Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([O:12]C)=[CH:9][CH:10]=2)[N:5]([CH2:14][CH3:15])[C:4]=1[C:16]#[C:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([CH:27]2[CH2:29][CH2:28]2)=[O:26])=[CH:20][CH:19]=1)#[N:2].B(Br)(Br)Br>>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[N:5]([CH2:14][CH3:15])[C:4]=1[C:16]#[C:17][C:18]1[CH:19]=[CH:20][C:21]([NH:24][C:25]([CH:27]2[CH2:28][CH2:29]2)=[O:26])=[CH:22][CH:23]=1)#[N:2]
Reactant: CCn1c(C#Cc2ccc(NC(=O)C3CC3)cc2)c(C#N)c2ccc(OC)cc21
Agent: BrB(Br)Br
Product: CCn1c(C#Cc2ccc(NC(=O)C3CC3)cc2)c(C#N)c2ccc(O)cc21
Yield: 54.1 %

Procedure:
Cyclopropanecarboxylic acid [4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]-amide (60 mg, 0.16 mmol), prepared as described in Example 1Za, is stirred in BBr3 (800 μL, 1M in CH2Cl2, 0.8 mmol) at room temperature for 1 hour. The reaction mixture is quenched with H2O, and is extracted with CH2Cl2. The organic layer is dried and concentrated. Purification by silica chromatography (EtOAC) gives impure product. This crude product is triturated with 1/1 hexanes/acetone to yield cyclopropanecarboxylic acid [4-(3-cyano-1-ethyl-6-hydroxy-1H-indol-2-ylethynyl)-phenyl]-amide (32 mg, 54%) as an off-white solid.
Reaction SMILES: Cl.[CH3:2][C:3]1[N:7]2[C:8]3[CH:14]=[CH:13][N:12]([S:15]([C:18]4[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=4)(=[O:17])=[O:16])[C:9]=3[N:10]=[CH:11][C:6]2=[CH:5][N:4]=1.C1C(=O)N([Br:32])C(=O)C1.O.C([O-])(O)=O.[Na+]>CN(C=O)C>[Br:32][C:5]1[N:4]=[C:3]([CH3:2])[N:7]2[C:8]3[CH:14]=[CH:13][N:12]([S:15]([C:18]4[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=4)(=[O:16])=[O:17])[C:9]=3[N:10]=[CH:11][C:6]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2cnc(C)n23)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2c(Br)nc(C)n23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.8 %

Procedure:
To a mixture of 1-methyl-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine hydrochloride (2.11 g, 5.81 mmol) in DMF (58 ml) was added NBS (1.03 g, 5.81 mmol). The mixture was stirred for about 2 h at rt. The mixture was poured into rapidly stirred water (˜300 mL). Saturated aqueous NaHCO3 (˜15 mL) was added and the mixture stirred for about 1 h. The solid was collected by filtration and washed with water (˜50 mL). The solid was dissolved in DCM (100 mL) and washed with saturated aqueous Na2CO3 (20 mL). The layers were separated and the aqueous layer was extracted with DCM (2×15 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (80 g Silicycle™ column) eluting with 10% EtOAc in DCM to give 3-bromo-1-methyl-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine (1.62 g, 69%): LCMS (Table 2, Method b) Rt=2.52 min.; MS m/z: 404.96, 406 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1)=[CH:7][CH2:6][CH2:5]2.[C:17]([Cu])#[N:18]>CN1CCCC1=O>[C:17]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1)=[CH:7][CH2:6][CH2:5]2)#[N:18]
Reactant: Brc1ccc2c(c1)CCC=C2n1ccnc1
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Product: N#Cc1ccc2c(c1)CCC=C2n1ccnc1

Procedure:
6-bromo-1-(1-imidazolyl)-3,4-dihydronaphthalene (Example 6) is converted by reaction with CuCN in 1-methylpyrrolidone into the title compound, m.p. 152°-153°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:15][C:14]3=[N:16][C:17]([CH3:20])=[C:18](I)[N:13]3[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:21]([C:23]1[CH:28]=[CH:27][C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][N:24]=1)#[N:22].C(Cl)Cl.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:15][C:14]3=[N:16][C:17]([CH3:20])=[C:18]([C:26]4[CH:27]=[CH:28][C:23]([C:21]#[N:22])=[N:24][CH:25]=4)[N:13]3[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CC1(C)OB(c2ccc(C#N)nc2)OC1(C)C
Reactant: COc1ccc(-c2nn3c(I)c(C)nc3s2)cc1OC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Solvent: O
Product: COc1ccc(-c2nn3c(-c4ccc(C#N)nc4)c(C)nc3s2)cc1OC
Temperature: 25 °C
Yield: 1.7 %

Procedure:
A mixture of 2-(3,4-dimethoxy-phenyl)-5-iodo-6-methyl-imidazo[2,1-b][1,3,4]thiadiazole (0.125 g, 0.312 mmol, 1 eq), 2-cyanopyridine-5-boronic acid pinacol ester (0.095 g, 0.414 mmol, 1.33 eq), Pd(dppf)Cl2.DCM (0.008 g, 0.009 mmol, 0.03 eq) and cesium carbonate (0.305 g, 0.935 mmol, 3 eq) in DME (4 mL) and water (0.1 mL) was heated in the microwave oven (45 min, 130° C.), cooled to RT, diluted with water, extracted with EtOAc and washed with brine. The organic layers were dried (MgSO4), filtered and concentrated, and the residue was purified by silica gel chromatography (0-100% DCM in hexane, then 0-3% MeOH in DCM). Product fractions were concentrated to give a solid that was further purified by preparative HPLC affording the pure product (0.002 g, 2% yield). HPLC-MS: (5-100% B in 8 min, 0.8 mL/min): tR=5.52 min, [M+H]+ m/z 378.1. 1H NMR (300 MHz, CDCl3) δ/ppm 9.16 (d, J=1.5, 1H), 8.18 (dd, J=8.4, 2.2, 1H), 7.82-7.67 (m, 1H), 7.41-7.28 (m, 2H), 6.89 (d, J=8.4, 0H), 3.91 (s, 3 H), 3.89 (s, 3 H), 2.54 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][C@H:17]([OH:19])[CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[OH-].[Na+].[CH3:27]O>>[CH3:27][O:14][C:13](=[O:15])[C@@H:12]1[CH2:16][C@@H:17]([OH:19])[CH2:18][N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Reactant: CO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1

Procedure:
To a solution of trans-1-benzyloxycarbonyl-4-hydroxy-L-proline (138 g) in methanol (1380 ml), conc. sulfuric acid (9.92 g) was added, and the resultant mixture was refluxed for 2 hours. The reaction mixture was neutralized with 1N aqueous sodium hydroxide solution, and methanol was removed therefrom. The residue was diluted with ethyl acetate, washed with aqueous sodium chloride solution and dried over magnesium sulfate. Removal of the solvent gave trans-1-benzyloxycarbonyl-4-hydroxy-L-proline methyl ester.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:11][C:12]([N+:23]([O-])=[O:24])([CH3:22])[CH2:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)(=O)C>C(O)C.[Zn]>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[N+:23]([C:12]([CH3:22])([CH3:11])[CH2:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[O-:24]
Reactant: CC(C)(COCc1ccccc1)[N+](=O)[O-]
Reactant: O=Cc1ccc(F)cc1F
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(COCc1ccccc1)[N+]([O-])=Cc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 7 h
Yield: 48 %

Procedure:
A suspension of 2,4-difluorobenzaldehyde (443.7 mg, 3.12 mmol), 2-methyl-2-nitro-1-benzyloxypropane (639.4 mg, 3.06 mmol) and zinc (326.4 mg, 4.99 mmol) in ethanol (6 ml) was cooled to 0° C. in ice-water bath. Acetic acid (0.57 ml, 9.9 mmol) was added dropwise to the mixture. The mixture was gradually warmed to room temperature and stirred for 7 hours. The mixture was filtered through Celite® bed and the filtrate was concentrated and purified by silica gel chromatography (hexane/ethyl acetate=10/1-4/1) to give the title compound (468.8 mg; 48%).
Reaction SMILES: CO[C:3]([C:5]1[S:9][C:8](/[CH:10]=[CH:11]/[C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:7][C:6]=1[CH3:22])=[O:4].[NH2:23][CH:24]([CH3:27])[CH2:25][OH:26]>>[OH:26][CH2:25][CH:24]([NH:23][C:3]([C:5]1[S:9][C:8](/[CH:10]=[CH:11]/[C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:7][C:6]=1[CH3:22])=[O:4])[CH3:27]
Reactant: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)OC)s1
Reactant: CC(N)CO
Product: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)NC(C)CO)s1
Yield: 79 %

Procedure:
As described for example 95, 2-[(E)-2-(3-butyl-5-methyl-isoxazol-4-yl)-vinyl]-4-methyl-thiazole-5-carboxylic acid methyl ester (60 mg, 0.19 mmol) was converted, using rac-2-amino-1-propanol instead of isopropylamine, to the title compound (45 mg, 79%) which was obtained as a colourless oil. MS: m/e=364.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([NH:26][C:27]([C:29]4[S:30][CH:31]=[CH:32][CH:33]=4)=[O:28])[CH:22]=[CH:23][C:24]=3[CH3:25])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:38].[NH2:39][CH:40]1[CH2:45][CH2:44][N:43](C(OC(C)(C)C)=O)[CH2:42][CH2:41]1>>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:39][CH:40]3[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([NH:26][C:27]([C:29]4[S:30][CH:31]=[CH:32][CH:33]=4)=[O:28])[CH:22]=[CH:23][C:24]=3[CH3:25])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:38]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Cc1ccc(NC(=O)c2cccs2)cc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Product: Cc1ccc(NC(=O)c2cccs2)cc1-c1nc(NC2CCNCC2)nc2c1ccc(=O)n2-c1c(F)cccc1F

Procedure:
The title compound was prepared as described in Example 2 from N-{3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylphenyl}-2-thiophenecarboxamide and 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate. LC-MS m/z 573 (M+H)+, 1.90 min (ret time).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH2:56][C:57]1[S:58][CH:59]=[CH:60][N:61]=1>CN(C)C=O>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:12]=[CH:13][C:14]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:16]=2)[C:8]([NH:56][C:57]2[S:58][CH:59]=[CH:60][N:61]=2)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(N2CCOCC2)cc1
Reactant: Nc1nccs1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 33.9 %

Procedure:
A solution of 3-cyclopentyl-2-(4-morpholin-4-yl-phenyl)-propionic acid (202.5 mg, 0.67 mmol) in dry N,N-dimethylformamide (3.3 mL) was treated with N,N-diisopropylethylamine (350 μL, 2.00 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (303.8 mg, 0.80 mmol), and 2-aminothiazole (133.7 mg, 1.34 mmol). The reaction mixture was stirred at 25° C. under nitrogen for 15 h. The reaction mixture was then concentrated in vacuo to remove N,N-dimethylformamide. The residue was diluted with ethyl acetate (150 mL), and the organic phase was washed with a 10% aqueous hydrochloric acid solution (1×75 mL) and a saturated aqueous sodium chloride solution (1×75 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-morpholin-4-yl-phenyl)-N-thiazol-2-yl-propionamide (87.5 mg, 34%) as a white solid: mp 244-246° C.; EI-HRMS m/e calcd for C21H27N3O2S (M+) 385.1824, found 385.1832.
Reaction SMILES: [C:1]([C:5]1[CH2:9][CH:8]([P:10](=[O:17])([O:14]CC)[O:11]CC)[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]>Br.C(O)(=O)C>[C:1]([C:5]1[CH2:9][CH:8]([P:10](=[O:11])([OH:17])[OH:14])[O:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOP(=O)(OCC)C1CC(C(C)(C)C)=NO1
Agent: Br
Solvent: CC(=O)O
Product: CC(C)(C)C1=NOC(P(=O)(O)O)C1

Procedure:
39.6 g (0.15 mol) of the compound from Example 26 are dissolved in a mixture of 100 ml of 33% strength HBr/glacial acetic acid solution and 50 ml of glacial acetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[N:7][N:8]3[C:15](=[O:16])[C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:13][C:12]([C:23]([OH:25])=[O:24])=[C:9]32)=[CH:4][CH:3]=1.[OH-].[K+]>CO>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[NH:7])[N:8]3[C:15](=[O:16])[C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:13][C:12]([C:23]([OH:25])=[O:24])=[C:9]32)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(-c2ccccc2)c(=O)n2ncc3ccc(Cl)cc3c12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: N=C1c2ccc(Cl)cc2-c2c(C(=O)O)cc(-c3ccccc3)c(=O)n21
Yield: 94.9 %

Procedure:
3.5 g of 10-chloro-4-oxo-3-phenyl-4H-pyrido[2,1-a]-phthalazine-1-carboxylic acid were added to a solution of 5.6 g of potassium hydroxide in 60 ml of methanol, whereupon the mixture was heated to boiling under reflux for 25 hours. The solvent was then removed in a vacuum and the residue was taken up in 60 ml of water. The product was precipitated by the addition of 2N hydrochloric acid. The crystals were filtered off under suction, washed with water and dried in a vacuum. There was obtained 3.32 g of 9-chloro-6-imino-4-oxo-3-phenyl-6H-pyrido[2,1-a]isoindole-1-carboxylic acid as yellowish crystals with a m.p. of 266°-268° (decomposition).
Reaction SMILES: [Mg].II.[CH2:4](Br)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=[CH2:14].Br[CH2:17][CH2:18][CH2:19][Cl:20].S(=O)(=O)(O)O>C1COCC1.[Cu](I)I>[CH2:19]([Cl:20])[CH2:18][CH2:17][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:5]=[CH2:4]
Reactant: C=CCCCCCCCCCBr
Reactant: ClCCCBr
Agent: I[Cu]I
Agent: II
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: C=CCCCCCCCCCCCCCl
Reaction time: 0.5 h
Yield: 51.4 %

Procedure:
This example illustrates a synthesis for inventive compound no. 351 3. To a suspension of magnesium (1.86 g, 77.2 mmol) and a crystal of iodine in THF (20 ml) was added 10-undecenyl bromide (6.00 g, 25.8 mmol) in THF (14 m) over 40 minutes and the reaction stirred for a further 30 minutes after completion of the addition. The solution was added via a canula over 50 minutes to a suspension of copper iodide (0.50 g, 2.58 mmol) and 1-bromo-3-chloropropane (3.84 ml, 38.7 mmol) in THF (20 ml) and stirred at 25° C. for 16 hours. Sulfuric acid (1.0 M, 50 ml) was added, extracted with diethyl ether (2×60 ml) and the organic solvent was dried over magnesium sulfate and subsequently evaporated The residue was distilled at 0.25 mmHg, producing 3.06 g of 13-tetradecenyl chloride as a colorless liquid (51% yield, b.p. 98°-100° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][NH:7][C:6]2=O.O=P(Cl)(Cl)[Cl:16].[OH-].[Na+]>>[Cl:16][C:6]1[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: COc1ccc2nc[nH]c(=O)c2c1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc2ncnc(Cl)c2c1
Temperature: 105 °C

Procedure:
A pressure resistant bottle was charged with 6-methoxyquinazolin-4(3H)-one (1.0 g, 5.68 mmol) and POCl3(17.5 ml, 187.3 mmol). The resulting mixture was heated at 105° C. for 18 hours. The reaction mixture was cooled to RT and poured onto ice slurry while stirring heavily. The solution was quickly neutralized with 6N NaOH, and product extracted with DCM. The organic layer was collected, dried over sodium sulfate and concentrated to afford 4-chloro-6-methoxyquinazoline as tan solid. MS: [M+H]=194.9; Calc'd for C9H7ClN2O: 194.6.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][C:9](=[O:16])OCC(Cl)(Cl)Cl)[O:4][N:3]=1.[CH2:17]([C:19]1[S:23][C:22]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[N:21][C:20]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:18].C(N(C(C)C)CC)(C)C.O>CS(C)=O>[CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][C:9]([N:27]2[CH2:28][CH2:29][N:24]([C:22]3[S:23][C:19]([CH2:17][CH3:18])=[C:20]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:21]=3)[CH2:25][CH2:26]2)=[O:16])[O:4][N:3]=1
Reactant: Cc1noc(NC(=O)OCC(Cl)(Cl)Cl)c1C
Reactant: CCc1sc(N2CCNCC2)nc1-c1ccccc1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1sc(N2CCN(C(=O)Nc3onc(C)c3C)CC2)nc1-c1ccccc1
Temperature: 70 °C
Reaction time: 15 h
Yield: 35.2 %

Procedure:
A mixture of 2,2,2-trichloroethyl (3,4-dimethylisoxazol-5-yl)carbamate (231 mg, 0.805 mmol), 1-(5-ethyl-4-phenyl-1,3-thiazol-2-yl)piperazine (200 mg, 0.732 mmol) and diisopropylethylamine (0.255 ml, 1.46 mmol) in dimethylsulfoxide (2.5 ml) was stirred at 70° C. for 15 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give the desired product (106 mg, 35.3%) as a solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[C:7]([CH3:10])[CH2:8][OH:9])[CH2:3][CH2:2]1>CCCCCC.ClCCl.ClCCl.[O-2].[O-2].[Mn+4]>[O:1]1[CH2:6][CH2:5][C:4](=[C:7]([CH3:10])[CH:8]=[O:9])[CH2:3][CH2:2]1
Reactant: CC(CO)=C1CCOCC1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(C=O)=C1CCOCC1
Temperature: 25 °C
Reaction time: 40 h
Yield: 101.4 %

Procedure:
To a suspension of 23 g (0.265 mmol) of activated manganese dioxide in a mixture of hexane-dichloromethane (20 mL+70 mL) was added a solution of 2.0 g (14.07 mmol) of 2-(tetrahydropyran-4-ylidene)propan-1-ol obtained in the above 2) in dichloromethane (4 mL), and stirred for 40 hours at 25° C. Upon filtration of the mixture and subsequent concentration of the filtrate, 2.0 g (yield 100%) of 2-(tetrahydropyran-4-ylidene)propionaldehyde (VII-15) was obtained as colorless liquid. Its physical properties are shown below.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[CH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:15])[CH2:13][CH3:14]>C(N(CC)C1C=CC=CC=1)C>[OH:1][C:2]1[C:3]([C:12](=[O:15])[CH2:13][CH3:14])=[CH:4][CH:5]=[C:6]2[C:7]=1[CH:11]=[CH:10][CH2:9][O:8]2
Reactant: C#CCOc1ccc(C(=O)CC)c(O)c1
Solvent: CCN(CC)c1ccccc1
Product: CCC(=O)c1ccc2c(c1O)C=CCO2
Yield: 45 %

Procedure:
A mixture of 1-(2-hydroxy-4-prop-2-ynyloxy-phenyl)-propan-1-one (19.8 g, 97 mmol) and N,N-diethylaniline (100 mL) was heated to reflux for 3 h. The reaction mixture was concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 5-10% EtOAc in Hexane) and thereafter recrystallized from EtOAc/Hexane, to give 8.91 g (45%) of 1-(5-hydroxy-2H-chromen-6-yl)-propan-1-one.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]1.[Cl:32][C:33]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[C:35]([F:48])[C:34]=1[OH:49]>>[Cl:32][C:33]1[CH:38]=[C:37]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:15][CH2:16]2)=[O:13])=[C:5]3[NH:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:30])[CH3:28])[CH2:20][CH2:19]2)[CH:36]=[C:35]([F:48])[C:34]=1[OH:49]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(F)c(O)c(Cl)c4)cc23)CC1

Procedure:
Following general procedure D, tert-butyl trans-4-[6-bromo-3-(cyclopropanecarbonyl)quinoline-4-ylamino]cyclohexylcarbamate (49 mg, 0.100 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (130 mg, 0.478 mmol) to afford the desired product (20 mg, 36%) as an off white solid: ESI MS m/z 554 [C30H33ClFN3O4+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[C:5]([Cl:8])=[N:6][CH:7]=1.[CH:12]([Mg]Br)=[CH:13][CH3:14]>O1CCCC1.CCOCC>[Br:1][C:2]1[CH:7]=[N:6][C:5]([Cl:8])=[C:4]2[NH:9][CH:12]=[C:13]([CH3:14])[C:3]=12
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Reactant: CC=C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1c[nH]c2c(Cl)ncc(Br)c12
Temperature: -40 °C

Procedure:
To a solution of 5-bromo-2-chloro-3-nitro-pyridine, (10.28 g) in dry tetrahydrofuran (450 ml) at −78° C. under an atmosphere of nitrogen was added dropwise, a solution of 1-propenylmagnesium bromide (0.5M in tetrahydrofuran; 305 ml), keeping the internal temperature below −70° C. The solution was allowed to warm to −40° C. over 1 h then quenched with saturated ammonium chloride (350 ml). The aqueous was extracted twice with ethyl acetate (2×200 ml) and the combined organics were dried (MgSO4), filtered and evaporated to give a brown oil. The mixture was dissolved in ether, a solid filtered off then evaporated. The residue was dissolved in ether, loaded onto four Biotage silica samplets and purified by Biotage chromatography over silica gel (4×100 g), eluting with 10% ethyl acetate/isohexane (1 L) followed by 15% ethyl acetate/isohexane (1 L). The fractions containing product from the four columns were combined and evaporated to afford an orange solid. The orange solid was triturated with isohexane, filtered and washed with isohexane and dried to give the title compound as an off white solid. (1.07 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14](Br)[CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[O:18][CH2:19][CH2:20][OH:21])[CH:5]=[CH:4][N:3]=1.[CH3:22][C:23]1[O:27][N:26]=[C:25]([C:28]([OH:32])([C:30]#[CH:31])[CH3:29])[CH:24]=1.C(N(CC)CC)C>CS(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14]([C:31]#[C:30][C:28]([C:25]4[CH:24]=[C:23]([CH3:22])[O:27][N:26]=4)([OH:32])[CH3:29])[CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[O:18][CH2:19][CH2:20][OH:21])[CH:5]=[CH:4][N:3]=1
Reactant: Nc1nccc(-n2c(OCCO)nc3ccc(Br)cc32)n1
Reactant: C#CC(C)(O)c1cc(C)on1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc(C(C)(O)C#Cc2ccc3nc(OCCO)n(-c4ccnc(N)n4)c3c2)no1
Yield: 30 %

Procedure:
A solution of 2-[[1-(2-aminopyrimidin-4-yl)-6-bromo-1H-1,3-benzodiazol-2-yl]oxy]ethan-1-ol (80 mg, 0.19 mmol), 2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol (80 mg, 0.53 mmol), bis(triphenylphosphine)palladium(II) dichloride (20 mg, 0.03 mmol) and triethylamine (0.7 mL) in dimethylsulfoxide (3 mL) under nitrogen in a 10-mL sealed tube was irradiated with microwave radiation for 30 min at 70° C. The reaction mixture was concentrated and the crude product (80 mg) was purified by Flash-Preparative HPLC to give 24 mg (28%) of 4-[1-(2-aminopyrimidin-4-yl)-2-(2-hydroxyethoxy)-1H-1,3-benzodiazol-6-yl]-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol as a yellow solid. 1H NMR (400 MHz, DMSO-d6) delta 8.39 (d, J=5.6 Hz, 1H), 8.19 (s, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.27 (d, J=8.0 Hz, 1H), 7.06 (s, 3H), 6.43 (s, 1H), 6.37 (s, 1H), 5.03 (t, J=5.2 Hz, 1H), 4.62 (s, 2H), 3.82 (d, J=4.0 Hz, 2H), 2.41 (s, 3H), 1.81 (s, 3H); LC-MS: m/z=+455 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[CH:8]=1)([O-])=O>CO.[Pd]>[N:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][N:7]2[CH:8]=[C:4]([NH2:1])[CH:5]=[N:6]2)=[CH:12][CH:13]=1
Reactant: O=[N+]([O-])c1cnn(CCc2ccncc2)c1
Agent: [Pd]
Solvent: CO
Product: Nc1cnn(CCc2ccncc2)c1
Yield: 50.9 %

Procedure:
A solution of 4-[2-(4-nitro-1H-pyrazol-1-yl)ethyl]pyridine (9.9 g; 34 mmol; 1.0 eq.) in MeOH (250 mL) in presence of a catalytic amount of Pd/C was hydrogenated under 14 bars of H2 at RT. After completion, the reaction mixture was filtered through a celite pad and concentrated. The crude was purified by flash chromatography on silica (DCM:MeOH, gradient from 100:0 to 80:20) to afford the title compound as a brown solid (3.26 g, 51%). MS (ESI+): 189.0 (purity 87.9%). 1H NMR (400 Mz, DMSO-d6) δ 842-8.41 (d, J=5.9 Hz, 2H), 7.15-7.14 (d, J=5.8 Hz, 2H), 6.96 (s, 1H), 6.91 (s, 1H), 4.21-4.19 (t, J=7.4 Hz, 2H), 3.99 (brs, 2H), 3.05-3.03 (t, J=7.1 Hz, 2H, t).