Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][N:14]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:16][C:11]=3[N:10]([CH2:20][CH:21]3[CH2:23][O:22]3)[N:9]=2)=[CH:4][C:3]=1[CH3:24].[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:36]=[C:35]([CH:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)[O:34][N:33]=2)=[CH:28][CH:27]=1.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3].CO.C(Cl)Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][N:14]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:16][C:11]=3[N:10]([CH2:20][CH:21]([OH:22])[CH2:23][N:40]3[CH2:39][CH2:38][CH:37]([C:35]4[O:34][N:33]=[C:32]([C:29]5[CH:30]=[CH:31][C:26]([Cl:25])=[CH:27][CH:28]=5)[N:36]=4)[CH2:42][CH2:41]3)[N:9]=2)=[CH:4][C:3]=1[CH3:24]
Reactant: Clc1ccc(-c2noc(C3CCNCC3)n2)cc1
Reactant: CC(=O)N1CCc2c(c(-c3ccc(Cl)c(C)c3)nn2CC2CO2)C1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CO
Solvent: ClCCl
Product: CC(=O)N1CCc2c(c(-c3ccc(Cl)c(C)c3)nn2CC(O)CN2CCC(c3nc(-c4ccc(Cl)cc4)no3)CC2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.9 %

Procedure:
1-[3-(4-Chloro-3-methyl-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone (0.069 g. 0.20 mmol) was dissolved in CH2Cl2 (1 mL), and 4-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]piperidine (0.105 g, 0.4 mmol) was added, followed by Yb(OTf)3 (0.031 g, 0.22 mmol). The mixture was stirred at room temperature for 16 h. Preparative TLC (silica, 7.5% MeOH/CH2Cl2) afforded 84 mg (69%) of the title compound. MS (electrospray): exact mass calculated for C31H34Cl2N6O3, 608.21; m/z found, 609.2 [M++H]. 1H NMR (400 MHz, CDCl3, 1:1 mixture of rotamers): 8.00 (d, J=8.4 Hz, 2H), 7.56-7.53 (m, 1H), 7.48-7.42 (d, J=8.6 Hz, 2H), 7.41-7.30 (m, 2H), 4.84 and 4.73 (A and B of AB quartet J=15.6 Hz, 1H), 4.62 (br s, 1H), 4.25-4.13 (m, 2H), 4.10-3.98 (m, 2H), 3.90-3.70 (m, 2H), 3.04-2.71 (m, 5H), 2.51-2.40 (m, 6H), 2.30-2.15 (m, 6H), 2.10-1.90 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.F[C:9]1[C:20]2=[C:21]3[N:16]([C:17](=[CH2:22])[CH2:18][CH2:19]2)[CH:15]=[C:14]([C:23]([OH:25])=[O:24])[C:13](=[O:26])[C:12]3=[CH:11][C:10]=1[F:27]>CS(C)=O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:9]2[C:20]3=[C:21]4[N:16]([C:17](=[CH2:22])[CH2:18][CH2:19]3)[CH:15]=[C:14]([C:23]([OH:25])=[O:24])[C:13](=[O:26])[C:12]4=[CH:11][C:10]=2[F:27])[CH2:4][CH2:3]1
Reactant: C=C1CCc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reactant: CN1CCNCC1
Solvent: CS(C)=O
Product: C=C1CCc2c(N3CCN(C)CC3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Yield: 16.5 %

Procedure:
400 mg of N-methylpiperazine and 6 ml of dimethyl sulfoxide were added to 400 mg of 8,9-difluoro-5-methylene-6,7-dihydro-1-oxo-1H,5H-benzo(ij)quinolizine-2-carboxylic acid and the resulting mixture was heated for 2.5 hours at 100°-110° C. (bath temperature). The solvent was distilled off in vacuo and water was added to the residue. The mixture was extracted with chloroform and the extract was dried. The solvent was distilled off and the residue was purified by silica gel column chromatography and then recrystallized from ethanol to give 85 mg of 8-(4-methyl-1-piperazinyl)-9-fluoro-5-methylene-6,7-dihydro-1-oxo-1H,5H-benzo(ij)quinolizine-2-carboxylic acid as microcrystals with 282°-285° C. (decomposition).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH2:13])=[O:12])=[C:5]2[S:14]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)(=[O:16])=[O:15].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:30][CH2:31][CH3:32].O>CN(C)C=O>[N:17]1([S:14]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([O:1][CH2:30][CH2:31][CH3:32])[CH:3]=3)[NH:7][C:6]=2[C:11]([NH2:13])=[O:12])(=[O:16])=[O:15])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: NC(=O)c1[nH]c2ccc(O)cc2c1S(=O)(=O)N1CCOCC1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOc1ccc2[nH]c(C(N)=O)c(S(=O)(=O)N3CCOCC3)c2c1
Reaction time: 1 h

Procedure:
To a solution of 5-hydroxy-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide from Example 50 (29 mg, 0.089 mmol) in 1 mL of dimethylformamide was added cesium carbonate (86 mg, 0.27 mmol) and 1-iodopropane (0.0094 mL, 0.096 mmol). After one hour, another portion (0.005 mL) of 1-iodopropane was added. After an additional hour, 0.5 mL of water was added to solubilize the material, and the resulting mixture was purified by preparative reversed phase HPLC to provide the titled product as a white solid. HRMS (ES) exact mass calculated for C16H22N3O5S (M+H+): 368.1275. Found 368.1291.
Reaction SMILES: Cl.[F:2][C:3]1[CH:24]=[C:23]([NH:25][C:26]([NH:28][C:29](=[O:37])[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[S:27])[CH:22]=[CH:21][C:4]=1[O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:19][CH3:20])=[C:13]([C:16](O)=[O:17])[CH:14]=2)[N:9]=[CH:8][CH:7]=1.[CH3:38][S:39]([CH2:42][CH2:43][NH2:44])(=[O:41])=[O:40].C(N(CC)CC)C>C(O)C>[F:2][C:3]1[CH:24]=[C:23]([NH:25][C:26]([NH:28][C:29](=[O:37])[CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[S:27])[CH:22]=[CH:21][C:4]=1[O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:19][CH3:20])=[C:13]([C:16]([NH:44][CH2:43][CH2:42][S:39]([CH3:38])(=[O:41])=[O:40])=[O:17])[CH:14]=2)[N:9]=[CH:8][CH:7]=1
Reactant: CS(=O)(=O)CCN
Reactant: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c2cc1C(=O)O
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c2cc1C(=O)NCCS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.1 %

Procedure:
Similar to the synthesis of Example 1, compound 1e (25 mg), 2-(methylsulfonyl)ethaneamine (6 mg), triethylamine (19 μL), and DMTMM•n-hydrate (20 mg) were dissolved in ethanol (1 mL), and the solution was stirred at room temperature for 1 hour, to thereby yield the titled compound 27 (20.6 mg, yield: 73%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([OH:21])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:22]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][CH2:32][C:33]2[CH:34]=[N:35][C:36]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[CH:37][CH:38]=2)=[CH:27][CH:26]=1)([CH3:24])[CH3:23]>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:31]([C:28]1[CH:27]=[CH:26][C:25]([CH:22]([CH3:24])[CH3:23])=[CH:30][CH:29]=1)[CH2:32][C:33]1[CH:34]=[N:35][C:36]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[CH:37][CH:38]=1)=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1ccc(NCc2ccc(N3CCOCC3)nc2)cc1
Reactant: O=C(O)C1CCCc2c(OCc3ccccc3)cccc21
Product: CC(C)c1ccc(N(Cc2ccc(N3CCOCC3)nc2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1
Yield: 78.8 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.56 g) and (4-isopropylphenyl)[(6-morpholinopyridin-3-yl)methyl]amine (0.62 g) as starting materials, 5-benzyloxy-N-(4-isopropylphenyl)-N-[(6-morpholinopyridin-3-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.90 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[O:5][CH2:6][C:7]1[CH:8]=[C:9]([N+:16]([O-])=O)[CH:10]=[C:11]([N+:13]([O-])=O)[CH:12]=1.O.NN>CO.[Ni]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[O:5][CH2:6][C:7]1[CH:8]=[C:9]([NH2:16])[CH:10]=[C:11]([NH2:13])[CH:12]=1
Reactant: O=[N+]([O-])c1cc(COc2ccc(Cl)c(Cl)c2)cc([N+](=O)[O-])c1
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: Nc1cc(N)cc(COc2ccc(Cl)c(Cl)c2)c1
Temperature: 25 °C

Procedure:
5-(3,4-dichlorophenoxymethyl)-1,3-dinitrobenzene in 5 ml MeOH was added to a solution of 10 ml 2.5 mmole hydrazine monohydrate and catalytic amount of Ra—Ni. The mixture was stirred under reflux for 30 min and then cooled to room temperature. GC-MS gave the peak of reduced product. The solution was filtered through Celite and MeOH was evaporated with rotaevaporation. The residue was used directly for next step without further purification.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[Cl-].[Cl-].[Cl-].[Al+3].[F:15][C:16]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=[C:21]([F:28])[C:17]=1[C:18](Cl)=[O:19]>[N+](C)([O-])=O>[F:15][C:16]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=[C:21]([F:28])[C:17]=1[C:18]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([I:1])[CH:3]=2)[NH:8][CH:9]=1)=[O:19]
Reactant: Ic1cnc2[nH]ccc2c1
Reactant: O=C(Cl)c1c(F)ccc([N+](=O)[O-])c1F
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Product: O=C(c1c(F)ccc([N+](=O)[O-])c1F)c1c[nH]c2ncc(I)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.2 %

Procedure:
In a reaction vial, 5-iodo-1H-pyrrolo[2,3-b]pyridine (43, 1.00 g, 4.10 mmol) is mixed with 22 mL of nitromethane and aluminum trichloride (3.28 g, 24.6 mmol) is added. The reaction is stirred at room temperature for 1 hour and 2,6-difluoro-3-nitro-benzoyl chloride (44, 1.36 g, 6.15 mmol) is added. The reaction is heated at 45° C. for 93 hours, then quenched with addition of methanol. The resulting precipitate is collected by filtration to provide the desired compound (45, 1.06 g).
Reaction SMILES: [S:1](=[O:37])(=[O:36])([O:3][CH2:4][C@@H:5]1[C@@H:9]([O:10][Si](C(C)(C)C)(C)C)[CH2:8][C@H:7]([N:18]2[C:22]3[N:23]=[CH:24][N:25]=[C:26]([NH:27][C:28](=[O:35])[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:21]=3[CH:20]=[CH:19]2)[O:6]1)[NH2:2]>N1C=CC=CC=1.C1COCC1.N1C=CC=CC=1>[S:1](=[O:36])(=[O:37])([O:3][CH2:4][C@@H:5]1[C@@H:9]([OH:10])[CH2:8][C@H:7]([N:18]2[C:22]3[N:23]=[CH:24][N:25]=[C:26]([NH:27][C:28](=[O:35])[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:21]=3[CH:20]=[CH:19]2)[O:6]1)[NH2:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](n2ccc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1COS(N)(=O)=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: NS(=O)(=O)OC[C@H]1O[C@@H](n2ccc3c(NC(=O)c4ccccc4)ncnc32)C[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
To a solution of ((2R,3S,5R)-5-[4-(benzoylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-3-{[tert-butyl(dimethyl)silyl]oxy}tetrahydrofuran-2-yl)methyl sulfamate (0.292 g, 0.533 mmol) in 5.4 mL pyridine/THF (1:1) was added approximately 5 drops of hydrofluoridic acid in pyridine. The solution was stirred at r.t. overnight, quenched by slowly adding saturated aq NaHCO3 (20 mL) and extracted with DCM (2×25 mL) and EtOAc (25 mL). The organics were combined, dried (Na2SO4), filtered, and concentrated. The crude material was purified by flash chromatography (1 to 10% MeOH/DCM) to afford the final compound (0.177 g, 77%).
Reaction SMILES: [C:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[Cl:15])[N:6]=[CH:5][C:4]=1[C:16]([O:18]CC)=O)#[N:2].[CH3:21][NH2:22]>CN(C=O)C>[C:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[Cl:15])[N:6]=[CH:5][C:4]=1[C:16]([NH:22][CH3:21])=[O:18])#[N:2]
Reactant: CCOC(=O)c1cnn(-c2ccc(Cl)cc2Cl)c1C#N
Reactant: CN
Solvent: CN(C)C=O
Product: CNC(=O)c1cnn(-c2ccc(Cl)cc2Cl)c1C#N
Temperature: 25 °C

Procedure:
To a solution of 2.5 g of 5-cyano-1-(2,4-dichlorophenyl)-1H-pyrazole-4-carboxylic acid, ethyl ester in 20 ml of DMF was added 20 ml of 40% aqueous monomethylamine. The reaction mixture was stirred at room temperature for approximately two and one-half hours whereupon the solution was poured into ice water. The precipitate was collected by filtration and recrystallized from methanol/water to afford 1.3 g of 5-cyano-1-(2,4-dichlorophenyl)-N-methyl-1H-pyrazole-4-carboxamide. MP=182°-183° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[N:10]=[C:11]([O:28]C)[C:12]2[CH2:18][N:17]([C:19]3[N:23]([CH3:24])[N:22]=[C:21]([CH:25]([CH3:27])[CH3:26])[CH:20]=3)[CH2:16][CH2:15][C:13]=2[N:14]=1.Cl.O.C([O-])(O)=O.[Na+]>CCO>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[C:9]1[N:10]=[C:11]([OH:28])[C:12]2[CH2:18][N:17]([C:19]3[N:23]([CH3:24])[N:22]=[C:21]([CH:25]([CH3:26])[CH3:27])[CH:20]=3)[CH2:16][CH2:15][C:13]=2[N:14]=1
Reactant: COc1nc(-c2c(C)cccc2C)nc2c1CN(c1cc(C(C)C)nn1C)CC2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cccc(C)c1-c1nc(O)c2c(n1)CCN(c1cc(C(C)C)nn1C)C2
Temperature: 90 °C

Procedure:
To a solution of 2-(2,6-dimethylphenyl)-6-(3-isopropyl-1-methyl-1H-pyrazol-5-yl)-4-methoxy-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (3.3 g, 8.51 mmol) in EtOH (30 mL) in a 150 mL sealed tube was added concentrated hydrochloride (21 mL). The tube was sealed, stirred, and heated at 90° C. for 16 h. The reaction mixture was cooled to r.t. and poured onto iced-water. Solid NaHCO3 was added to neutralize the mixture. The mixture was extracted by DCM three times. The combined organic layers were dried over Na2SO4. After filtration and concentration, the resulting residue was purified via silica gel FCC (0-100% EtOAc/heptane) to give 2-(2,6-dimethylphenyl)-6-(3-isopropyl-1-methyl-1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ol. 1H NMR (400 MHz, CD2Cl2) δ ppm 9.95 (br. s., 1 H), 7.21-7.36 (m, 1 H), 7.13 (d, J=7.3 Hz, 2 H), 5.76 (s, 1 H), 3.87 (s, 2 H), 3.68 (s, 3 H), 3.22 (t, J=5.7 Hz, 2 H), 2.77-2.97 (m, 3 H), 2.22 (s, 6 H), 1.22 (d, J=7.1 Hz, 6 H). MS (ESI+) m/z 378.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][S:14][C:15]2[S:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[C:8]=1[CH3:24].ClC1C=CC=C(C(OO)=[O:33])C=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>ClCCl>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][S:14]([C:15]2[S:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)=[O:33])[C:8]=1[CH3:24]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COCCCOc1ccnc(CSc2nc3ccccc3s2)c1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCCOc1ccnc(CS(=O)c2nc3ccccc3s2)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.1 %

Procedure:
0.6 g of 2-{4-(3-methoxypropoxy)-3-methylpyridine-2-yl}methylthiobenzothiazole was dissolved in 20 ml of dichloromethane to obtain a solution. 0.36 g of 80% m-chloroperbenzoic acid was added to the solution at -45° C. After one hour, 0.34 g of triethylamine and 30 ml of a saturated aqueous solution of sodium hydrogencarbonate were added to the obtained mixture. The resulting mixture was stirred at a room temperature for 30 minutes. The dichloromethane layer was separated, washed with a saturated aqueous solution of sodium hydrogencarbonate twice, dried over magnesium sulfate and filtered. The filtrate was concentrated to obtain a residue. This residue was purified by silica gel column chromatography to obtain 0.17 g of the title compound as a white crystal.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=1.O.C(=O)(O)[O-].[Na+].Cl[CH2:16][CH:17]=O>[Na+].[Cl-].CCO>[N:1]1[CH:16]=[CH:17][N:3]2[C:4]([NH2:8])=[CH:5][CH:6]=[CH:7][C:2]=12
Reactant: O=CCCl
Reactant: Nc1cccc(N)n1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1cccc2nccn12
Temperature: 70 °C
Yield: 36 %

Procedure:
To a solution of 2,6-diaminopyridine (5.00 g, 45.8 mmol) in 1:1 H2O:EtOH (10 mL) were added sodium bicarbonate (5.00 g, 59.5 mmol) and chloroacetaldehyde (4.31 g, 27.5 mmol). The reaction mixture was heated to 70° C. overnight, then cooled to rt, diluted with saturated aqueous NaCl (100 mL), and extracted with n-butanol (3×200 mL). The organic layers were combined, dried (MgSO4), and concentrated. The crude residue was purified (FCC, 2 N NH3 in MeOH/DCM) to give imidazo[1,2-a]pyridin-5-ylamine (1.32 g, 22%). MS (ESI+): calcd for C7H7N3 m/z 133.06, found 134.1 (M+H)+. 1H NMR (d6-DMSO): 8.23-8.21 (m, 1H), 7.91 (d, J=1.3, 1H), 7.50 (dd, J=8.8, 7.4, 1H), 7.22 (d, J=8.8, 1H), 6.97 (br s, 2H), 6.37 (dd, J=7.4, 0.9, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[O:20][C:19]([CH:21]=O)=[CH:18][CH:17]=1>>[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[O:20][C:19]([CH:21]=[N:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[OH:8])=[CH:18][CH:17]=1
Reactant: Nc1ccccc1O
Reactant: O=Cc1ccc(-c2ccccc2Cl)o1
Product: Oc1ccccc1N=Cc1ccc(-c2ccccc2Cl)o1

Procedure:
Using 2-aminophenol and 5-(2-chlorophenyl)furan-2-carbaldehyde, 2.69 g of 2-{[5-(2-chlorophenyl)furan-2-yl]methyleneamino}phenol were obtained as a yellow powder (yield 75%).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][C:12]=2[N:14]2[CH2:19][CH2:18][N:17]([C:20](=[O:38])[C@H:21]([NH:30]C(=O)OC(C)(C)C)[CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[CH2:16][CH2:15]2)[NH:7][CH:6]=1)(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>C(Cl)Cl>[NH2:30][C@H:21]([CH2:22][C:23]1[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=1)[C:20]([N:17]1[CH2:16][CH2:15][N:14]([C:12]2[CH:11]=[CH:10][N:9]=[C:8]3[NH:7][CH:6]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[C:13]=23)[CH2:19][CH2:18]1)=[O:38]
Reactant: CC(=O)Nc1c[nH]c2nccc(N3CCN(C(=O)[C@@H](Cc4ccc(Cl)cc4)NC(=O)OC(C)(C)C)CC3)c12
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1c[nH]c2nccc(N3CCN(C(=O)[C@H](N)Cc4ccc(Cl)cc4)CC3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.3 %

Procedure:
(R)-tert-Butyl 1-(4-(3-acetamido-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-3-(4-chlorophenyl)-1-oxopropan-2-ylcarbamate (0.047 g, 0.087 mmol) was placed in DCM (5 mL) at room temperature. TFA (0.5 mL) was then added, and the reaction was stirred at room temperature for 1 hour. The reaction was then concentrated to dryness. The crude residue was then dissolved in minimal DCM and added dropwise to a stirring solution of 1M HCl in ether. The resulting solid was filtered, washed with ether and dried to give (R)—N-(4-(4-(2-amino-3-(4-chlorophenyl)propanoyl)piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acetamide (0.04 g, 90% yield) as the dihydrochloride salt. MS APCI (+) m/z 441 detected.
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][N:10]1[C:15](=[O:16])[NH:14][C:13](=[O:17])[O:12][C:11]1=[O:18]>>[CH3:9][N:10]1[C:15](=[O:16])[N:14]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:13](=[O:17])[O:12][C:11]1=[O:18]
Reactant: Cn1c(=O)[nH]c(=O)oc1=O
Reactant: ClCc1ccccc1
Product: Cn1c(=O)oc(=O)n(Cc2ccccc2)c1=O
Yield: 83 %

Procedure:
The process described in example 1 is carried out. 15.2 g of benzyl chloride (0.12 mole) are added to the obtained solution of the salt of 3-methyl-1,3,5-oxadiazine-2,4,6-trione. After 3 hours of reaction at a temperature of 60° C., one obtains 19.4 g of 3-methyl-5-benzyl-1,3,5oxadiazine-2,4,6-trione (yield: 83%) which is an asymmetrical disubstituted 1,3,5-oxadiazine trione of the formula (III).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.C(N(CC)CC)C.[Cl:17][CH:18]([Cl:22])[C:19](Cl)=[O:20]>ClCCl>[Cl:17][CH:18]([Cl:22])[C:19]([NH:1][C:2]1[CH:7]=[N:6][C:5]([C:8]#[N:9])=[CH:4][CH:3]=1)=[O:20]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: N#Cc1ccc(N)cn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc(NC(=O)C(Cl)Cl)cn1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
5-Amino-2-cyanopyridine (0.500 g, 4.2 mmol) was suspended in dry dichloromethane (10 mL) and triethylamine (0.635 g, 6.3 mmol) was added to it under stirring at 0° C. To the reaction mixture 2,2-dichloroacetyl chloride (0.800 g, 6.3 mmol) was added dropwise under stirring at 0° C. and stirring was further continued for about 10 minutes at about 0° C. and then at room temperature for 4 hours. The reaction mixture was diluted with dichloromethane (50 mL) and washed with saturated sodium bicarbonate solution (50 mL) and water (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was purified using column chromatography (silica gel, 30% ethyl acetate in petroleum ether as an eluent) and further crystallized from ethyl acetate and petroleum ether to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6]([C:12]1[CH:13]=[CH:14][C:15]([O:31][CH3:32])=[C:16]([NH:18][S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-])=O)[CH:23]=3)(=[O:21])=[O:20])[CH:17]=1)=[CH:5]2>C(O)(=O)C.[Zn]>[NH2:28][C:24]1[CH:23]=[C:22]([S:19]([NH:18][C:16]2[CH:17]=[C:12]([C:6]3[NH:7][C:8]4[C:4]([CH:5]=3)=[CH:3][C:2]([F:1])=[C:10]([F:11])[CH:9]=4)[CH:13]=[CH:14][C:15]=2[O:31][CH3:32])(=[O:20])=[O:21])[CH:27]=[CH:26][CH:25]=1
Reactant: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1NS(=O)(=O)c1cccc([N+](=O)[O-])c1
Agent: [Zn]
Solvent: CC(=O)O
Product: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1NS(=O)(=O)c1cccc(N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.1 %

Procedure:
The product from Example 15 (0.388 g, 0.84 mmol) was taken up in glacial acetic acid (25 mL), and zinc dust (2.8 g, 325 mesh) was added in portions over 3 minutes and was then stirred 2 hours at room temperature. The zinc was filtered off and washed with ethyl acetate and tetrahydrofuran. The organic solution was concentrated to dryness, the residue partitioned between ethyl acetate (200 mL) and sodium bicarbonate solution (200 mL), the organic layer washed with brine and dried (magnesium sulfate), filtered, concentrated, and the resulting solid triturated with hexanes/ethyl acetate, 3/1, v/v and the insoluble portion collected by filtration to give the product as a faintly yellow solid (0.296 g), mp 235-238° C.
Reaction SMILES: [CH2:1](Br)[C:2]#[C:3][CH3:4].[F:6][CH:7]([F:18])[O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[OH:17].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([O:17][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:9]=1[O:8][CH:7]([F:6])[F:18])[CH:13]=[O:14])[C:2]#[C:3][CH3:4]
Reactant: O=Cc1ccc(OC(F)F)c(O)c1
Reactant: CC#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC#CCOc1cc(C=O)ccc1OC(F)F
Yield: 95.9 %

Procedure:
But-2-ynyl bromide (0.29 mL, 3.4 mmol) was added to a suspension of 4-difluoromethoxy-3-hydroxybenzaldehyde (0.43 g, 2.3 mmol) and potassium carbonate (0.95 g, 6.9 mmol) in acetonitrile (5 mL). The suspension was heated to reflux for 16 h and then concentrated under reduced pressure. Water was added and the aqueous phase was extracted with EtOAc. The combined organic fractions were washed with water, brine, dried. The product was concentrated under reduced pressure providing 3-(but-2-ynyloxy)-4-difluoromethoxybenzaldehyde (0.53 g, 97%) as a yellow crystalline solid; mp 46-47° C.; δH (500 MHz, CDCl3) 1.86 (t, J=2.5 Hz, 3H, C≡CCH3), 4.81 (q, J=2.5 Hz, 2H, OCH2), 6.68 (t, J=72.0 Hz, 1H, CHF2), 7.33 (d, J5,6=8.0 Hz, 1H, H5), 7.50 (dd, J5,6=8.0, J2,6=2.0 Hz, 1H, H6), 7.63 (d, J2,6=2.0 Hz, 1H, H2), 9.96 (s, 1H, CHO); δC (125 MHz, CDCl3) 3.7, 57.5, 72.7, 85.3, 113.4, 115.6 (t, J=256 Hz), 121.8, 125.1, 134.4, 145.3, 149.7, 190.7; νmax 1123, 1268, 1435, 1505, 1597, 1698, 2858 cm−1.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH:16]1[CH2:18][CH2:17]1)=[O:14].[CH3:19][O:20][C:21]1[C:26](B(O)O)=[CH:25][CH:24]=[C:23]([O:30][CH3:31])[N:22]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:26]3[C:21]([O:20][CH3:19])=[N:22][C:23]([O:30][CH3:31])=[CH:24][CH:25]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH:16]1[CH2:18][CH2:17]1)=[O:14]
Reactant: Nc1c(C(=O)NC2CC2)nnc2c(Br)cccc12
Reactant: COc1ccc(B(O)O)c(OC)n1
Product: COc1ccc(-c2cccc3c(N)c(C(=O)NC4CC4)nnc23)c(OC)n1
Yield: 76.9 %

Procedure:
Using Method A, 4-amino-8-bromo-N-cyclopropyl-cinnoline-3-carboxamide (143 mg, 0.47 mmol) and 2,6-dimethoxypyridine-3-boronic acid (170 mg, 0.94 mmol) were reacted. After purification the title compound (132 mg, 77% yield) was obtained as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 9.03 (d, J=4.9 Hz, 1H), 8.38 (d, J=8.0 Hz, 1H), 7.76 (m, 2H), 7.67 (d, J=8.0 Hz, 1H), 6.48 (d, J=8.0 Hz, 1H), 3.93 (s, 3H), 3.77 (s, 3H), 2.96 (m, 1H), 0.70(m, 4H). MS APCI, m/z=366.