Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[N:12]=[CH:13][N:14]([CH3:16])[CH3:15])#[N:2].C1CCCCC=1>CO.[Pd]>[NH2:9][C:7]1[CH:6]=[CH:5][C:4]([N:12]=[CH:13][N:14]([CH3:15])[CH3:16])=[C:3]([C:1]#[N:2])[CH:8]=1
Reactant: CN(C)C=Nc1ccc([N+](=O)[O-])cc1C#N
Agent: [Pd]
Solvent: CO
Solvent: C1=CCCCC1
Product: CN(C)C=Nc1ccc(N)cc1C#N

Procedure:
A solution of 6.0 g (27.5 mmol) of N'-(2-cyano-4-nitrophenyl)-N,N-dimethylformamidine, 33.9 g (41.8 ml, 412.4 mmol) of cyclohexene, and 0.6 g of 10% Pd/C in 360 ml of methanol was refluxed for 4 hrs. The hot mixture was filtered through Celite. Solvent was removed and the residue was recrystallized from chloroform-carbon tetrachloride giving 4.9 g (95%) of the title compound as a light gray crystalline solid. mass spectrum (m/e):188.9 (M+H, electrospray).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:18][CH3:19])[C:10]=2[C:14]([F:17])([F:16])[F:15])[C:5]=1[C:20]([NH:22][C:23](=[O:27])[O:24][CH2:25][CH3:26])=[O:21].Br[CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]>O1CCCC1>[F:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:18][CH3:19])[C:10]=2[C:14]([F:16])([F:17])[F:15])[C:5]=1[C:20]([N:22]([C:23]([O:24][CH2:25][CH3:26])=[O:27])[CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:21]
Reactant: CCOC(=O)NC(=O)c1c(F)ccc2c(C(F)(F)F)c(OC)ccc12
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)N(CC(=O)OC(C)(C)C)C(=O)c1c(F)ccc2c(C(F)(F)F)c(OC)ccc12
Temperature: 60 °C
Reaction time: 0.75 h
Yield: 81 %

Procedure:
Sodium hydride (80% by weight dispersion in mineral oil 0.208 g, 1.1 eq) was added to a stirred solution of N-[[2-fluoro-6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]carbamic acid, ethyl ester (2.26 g, 6.29 mmol) in anhydrous tetrahydrofuran (75 mL) at room temperature under a dry nitrogen atmosphere. After 45 minutes, the t-butyl bromoacetate (1.52 mL, 1.5 eq) was added and the reaction was heated to 60° C. After 11/4 hours of heating, the reaction was cooled to room temperature and the THF was removed. The residue was suspended in ether (150 mL), washed with water (2×75 mL) and saturated aqueous NaCl (1×50 mL), dried with MgSO4, and the ether was removed. The crude oil was flash chromatographed (4:1 petroleum ether:ethyl acetate, silica) then triturated with petroleum ether (3×30 mL) to provide the title compound as a white powder (2.40 g, 81%), m.p. 81°-83° C.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[F-:10].[K+]>CS(C)=O>[F:10][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(Cl)cc1
Reactant: [F-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1ccc(F)cc1
Temperature: 180 °C
Yield: 75 %

Procedure:
200 g of 4-chlorobenzonitrile, 101.4 g of potassium fluoride, 25 g of dimethyl sulfoxide, and 5.60 g of (N,N-dimethylimidazolidino)tetramethyl-guanidinium chloride were placed in a 1 liter 4-neck flask equipped with anchor stirrer, thermometer, and reflux condenser with bubble counter. The mixture was then heated with stirring to 180° C. and this temperature was maintained for 16 hours. The mixture was then cooled to room temperature, water was added to the reaction mixture in a volumetric ratio of 1:1, and the mixture was extracted with diethyl ether. After washing, concentration, and drying the separated organic phase, 4-fluorobenzo-nitrile was isolated in a yield of 75%.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>CS(C)=O.O>[CH3:13][O:12][C:4]1[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=[C:2]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH:3]=1
Reactant: C1COCCN1
Reactant: COc1cc(F)cc(O)c1[N+](=O)[O-]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(N2CCOCC2)cc(O)c1[N+](=O)[O-]
Temperature: 100 °C
Yield: 26.2 %

Procedure:
To a stirred solution of 5-fluoro-3-methoxy-2-nitro-phenol (2.0 g, 10.6 mmol) in dimethylsulfoxide (25 ml) is added morpholine (9.2 ml, 106 mmol) at room temperature. The resulting mixture is heated at 100° C. for 2 h. After completion of reaction (monitored by TLC), the mixture is diluted with water (40 ml) and the aqueous layer is extracted with ethyl acetate (3×30 ml). The combined organic layers are washed with water (30 ml), brine (20 ml), dried over sodium sulfate and concentrated in vacuo. The crude product is purified by flash column chromatography (45% ethyl acetate/hexane) to yield 3-methoxy-5-morpholin-4-yl-2-nitro-phenol (0.71 g, 2.78 mmol, 26%).
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:27]([OH:30])[CH:28]=[CH2:29]>O>[CH2:27]([O:30][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1)[CH:28]=[CH2:29]
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Reactant: C=CCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C=CCOc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Temperature: 100 °C

Procedure:
A mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.27 g of potassium carbonate and 3 ml of allyl alcohol was stirred while heating at 100° C. for two hours. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.24 g of 2-(3-allyloxypyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 74”).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([F:19])([F:18])[F:17].C([O-])([O-])=O.[K+].[K+]>CC#N>[F:17][C:16]([F:19])([F:18])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: FC(F)(F)CCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=Cc1ccc(OCCCCCC(F)(F)F)cc1

Procedure:
To a suspension of 4-hydroxybenzaldehyde (488 mg, 4 mmol) and 6-bromo-1,1,1-trifluorohexane (657 mg, 3 mmol) in MeCN (10 mL) was added K2CO3 (829 mg, 6.00 mmol). The resulting mixture was reflux overnight. Insoluble material was filtered off and rinsed with MeCN. The combined filtrate was concentrated to afford a white solid. This white solid was partitioned between EtOAc and 1 N NaOH solution. The organic layer was separated, washed with sat'd NH4Cl, dried over MgSO4, filtered and concentrated to afford Intermediate 8A as a clear liquid. LCMS Anal. Calc'd for C13H15F3O2 260.10, found [M+H] 261.0.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[N:18]([C:21]([CH3:27])([CH3:26])[CH2:22][C:23](Cl)=[O:24])=[N+:19]=[N-:20].Cl>ClCCCl>[N:18]([C:21]([CH3:27])([CH3:26])[CH2:22][C:23]([N:5]1[CH2:6][CH2:7][C:2]([CH3:8])([CH3:1])[CH2:3][CH2:4]1)=[O:24])=[N+:19]=[N-:20]
Reactant: CC(C)(CC(=O)Cl)N=[N+]=[N-]
Reactant: CC1(C)CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC1(C)CCN(C(=O)CC(C)(C)N=[N+]=[N-])CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.7 %

Procedure:
To a stirred ice cold solution of 4,4-dimethylpiperidine (4.21 g, 1 equiv, 37.2 mmol) and DIEA (9.73 mL, 1.5 equiv, 55.9 mmol) in anhydrous DCE (65 mL) was added 3-azido-3-methylbutanoyl chloride (6.02 g, 37.2 mmol) in small portions. The reaction was stirred and left at 0° C. for 1 h. Aqueous 1 M HCl (100 mL) was added to the reaction mixture and the contents poured into a separatory funnel. The organic layer was separated and washed with 1 M HCl (100 mL). It was dried over anhydrous MgSO4, filtered, concentrated and dried under high vacuum to give a crude oil (7.72 g, 87.1%). The crude oil was purified on an ISCO purification system with gradient elution from 20-50% ethyl acetate in hexanes. The desired fractions were collected and concentrated to give a colorless oil (6.00 g, yield: 67.7%). 1H NMR (CDCl3, 400 MHz): δ 0.98 (s, 6H), 1.32-1.39 (m, 4H), 1.45 (s, 6H), 2.52 (s, 2H), 3.42-3.47 (m, 2H), 3.55-3.60 (m, 2H). LRMS (ESI+) for C12H22N4O (238.2); Found: 239 (M+).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[CH:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>C1COCC1.CCOC(C)=O>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:38]4[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]4)(=[O:22])=[O:21])[CH:15]=3)[CH:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc(S(=O)(=O)Cl)c3)c2)n1
Reactant: CN1CCNCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc(S(=O)(=O)N4CCN(C)CC4)c3)c2)n1
Temperature: 25 °C
Yield: 37 %

Procedure:
The title compound was prepared from the solution of 3-[6-methyl-4-(4-trifluoromethylphenyl)-[2,4′]bipyridinyl-2′-yl]-benzenesulfonyl chloride (example 346 step 2) (ca. 0.2 g, 0.41 mmol) by treatment with excess N-methylpiperazine in THF (5 mL) at 50° C. for 16 h. Cooled to rt, diluted with EtOAc, washed with 1 N HCl, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with n-heptane/EtOAc followed by trituration with n-heptane/diethyl ether to give the title compound (0.085 g, 37%) as a white solid. MS (ISP) 552 8 [(M+H)+]; mp 180° C. (dec.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[CH2:11][CH2:10][C@H:9]1[C:23](O)=[O:24])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][C:28]=1[O:34][CH3:35].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[CH2:11][CH2:10][C@H:9]1[C:23](=[O:24])[NH:31][C:30]1[CH:32]=[CH:33][C:27]([Cl:26])=[C:28]([O:34][CH3:35])[CH:29]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1ccc([C@H]2CC[C@@H](C(=O)O)N2C(=O)OC(C)(C)C)cc1OC
Reactant: COc1cc(N)ccc1Cl
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(NC(=O)[C@@H]2CC[C@H](c3ccc(OC)c(OC)c3)N2C(=O)OC(C)(C)C)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
A solution of (2S,5R)5-(3,4-dimethoxy-phenyl)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (2.50 g, 7.11 mmol, 1.0 equivalent), 4-chloro-3-methoxyaniline (1.12 g, 7.11 mmol, 1.0 equivalent), PyBrop coupling reagent (3.98 g, 8.54 mmol, 1.2 equivalents), and DIEA (1.86 ml, 10.7 mmol, 1.5 equivalents) in dichloromethane (35 ml) was allowed to stir at room temperature overnight. The reaction mixture was concentrated in vacuo. The resulting residue was dissolved in ethyl acetate (100 ml) and washed with 1N NaOH (3×100 ml). The organic extract was dried over anhydrous Na2SO4 and concentrated in vacuo. The crude oil was filtered through a layer of silica and eluted with ethyl acetate:hexanes (1:1). The filtrate was concentrated in vacuo to afford (2S,5R)2-(4-chloro-3-methoxy-phenylcarbamoyl)-5-(3,4-dimethoxy-phenyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (3.48 g, 7.09 mmol, 100% yield). Analysis H1 NMR (400 MHz, CDCl3): 7.59 (1H, broad s), 7.23 (1H, m), 6.85–6.60 (4H, m) 4.64 (2H, m), 3.00 (3H, s), 3.83 (3H, s), 3.56 (3H, broad s), 2.62 (1H, broad m), 2.36 (1H, m), 2.11–1.89 (2H, m), 1.22 (9H, broad s). MS (LC-MS): Calculated for C25H31ClN2O6 490.19, found 491.15 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[C:6](=[O:7])[O:5][C:4]2[CH:8]=[CH:9][C:10]3[C:15]([C:3]1=2)=[CH:14][C:13]([CH:16](OS(C1C=CC(C)=CC=1)(=O)=O)[C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3.[NH:33]1[CH:37]=[N:36][CH:35]=[N:34]1.O>S1(=O)(=O)CCCC1>[CH3:1][C:2]1([CH3:32])[C:6](=[O:7])[O:5][C:4]2[CH:8]=[CH:9][C:10]3[C:15]([C:3]1=2)=[CH:14][C:13]([CH:16]([N:33]1[CH:37]=[N:36][CH:35]=[N:34]1)[C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3
Reactant: c1nc[nH]n1
Reactant: Cc1ccc(S(=O)(=O)OC(c2ccc3ccc4c(c3c2)C(C)(C)C(=O)O4)C(F)(F)F)cc1
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: CC1(C)C(=O)Oc2ccc3ccc(C(n4cncn4)C(F)(F)F)cc3c21

Procedure:
A solution of 1,1-dimethyl-8-(2,2,2-trifluoro-1-tosyloxyethyl)-2(1H)-naphtho[2,1-b]furanone and 1,2,4-triazole (0.5 g) in tetrahydrothiophen-1,1-dioxide (1 ml) was heated at 140° for 18 h. The mixture was treated with water (20 ml) and extracted twice with diethyl ether, and the combined ether extracts were dried and evaporated to dryness under reduced pressure. The residue was purified by flash chromatography, using ethyl acetate: pentane, 1:1 v/v, as eluant, to give 1,1-dimethyl-8-[1-(1H-1,2,4-triazol-1-yl)-2,2,2-trifluoroethyl]-2(1H)-naphtho[2,1-b]furanone. Nmr in deuteriochloroform: δ 8.35(1H,s); 8.15(1H,d); 8.09(1H,s); 7.98(1H,d); 7.87(1H,d); 7.51(1H,dd); 7.46(1H,d); 6.14(1H,q); 1.78(3H,s); 1.75(3H,s).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[CH:15][N:14](/[CH:17]=[CH:18]\[C:19]([O:21]C(C)C)=[O:20])[N:13]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Li+].[OH-]>C1COCC1.O>[OH:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[CH:15][N:14](/[CH:17]=[CH:18]\[C:19]([OH:21])=[O:20])[N:13]=2)[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: CC(C)OC(=O)/C=C\n1cnc(-c2cc(O)cc(C(F)(F)F)c2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)/C=C\n1cnc(-c2cc(O)cc(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 85.5 %

Procedure:
A solution of (Z)-isopropyl 3-(3-(3-hydroxy-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylate (4 g, 1.0 eq.) in THF (40 mL) and water (40 mL) was treated with LiOH (1.92 g, 4 eq.). The reaction mixture was stirred at RT for 2-3 hrs then quenched with acidic ice-water slurry (300 mL) and extracted with EtOAc (3×250 mL). The combined organic layers were washed with dil HCl solution (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford 3 g of crude compound. The resulting crude off-white compound was used as such in the following step. Yield: 85.5%. Mass: (ES+) 299.92 (M+1).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[N:17]3[C:18]([N+:21]([O-])=O)=[CH:19][N:20]=[C:16]3[CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3]>C(Cl)Cl.[H][H].[C].[Pd]>[NH2:21][C:18]1[N:17]2[C:12]([O:11][CH:8]3[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH2:7]3)=[CH:13][CH:14]=[CH:15][C:16]2=[N:20][CH:19]=1
Reactant: [H][H]
Reactant: CS(=O)(=O)N1CCC(Oc2cccc3ncc([N+](=O)[O-])n23)CC1
Agent: [Pd]
Solvent: ClCCl
Product: CS(=O)(=O)N1CCC(Oc2cccc3ncc(N)n23)CC1
Yield: 132.6 %

Procedure:
To a solution of 5-[1-(methylsulfonyl)-4-piperidyloxy]-3-nitroimidazo[1,2-a]pyridine (70 mg, 0.226 mmole) in methylene chloride (10 ml) was added 10% palladium-carbon (50 ml) and the mixture was stirred in hydrogen atmosphere at room temperature for 1.5 hours. After the reaction mixture was treated with Cellite, the solvent was distilled off. To the residue was added chloroform, which was washed in turn with an aqueous saturated sodium bicarbonate solution and water and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by column chromatography [eluent: chloroform/methanol (15:1)] to obtain 93 mg of the desired product (30.0%, brown oily product).
Reaction SMILES: [Br:1]Br.[N:3]1[CH:4]=[CH:5][N:6]2[C:11]=1[CH:10]=[CH:9][CH:8]=[N:7]2.[OH-].[Na+].C(=O)(O)[O-].[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Br:1][C:5]1[N:6]2[N:7]=[CH:8][CH:9]=[CH:10][C:11]2=[N:3][CH:4]=1
Reactant: BrBr
Reactant: c1cnn2ccnc2c1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Brc1cnc2cccnn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Bromine (0.649 mL, 12.6 mmol) was added dropwise to a stirred mixture of Imidazo[1,2-b]pyridazine (1.0 g, 8.39 mmol) in acetic acid (42 ml) and the mixture was stirred at room temperature for 1 h. The mixture was neutralized with 1 N sodium hydroxide (100 mL) and solid sodium hydroxide, poured into ethyl acetate and sodium bicarbonate solution, and extracted with ethyl acetate (3×200 mL). The combined organics were washed with brine, dried (MgSO4), and concentrated to afford the title compound. 1H NMR (600 MHz, CD3SOCD3) δ 8.66 (d, 1H); 8.17 (d, 1H); 7.93 (s, 1H); 7.31 (dd, 1H). LRMS (APCI) calc'd for (C6H5BrN3) [M+H]+, 198.0. found 198.0.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[CH3:34][C:35]1[C:36]([N:44]2[CH2:49][CH2:48][N:47]([CH2:50][CH2:51][S:52]([CH3:55])(=[O:54])=[O:53])[CH2:46][CH2:45]2)=[CH:37][C:38]([O:42][CH3:43])=[C:39]([CH:41]=1)[NH2:40].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C(Cl)Cl.CC(O)C>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:31]=[CH:32][CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:40][C:39]3[CH:41]=[C:35]([CH3:34])[C:36]([N:44]4[CH2:49][CH2:48][N:47]([CH2:50][CH2:51][S:52]([CH3:55])(=[O:54])=[O:53])[CH2:46][CH2:45]4)=[CH:37][C:38]=3[O:42][CH3:43])[N:7]=2)[CH:18]=1
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Reactant: COc1cc(N2CCN(CCS(C)(=O)=O)CC2)c(C)cc1N
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Product: COc1cc(N2CCN(CCS(C)(=O)=O)CC2)c(C)cc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 120 °C
Yield: 49.1 %

Procedure:
3-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1) (90 mg, 0.195 mmol), 5-methyl-2-(methyloxy)-4-{4-[2-(methylsulfonyl)ethyl]-1-piperazinyl}aniline (57 mg, 0.175 mmol), and p-toluenesulfonic acid (89 mg, 0.47 mmol) were weighed into a 20 mL vial. 10 mL of iPrOH was added and the mixture was heated to 120° C. for 48 h. The mixture was transferred to a 50 mL round bottom and neutralized with 2 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 10 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (65 mg, 0.086 mmol, 49%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.22 (s, 1H), 9.39 (s, 1H), 8.46 (s, 1H), 8.32 (s, 1H), 8.22 (d, J=5.31 Hz, 1H), 8.04 (d, J=7.69 Hz, 1H), 7.80 (d, J=7.87 Hz, 1H), 7.72 (d, J=8.97 Hz, 1H), 7.59 (t, J=7.69 Hz, 1H), 7.42-7.51 (m, 2H), 7.34-7.42 (m, 1H), 7.13-7.23 (m, 2H), 6.97 (t, J=6.68 Hz, 1H), 6.75 (s, 1H), 6.48 (d, J=5.31 Hz, 1H), 3.79 (s, 3H), 3.30-3.35 (m, 2H), 3.05 (s, 3H), 2.82-2.90 (m, 4H), 2.76 (t, J=6.68 Hz, 2H), 2.53-2.64 (m, 4H), 2.13 (s, 3H). MS (ESI): 753 [M+H]+.
Reaction SMILES: [N:1](C(OCC)=O)=NC(OCC)=O.O[CH2:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[CH2:24][CH2:25][NH:26][C:27](=[O:36])[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(=O)NC(=O)C2=CC=CC=C12>O1CCCC1>[NH2:1][CH2:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[CH2:24][CH2:25][NH:26][C:27](=[O:36])[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(NCCc1c[nH]c2ccc(CO)cc12)OCc1ccccc1
Reactant: CCOC(=O)N=NC(=O)OCC
Agent: O=C1NC(=O)c2ccccc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: NCc1ccc2[nH]cc(CCNC(=O)OCc3ccccc3)c2c1
Reaction time: 4 h

Procedure:
A solution of diethyl azodicarboxylate (1.48 g) in dry tetrahydrofuran (THF) (8 ml) was added over 2 min., keeping the temperature at 25°, to a stirred solution of phenylmethyl [2-[5-(-hydroxymethyl)-1H-indol-3-yl]ethyl]-carbamate (2.6 g), triphenylphosphine (2.35 g) and phthalimide (1.75 g) in THF (20 ml). After 4 h, the solvent was evaporated in vacuo and the residue was dissolved in a solution of hydrazine hydrate (15 ml) in ethanol (100 ml).
Reaction SMILES: [NH2:1][C:2]1[C:6]2=[N+:7]([O-])[CH:8]=[CH:9][CH:10]=[C:5]2[S:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13].S(OC)(OC)(=O)=O.[C-:23]#[N:24].[K+]>O>[NH2:1][C:2]1[C:6]2=[N:7][C:8]([C:23]#[N:24])=[CH:9][CH:10]=[C:5]2[S:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: [C-]#N
Reactant: COC(=O)c1sc2ccc[n+]([O-])c2c1N
Agent: [K+]
Solvent: O
Solvent: COS(=O)(=O)OC
Product: COC(=O)c1sc2ccc(C#N)nc2c1N
Temperature: 80 °C
Reaction time: 2 h
Yield: 46.6 %

Procedure:
3-Amino-2-carbomethoxythieno[3,2-b]pyridine-4-oxide (3.1 g, 13.8 mmol) is stirred mechanically under N2 at 25° C. as dimethyl sulfate (1.3 mL, 14 mmol) is added dropwise. After stirring at 80° C. for 2 h, the reaction is cooled to 250C and the resulting solid is washed with acetone (50 mL) is added. The solid is dissolved in 10 mL H2O and is added dropwise to a 0° C. solution of KCN (2.7 g, 41 mmol) in H2O (10 mL). After stirring at 25° C. 18 h. The reaction was extracted with CH2Cl2. The organic layer was dried (MgSO4), filtered, concentrated, and chromatographed (CH2Cl2). 1.5 g (47%) of the title compound was obtained: 1H NMR (300 MHz, CDCl3) δ3.94 (s, 3H), 6.25 (bs, 2H), 7.70 (d, 1H), 8.20 (d, 1H); MS (DCI/NH3) m/e 234 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(C1C=CC(S([O-])(=O)=O)=CC=1)(=O)C.[Na+].[CH2:28]([NH:30][CH2:31][CH3:32])[CH3:29]>>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:30]([CH2:31][CH3:32])[CH2:28][CH3:29])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CCNCC
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Agent: CC(=O)c1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Product: CCN(CC)S(=O)(=O)c1ccc(C(C)=O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The damp 4-acetylbenzenesulfonyl chloride from 100 g. of sodium 4-acetylbenzenesulfonate is added to a stirred solution of 500 ml. of 50% aqueous diethylamine. The mixture is stirred at room temperature for 4 hours, cooled, and the precipitated 4-acetyl-N,N-diethylbenzenesulfonamide removed by filtration, washed with water and dried; m.p. 78°-79° C. after crystallization from 2-propanol.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]=O)=[CH:7][C:6]=2[CH:12]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH2:21][CH2:22][NH2:23])[CH:17]=[CH:18][C:19]=1[Cl:20]>>[Cl:13][C:14]1[CH:15]=[C:16]([CH2:21][CH2:22][NH:23][CH2:10][C:8]2[O:9][C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:12][C:6]=3[CH:7]=2)[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: NCCc1ccc(Cl)c(Cl)c1
Reactant: Cc1ccc2oc(C=O)cc2c1
Product: Cc1ccc2oc(CNCCc3ccc(Cl)c(Cl)c3)cc2c1
Yield: 89.3 %

Procedure:
In analogy to example S1) 111 mg (0.69 mmol) of 5-methyl-benzofuran-2-carbaldehyde and 144 mg (0.76 mmol) of 2-(3,4-dichloro-phenyl)-ethylamine were reacted to yield 206 mg (89%) of [2-(3,4-dichloro-phenyl)-ethyl]-(5-methyl-benzofuran-2-ylmethyl)-amine as light brown oil. 1HNMR (CDCl3, 300 MHz): δ 2.42 (s, 3H), 2.77 (t, J=6.7 Hz, 2H), 2.89 (t, J=6.7 Hz, 2H), 3.91 (s, 2H), 6.46 (s, 1H), 7.04 (m, 2H), 7.32 (m, 4H).