzaldehyde (0.40 ml, 3.92 mmol) was added dropwise and the final mixture was refluxed for 2 hours. The resulting suspension was let to cool down and the final product (514 mg, 76%-yield) was collected by filtration.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:8]([C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[C:7]2[CH:17]=[CH:18][CH:19]=[CH:20][C:6]=2[N:5]=1)[CH3:3].Cl[C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[N:24]=[CH:25][N:26]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[N:30]1[C:22]([NH:1][C@H:2]([C:4]2[N:8]([C:9]3[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=3)[C:12]#[N:13])[C:7]3[CH:17]=[CH:18][CH:19]=[CH:20][C:6]=3[N:5]=2)[CH3:3])=[C:23]2[C:27]([NH:26][CH:25]=[N:24]2)=[N:28][CH:29]=1
Reactant: C[C@H](N)c1nc2ccccc2n1-c1cccc(C#N)c1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccccc2n1-c1cccc(C#N)c1
Temperature: 90 °C
Yield: 36.3 %

Procedure:
A mixture of 3-[2-((S)-1-aminoethyl)benzoimidazol-1-yl]benzonitrile (54 mg, 0.21 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (69 mg, 0.29 mmol) and DIPEA (65 mL, 0.37 mmol) in n-butanol (0.5 mL) was heated at 90° C. in a sealed vial for 16 h. After cooling to RT, the crude reaction mixture was loaded onto an Isolute® SCX-2 cartridge and washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) then by preparative HPLC (Phenomenex Gemini 5 μm C18 on a gradient 20-98%, 0.1% HCO2H in acetonitrile/water) to afford 170 as a white solid (29 mg, 37%). LCMS (Method K): RT 3.03 min [M+H]+ 381.0. 1H NMR (DMSO-d6, 400 MHz): δ 12.90 (1H, s), 8.25-7.49 (8H, m), 7.32-7.17 (2H, m), 7.09 (1H, d, J=7.84 Hz), 5.60 (1H, s), 1.64 (3H, d, J=6.81 Hz)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([O:22][CH2:23][CH3:24])(=[O:21])[CH2:17][C:18]([CH3:20])=O>>[CH2:23]([O:22][C:16](=[O:21])[CH:17]=[C:18]([NH:13][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:15][CH:14]=1)[CH3:20])[CH3:24]
Reactant: Nc1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)C=C(C)Nc1ccc(OCc2ccccc2)cc1
Yield: 49.9 %

Procedure:
4-Benzyloxyaniline (10 g) and ethyl acetoacetate (6.9 g) were heated at 120° C. for 3 hours. The residue was purified by chromatography on silica eluting with a mixture of dichloromethane, and pentane. The desired fractions were concentrated and the sample evaporated to give the sub-title compound (7.8 g).
Reaction SMILES: [H-].[Na+].[N:3]1([C:9](=[O:13])[C@H:10]([OH:12])[CH3:11])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.Cl>O1CCCC1.C(OCC)C>[CH3:24][C:14]1[CH:19]=[CH:18][C:17]([S:20]([O:12][C@H:10]([CH3:11])[C:9]([N:3]2[CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)=[O:13])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@@H](O)C(=O)N1CCOCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)O[C@H](C)C(=O)N2CCOCC2)cc1
Yield: 57 %

Procedure:
To a suspension of sodium hydride (60% in paraffin liquid) (8.41 g, 210 mmol) in tetrahydrofuran (120 ml was dropped (2R)-1-morpholin-4-yl-1-oxopropane-2-ol (32.1 g) in tetrahydrofuran (150 ml) under stirring, ice cooling and an atmosphere of nitrogen. The mixture was then stirred for 30 minutes at 50° C. After being ice-cooled, thereto was dropped a solution of p-toluenesulfonyl chloride (45.8 g, 234 mmol) in tetrahydrofuran (180 ml), and the mixture was stirred for 4 hours at room temperature. Thereto was added 1N hydrochloric acid and the mixture was extracted with ethyl acetate. The organic layer was washed with water and an aqueous saturated sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure to give the oily residue. Thereto was added diethyl ether and the resulting precipitate was taken by filtration, washed with diethyl ether and dried under reduced pressure to give the subject compound as a white solid (36.1 g, 115 mmol, 58%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([C:28]([C:30]2[CH:31]=[C:32]3[C:36](=[C:37]([CH3:39])[CH:38]=2)[N:35]([CH3:40])[N:34]=[CH:33]3)=[O:29])[CH:23]=1>CN(C=O)C>[CH3:40][N:35]1[C:36]2[C:32](=[CH:31][C:30]([C:28]([C:24]3[N:25]=[CH:26][N:27]=[C:22]([N:17]4[CH2:18][CH2:19][CH:14]([N:10]5[CH2:9][CH2:8][C:7]6[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=6[NH:12][C:11]5=[O:13])[CH2:15][CH2:16]4)[CH:23]=3)=[O:29])=[CH:38][C:37]=2[CH3:39])[CH:33]=[N:34]1
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2cnn(C)c12
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5c(cnn5C)c4)ncn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
33 mg (0.12 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 45 mg (0.13 mmol) (6-chloro-pyrimidin-4-yl)-(1,7-dimethyl-1H-indazol-5-yl)-methanone and 25 μL (0.18 mmol) TEA were combined in 1 mL DMF and stirred overnight at RT. The reaction mixture was purified by preparative HPLC. The fractions containing the product were combined and evaporated down to approx. 10 mL. This residue was neutralised with saturated sodium hydrogen carbonate solution, the precipitate formed was suction filtered and dried.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([Li])CCC.[CH:18]1([C:21](N(OC)C)=[O:22])[CH2:20][CH2:19]1>C(OC(C)C)(C)C>[CH:18]1([C:21]([C:2]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[O:22])[CH2:20][CH2:19]1
Reactant: CON(C)C(=O)C1CC1
Reactant: COc1ccc(Br)c(C(=O)O)c1
Agent: [Li]CCCC
Solvent: CC(C)OC(C)C
Product: COc1ccc(C(=O)C2CC2)c(C(=O)O)c1

Procedure:
This compound is synthesized according to the method described in 3.2. by reacting 2-bromo-5-methoxybenzoic acid pretreated with n-butyllithium with cyclopropyl-N-methoxy-N-methylcarboxamide. A yellow powder is obtained by precipitation in isopropyl ether.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:7][C:8]1[CH:12]=[N:11][N:10]([CH3:13])[C:9]=1[C:14]1[CH:15]=[C:16]([NH:21][C:22](=[O:33])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[CH:17]=[CH:18][C:19]=1[OH:20].CS(O[CH2:39][C:40]([CH3:45])([N+:42]([O-:44])=[O:43])[CH3:41])(=O)=O.O>CC(N(C)C)=O>[N+:42]([C:40]([CH3:45])([CH3:41])[CH2:39][O:20][C:19]1[CH:18]=[CH:17][C:16]([NH:21][C:22](=[O:33])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:31])([F:30])[F:32])[CH:24]=2)=[CH:15][C:14]=1[C:9]1[N:10]([CH3:13])[N:11]=[CH:12][C:8]=1[Cl:7])([O-:44])=[O:43]
Reactant: Cn1ncc(Cl)c1-c1cc(NC(=O)c2cccc(C(F)(F)F)c2)ccc1O
Reactant: CC(C)(COS(C)(=O)=O)[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cn1ncc(Cl)c1-c1cc(NC(=O)c2cccc(C(F)(F)F)c2)ccc1OCC(C)(C)[N+](=O)[O-]
Temperature: 160 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
Cesium carbonate (815 mg, 2.50 mmol) was added to a solution of N-(3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-hydroxyphenyl)-3-(trifluoromethyl)benzamide (396 mg, 1.00 mmol) and 2-methyl-2-nitropropyl methanesulfonate (276 mg, 1.40 mmol) in DMA (2.0 mL), and the mixture was stirred at 160° C. After 1 hour, the mixture was allowed to cool to room temperature and poured into water, and the resulting suspension was extracted with dichloromethane. The extract was dried with sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by flash chromatography (ethyl acetate-hexanes 1:2) to afford the title compound (338 mg, 68%) as a yellow oil. LCMS m/z (%)=499.5 (M+H, 37Cl 31.5), 497.4 (M+H, 35Cl 100.0). 1H NMR (400 MHz, CDCl3) δ 1.51 (s, 3H) 1.57 (s, 3H) 3.64 (s, 3H) 4.01 (d, J=9.85 Hz, 1H) 4.49 (d, J=9.85 Hz, 1H) 7.08 (d, J=8.84 Hz, 1H) 7.49 (d, J=2.53 Hz, 1H) 7.51 (s, 1H) 7.65 (t, J=7.71 Hz, 1H) 7.79-7.89 (m, 3H) 8.07 (d, J=7.83 Hz, 1H) 8.13 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([NH2:13])[CH:7]=1.C[O:16][C:17](=O)[CH:18]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH2:33][CH3:34])(=[O:32])=[O:31])=[CH:26][CH:25]=1)[C:19](=O)[CH2:20][CH3:21].O1CCOCC1>O>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:7]=1[C:17](=[O:16])[C:18]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([S:30]([CH2:33][CH3:34])(=[O:31])=[O:32])=[CH:28][CH:29]=1)=[C:19]([CH2:20][CH3:21])[NH:13]2
Reactant: CCC(=O)C(Cc1ccc(S(=O)(=O)CC)cc1)C(=O)OC
Reactant: COC(=O)COc1ccc(F)c(N)c1
Solvent: C1COCCO1
Solvent: O
Product: CCc1[nH]c2c(F)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(S(=O)(=O)CC)cc1
Temperature: 120 °C

Procedure:
A mixture of (3-amino-4-fluorophenoxy)acetic acid methyl ester (0.90 g), 2-(4-ethanesulfonylbenzyl)-3-oxopentanoic acid methyl ester (1.4 g), polyphosphoric acid (10 g) and dioxane (10 mL) was heated at 120° C. for 17 hours. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts were washed with water, dried over magnesium sulfate and the solvent removed under reduced pressure to afford title compound, 1.9 g.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[S:12]([N:15]([CH3:17])[CH3:16])(=[O:14])=[O:13].[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([NH:25][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[S:12]([N:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCc1ccccc1
Reactant: CN(C)S(=O)(=O)c1cc(C(F)(F)F)ccc1Cl
Product: CN(C)S(=O)(=O)c1cc(C(F)(F)F)ccc1NCc1ccccc1

Procedure:
A solution of 2-Chloro-N,N-dimethyl-5-trifluoromethyl-benzenesulfonamide (2.10 g, 0.00730 mol) in Benzylamine (5 mL, 0.04 mol) was heated at 100° C. for 5 hours. The benzylamine was evaporated under reduced pressure. The residue was partitioned between water (50 mL) and ethyl acetate (50 mL). The organic layer was washed with water (3×50 mL), dried over magnesium sulfate, filtered and evaporated. The material was purified via silica gel chromatography using 0% 25% Ethyl Acetate:Hexane solvent gradient. 2-Benzylamino-N,N-dimethyl-5-trifluoromethyl-benzenesulfonamide isolated as a pale yellow solid (1.84 g, 70%).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[Cl:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[C:24]([Cl:26])[CH:25]=1>>[Cl:19][C:20]1[CH:21]=[C:22]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)[CH:23]=[C:24]([Cl:26])[CH:25]=1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCCNC1=O
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Product: N#Cc1cc(-c2cc(Cl)cc(Cl)c2)c2c(c1)cc1n2CCCNC1=O

Procedure:
The title compound, off-white solid (75 mg, 81%), MS (ISP) m/z=372.4 [(M+H)+], mp 244° C., was prepared in accordance with the general method of example 1 from 7-bromo-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 20) (76.0 mg, 0.25 mmol) and commercially available 3,5-dichloro-phenylboronic acid (62.0 mg, 0.325 mmol).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.C[Al](C)C.CCCCCCC.C([O:22][C:23]([C:25]1[N:26]=[C:27]([CH3:37])[S:28][C:29]=1[NH:30][C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1)=O)C>O1CCOCC1>[CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:23]([C:25]2[N:26]=[C:27]([CH3:37])[S:28][C:29]=2[NH:30][C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)=[O:22])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(N)ccn1
Reactant: CCOC(=O)c1nc(C)sc1Nc1cccnc1
Agent: C[Al](C)C
Solvent: CCCCCCC
Solvent: C1COCCO1
Product: Cc1cc(NC(=O)c2nc(C)sc2Nc2cccnc2)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
A solution of 2-methyl-pyridin-4-ylamine (0.10 g, 0.91 mmol) in dry dioxane (2.00 ml) was added to a 2N solution of trimethylaluminium in heptane (0.46 ml, 0.91 mmol). The mixture was stirred at room temperature for 1 h, then 2-methyl-5-(pyridin-3-ylamino)-thiazole-4-carboxylic acid ethyl ester (0.08 g, 0.30 mmol) was added and the reaction mixture was irradiated in a microwave oven at 150° C. for 15 min. The mixture was quenched with water (1.00 ml) and diluted with dichloromethane. After drying with sodium sulphate, the solvent was evaporated. The residue was purified by flash chromatography (dichloromethane/methanol) yielding the title compound (0.04 g, 41%) as a yellow solid, MS (ISP): m/e=326.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Cl:8].[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1[S:17](Cl)(=[O:19])=[O:18]>>[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1[S:17]([NH:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Cl:8])(=[O:18])=[O:19]
Reactant: Cc1ccc(C)c(S(=O)(=O)Cl)c1
Reactant: Cc1noc(N)c1Cl
Product: Cc1ccc(C)c(S(=O)(=O)Nc2onc(C)c2Cl)c1
Yield: 82 %

Procedure:
2,5-Dimethyl-N-(4-chloro-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared from 5-amino-4-chloro-3-methylisoxazole and 2,5-dimethylbenzenesulfonyl chloride according to the procedures described in Example 1b. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a light yellow solid, m.p. 92°-93° C., yield 82%.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH3:20])=[CH:14][CH:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[NH2:21][C@H:22]1[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23]1>O>[NH2:21][C@H:22]1[CH2:26][CH2:25][N:24]([C:2]2[CH:3]=[C:4]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH3:20])=[CH:14][CH:13]=3)[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[N:7]=2)[CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Reactant: CCOc1ccc(Nc2cc(Cl)nn3ccnc23)cc1
Solvent: O
Product: CCOc1ccc(Nc2cc(N3CC[C@H](N)C3)nn3ccnc23)cc1
Yield: 3 %

Procedure:
To 6-chloro-N-(4-ethoxyphenyl)imidazo[1,2-b]pyridazin-8-amine (26 mg, 0.090 mmol), prepared as described in example 1, step (1c) was added (S)-3-amino-1-N-boc-pyrrolidine (180 mg, 0.96 mmol). The mixture was microwaved at 225° C. for one hour. The melt was then cooled, water was added followed by extraction with dichloromethane. The organic layer was then concentrated in vacuo and purified by preparative HPLC to give 0.9 mg (2%) of the title compound as a TFA salt, (Note that during the reaction the Boc cleaves and the 1-nitrogen of the pyrrolidine adds). 1H NMR (500 MHz, MeOH) δ ppm 7.99 (1H, s), 7.88 (1H, s), 7.31 (2H, d, J=7.7 Hz), 7.03 (2H, d, J=7.7 Hz), 6.18 (1H, s), 4.07 (2H, q, J=6.9 Hz), 4.0 (1H, m), 3.80 (1H, m), 3.55 (3H, m), 2.50 (1H, m), 2.15 (1H, m), 1.40 (3H, t, J=6.9 Hz). LC/MS, m/e 339 (M+1). HPLC Rt, 1.83 min. YMC ODSC18 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: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][C:23]=2[N+:25]([O-:27])=[O:26])[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2cccc([N+](=O)[O-])c21
Product: CC1c2c(cccc2[N+](=O)[O-])CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-8-nitro-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [N:1]1([C:6]2[CH:15]=[CH:14][C:9]([C:10](=O)[CH2:11]Br)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][N:18]=1>C(#N)C>[I:23][C:20]1[CH:21]=[CH:22][C:17]2[N:18]([CH:11]=[C:10]([C:9]3[CH:14]=[CH:15][C:6]([N:1]4[CH:5]=[CH:4][CH:3]=[CH:2]4)=[CH:7][CH:8]=3)[N:16]=2)[CH:19]=1
Reactant: Nc1ccc(I)cn1
Reactant: O=C(CBr)c1ccc(-n2cccc2)cc1
Solvent: CC#N
Product: Ic1ccc2nc(-c3ccc(-n4cccc4)cc3)cn2c1
Temperature: 25 °C
Yield: 68.7 %

Procedure:
120 mg (corresponding to 0.454 mmol) of 4-(1H-pyrrole-1-yl)phenacylbromide and 99.9 mg (corresponding to 0.454 mmol) of 2-amino-5-iodopyridine were dissolved in 2.0 mL of acetonitrile. The resulting solution was heated under reflux for 2 hours. After the completion of the reaction, the reaction solution was cooled down to room temperature, and precipitates were filtered. The precipitates were washed with acetonitrile and dried under reduced pressure. The resulting crude crystals were suspended in a mixed solution of 10 mL of water and 10 mL of methanol. Then, about 20 mL of a saturated sodium hydrogencarbonate solution was added thereto, and the mixture was sonicated for 20 minutes using an ultrasonic washing machine. Precipitates were filtered and recovered from the resulting mixture, sufficiently washed with water, and dried under reduced pressure, to obtain 120 mg (corresponding to 0.312 mmol) of 6-iodo-2-[4-(1H-pyrrole-1-yl)phenyl]imidazo[1,2-a]pyridine (FIG. 2, step 2).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]([CH3:14])=[C:12]3[C:15]([CH3:23])([C:20]([NH2:22])=[O:21])[CH2:16][C:17]([CH3:19])([CH3:18])[C:11]3=[C:10]2[CH3:24])[CH:6]=[CH:7][CH:8]=1.C(OO)=[O:26]>CC(C)=O>[CH3:1][S:2]([C:3]1[CH:4]=[C:5]([N:9]2[C:13]([CH3:14])=[C:12]3[C:15]([CH3:23])([C:20]([NH2:22])=[O:21])[CH2:16][C:17]([CH3:19])([CH3:18])[C:11]3=[C:10]2[CH3:24])[CH:6]=[CH:7][CH:8]=1)=[O:26]
Reactant: O=COO
Reactant: CSc1cccc(-n2c(C)c3c(c2C)C(C)(C(N)=O)CC3(C)C)c1
Solvent: CC(C)=O
Product: Cc1c2c(c(C)n1-c1cccc(S(C)=O)c1)C(C)(C(N)=O)CC2(C)C

Procedure:
Reaction of the 2-(3-methylmercaptophenyl)-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carboxamide described above in Example 20CB with one molar equivalent of performic acid in acetone at room temperature affords 2-(3-methylsulfinylphenyl)-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carboxamide.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[OH:13][C:14]1[CH:15]=[C:16]([C:20]2([O:28][CH3:29])[CH2:25][CH:24]([CH3:26])[O:23][CH:22]([CH3:27])[CH2:21]2)[CH:17]=[CH:18][CH:19]=1>>[CH3:29][O:28][C:20]1([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([O:13][CH2:2][C:3]3[CH:12]=[CH:11][C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=3)[CH:15]=2)[CH2:25][CH:24]([CH3:26])[O:23][CH:22]([CH3:27])[CH2:21]1
Reactant: COC1(c2cccc(O)c2)CC(C)OC(C)C1
Reactant: BrCc1ccc2ccccc2c1
Product: COC1(c2cccc(OCc3ccc4ccccc4c3)c2)CC(C)OC(C)C1
Yield: 91 %

Procedure:
Using the procedure described in Example 5, 2-bromomethylnaphthalene (0.234 g) was reacted with 4-(3-hydroxyphenyl)-4-methoxy-2,6-dimethyltetrahydropyran (0.2 g, less polar isomer) to give 4-methoxy-2,6-dimethyl-4-[3-(naphth-2-ylmethoxy)phenyl]tetrahydropyran (0.29 g, 92%), m.p. 105°-107° C.