Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:11]3[CH:19]=[N:20][CH:21]=[CH:22][C:10]=3[NH:9][C:8]2=[O:23])[CH2:3][CH2:2]1.Cl.C(O)C.[S:28]1[CH:32]=[CH:31][C:30]([CH:33]=O)=[CH:29]1.C([BH3-])#N.[Na+]>CO>[S:28]1[CH:32]=[CH:31][C:30]([CH2:33][N:1]2[CH2:2][CH2:3][CH:4]([N:7]3[CH:12]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[C:11]4[CH:19]=[N:20][CH:21]=[CH:22][C:10]=4[NH:9][C:8]3=[O:23])[CH2:5][CH2:6]2)=[CH:29]1
Reactant: O=Cc1ccsc1
Reactant: O=C1Nc2ccncc2C(c2ccccc2)N1C1CCNCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: O=C1Nc2ccncc2C(c2ccccc2)N1C1CCN(Cc2ccsc2)CC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 84 %

Procedure:
To a solution of 500 mg (1.62 mmol) of 3-(piperidin-4-yl)-4-phenyl-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidine in 30 mL of methanol were added 1,200 mg of 10% HCl/ethanol solution, 727 mg (6.48 mmol) of 3-thiophenecarboxaldehyde and 407 mg (6.48 mmol) of sodium cyanoborohydride under ice-cooling, and the mixture was stirred for 10 hours at ambient temperature. Then, the reaction mixture was concentrated in vacuo, and water was added to the residue. The mixture was adjusted to pH 10 and extracted with chloroform. The organic layer separated was dried on potassium carbonate, and then concentrated in vacuo. The residue was purified by means of column chromatography (silica gel, 1:9 methanol:chloroform) to give 550 mg (1.36 mmol) of the title compound.
Reaction SMILES: [CH2:1]([C:8]1[C:9](=[O:18])[NH:10][N:11]([CH:16]=[O:17])[C:12]=1[CH:13]([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:25]([O:31][C@@H:32]1[C@@H:37]([O:38][C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41])[C@H:36]([O:45][C:46](=[O:51])[C:47]([CH3:50])([CH3:49])[CH3:48])[C@@H:35]([CH2:52][O:53][C:54](=[O:59])[C:55]([CH3:58])([CH3:57])[CH3:56])[O:34][C@H:33]1Br)(=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27]>C(#N)C>[CH2:1]([C:8]1[C:9]([O:18][C@@H:33]2[O:34][C@H:35]([CH2:52][O:53][C:54](=[O:59])[C:55]([CH3:58])([CH3:57])[CH3:56])[C@@H:36]([O:45][C:46](=[O:51])[C:47]([CH3:48])([CH3:49])[CH3:50])[C@H:37]([O:38][C:39](=[O:44])[C:40]([CH3:41])([CH3:42])[CH3:43])[C@H:32]2[O:31][C:25](=[O:30])[C:26]([CH3:29])([CH3:27])[CH3:28])=[N:10][N:11]([CH:16]=[O:17])[C:12]=1[CH:13]([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1c(Cc2ccccc2)c(=O)[nH]n1C=O
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Br)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)c1c(Cc2ccccc2)c(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)nn1C=O
Temperature: 25 °C
Yield: 45.8 %

Procedure:
To solution of 4-benzyl-1,2-dihydro-1-formyl-5-isopropyl-3H-pyrazol-3-one (1.07 g) in acetonitrile (20 mL) were added potassium carbonate (0.905 g) and 2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyl bromide (2.65 g) under stirring at room temperature. In addition, the mixture was heated to 50° C. and stirred for 1 hour. After the reaction completed, the insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=10/1) to give 4-benzyl-1-formyl-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyl-oxy)-1H-pyrazole (1.49 g).
Reaction SMILES: [C@H:1]12[CH2:22][C@H:4]([N:5]([C:7]([C:9]3[N:13]4[CH:14]=[C:15]([C:19](=[O:21])[CH3:20])[CH:16]=[C:17](Br)[C:12]4=[N:11][CH:10]=3)=[O:8])[CH2:6]1)[CH2:3][O:2]2.CC1(C)C(C)(C)OB([C:31]2[O:35][C:34]([Si](C(C)C)(C(C)C)C(C)C)=[N:33][CH:32]=2)O1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C@H:1]12[CH2:22][C@H:4]([N:5]([C:7]([C:9]3[N:13]4[CH:14]=[C:15]([C:19](=[O:21])[CH3:20])[CH:16]=[C:17]([C:31]5[O:35][CH:34]=[N:33][CH:32]=5)[C:12]4=[N:11][CH:10]=3)=[O:8])[CH2:6]1)[CH2:3][O:2]2
Reactant: CC(=O)c1cc(Br)c2ncc(C(=O)N3C[C@@H]4C[C@H]3CO4)n2c1
Reactant: CC(C)[Si](c1ncc(B2OC(C)(C)C(C)(C)O2)o1)(C(C)C)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CC(=O)c1cc(-c2cnco2)c2ncc(C(=O)N3C[C@@H]4C[C@H]3CO4)n2c1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
A mixture of the obtained 1-(3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carbonyl)-8-bromoimidazo[1,2-a]pyridin-6-yl)ethanone obtained in Step E of Example 155, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(triisopropylsilyl)oxazole (80 mg), tetrakis(triphenylphosphine)palladium(0) (25 mg) and potassium carbonate (61 mg) in DME/water (2/0.5 mL) was stirred with microwave irradiation at 120° C. for 30 min. The reaction mixture was diluted with water, and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in THF (3 mL), and 1N hydrochloric acid (1 mL) was added thereto. The reaction mixture was stirred at room temperature for 2 hr, saturated aqueous sodium bicarbonate solution was added thereto, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the obtained solid was recrystallized from ethyl acetate/hexane to give the title compound (13 mg).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([F:9])=[N:7][CH:8]=1.[NH:10]1[CH2:15][CH2:14][S:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:9][C:6]1[N:7]=[CH:8][C:3]([CH2:2][N:10]2[CH2:15][CH2:14][S:13][CH2:12][CH2:11]2)=[CH:4][CH:5]=1
Reactant: C1CSCCN1
Reactant: Fc1ccc(CBr)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1ccc(CN2CCSCC2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.6 %

Procedure:
A solution of 5-(bromomethyl)-2-fluoropyridine (3.61 g, 19.00 mmol) in anhydrous DMF (22 mL) at 0° C. was treated with thiomorpholine (2.254 g, 21.85 mmol) (TCI America) in 3 mL of DMF and potassium carbonate (3.28 g, 23.75 mmol). The suspension was slowly warmed to RT and stirred at RT for 2 h. The reaction was quenched with 30 mL of ice water, stirred at RT for 30 min, and the solid was collected by filtration, and rinsed with water followed by ether to give 4-((6-fluoropyridin-3-yl)methyl)thiomorpholine (3.33 g, 15.69 mmol, 83% yield) as an off-white crystalline solid. 1H NMR (400 MHz, d6-DMSO) δ 8.12 (s, 1H); 7.89 (td, J=8.20, 2.2 Hz, 1H); 7.14 (dd, J=8.10, 2.80 Hz, 1H); 3.53 (s, 2H); 2.63-2.59 (br. 8H). m/z (ESI, +ve ion) 213 (M+H)+.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)[CH2:2][CH3:3].ClC1C=CC(C2C=CC([C@H]3CC[C@H](CC[C@H]4CC[C@H](CCCCCC)CC4)CC3)=CC=2)=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].C(Cl)(=O)[C:62]([Cl:64])=[O:63]>C(Cl)Cl.O>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C@H:10]2[CH2:11][CH2:12][C@H:13]([CH2:16][CH2:17][C:18]3[CH:19]=[CH:20][C:21]([C:62]([Cl:64])=[O:63])=[CH:22][CH:23]=3)[CH2:14][CH2:15]2)=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccc([C@H]2CC[C@H](CCc3ccccc3)CC2)cc1
Reactant: O=C(Cl)C(=O)Cl
Agent: CCCCCC[C@H]1CC[C@H](CC[C@H]2CC[C@H](c3ccc(-c4ccc(Cl)cc4)cc3)CC2)CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CCCc1ccc([C@H]2CC[C@H](CCc3ccc(C(=O)Cl)cc3)CC2)cc1
Temperature: 0 °C

Procedure:
After 27.6 g of the (2-(trans-4-(4-n-propylphenyl)cyclohexyl)ethyl)benzene obtained in (7) of Example 2 was dissolved in 200 ml of methylene chloride, it was cooled down to 0° C., and 24 g of aluminum chloride was added to the solution and stirred. Oxalyl chloride in an amount of 22.8 g was added dropwise little by little to the solution, and after the temperature of the solution was raised up to room temperature, it was stirred for 2 hours. After finishing of the reaction, it was added to 500 ml of water and extracted with 200 ml of methylene chloride. Organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under a reduced pressure to obtain 20 g of 4-(2-(trans-4-(4-n-propylphenyl)cyclohexyl)ethyl)benzoyl chloride.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:22][C:15]3[N:16]=[CH:17][C:18]([F:21])=[C:19](O)[C:14]=3[C:13]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:8][CH:7]=1.C(Cl)(=O)C([Cl:33])=O>C(Cl)(Cl)Cl>[Cl:33][C:19]1[C:18]([F:21])=[CH:17][N:16]=[C:15]2[O:22][C:12]([C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][N:2]([CH3:29])[CH3:1])=[CH:7][CH:8]=3)=[C:13]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:14]=12
Reactant: O=C(Cl)C(=O)Cl
Reactant: CN(C)CCOc1ccc(-c2oc3ncc(F)c(O)c3c2-c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: CN(C)CCOc1ccc(-c2oc3ncc(F)c(Cl)c3c2-c2ccccc2)cc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
The mixture of 2-[4-(2-dimethylaminoethoxy)-phenyl]-5-fluoro-3-phenyl-furo[2,3-b]pyridin-4-ol (6) (121.0 mg, 0.31 mmol) and oxalyl chloride (196.0 mg, 1.54 mmol) in chloroform (3.0 mL) was stirred at 60° C. for 1 hr. The solvent was removed, and the residue was purified by preparative HPLC to give the title compound. MS (m/z), M+H+ 411.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:7]([C:8]([OH:10])=[O:9])[C:6]([CH:12]=O)=[CH:5][CH:4]=1.[S:14]1[CH2:20][C:18](=[O:19])[NH:17][C:15]1=[S:16].C(O)(=O)C.C([O-])(=O)C.[Na+]>O>[C:8]([C:7]1[CH:11]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[CH:12]=[C:20]1[S:14][C:15](=[S:16])[NH:17][C:18]1=[O:19])([OH:10])=[O:9]
Reactant: COc1ccc(C=O)c(C(=O)O)c1
Reactant: O=C1CSC(=S)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(C=C2SC(=S)NC2=O)c(C(=O)O)c1

Procedure:
To a hot stirred solution of 0.90 g. (5.0 mM) of 5-methoxyphthalaldehydic acid and 0.67 g. (5.0 mM) of rhodanine in 4 ml. of acetic acid is added 1.35 g. (16.4 mM) of anhydrous sodium acetate. After refluxing 0.5 hour, the solid yellow mass is cooled, poured into water, and filtered to separate 5-(2-carboxy-4-methoxybenzylidene)rhodanine as a yellow solid.
Reaction SMILES: C[Si](Cl)(C)C.BrCCBr.[CH:10]1(I)[CH2:14][CH2:13][CH2:12][CH2:11]1.[Cl:16][C:17]1[C:22](Cl)=[N:21][CH:20]=[CH:19][N:18]=1>CN(C)C(=O)C.[Zn].[Cu]I>[Cl:16][C:17]1[C:22]([CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:21][CH:20]=[CH:19][N:18]=1
Reactant: Clc1nccnc1Cl
Reactant: IC1CCCC1
Agent: [Cu]I
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: CC(=O)N(C)C
Solvent: BrCCBr
Product: Clc1nccnc1C1CCCC1
Temperature: 80 °C
Reaction time: 0.08 h

Procedure:
To a suspension of zinc dust (2.00 g, 30.6 mmol) in N,N-dimethylacetamide (20 mL) was added a mixture of trimethylsilyl chloride and 1,2-dibromoethane (7:5, v/v, 0.95 mL total volume) dropwise over 5 minutes. The mixture was stirred for 15 min before cyclopentyl iodide (5.00 g, 25.5 mmol) was added dropwise over 15 min. This mixture was stirred for an additional 15 min and then was added via syringe over 5 min to a mixture of copper(I) iodide (0.30 g, 1.60 mmol), dichloro(1,1-bis(diphenylphosphinoferrocene))palladium(II) (0.65 g, 0.80 mmol), and 2,3-dichloropyrazine (1.66 mL, 16.0 mmol) in N,N-dimethylacetamide (30 mL) under argon atmosphere. The mixture was heated to 80° C. for 7 h, cooled to room temperature and partitioned between ethyl acetate and saturated aqueous ammonium chloride. The resulting layers were separated and the aqueous layer was extracted with ethyl acetate (1×). The combined extracts were washed with water (2×), saturated aqueous sodium chloride (1×), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography to give 2-chloro-3-cyclopentylpyrazine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH2:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(NC(C)C)(C)C>C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:13]1(/[CH:12]=[CH:11]/[C:2]2[CH:3]=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C=Cc1ccccc1
Reactant: O=[N+]([O-])c1cccc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC(C)NC(C)C
Solvent: CCOCC
Product: O=[N+]([O-])c1cccc(/C=C/c2ccccc2)c1

Procedure:
A mixture of 3-bromonitrobenzene (1 g), styrene (1.7 mL), palladium(II) acetate (95 mg), tris(2-methylphenyl)phosphine (0.3 g) and N,N-diisopropylamine (5 mL) was heated for reflux for 24 hours. The reaction mixture was diluted with diethyl ether, and the resulting mixture was washed with 1 mol/L hydrochloric acid, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate =10/1) to give 3-((E)-2-phenylvinyl)nitrobenzene (0.76 g). To the solution of the obtained 3-((E)-2-phenylvinyl)nitrobenzene (0.26 g) in methanol (10 mL) was added 10% palladium-carbon powder (50 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (0.22 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:29][C:30]2[CH:38]=[CH:37][C:33]3[O:34][CH2:35][O:36][C:32]=3[CH:31]=2)[S:7](=[O:28])(=[O:27])[C:8]2[CH:22]=[C:21](OC)[C:20](OC)=[CH:19][C:9]=2[C:10]=1OS(C(F)(F)F)(=O)=O)=[O:4].[O:39]1[C:43]2[CH:44]=[CH:45][C:46]([S-:48])=[CH:47][C:42]=2[O:41][CH2:40]1.[Na+].O1C2C=CC(S)=CC=2OC1.[H-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:29][C:30]2[CH:38]=[CH:37][C:33]3[O:34][CH2:35][O:36][C:32]=3[CH:31]=2)[S:7](=[O:28])(=[O:27])[C:8]2[CH:22]=[CH:21][CH:20]=[CH:19][C:9]=2[C:10]=1[S:48][C:46]1[CH:45]=[CH:44][C:43]2[O:39][CH2:40][O:41][C:42]=2[CH:47]=1)=[O:4]
Reactant: [S-]c1ccc2c(c1)OCO2
Reactant: COC(=O)C1=C(OS(=O)(=O)C(F)(F)F)c2cc(OC)c(OC)cc2S(=O)(=O)N1Cc1ccc2c(c1)OCO2
Agent: Sc1ccc2c(c1)OCO2
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C1=C(Sc2ccc3c(c2)OCO3)c2ccccc2S(=O)(=O)N1Cc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 79 %

Procedure:
To 2-Benzo[1,3]dioxol-5-ylmethyl-4-hydroxy-1,1-dioxo-1,2-dihydro-1λ6 -benzo[e][1,2]thiazine-3-carboxylic acid methyl ester in dichloromethane (6 mL) and pyridine (0.65 mL, 7.75 mmol) was added trifluoromethanesulfonic anhydride (0.32 mL, 1.71 mmol). This mixture was stirred at room temperature for 30 minutes. Diluted with ethyl acetate (100 mL), washed with 1N HCl (2×50 mL), brine (50 mL), dried with magnesium sulfate and then evaporated in vacuo to afford the crude 2-benzo[1,3]dioxol-5-ylmethyl-6,7-dimethoxy-1,1-dioxo-4-(trifluoro-methanesulfonyloxy)-1,2-dihydro-1λ6 -benzo[e][1,2]thiazine-3-carboxylic acid methyl ester. A solution of this ester, in DMF (3 mL), was added to sodium 1,3-benzodioxole-5-thiolate (0.31 g, 2.0 mmol) {prepared by dissolving 1,3-benzodioxole-5-thiol (0.31 g, 2.0 mmol) in DMF (3 mL) and stirring with sodium hydride (0.081 g, 2.0 mmol) for 5 minutes} in DMF (3 mL). After stirring at room temperature for 16 hours the mixture was diluted with ethyl acetate (100 mL), washed with 1N NaOH(2×50 mL), brine (50 mL), dried with magnesium sulfate, and evaporated in vacuo. Silica gel column chromatography eluting with 25% ethyl acetate in hexane afforded the title compound as a foam (0.64 g, 79%);
Reaction SMILES: [CH2:1]([CH2:10][CH2:11][NH:12][C:13]1[C:21]2[C:16](=[CH:17][C:18]([Cl:23])=[CH:19][C:20]=2[Cl:22])[N:15](C(OC(C)(C)C)=O)[C:14]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH2:1]([CH2:10][CH2:11][NH:12][C:13]1[C:21]2[C:16](=[CH:17][C:18]([Cl:23])=[CH:19][C:20]=2[Cl:22])[NH:15][C:14]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: CCOC(=O)c1c(NCCCC(=O)c2ccccc2)c2c(Cl)cc(Cl)cc2n1C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1NCCCC(=O)c1ccccc1
Reaction time: 4 h
Yield: 34.9 %

Procedure:
Dissolve 3-[(phenacyl)ethylamino]-2-carbethoxy-4,6-dichloro-1-tert-butyloxycarbonyl-indole (0.79 g, 1.57 mmol) in methylene chloride (5 mL) and add, by dropwise addition, trifluoroacetic acid (5 mL). Stir for 4 hours and pour carefully into saturated sodium hydrogen carbonate (100 mL). Extract into ethyl acetate, dry (MgSO4) and evaporate the solvent in vacuo to giveas yellow oil. Recrystallize (ethyl acetate/hexane) to give the title compound (0.23 g, 36%); mp 203°-5° C.
Reaction SMILES: [N:1]1([CH2:7][C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]3[C:21](=[O:24])[NH:22][N:23]=[C:13]3[C:12]3[CH:25]=[CH:26][CH:27]=[N:28][C:11]2=3)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[CH2:32][CH2:33][N:34]([CH3:36])[CH3:35]>CN(C)C=O.C1(C)C(C)=CC=CC=1>[CH3:35][N:34]([CH3:36])[CH2:33][CH2:32][N:22]1[C:21](=[O:24])[N:14]2[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:10]([C:8](=[O:9])[CH2:7][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[C:11]3[N:28]=[CH:27][CH:26]=[CH:25][C:12]=3[C:13]2=[N:23]1
Reactant: CN(C)CCCl
Reactant: O=C(CN1CCCCC1)N1c2ccccc2-n2c(n[nH]c2=O)-c2cccnc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1C
Product: CN(C)CCn1nc2n(c1=O)-c1ccccc1N(C(=O)CN1CCCCC1)c1ncccc1-2
Reaction time: 22 h

Procedure:
In the manner given in Example 25, to 2,9-dihydro-9-(piperidinoacetyl)-3 H-pyrido[3,2-c]-s-triazolo-[4,3-a][1,5]benzodiazepin-3-one in dimethylformamide is added a solution of sodium hydride in mineral oil. The mixture is allowed to react at about 95° C. for 40 minutes and after cooling (2-chloroethyl)dimethylamine in xylene is added. The mixture is kept at 95°-100° C. for a period of 22 hours, evaporated and worked up as in example 25 to give 2,9-dihydro-2-[2-(dimethylamino)ethyl]-9-(piperidinoacetyl)-3H-pyrido[3,2-c]-s-triazolo[4,3-a]-[1,5]benzodiazepin-3-one.
Reaction SMILES: Cl[CH2:2]/[CH:3]=[CH:4]\[CH2:5]Cl.[C:7]([NH:10][C:11]#[N:12])(=[O:9])[CH3:8].[Na]>CC(N(C)C)=O>[C:7]([N:10]([CH2:2]/[CH:3]=[CH:4]\[CH2:5][N:10]([C:11]#[N:12])[C:7](=[O:9])[CH3:8])[C:11]#[N:12])(=[O:9])[CH3:8]
Reactant: ClC/C=C\CCl
Reactant: CC(=O)NC#N
Agent: [Na]
Solvent: CC(=O)N(C)C
Product: CC(=O)N(C#N)C/C=C\CN(C#N)C(C)=O

Procedure:
25.0 g (0.2 mol) of cis-1,4-dichlorobut-2-ene and 46.7 g (0.4 mol+10% excess) of sodium acetylcyanamide are reacted in 80 ml of dimethylacetamide at 70°-88° C. for 4 hours. The reaction mixture is then filtered with suction, the filtrate is introduced into 400 g of ice and the resulting suspension is filtered. The residue is dried over phosphorus pentoxide at room temperature under 0.13 mbar to give 29.4 g (66.7% of theory) of the desired compound, which has a melting point of 73.8°-75.2° C.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:20][C@H:21]([CH3:25])[C:22]([NH2:24])=[O:23])=[N:7][C:8]=1[NH:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[CH:15][CH:14]=[CH:13]2)#[N:2].[OH-].[Na+].OO.CC(O)=[O:32]>CCO.CS(C)=O>[NH2:24][C:22](=[O:23])[C@H:21]([NH:20][C:6]1[N:7]=[C:8]([NH:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)[C:3]([C:1]([NH2:2])=[O:32])=[N:4][CH:5]=1)[CH3:25]
Reactant: CC(=O)O
Reactant: C[C@@H](Nc1cnc(C#N)c(Nc2ccc3ncccc3c2)n1)C(N)=O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: C[C@@H](Nc1cnc(C(N)=O)c(Nc2ccc3ncccc3c2)n1)C(N)=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of (R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)propanamide (97 mg, 0.430 mmol), 6-aminoquinoline (62 mg, 0.430 mmol), K2CO3 (100 mg, 0.724 mmol), BINAP (30 mg, 0.048 mmol) and Pd(OAc)2 (15 mg, 0.066 mmol) in dioxane (2 mL) was degassed with Ar, then was stirred at 110 C for 20 h. The mixture was concentrated in vacuo. The residue was purified by HPLC to give (R)-2-(5-cyano-6-(quinolin-6-ylamino)pyrazin-2-ylamino)propanamide (15 mg). The compound (R)-2-(5-cyano-6-(quinolin-6-ylamino)pyrazin-2-ylamino)propanamide (15 mg, 0.045 mmol) was dissolved in EtOH (1 mL) and DMSO (0.5 mL), aq. 1N NaOH (0.5 mL) and aq. H2O2 (50%, 0.5 mL) were added. The mixture was stirred at room temperature for 90 min. HOAc (0.5 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (14 mg). MS 352.58 (M+H); UV 202.9, 265.2, 297.2, 357.9 nm; t 0.335 min.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:23]=[CH:22][C:15]4[N:16]=[C:17](S(C)=O)[S:18][C:14]=4[CH:13]=3)[CH:9]=[N:10][C:5]2=[CH:4][CH:3]=1.[CH2:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@@H:26]([NH2:33])[C@@H:25]1[OH:34].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[Br:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:23]=[CH:22][C:15]4[N:16]=[C:17]([NH:33][C@@H:26]5[C:27]6[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=6)[CH2:24][C@H:25]5[OH:34])[S:18][C:14]=4[CH:13]=3)[CH:9]=[N:10][C:5]2=[CH:4][CH:3]=1
Reactant: CS(=O)c1nc2ccc(Cn3cnc4ccc(Br)nc43)cc2s1
Reactant: N[C@@H]1c2ccccc2C[C@H]1O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: O[C@@H]1Cc2ccccc2[C@H]1Nc1nc2ccc(Cn3cnc4ccc(Br)nc43)cc2s1
Temperature: 140 °C
Yield: 14.7 %

Procedure:
A stirred mixture of 6-((5-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (130 mg, 0.332 mmol) from Step 4 of Example 78, (1R,2R)-(−)-trans-1-amino-2-indanol (198 mg, 1.33 mmol), and DIEA (214 mg, 1.66 mmol) in anhydrous DMA (2 mL) in a sealed reaction vessel was heated in a Biotage microwave synthesizer at 140° C. for 1.5 h. LCMS indicated that the reaction was incomplete. Additional (1R,2R)-(−)-trans-1-amino-2-indanol (50 mg, 0.335 mmol) was added, and the mixture was heated in a Biotage microwave synthesizer at 140° C. for a further 45 min. The reaction mixture was cooled to rt and purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs diphenyl column as the stationary phase to afford (1R,2R)-1-((6-((5-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)-2,3-dihydro-1H-inden-2-ol (24 mg, 15%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.47 (d, J=7.9 Hz, 1H), 8.08 (d, J=8.3 Hz, 1H), 7.69 (s, 1H), 7.49 (d, J=8.3 Hz, 1H), 7.37 (d, J=8.3 Hz, 1H), 7.11-7.28 (m, 5H), 5.45-5.54 (m, 3H), 5.18 (t, J=7.1 Hz, 1H), 4.24-4.35 (m, 1H), 3.16 (dd, J=6.9, 15.5 Hz, 1H), 2.74 (dd, J=7.1, 15.5 Hz, 1H). LCMS (ESI) m/z 492 and 494 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[C:8]2[NH:9][C:10]([CH2:12][N:13]([CH3:27])[S:14]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([O:24][CH3:25])=[CH:19][C:18]=3[CH3:26])(=[O:16])=[O:15])=[N:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].Cl.Cl.[N:36]1[CH:41]=[CH:40][C:39]([N:42]2[CH2:52][CH2:51][C:45]3([CH2:50][CH2:49][NH:48][CH2:47][CH2:46]3)[CH2:44][CH2:43]2)=[CH:38][CH:37]=1>CC(C)=O>[CH3:25][O:24][C:20]1[CH:21]=[C:22]([CH3:23])[C:17]([S:14]([N:13]([CH3:27])[CH2:12][C:10]2[NH:9][C:8]3[C:3]([CH2:2][N:48]4[CH2:47][CH2:46][C:45]5([CH2:51][CH2:52][N:42]([C:39]6[CH:40]=[CH:41][N:36]=[CH:37][CH:38]=6)[CH2:43][CH2:44]5)[CH2:50][CH2:49]4)=[CH:4][CH:5]=[CH:6][C:7]=3[N:11]=2)(=[O:16])=[O:15])=[C:18]([CH3:26])[CH:19]=1
Reactant: c1cc(N2CCC3(CCNCC3)CC2)ccn1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2nc3cccc(CCl)c3[nH]2)c(C)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2nc3cccc(CN4CCC5(CC4)CCN(c4ccncc4)CC5)c3[nH]2)c(C)c1
Yield: 25 %

Procedure:
A mixture of N-((7-(chloromethyl)-1H-benzo[d]imidazol-2-yl)methyl)-4-methoxy-N,2,6-trimethylbenzenesulfonamide (0.74 mmol, 1.0 eq.), K2CO3 (2.5 eq.) and 9-pyridin-4-Yl-3,9-diazaspiro[5.5]undecane dihydrochloride (AMN-01) (0.88 mmol, 1.2 eq.) in abs. acetone (20 ml) was heated under reflux for 16 h. The reaction mixture was filtered off and the filtrate was concentrated in order to obtain the crude product, which was purified by column chromatography over neutral aluminium oxide. Yield: 25%