Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[C:17]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH:16]=[CH:15][C:14]=3[S:23]([NH:26]C(C)(C)C)(=[O:25])=[O:24])=[CH:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.B(Cl)(Cl)Cl.O>C(Cl)Cl>[N:1]1([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([C:13]3[CH:18]=[C:17]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH:16]=[CH:15][C:14]=3[S:23]([NH2:26])(=[O:24])=[O:25])=[CH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(C)Cc1ccc(S(=O)(=O)NC(C)(C)C)c(-c2ccc(Cn3ccnc3)cc2)c1
Agent: ClB(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: CC(C)Cc1ccc(S(N)(=O)=O)c(-c2ccc(Cn3ccnc3)cc2)c1
Reaction time: 0.5 h

Procedure:
To a solution of 2-(4-imidazol-1-ylmethylphenyl)-4-iso-butyl-N-tert-butylbenzene-sulfonamide (0.211 mmol, 90.0 mg, see step (c) above) in CH2Cl2 (5 mL) was added BCl3 (1.5 mL, 1M, 1.5 mmol) under N2 (g). The mixture was stirred for 0.5 h. Water (50 mL) was added and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic phases were washed with brine and dried over MgSO4 and the solvent was removed in vacuo. The crude product was used directly in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[CH2:16][CH2:15]1.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[C:32]([CH:35]=O)[S:33][CH:34]=2)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[O:20]=[S:17]1(=[O:21])[CH2:18][CH2:19][CH:14]([C:5]2[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=[C:2]([C:30]4[CH:31]=[C:32]([CH2:35][N:7]([CH2:6][CH3:5])[CH3:8])[S:33][CH:34]=4)[CH:3]=3)[NH:7][CH:6]=2)[CH2:15][CH2:16]1
Reactant: CC1(C)OB(c2csc(C=O)c2)OC1(C)C
Reactant: NC(=O)c1cc(Br)cc2c(C3CCS(=O)(=O)CC3)c[nH]c12
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: O
Solvent: C1COCCO1
Product: CCN(C)Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCS(=O)(=O)CC4)c3c2)cs1
Temperature: 150 °C
Yield: 5.4 %

Procedure:
To 5-bromo-3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-indole-7-carboxamide (400 mg, 1.08 mmol) in dioxane and water (4 mL/1 mL) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-thiophenecarbaldehyde (462 mg, 1.94 mmol), Pd(PPh3)4 (100 mg) and K2CO3 (447 mg, 3.24 mmol). The reaction mixture was heated to 150° C. for 20 minutes by microwave irradiation. The organic phase was concentrated and redissolved in DMSO (10 mL). The resulting solution was split to eight. NaBH3CN (30 mg), ZnCl2 (30 mg) and methyl ethylamine (50 mg) were added. The mixture was heated at 100° C. for 30 minutes which was then filtered and purified by HPLC with TFA to afford the title compound (13 mg).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=1[CH3:17].O=P(Cl)(Cl)Cl>>[CH3:10][C:11]1[CH:12]=[C:13]([CH:14]=[CH:15][C:16]=1[CH3:17])[C:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:9]
Reactant: Cc1ccccc1C
Reactant: O=C(O)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc(C(=O)c2ccccc2)cc1C
Temperature: 140 °C

Procedure:
Synthesis of the novel compounds was carried out according to the following method. Benzoic acid (1.68 moles) was added to 3.96 moles of o-xylene and 0.6 mole POCl3 and refluxed at 140° C. for 11 hours. The reaction product was cooled to room temperature, washed once with 500 ml. of water, twice with 300 ml. of 5% of Na2C03 and twice again with 500 ml. of water. After washing, the xylene was distilled and the residue was vacuum distilled to obtain 3,4-dimethylbenzophenone. A mixture of 3,4-dimethylbenzophenone (1.0 mole), benzoyl peroxide (5 grams), chlorobenzene (800 ml.) and 3.0 moles of sulfuryl chloride was heated at 90° C. for 31/2 hours. During the last 30 minutes of the reaction nitrogen was passed through the reactor to remove the excess sulfuryl chloride. The resultant mixture was cooled and 50 grams of carbon black was added and the mixture stirred for 30 minutes, after which the carbon black was removed by filtration. The product 3,4-bis(chloromethyl)benzophenone was isolated by stripping of the solvent. Analysis found: 62.1% C, 4.3% H, and 27.1% Cl. Theoretical: 64.5% C, 4.3% H, and 25.5% Cl.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:16][C:17]([OH:19])=O.C(Cl)(=O)C(Cl)=O.C[N:27](C)C=O.O>O1CCCC1>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:16][C:17]([NH2:27])=[O:19]
Reactant: O=C(O)Cc1ccc2c(c1)CCc1ccccc1S2
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)Cc1ccc2c(c1)CCc1ccccc1S2
Temperature: 25 °C
Reaction time: 14 h
Yield: 66 %

Procedure:
To 100 mg of (10,11-dihydro dibenzo[b,f]thiepin-2-yl)-acetic acid in 5 ml of dry tetrahydrofuran were added 0.2 g of oxalyl chloride and a drop of dimethylformamide, and the mixture was stirred with ice cooling under a dry atmosphere for 3 hours. To the mixture was added 5 ml of tetrahydrofuran containing 1% ammonia, and the mixture was stirred under a dry atmosphere at room temperature for 14 hours. After the addition of water, the mixture was extracted with ethyl acetate. The extract was washed with a 1% sodium hydroxide solution and then with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a residue, which was recrystallized from ethyl acetate, thereby obtaining 66 mg (yield: 66%) of (10,11-dihydro dibenzo[b,f]thiepin-2-yl)-acetamide as colorless crystals having a melting point of 188°-189° C.
Reaction SMILES: [ClH:1].[NH2:2][N:3]=[CH:4][NH:5][NH:6][CH2:7][C:8]([OH:10])=[O:9].[CH2:11](O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[ClH:1].[C:12]1([CH2:11][O:9][C:8](=[O:10])[CH2:7][NH:6][NH:5][CH:4]=[N:3][NH2:2])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCc1ccccc1
Reactant: NN=CNNCC(=O)O
Agent: Cl
Product: NN=CNNCC(=O)OCc1ccccc1
Yield: 82 %

Procedure:
HCl (g) was bubbled through a suspension of [2-(aminoiminomethyl)hydrazino]-acetic acid (2.00 g, 15.2 mmol) in benzyl alcohol (30 mL). The reaction was stirred for about an hour until everything was in solution. The crude product was precipitated out by adding Et2O. This material was recrystallized from MeOH/EtOAc to yield [2-(aminoiminomethyl)hydrazino] acetic acid phenylmethyl ester monohydrochloride (3.20 g, 82%) as a white crystalline solid.
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[C:11](O)=[O:12])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.S(Cl)([Cl:21])=O>>[CH3:1][C:2]1([C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[C:11]([Cl:21])=[O:12])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COc1ccc(C(=O)O)cc1C1(C)CCCCC1
Reactant: O=S(Cl)Cl
Product: COc1ccc(C(=O)Cl)cc1C1(C)CCCCC1
Yield: 100 %

Procedure:
1.24 g (5 mmoles) of 3-(1-methylcyclohexyl)-4-methoxybenzoic acid and 15 ml of thionyl chloride are heated at reflux until the cessation of gas evolution. The reaction mixture is evaporated to dryness. 1.32 g (100% yield) of crude 3-(1-methylcyclohexyl)-4-methoxybenzoic acid chloride which is used as such for the following synthesis are obtained.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]23[CH2:18][CH2:17][C:14]([NH2:19])([CH2:15][CH2:16]2)[CH2:13][CH2:12]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:20]([N:28]=[C:29]=[S:30])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[C:20]([NH:28][C:29]([NH:19][C:14]12[CH2:17][CH2:18][C:11]([C:8]3[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=3)([CH2:16][CH2:15]1)[CH2:12][CH2:13]2)=[S:30])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CS(=O)(=O)c1ccc(C23CCC(N)(CC2)CC3)cc1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C23CCC(NC(=S)NC(=O)c4ccccc4)(CC2)CC3)cc1
Yield: 97.4 %

Procedure:
To a 100 mL round-bottomed flask equipped with magnetic stirring was added 4-(4-(methylsulfonyl)phenyl)bicyclo[2.2.2]octan-1-amine (120 mg, 429 μmol) in 2 mL of CH2Cl2, and benzoyl isothiocyanate (63.6 μl, 472 μmol). The reaction was stirred at ambient temperature for ca. 26 h, and then it was concentrated in vacuo to give 1-benzoyl-3-(4-(4-(methylsulfonyl)phenyl)bicyclo[2.2.2]octan-1-yl)thiourea (mass=185 mg, Mass spec. m/z+ion=443.2). The crude reaction product was taken onto the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].Br[CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C1COCC1.O.[I-].[K+]>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: Oc1ccc(F)cc1Br
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(C)Oc1ccc(F)cc1Br
Reaction time: 2 h
Yield: 86.6 %

Procedure:
Scheme IA, step A: 2-bromo-4-fluorophenol (15.0 g, 78.5 mmol) was dissolved in THF (200 mL) and treated with potassium carbonate (13.0 g, 94.2 mmol) and ethyl 2-bromopropionate (11.2 mL, 86.4 mmol). The reaction mixture was heated at reflux for 3 hours. Potassium iodide (0.1 g) was added and the reaction mixture was stirred for an additional 2 hours at reflux. The reaction was then cooled, diluted with water and extracted with ethyl acetate. The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by flash chromatography to provide ethyl 2-(2′-bromo-4′-fluorophenoxy)propionate (19.8 g) as a clear oil.
Reaction SMILES: C[O:2][C:3](=[O:40])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:10]([OH:39])=[C:11]2[C:16](=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[N:18]=1)[N:15]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:14](=[O:32])[C:13]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[CH:12]2)=[O:8].[OH-].[Na+].CO.C1COCC1>C([O-])(O)=O.[Na+]>[CH2:25]([N:15]1[C:16]2[C:11](=[C:10]([OH:39])[C:9]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:40])=[O:2])=[O:8])=[N:18][C:17]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:12]=[C:13]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:14]1=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)CCNC(=O)c1nc(-c2ccccn2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCNC(=O)c1nc(-c2ccccn2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 29.8 %

Procedure:
A mixture of 3-[(1-benzyl-5-hydroxy-2-oxo-3-phenyl-8-pyridin-2-yl-1,2-dihydro-[1,7]naphthyridine-6-carbonyl)-amino]-propionic acid methyl ester (62 mg, 0.116 mmol), 2 M NaOH (3 mL), MeOH (3 mL) and THF (3 mL) was stirred at r.t. for 16 h, then concentrated to approximately one-third of its original volume. 1 M HCl was added until pH was about 3-4, and the resulting suspension was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The crude product was purified twice by silica gel chromatography (100% EtOAc, then 10-60% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4, and the resulting precipitate was isolated by filtration to give 18 mg of the title compound. MS: (+) m/z 521.41 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.[H-].[Na+].Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>C1COCC1>[CH2:19]([C:5]1([CH2:13][CH2:14][CH2:2][CH2:3][CH2:4][CH2:12][CH2:11][CH3:10])[C:4]2[CH:3]=[C:2]([Br:1])[CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=2)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCBr
Reactant: Brc1ccc2c(c1)Cc1cc(Br)ccc1-2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCC1(CCCCCCCC)c2cc(Br)ccc2-c2ccc(Br)cc21
Temperature: 60 °C
Yield: 150.4 %

Procedure:
To a solution of 28.5 g (88 mmol) 2,7-dibromofluorene in 800 mL THF was added 8.8 g (220 mmol) sodium hydride (60%) in several portions at room temperature. The mixture was heated at 60° C. and 43 g (220 mmol) bromooctane in 200 mL THF was added dropwisely into the mixture and refluxed overnight. The mixture was concentrated and diluted with water, and then extracted with diethyl ether. After washing with brine, the ether solution was dried over anhydrous MgSO4 and the ether was then removed by evaporation. This crude solid was purified by a silica chromography with hexane and recrystallized from ethanol to give white solid (36.3 g, yield 75.3%, mp. 52˜54° C.). 1H NMR (500 MHz, CDCl3), δ (ppm): 7.51 (2H, d), 7.44 (2H, d), 7.41 (2H, s), 1.89 (4H, m), 1.02˜1.20 (20H, m), 0.81 (6H, t), 0.56 (4H, m).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si](C(C)(C)C)(C)C)[CH2:12][C@@H:11]([N:23]2[C:27]3[N:28]=[CH:29][N:30]=[C:31]([NH:32][CH2:33][CH:34]4[CH2:36][CH2:35]4)[C:26]=3[CH:25]=[CH:24]2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C1COCC1.N1C=CC=CC=1.F.N1C=CC=CC=1>[Si:1]([O:8][C@H:9]1[CH2:10][C@H:11]([N:23]2[C:27]3[N:28]=[CH:29][N:30]=[C:31]([NH:32][CH2:33][CH:34]4[CH2:36][CH2:35]4)[C:26]=3[CH:25]=[CH:24]2)[CH2:12][C@H:13]1[CH2:14][OH:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](n2ccc3c(NCC4CC4)ncnc32)C[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: F
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](n2ccc3c(NCC4CC4)ncnc32)C[C@H]1CO
Reaction time: 5 h
Yield: 60 %

Procedure:
7-[(1R,3S,4S)-3-{[tert-Butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]-oxy}methyl)cyclopentyl]-N-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (100. mg, 0.188 mmol) was dissolved in THF (0.900 mL) and pyridine (0.900 mL). Pyridine hydrofluoride (7 drops) was added and the reaction was stirred for 5 h. Additional pyridine hydrofluoride (3 drops) was added and the reaction was stirred for 2 h before being quenched with saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted using EtOAc (3×10 mL), and the combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with a gradient of 0 to 50% EtOAc in hexanes to afford the title compound (47.0 mg, 50%). LC/MS: Rt=1.53 min, ES+ 417 (FA standard).
Reaction SMILES: [CH3:1][C:2]1[N:7]2[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)=[C:9]([NH2:11])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:28]([CH2:32][C:33](Cl)=[O:34])([CH3:31])([CH3:30])[CH3:29]>C(#N)C>[CH3:29][C:28]([CH3:31])([CH3:30])[CH2:32][C:33]([NH:11][C:9]1[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]2[C:8]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=1)=[O:34]
Reactant: Cc1cccc2nc(N)c(-c3cccc(C(F)(F)F)c3)n12
Reactant: CC(C)(C)CC(=O)Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: Cc1cccc2nc(NC(=O)CC(C)(C)C)c(-c3cccc(C(F)(F)F)c3)n12
Temperature: 25 °C
Reaction time: 4 h
Yield: 50.1 %

Procedure:
5-Methyl-3-(3-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridin-2-ylamine (compound s, 0.05 g, 0.0002 mol) was dissolved in acetonitrile (0.9 mL) and pyridine (0.03 mL, 0.0003 mol). t-butylacetyl chloride (0.028 mL, 0.00020 mol) was added and the mixture was stirred at room temperature for 4 hours. Solvent was removed then ethyl acetate and saturated sodium bicarbonate was added. The layers were separated and the organic layer dried (magnesium sulfate) then removed. The crude product was chromatographed using 60% ethyl acetate/hexanes to give 39 mg of 3,3-Dimethyl-N-[5-methyl-3-(3-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridin-2-yl]-butyramide as a white solid. Rf 0.27, 100% ethyl acetate; MS m/z 390 (M+H). SH-SY5Y_EC50: 0.3399.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9](=O)[CH:8](Br)[CH2:7]1)=[O:5])[CH3:2].[C:14]([NH2:24])(=[O:23])/[CH:15]=[CH:16]/[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9]2[N:24]=[C:14](/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:23][C:8]=2[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(=O)C(Br)C1
Reactant: NC(=O)/C=C/c1ccccc1
Product: CCOC(=O)N1CCc2nc(/C=C/c3ccccc3)oc2C1
Temperature: 125 °C
Reaction time: 60 h
Yield: 26.7 %

Procedure:
A mixture of 3-bromo-4-oxo-1-piperidinecarboxylic acid ethyl ester (13.5 g, 26.99 mmol) and trans-cinnamamide (3.0 g, 20.7 mmol) was supported in silica gel (48 g) and mechanically stirred at 125° C. for 60 hours. The product was eluted from the silica gel with a 7M solution of ammonia in MeOH (3×140 mL). The filtrate was evaporated in vacuo and the crude product was basified with a saturated solution of NaHCO3 and extracted with DCM. The organic layer was separated, dried (Na2SO4), filtered and the solvent evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 20/80). The desired fractions were collected and the solvents evaporated in vacuo to yield 6,7-dihydro-2-[(E)-2-phenylethenyl]-oxazolo[5,4-c]pyridine-5(4H)-carboxylic acid ethyl ester (1.65 g, 27% yield) as an orange oil. C17H18N2O3 LCMS: Rt 2.91, m/z 299 [M+H]+ (using method, LC-MS Method 6)
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[CH:21]=[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:19]=[C:18]([NH2:28])[N:17]=3)=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[N:29]1([CH2:35][CH2:36][OH:37])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.[OH-].[K+].C1OCCOCCOCCOCCOCCOC1>C1(C)C=CC=CC=1.O>[N:29]1([CH2:35][CH2:36][O:37][C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:14]=[CH:13][C:12]([NH:15][C:16]4[CH:21]=[C:20]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[N:19]=[C:18]([NH2:28])[N:17]=4)=[CH:11][CH:10]=3)[CH:5]=[CH:4][N:3]=2)[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1
Reactant: OCCN1CCOCC1
Reactant: Nc1nc(Nc2ccc(Oc3ccnc(Cl)c3)cc2)cc(-c2ccccc2)n1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: Nc1nc(Nc2ccc(Oc3ccnc(OCCN4CCOCC4)c3)cc2)cc(-c2ccccc2)n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 15.2 %

Procedure:
N4-[4-(2-chloro-pyridin-4-yloxy)-phenyl]-6-phenyl-pyrimidine-2,4-diamine (Example 48, 75 mg, 0.19 mmol) was dissolved in toluene (1.5 mL). 2-Morpholin-4-yl-ethanol (61 mg, 0.46 mmol), powdered KOH (22 mg, 0.38 mmol), and 18-crown-6 (20 mg, 0.08 mmol) were subsequently added. The mixture was stirred at 90° C. overnight, after which time it was diluted with water and extracted with both ethyl acetate and dichloromethane. The combined organic extracts were concentrated and the residue was purified by prep HPLC to give the title compound (14 mg, 15%). 1H NMR (DMSO-d6) δ 10.79 (br s, 1H), 9.99 (br s, 1H), 8.08 (d, J=5.8 Hz, 1H), 7.90 (m, 2H), 7.77 (dd, J=7.6, 2.0 Hz, 2H), 7.64 (m, 3H), 7.21 (d, J=8.9 Hz, 2H), 6.69 (dd, J=5.8, 2.1 Hz, 1H), 6.60 (s, 1H), 6.22 (d, J=2.2 Hz, 1H), 4.57 (t, J=5.1 Hz, 2H), 3.96 (m, 2H), 3.68 (m, 2H), 3.50 (m, 4H), 3.15 (m, 2H); MS ES: 485 (M+H)+, calcd 485, RT=1.96 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10].CO[CH:13]1[CH2:17][CH2:16][CH:15](OC)O1>C(O)(=O)C>[N:1]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]#[N:10])[CH:13]=[CH:17][CH:16]=[CH:15]1
Reactant: N#CCc1ccccc1N
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Product: N#CCc1ccccc1-n1cccc1

Procedure:
Under inert atmosphere a solution of 500 mg (3.783 mmol) of 2-Aminophenylacetonitrile and 1 mL (7.566 mmol) of 2,5-Dimethoxytetrahydrofuran in 5 mL of acetic acid was heated to 60° C. for 2 hours. After cooling the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on SiO2 using cyclohexane/ethyl acetate mixture of increasing polarity (from 100% cyclohexane to 100% ethyl acetate) as eluent. The title compound was obtained as a light yellow oil (470 mg, 68.2%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:39])[C:5]([C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]3[O:36][CH2:35][CH2:34][C@H:17]4[S:18](=[O:33])(=[O:32])[C:19]([CH3:31])([CH3:30])[C:20]([NH:22]C(=O)OC(C)(C)C)=[N:21][C@:16]4([CH3:37])[C:15]=3[CH:38]=2)=[O:9])=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:22][C:20]1[C:19]([CH3:31])([CH3:30])[S:18](=[O:32])(=[O:33])[C@@H:17]2[CH2:34][CH2:35][O:36][C:14]3[CH:13]=[CH:12][C:11]([NH:10][C:8](=[O:9])[C:5]4[C:4]([CH3:39])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=4)=[CH:38][C:15]=3[C@@:16]2([CH3:37])[N:21]=1
Reactant: Cc1cc(Cl)cnc1C(=O)Nc1ccc2c(c1)[C@@]1(C)N=C(NC(=O)OC(C)(C)C)C(C)(C)S(=O)(=O)[C@@H]1CCO2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(Cl)cnc1C(=O)Nc1ccc2c(c1)[C@@]1(C)N=C(N)C(C)(C)S(=O)(=O)[C@@H]1CCO2
Yield: 97.9 %

Procedure:
A solution of trans-isomer tert-butyl ((4aR,11bR)-10-(5-chloro-3-methylpicolinamido)-3,3,11b-trimethyl-4,4-dioxido-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazin-2-yl)carbamate (110 mg, 0.191 mmol) in DCM (2 ml) was treated with TFA (0.7 ml, 9.53 mmol) for 10 min at RT. The mixture was concentrated to dryness, redissolved in 0.5 ml of MeOH and neutralized with saturated solution NaHCO3. Precipitated material was extracted with ethyl acetate, organic extract was washed with water, brine, filtered through pad of celite and concentrated to afford N-((4aR,11bR)-2-amino-3,3,11b-trimethyl-4,4-dioxido-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazin-10-yl)-5-chloro-3-methylpicolinamide (89 mg, 0.187 mmol, 98% yield). LC/MS (ESI+) m/z=477.
Reaction SMILES: [C:1]([CH:3]([NH:9][C:10]([C:12]1[S:16][C:15](Br)=[N:14][C:13]=1[CH2:18][CH3:19])=[O:11])[C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)#[N:2].C(N(CC)CC)C.[CH2:27]([NH2:30])[CH:28]=[CH2:29]>O1CCCC1>[C:1]([CH:3]([NH:9][C:10]([C:12]1[S:16][C:15]([NH:30][CH2:27][CH:28]=[CH2:29])=[N:14][C:13]=1[CH2:18][CH3:19])=[O:11])[C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: C=CCN
Reactant: CCc1nc(Br)sc1C(=O)NC(C#N)c1cccs1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCNc1nc(CC)c(C(=O)NC(C#N)c2cccs2)s1
Yield: 61 %

Procedure:
1.0g of 2-bromo-4-ethyl-thiazole-5-carboxylic acid (cyano-thiophen-2-yl-methyl)-amide, 0.40ml of triethylamine and 0.66ml of allylamine were added to 10ml of tetrahydrofuran. The reaction mixture was stirred under reflux for 12 hours and then treated according to the same procedure as EXAMPLE 10 to obtain 0.57g (Yield 61%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([N:11]([CH3:13])[CH3:12])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])(=O)C.[Na+].[Br:26]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.C(O)(=O)C>[NH2:1][C:2]1[N:10]=[C:9]([N:11]([CH3:12])[CH3:13])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:26])[N:6]2[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrBr
Reactant: CN(C)c1nc(N)c2ncn(Cc3ccccc3)c2n1
Agent: CC(=O)[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN(C)c1nc(N)c2nc(Br)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
6-Amino-9-benzyl-2-dimethylaminopurine (66 mg, 0.25 mmol) was dissolved in a mixture of methylene chloride (50 ml) and acetic acid (10 ml). To the solution were added sodium acetate (202 mg, 2.46 mmol) and bromine (0.5 ml), and the mixture was stirred at room temperature for 1 hour. Aqueous sodium thiosulfate was added to the reaction mixture. The organic layer was separated, washed with aqueous saturated sodium hydrogen carbonate, dried on sodium sulfate and filtered. The solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (68 mg, yield 80%).