Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].C(O)C.C(=O)([O-])[O-].[Na+].[Na+].[F:30][C:31]1[CH:45]=[C:44](B2OC(C)(C)C(C)(C)O2)[CH:43]=[CH:42][C:32]=1[CH2:33][NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38]>C1(C)C=CC=CC=1.C(Cl)Cl.O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:37]([O:36][C:35]([NH:34][CH2:33][C:32]1[CH:42]=[CH:43][C:44]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:20])=[CH:45][C:31]=1[F:30])=[O:41])([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)(C)OC(=O)NCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(CNC(=O)OC(C)(C)C)c(F)c3)ccn2c1=O
Temperature: 90 °C
Yield: 31.6 %

Procedure:
Methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (46 mg, 0.158 mmol) was dissolved in toluene (500 μL), ethanol (96%) (237 μL) and aqueous sodium carbonate 2M (237 μL, 0.473 mmol). tert-Butyl 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (97 mg, 0.21 mmol) was added. The mixture was degassed with argon and 1,1′-bis(diphenylphosphino)-ferrocene palladium(II) dichloride (11.5 mg, 0.016 mmol) was added. The mixture was heated at 90° C. for 4 h. After cooling, the mixture was diluted with CH2Cl2 (3 mL) and water (3 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (3×2 mL). The organic layer was concentrated in vacuo. The crude product was purified with flash silica column chromatography (heptane:ethyl acetate) (1:1 to 1:2) to afford the title compound as a yellow solid (24 mg, 32%). ESI-MS m/z: 481 (M+H)+.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH3:17])[N:11]=1)(C(C)(C)C)(C)C.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH3:17])[N:11]=1
Reactant: CNc1nccc(CO[Si](C)(C)C(C)(C)C)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CNc1nccc(CO)n1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 269.5 %

Procedure:
4-tert-Butyldimethylsilyloxymethyl-2-methylaminopyrimidine (40 mg, 0.16 mmol, Reference Compound No. 6-1) was dissolved in tetrahydrofuran (3.0 mL), then a solution of tetrabutylammonium fluoride trihydrate (55 mg, 0.17 mmol) in tetrahydrofuran (3.0 mL) was added thereto, and the mixture was stirred for 40 minutes at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was suspended into 25% methanol-chloroform solution, and the mixture was filtered with silica gel (2.0 g). The filtrate was concentrated under reduced pressure to give 60 mg of the mixture of the title Reference Compound and tetrabutylammonium fluoride as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][O:7][C:8]2=[O:9])=[CH:4][CH:3]=1.[C-:12]#[N:13].[K+].Cl>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:12]#[N:13])=[C:10]([C:8]([OH:7])=[O:9])[CH:11]=1
Reactant: O=C1OCc2ccc(Cl)cc21
Reactant: [C-]#N
Agent: Cl
Agent: [K+]
Solvent: O
Product: N#CCc1ccc(Cl)cc1C(=O)O
Temperature: 180 °C
Reaction time: 4 h
Yield: 73.3 %

Procedure:
A mixture of 6-chlorophthalide (2.0 g) and potassium cyanide (2.0 g) was stirred at a temperature of 180° C. for a period of 4 hours. The solid was cooled, dissolved in water and the solution was acidified with concentrated hydrochloric acid. The dark brown solid was collected, washed with water and dried. The crude solid was dissolved in ethyl acetate, the solution was treated with charcoal, filtered, and the solvent was evaporated to give 4-chloro-2-carboxyphenylacetonitrile (1.70 g) as pale yellow crystals mp 120° C.
Reaction SMILES: [P:1]([O:8][CH2:9][CH3:10])([O:5]CC)[O:2][CH2:3][CH3:4].[CH3:11][O:12][CH:13](OC)[C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[C:16]([O:23][CH3:24])[CH:15]=1.B(F)(F)F.CCOCC>C(Cl)Cl>[CH3:11][O:12][CH:13]([C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[C:16]([O:23][CH3:24])[CH:15]=1)[P:1]([O:2][CH2:3][CH3:4])(=[O:5])[O:8][CH2:9][CH3:10]
Reactant: CCOP(OCC)OCC
Reactant: COc1cc(C(OC)OC)cc([N+](=O)[O-])c1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCOP(=O)(OCC)C(OC)c1cc(OC)cc([N+](=O)[O-])c1
Yield: 86.8 %

Procedure:
Triethyl phosphite (0.98 ml, 5.7 mmol) was added dropwise to a solution of dimethyl acetal 27 (1.08 g, 4.7 mmol), boron trifluoride etherate (1.2 ml, 9.8 mmol) and CH2Cl2 (10 ml) at 0° C. After warming the reaction to room temperature overnight, the solution was partitioned with 3N HCl and the aqueous layer was washed with CH2Cl2 twice. The organic layers were washed with dilute NaHCO3, dried over Na2SO4, decanted and evaporated. The crude residue was purified on a silica gel column, eluting with 0-80% EtOAc/hexanes, to give 1.36 g (86%) phosphonate 28 as a slightly yellow oil.
Reaction SMILES: C(=O)([O-])[O-].[Ca+2].[C:6]1([S:12](Cl)(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:16][C:17]1[CH:18]=[C:19]([CH:21]=[C:22]([CH3:29])[C:23]=1[S:24][CH2:25][N+:26]([O-:28])=[O:27])[NH2:20].O>O1CCCC1>[CH3:29][C:22]1[CH:21]=[C:19]([NH:20][S:12]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)(=[O:14])=[O:13])[CH:18]=[C:17]([CH3:16])[C:23]=1[S:24][CH2:25][N+:26]([O-:28])=[O:27]
Reactant: Cc1cc(N)cc(C)c1SC[N+](=O)[O-]
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(NS(=O)(=O)c2ccccc2)cc(C)c1SC[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 72 h
Yield: 67.7 %

Procedure:
0.75 g (7.49 mmol) of calcium carbonate and then 1.0 g (5.66 mmol) of benzenesulphonyl chloride are added to a solution, maintained under a nitrogen atmosphere, of 0.80 g (3.77 mmol) of 3,5-dimethyl-4-[(nitromethyl)thio]aniline in 30 ml of anhydrous tetrahydrofuran. After stirring for 3 days at room temperature, the reaction medium is poured into water and extracted with methylene chloride. The combined organic extracts are washed with water, dried over sodium Sulphate and concentrated to dryness under reduced pressure. The residue obtained is purified by chromatography on a column of silica (eluent: methylene chloride) to give 0.9 g (68%) of N-[3,5-dimethyl-4-[(nitromethyl)thio]phenyl]benzenesulphonamide.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:8][NH2:9])=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.C[O:18][C:19](=O)[N:20]=[C:21](SC)[C:22]([C:36]1[CH:46]=[C:45]([O:47][CH3:48])[C:39]2[O:40][CH2:41][CH2:42][CH2:43][O:44][C:38]=2[CH:37]=1)=[N:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[N:34]=[C:33]([CH3:35])[O:32][N:31]=2)=[CH:26][CH:25]=1>CN(C=O)C>[F:1][C:2]1[C:3]([N:8]2[C:19](=[O:18])[NH:20][C:21]([CH:22]([C:36]3[CH:46]=[C:45]([O:47][CH3:48])[C:39]4[O:40][CH2:41][CH2:42][CH2:43][O:44][C:38]=4[CH:37]=3)[NH:23][C:24]3[CH:25]=[CH:26][C:27]([C:30]4[N:34]=[C:33]([CH3:35])[O:32][N:31]=4)=[CH:28][CH:29]=3)=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)c2c(c1)OCCCO2
Reactant: NNc1ncccc1F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccc3F)c(=O)[nH]2)cc2c1OCCCO2
Temperature: 85 °C
Reaction time: 8 h

Procedure:
After adding 28 mg of (3-fluoropyridin-2-yl)hydrazine and 50 μl of triethylamine to a solution of 119 mg of {2-(9-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester in 2 ml of DMF, the mixture was stirred overnight at 85° C. under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 3 ml of methanol and 0.3 ml of acetic acid. After adding 100 mg of sodium cyanotrihydroborate to the reaction mixture, it was stirred at room temperature for 1 hour. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give 2-(3-fluoropyridin-2-yl)-5-{(9-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-2,4-dihydro-[1,2,4]triazol-3-one.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:13][CH3:14])=[C:7]([CH:12]=1)[C:8]([O:10]C)=[O:9])=[O:2].[OH-].[K+:16]>C(O)C>[CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:13][CH3:14])=[C:7]([CH:12]=1)[C:8]([O-:10])=[O:9])=[O:2].[K+:16]
Reactant: COC(=O)c1cc(C=O)ccc1OC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C=O)cc1C(=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
13.6 g of methyl 5-formyl-2-methoxybenzoate was dissolved in 68 ml of ethanol. Thereto was added 24 ml of an aqueous solution containing 4.0 g of potassium hydroxide. The mixture was stirred for 1 hour at room temperature. The solvent was removed by distillation under reduced pressure to obtain potassium 5-formyl-2-methoxybenzoate.
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1Br.[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(NC(C)C)(C)C.CN(C)C=O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[Na+].[Na+].[Na+].P(C1C=C(S([O-])(=O)=O)C=CC=1)(C1C=C(S([O-])(=O)=O)C=CC=1)C1C=C(S([O-])(=O)=O)C=CC=1.C(OCC)(=O)C.O>[NH2:1][C:2]1[C:3]([C:20]2[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=2)=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13]
Reactant: OB(O)c1ccc(F)cc1
Reactant: COC(=O)c1cc(Br)c(N)c([N+](=O)[O-])c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=S(=O)([O-])c1cccc(P(c2cccc(S(=O)(=O)[O-])c2)c2cccc(S(=O)(=O)[O-])c2)c1
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(C)NC(C)C
Product: COC(=O)c1cc(-c2ccc(F)cc2)c(N)c([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To a solution of methyl 4-amino-3-bromo-5-nitrobenzoate (1.0 g, 3.64 mmol), (4-fluorophenyl)-boronic acid (0.76 g, 5.45 mmol), 3,3′,3″-phosphinidynetris (benzensulfonic acid) trisodium salt (0.18 g, 0.27 mmol), palladium(II) acetate (20.0 mg, 0.09 mmol) and diisopropylamine (0.52 mL, 3.64 mmol) were added N,N-dimethylformamide (13.6 mL) and water (4.5 mL). The mixture was heated to 80° C. After 1 h, the mixture was cooled to ambient temperature and ethyl acetate was added. The organic layer was dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% hexanes→50% hexanes/ethyl acetate) gave the title compound (0.93 g): LC-MS [M+1]=291.2.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH2:18][CH3:19])([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[C:6]=2[CH:20]=1.[F:21][C:22]1[CH:23]=[C:24]([C:31]#[N:32])[CH:25]=[C:26](B(O)O)[CH:27]=1>>[CH2:18]([C:7]1([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[O:8][CH2:9][C:10](=[O:12])[NH:11][C:5]2[CH:4]=[CH:3][C:2]([C:26]3[CH:25]=[C:24]([CH:23]=[C:22]([F:21])[CH:27]=3)[C:31]#[N:32])=[CH:20][C:6]1=2)[CH3:19]
Reactant: N#Cc1cc(F)cc(B(O)O)c1
Reactant: CCC1(c2cccs2)OCC(=O)Nc2ccc(Br)cc21
Product: CCC1(c2cccs2)OCC(=O)Nc2ccc(-c3cc(F)cc(C#N)c3)cc21

Procedure:
Prepared from 7-bromo-5-ethyl-5-thien-2-yl-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and 5-fluoro-3-cyanobenzeneboronic acid using the coupling procedure described in example 1. 1H-NMR (DMSO-d6) δ 10.12 (s, 1H), 8.07 (s, 1H), 7.95 (dt, J=10.3, 2.0 Hz, 1H), 7.81 (m, 2H), 7.69 (d, J=2.0 Hz, 1H), 7.57 (dd, J=5.0, 0.9 Hz, 1H), 7.29 (d, J=8.5 Hz, 1H), 7.01 (m, 1H), 6.95 (m, 1H), 4.10 (d, J=15.5 Hz, 1H), 4.01 (d, J=15.5 Hz, 1H), 2.65 (m, 2H), 0.78 (t, J=7.0 Hz, 3H); MS (ES) m/z 391 (M−H)−.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[S:18][C:17]([C:19](O)=[O:20])=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[NH2:28][CH2:29][C:30]([N:32]([CH3:34])[CH3:33])=[O:31]>>[CH3:33][N:32]([CH3:34])[C:30]([CH2:29][NH:28][C:19]([C:17]1[S:18][C:13]2[C:12]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)=[N:11][C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[C:9]4[C:4]=3[CH:3]=[N:2][NH:1]4)=[N:15][C:14]=2[CH:16]=1)=[O:20])=[O:31]
Reactant: CN(C)C(=O)CN
Reactant: O=C(O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Product: CN(C)C(=O)CNC(=O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1

Procedure:
30 mg of 2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylic acid 13 was coupled to 2-amino-N,N-dimethylacetamide via General Procedure B. The product was purified via reverse phase HPLC to give 6.5 mg of 248. MS (Q1) 465.8 (M)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][C:16](=O)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:4][CH:3]=1.C1(C)C(C)=CC=CC=1.BrC1C=CC(NC2C=CC=CC=2[N+]([O-])=O)=CC=1.C(OCC)(=O)C>O.ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:15]=[C:16]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccccc1Nc1ccc(Br)cc1)c1ccccc1
Agent: O=[N+]([O-])c1ccccc1Nc1ccc(Br)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1C
Product: Brc1ccc(-n2c(-c3ccccc3)nc3ccccc32)cc1
Yield: 50.2 %

Procedure:
Suspending 2.1 g (5.7 mmol) of N-[2-(4-bromophenylamino)phenyl]benzamide obtained in the above step (2) into 30 milliliter of xylene, and adding 0.6 g (2.9 mmol) of p-toluenesulfonic acid 1 hydrate, the resultant solution was azeotropically dehydrated while refluxing with heating for 3 hours. After naturally cooling the reacted solution, ethyl acetate, dichloromethane and water were added to the reacted solution, followed by separating an insoluble substance by filtration. Extracting an organic layer from mother liquor, the organic layer was washed with water and a saturated solution of sodium chloride and then, dried with anhydrous sodium sulfate, followed by removing the solvent by distillation under reduced pressure. Refining the residue with silicagel column chromatography, 1.0 g of 1-(4-bromophenyl)-2-phenyl-1H-benzimidazole was obtained as white crystals with a slight pink color (yield: 52%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([O-])(=O)C.[K+].[CH3:29][O:30][C:31]1[CH:36]=[CH:35][N:34]=[C:33]([CH2:37][CH2:38][C:39]2[NH:48][C:42]3=[N:43][CH:44]=[C:45](I)[CH:46]=[C:41]3[N:40]=2)[CH:32]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Li+]>O1CCOCC1.O.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:29][O:30][C:31]1[CH:36]=[CH:35][N:34]=[C:33]([CH2:37][CH2:38][C:39]2[NH:48][C:42]3=[N:43][CH:44]=[C:45]([C:2]4[CH:3]=[CH:4][C:5]([S:8]([N:11]5[CH2:12][CH2:13][N:14]([CH2:17][C:18]6[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=6)[CH2:15][CH2:16]5)(=[O:9])=[O:10])=[CH:6][CH:7]=4)[CH:46]=[C:41]3[N:40]=2)[CH:32]=1
Reactant: COc1ccnc(CCc2nc3cc(I)cnc3[nH]2)c1
Reactant: O=S(=O)(c1ccc(Br)cc1)N1CCN(Cc2ccccc2)CC1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccnc(CCc2nc3cc(-c4ccc(S(=O)(=O)N5CCN(Cc6ccccc6)CC5)cc4)cnc3[nH]2)c1
Temperature: 90 °C
Yield: 23.1 %

Procedure:
A mixture of 0.593 g of 1-(4-bromo-benzene-sulfonyl)-4-benzyl-piperazine, 0.42 g of bis-(pinacolato)-diboron, 0.025 g of 1,1′-bis-(diphenylphosphino)-ferrocene, 0.033 g of [1,1′-bis(diphenyl-phosphino)ferrocene]palladium-dichloride (complex with CH2Cl2), 0.442 g of potassium acetate in 8 ml of degassed dioxane are heated to 90° C. in a sealed tube under N2for 16 hours. To the resulting mixture 4 ml of degassed dioxane, 0.371 g of 2-[2-(4-methoxypyridin-2-yl)ethyl]-iodo-3H-imidazo[4,5b]pyridine (starting material A1), 0.113 g of tetrakis(triphenylphosphine)-palladium(0) and a solution of 0.27 g of potassium carbonate and 0.083 g of lithium chloride in 4 ml of degassed water are added under N2. The tube is sealed again, the mixture is heated to 110° under N2 for 17 hours and, after cooling, addition of water and adjusting the pH to 7, it is extracted three times with ethylacetate. The combined organic phases are dried over sodium sulfate, concentrated and the residue is chromatographed on a silica gel column (dichloromethane/methanol 22-20:1+1% NEt3). Concentration of the chromatographically pure fractions and crystallization of the residue from ethylacetate gives 0.128 g of the title compound as a brownish solid of m.p. 160-162° C. The mass spectrum shows the molecular peak MH+ at 569.4 Da.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH2:17])=[N:14][CH:13]=[N:12][C:11]=3[S:10][C:9]=2[CH3:18])=[CH:4][CH:3]=1.[C:19](OC=O)(=O)C.COCCO[AlH2-]OCCOC.[Na+].C1(C)C=CC=CC=1>ClCCl.C1COCC1>[CH3:18][C:9]1[S:10][C:11]2[N:12]=[CH:13][N:14]=[C:15]([NH2:17])[C:16]=2[C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([NH:1][CH3:19])=[CH:7][CH:6]=1
Reactant: Cc1sc2ncnc(N)c2c1-c1ccc(N)cc1
Reactant: CC(=O)OC=O
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CNc1ccc(-c2c(C)sc3ncnc(N)c23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.4 %

Procedure:
A −20° C. suspension of Example 1E (400 mg, 1.56 mmol) in dichloromethane (10 mL) and THF (10 mL) was treated with formic acetic anhydride (0.135 mL, 1.7 mmol), stirred for 1 hour, and concentrated. The concentrate was suspended in benzene (50 mL), treated with 65% Red-Al in toluene (2.4 mL, 7.8 mmol), stirred at room temperature for 20 minutes than heated to reflux for 6 hours. The reaction was cooled to room temperature and partitioned between Rochelle's salt and ethyl acetate. The aqueous phase was extracted three times with ethyl acetate and the combined extracts were washed with water and brine, dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 7% methanol/dichloromethane to provide the desired product (86 mg). MS(ESI(+)) m/e 271 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:9]=[C:10]([C:14]3[N:15]=[C:16]4[CH:21]=[CH:20][CH:19]=[N:18][N:17]4[CH:22]=3)[CH:11]=[CH:12][CH:13]=2)[N:4]=1.[CH3:23][O:24][CH2:25][CH2:26][NH2:27]>CCO>[N:15]1[C:14]([C:10]2[CH:9]=[C:8]([C:5]3[N:4]=[C:3]([CH2:2][NH:27][CH2:26][CH2:25][O:24][CH3:23])[O:7][N:6]=3)[CH:13]=[CH:12][CH:11]=2)=[CH:22][N:17]2[C:16]=1[CH:21]=[CH:20][CH:19]=[N:18]2
Reactant: COCCN
Reactant: ClCc1nc(-c2cccc(-c3cn4ncccc4n3)c2)no1
Solvent: CCO
Product: COCCNCc1nc(-c2cccc(-c3cn4ncccc4n3)c2)no1

Procedure:
A mixture of 2-(3-(5-(chloromethyl)-1,2,4-oxadiazol-3-yl)phenyl)imidazo[1,2-b]pyridazine(1.5 mmol), sodium iodide(cat.) and 2-methoxyethanamine(3 mmol) in 25 mL EtOH was stirred under reflux for 2 h. The mixture was concentrated in vacuo and the crude product was purified by column chromatography on silica gel to give the N-((3-(3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-2-methoxyethanamine.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]#[N:12])[CH:8]=2)[NH:3]1.Cl.[H][H]>CO>[NH2:12][CH2:11][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:3][C:2](=[O:1])[CH2:10]2
Reactant: N#Cc1ccc2c(c1)CC(=O)N2
Reactant: [H][H]
Agent: Cl
Solvent: CO
Product: NCc1ccc2c(c1)CC(=O)N2

Procedure:
A solution of the compound obtained in Step B (35 mmoles) in MeOH (500 ml) is added to 6 ml of concentrated HCl. The reaction mixture is stirred for 3 days under 10 bars of hydrogen. After filtration over Celite, the filtrate is evaporated to dryness to yield the title product in the form of a white powder, which is used directly in the next reaction.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[C:4]([NH:6][C:7]1[NH:11][N:10]=[N:9][N:8]=1)=[O:5].[CH2:17](OC(OCC)OCC)C>>[Cl:16][C:13]1[CH:12]=[C:3]2[C:2](=[CH:15][CH:14]=1)[N:1]=[CH:17][N:6]([C:7]1[NH:11][N:10]=[N:9][N:8]=1)[C:4]2=[O:5]
Reactant: Nc1ccc(Cl)cc1C(=O)Nc1nnn[nH]1
Reactant: CCOC(OCC)OCC
Product: O=c1c2cc(Cl)ccc2ncn1-c1nnn[nH]1

Procedure:
A suspension of 2.73 g of 2-amino-5-chloro-N-(1H-tetrazol-5-yl)benzamide in 9 ml of triethoxymethane was refluxed for 4.5 hours to give 6-chloro-3-(1H-tetrazol-5-yl)-4(3H)-quinazolinone melting at about 241° C. (dec).
Reaction SMILES: [C:1]([NH:9][CH:10]1[CH2:15][CH2:14][N:13]([NH:16][C:17]([C:19]2[CH:39]=[CH:38][C:22]3[N:23]([CH3:37])[C:24]([CH2:26][CH2:27][C:28]4[CH:33]=[CH:32][C:31]([C:34](=[NH:36])[NH2:35])=[CH:30][CH:29]=4)=[N:25][C:21]=3[CH:20]=2)=[O:18])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:47](Cl)(=[O:54])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.O>CN(C)C=O>[C:1]([NH:9][CH:10]1[CH2:11][CH2:12][N:13]([NH:16][C:17]([C:19]2[CH:39]=[CH:38][C:22]3[N:23]([CH3:37])[C:24]([CH2:26][CH2:27][C:28]4[CH:29]=[CH:30][C:31]([C:34](=[NH:35])[NH:36][C:47](=[O:54])[C:48]5[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=5)=[CH:32][CH:33]=4)=[N:25][C:21]=3[CH:20]=2)=[O:18])[CH2:14][CH2:15]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1c(CCc2ccc(C(=N)N)cc2)nc2cc(C(=O)NN3CCC(NC(=O)c4ccccc4)CC3)ccc21
Reactant: O=C(Cl)c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1c(CCc2ccc(C(=N)NC(=O)c3ccccc3)cc2)nc2cc(C(=O)NN3CCC(NC(=O)c4ccccc4)CC3)ccc21
Temperature: 0 °C

Procedure:
1.0 g (2 mmol) of 2-[2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylic acid-(4-benzamido-piperidinyl)-amide and 3.2 ml Triethylamine (23 mmol) are dissolved in 10 ml of dimethyl formamide. The mixture is cooled down to 0° C. and 0.418 ml of benzoyl chloride (3.6 mmol) are slowly added dropwise. After 2 hours 20 ml of water are added to the mixture, and the aqueous phase is extracted with 20 ml of acetic ester. The organic phase is again washed with waterand dried over sodium sulphate. The solvent is distilled off under vacuum. The residue is chromatographed over silica gel with acetic ester, and the oily product is triturated with petroleum ether. The precipate is filtered and washed with petroleum ether. Yield: 0.160 g (15%); MPt: 150-154° C.;
Reaction SMILES: CC(C)(C)C[O:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[C:20]([NH:21][C:22](=[O:32])[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=3)=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:33])=[CH:10][CH:9]=1)(=[O:7])=[O:6]>[Cl-].C([N+](CC)(CC)CC)C.CN(C=O)C>[Cl:33][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([NH:21][C:22](=[O:32])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=2)[C:15]=1[O:14][C:11]1[CH:10]=[CH:9][C:8]([S:5]([OH:7])(=[O:6])=[O:4])=[CH:13][CH:12]=1
Reactant: CC(C)(C)COS(=O)(=O)c1ccc(Oc2c(Cl)cccc2NC(=O)c2cccc([N+](=O)[O-])c2)cc1
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(Cl)c1Oc1ccc(S(=O)(=O)O)cc1)c1cccc([N+](=O)[O-])c1
Yield: 49 %

Procedure:
A mixture of 4-[2-chloro-6-(3-nitrobenzoylamino)phenoxy]benzenesulfonic acid 2,2-dimethyl-propyl ester (52 mg, 0.10 mmol) and tetraethyl ammonium chloride (54 mg, 0.5 mmol) in DMF (5 ml) was stirred at reflux temperature for 24 hours. The reaction mixture was evaporated and purified on preparative HPLC (Gilson semi-prep.column prep-NOVA-PaK®HRC18, 6 microM, 60 Å; Flow 15 ml/min Gradient: 5-100% MeCN in water (20 min)) to give 4-[2-chloro-6-(3-nitrobenzoylamino)phenoxy]benzenesulfonic acid (yield 22 mg (25%)). LC/MS: m/e 449 (M+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-])=O)=[C:6]([NH:8][C:9]2[CH:13]=[CH:12][N:11]([CH3:14])[N:10]=2)[CH:7]=1>CCOC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:13]=[CH:12][N:11]([CH3:14])[N:10]=2)[C:5]([NH2:15])=[CH:4][CH:3]=1
Reactant: Cn1ccc(Nc2cc(F)ccc2[N+](=O)[O-])n1
Solvent: CCOC(C)=O
Product: Cn1ccc(Nc2cc(F)ccc2N)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 104.1 %

Procedure:
A mixture of (5-fluoro-2-nitro-phenyl)-(1-methyl-1H-pyrazol-3-yl)amine (386 mg, 1.63 mmol) in EtOAc (10 mL) was degassed with a stream of nitrogen prior to the addition of 10% Pd/C (50 mg) and was stirred at RT under a hydrogen atmosphere for 24 h. The mixture was filtered and the filtrate was concentrated in vacuo to afford the title compound as a grey oil (350 mg, quant.). LCMS (Method C): RT 1.63 min [M+H]+ 207.17