Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[C:5]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].N1C=CC=CC=1.[CH2:22]([O:29][C:30](Cl)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:22]([O:29][C:30]([N:13]1[CH2:12][CH2:11][N:10]([C:5]2[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=[CH:7][N:6]=2)[CH2:15][CH2:14]1)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=[N+]([O-])c1cccnc1N1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(OCc1ccccc1)N1CCN(c2ncccc2[N+](=O)[O-])CC1
Reaction time: 1.5 h

Procedure:
1-(3--Nitro-2-pyridinyl)piperazine is dissolved in 175 ml of methylene chloride and cooled to 0°. Then pyridine is added followed by benzylchloroformate (16.5 ml). The reaction is stirred 1.5 hr, then poured into saturated aqueous sodium bicarbonate and extracted with chloroform, dried over anhydrous sodium sulfate and concentrated in vacuo to afford the title compound, NMR (300 MHz, CDCl3) 8.34, 8.15, 7.38-7.32, 6.81, 5.17, 3.65 and 3.45 δ.
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:33])[NH:6][C:7]1[C:8]([CH3:32])=[C:9]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[C:11]=2[C:24]=1[CH3:25].[NH2:36][CH2:37][CH2:38][OH:39]>CCCCCC.C(OCC)(=O)C>[OH:39][CH2:38][CH2:37][NH:36][C:5]([NH:6][C:7]1[C:8]([CH3:32])=[C:9]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:22])[CH3:23])=[CH:17][CH:16]=3)[C:11]=2[C:24]=1[CH3:25])=[O:33]
Reactant: NCCO
Reactant: Cc1c(NC(=O)OCC(Cl)(Cl)Cl)c(C)c2c(c1-c1ccccc1)OCC2c1ccc(C(C)C)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1c(NC(=O)NCCO)c(C)c2c(c1-c1ccccc1)OCC2c1ccc(C(C)C)cc1
Yield: 59 %

Procedure:
Using 2,2,2-trichloroethyl(3-(4-isopropylphenyl)-4,6-dimethyl-7-phenyl-2,3-dihydro-1-benzofuran-5-yl)carbamate obtained in Example 142 and 2-aminoethanol, the title compound was synthesized in the same manner as in Example 143. Yield: 59%. Melting point: 152-155° C. (hexane-ethyl acetate).
Reaction SMILES: N[C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.[Cl:12][Si](Cl)(C)C.N(OCCC(C)C)=O>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.CCCCCCC>[Cl:12][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Reactant: C[Si](C)(Cl)Cl
Agent: CC(C)CCON=O
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: CCCCCCC
Product: Clc1nc(Cl)c2[nH]cnc2n1
Temperature: 55 °C
Reaction time: 17 h
Yield: 66 %

Procedure:
2-Amino-6-chloropurine (5.00 g, 29.5 mmol), dichlorodimethylsilane (11.42 g, 88.5 mmol), benzyltriethylammonium chloride (0.40 g, 1.8 mmol) and isoamyl nitrite (5.18 g, 44.2 mmol) were added to heptane (25 ml), and the mixture was heated to 50-60° C. and stirred for 17 hr. After the completion of the reaction, the mixture was filtrated. The obtained crystals were diluted with water (25 ml) and adjusted to pH 4-5 with a 2M aqueous sodium hydroxide solution. After aging under ice-cooling for 1 hr, the mixture was filtrated, and the obtained crystals were recrystallized from methanol. The mixture was dried under reduced pressure at 60° C. to give 2,6-dichloropurine as a white powder (3.68 g, yield 66.1%). The properties of the obtained compound were the same as in Example 1(2).
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:9]([NH:11][C@H:12]([C:16]([NH:18][CH:19]([CH:27]([OH:54])[CH:28]([NH:36][C:37](=[O:53])[C@H:38]([CH:50]([CH3:52])[CH3:51])[NH:39][C:40](=[O:49])[C@H:41]([CH:46]([CH3:48])[CH3:47])[NH:42][C:43](=[O:45])[CH3:44])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[CH:6]([CH3:8])[CH3:7])(=[O:3])[CH3:2]>CC(C)=O.[Cr](O)(O)(=O)=O>[C:1]([NH:4][C@H:5]([C:9]([NH:11][C@H:12]([C:16]([NH:18][CH:19]([C:27](=[O:54])[CH:28]([NH:36][C:37](=[O:53])[C@H:38]([CH:50]([CH3:52])[CH3:51])[NH:39][C:40](=[O:49])[C@H:41]([CH:46]([CH3:48])[CH3:47])[NH:42][C:43](=[O:45])[CH3:44])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:17])[CH:13]([CH3:14])[CH3:15])=[O:10])[CH:6]([CH3:7])[CH3:8])(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@H](C(=O)N[C@H](C(=O)NC(Cc1ccccc1)C(O)C(Cc1ccccc1)NC(=O)[C@@H](NC(=O)[C@@H](NC(C)=O)C(C)C)C(C)C)C(C)C)C(C)C
Agent: O=[Cr](=O)(O)O
Solvent: CC(C)=O
Product: CC(=O)N[C@H](C(=O)N[C@H](C(=O)NC(Cc1ccccc1)C(=O)C(Cc1ccccc1)NC(=O)[C@@H](NC(=O)[C@@H](NC(C)=O)C(C)C)C(C)C)C(C)C)C(C)C
Reaction time: 1.25 h
Yield: 8.8 %

Procedure:
A solution of the resultant compound of Example 59 (0.056 mmol) in 10 ml of acetone was cooled to 0° C. and treated with 5 drops of aqueous chromic acid. After 1.25 h, the solution was quenched with 2-propanol and aqueous NaHCO3, filtered through Celite, extracted with 10% methanol in chloroform, and concentrated in vacuo. Flash chromatography using 7.5% methanol in chloroform gave 3.7 mg (9%) of the desired compound (Rf 0.39, 10% methanol in chloroform). Mass spectrum (M+H)+ =749.
Reaction SMILES: ClC1N=C(N2CCOCC2)C2SC=CC=2N=1.[NH2:17][C:18]1[CH:22]=[CH:21][S:20][C:19]=1[C:23]([O:25]C)=O.[O-:27][C:28]#[N:29].[K+]>C(O)(=O)C.O>[NH:17]1[C:18]2[CH:22]=[CH:21][S:20][C:19]=2[C:23](=[O:25])[NH:29][C:28]1=[O:27]
Reactant: COC(=O)c1sccc1N
Reactant: N#C[O-]
Agent: Clc1nc(N2CCOCC2)c2sccc2n1
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]c(=O)c2sccc2[nH]1

Procedure:
Scheme 1 shows the synthesis of 4-(2-chlorothieno[3,2-d]primidin-4-yl)morpholine 4 starting by cyclization of methyl 3-amino-thiophenecarboxylate 1 and potassium cyanate in acetic acid and water at room temperature to give thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione 2. This is an improvement over cyclization of 1 with urea which requires high temperature and evolution of ammonia gas. Thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione 2 was converted to 2,4-dichlorothieno[3,2-d]pyrimidine 3 with phosphorous oxychloride and a catalytic amount of N,N-dimethylaniline (0.75 equiv.) in acetonitrile. Selective substitution at the 4-position with morpholine gave 4.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]([NH:18][CH3:19])=[O:17])[CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:3]=1[C:29]#[N:30].Cl.[NH:32]1[CH2:35][CH:34]([OH:36])[CH2:33]1.C(N(CC)CC)C>CN(C=O)C>[C:20]([C:5]1[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]([NH:18][CH3:19])=[O:17])[CH:11]=2)=[N:7][C:2]([N:32]2[CH2:35][CH:34]([OH:36])[CH2:33]2)=[C:3]([C:29]#[N:30])[C:4]=1[C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)#[N:21]
Reactant: CNC(=O)c1cc(COc2nc(Cl)c(C#N)c(-c3ccc(F)cc3)c2C#N)ccn1
Reactant: OC1CNC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1cc(COc2nc(N3CC(O)C3)c(C#N)c(-c3ccc(F)cc3)c2C#N)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50 mg (0.12 mmol) of 4-({[6-chloro-3,5-dicyano-4-(4-fluorophenyl)pyridin-2-yl]oxy}methyl)-N-methylpyridine-2-carboxamide Example 81A were initially charged in 1.5 ml of DMF. After addition of 26 mg (0.24 mmol) of azetidin-3-ol hydrochloride and 24 mg (0.24 mmol) of triethylamine, the mixture was stirred at RT overnight. The reaction mixture was purified by preparative HPLC (Chromasil, water/acetonitrile).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C@H:3]([N:7]1[CH:11]=[C:10]([C:12]2[C:13]3[CH:20]=[CH:19][N:18]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:14]=3[N:15]=[CH:16][N:17]=2)[CH:9]=[N:8]1)[CH2:4][C:5]#N.[H-].C([Al+]CC(C)C)C(C)C.C[OH:42].Cl>C(Cl)Cl.O>[F:1][C:2]([F:29])([F:30])[C@H:3]([N:7]1[CH:11]=[C:10]([C:12]2[C:13]3[CH:20]=[CH:19][N:18]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:26])([CH3:27])[CH3:28])[C:14]=3[N:15]=[CH:16][N:17]=2)[CH:9]=[N:8]1)[CH2:4][CH:5]=[O:42]
Reactant: CO
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn([C@H](CC#N)C(F)(F)F)c3)ncnc21
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: O
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn([C@H](CC=O)C(F)(F)F)c3)ncnc21
Temperature: -47.5 °C
Reaction time: 3 h
Yield: 84.3 %

Procedure:
To a −70° C. solution of (3R)-4,4,4-trifluoro-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile (1.06 g, 0.00243 mol) (see, Example 93, Step 1) in DCM (10 mL, 0.2 mol) was added 1.0 M diisobutylaluminum hydride in DCM (4.8 mL). The resulting mixture was stirred for 3 h and allowed to warm during this time interval from −70 to −25° C., after which the reaction was cooled back at −70° C. Methanol (1.5 mL, 0.037 mol) was added, followed by 2.0 M HCl in water (15 mL). Insoluble material was then filtered from the reaction mixture. The organic filtrate was washed sequentially with: 2.0 M HCl in water, water and saturated aqueous NaCl. The washed organic phase was dried over sodium sulfate and was concentrated using a rotory evaporator to give 0.58 g of the crude product as a pale yellow foam/solid. The crude product was chromatographed with 0-80% ethyl acetate/hexanes to give the purified product (0.9 g) as a pale orange oil (47% yield).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].[Cl:7][C:8]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:11]=[C:10]2[NH:18][CH:19]=[C:20]([NH2:21])[C:9]=12.[Li+].[OH-]>N1C=CC=CC=1.C1COCC1>[Cl:7][C:8]1[C:13]([C:14]([F:17])([F:15])[F:16])=[CH:12][N:11]=[C:10]2[NH:18][CH:19]=[C:20]([NH:21][C:4](=[O:5])[CH2:3][O:2][CH3:1])[C:9]=12
Reactant: Nc1c[nH]c2ncc(C(F)(F)F)c(Cl)c12
Reactant: COCC(=O)Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COCC(=O)Nc1c[nH]c2ncc(C(F)(F)F)c(Cl)c12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 98.1 %

Procedure:
2-Methoxyacetyl chloride (0.074 mL, 0.76 mmol) was added to a solution of 4-chloro-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-amine (120 mg, 0.51 mmol, Example 12, Steps A-G) in pyridine (5 mL) at 0° C. The reaction was stirred at 0° C. for 10 minutes, and the pyridine was removed in vacuo. The residue obtained was dissolved in THF (5 mL), treated with 2N LiOH (3 mL) and stirred for 20 minutes. THF was then removed under reduced pressure, and the aqueous slurry obtained was extracted with water (20 mL) and ethyl acetate (50 mL). The organic layer was separated, washed with brine, dried (Na2SO4) and concentrated in vacuo to provide N-(4-chloro-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxyacetamide (154 mg, 98% yield) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[CH:6]=[CH:5][C:4]=1[NH2:17].CS([C:21]1[N:26]=[CH:25][C:24]2=[CH:27][CH:28]=[C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[N:36]([CH3:41])[S:37]([CH3:40])(=[O:39])=[O:38])[N:23]2[N:22]=1)=O>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[CH:6]=[CH:5][C:4]=1[NH:17][C:21]1[N:26]=[CH:25][C:24]2=[CH:27][CH:28]=[C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[N:36]([CH3:41])[S:37]([CH3:40])(=[O:39])=[O:38])[N:23]2[N:22]=1
Reactant: CN(c1ccccc1-c1ccc2cnc(S(C)=O)nn12)S(C)(=O)=O
Reactant: COc1cc(OC2CCN(C)CC2)ccc1N
Product: COc1cc(OC2CCN(C)CC2)ccc1Nc1ncc2ccc(-c3ccccc3N(C)S(C)(=O)=O)n2n1
Yield: 7.2 %

Procedure:
Following a procedure analogous to 251c, 2-Methoxy-4-(1-methyl-piperidin-4-yloxy)-phenylamine (0.17 g, 0.72 mmol) and N-[2-(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-N-methyl-methanesulfonamide (130 mg, 0.36 mmol) were converted to the title compound (14 mgs, 7%). (CDCl3) δ 8.73 (s, 1H), 8.02 (d, J=10.7 Hz, 1H), 7.97-7.94 (m, 1H), 7.30 (s, 1H), 7.02-7.00 (m, 1H), 6.87-6.83 (m, 1H), 6.52 (s, 1H), 6.33 (d, J=10.6 Hz, 1H), 4.25 (Broad s, 1H), 3.89 (s, 3H), 3.15 (s, 3H), 2.75-2.68 (m, 2H), 2.66 (s, 3H), 2.32 (s, 3H), 2.31-2.26 (m, 2H), 2.04-1.98 (m, 2H), 1.87-1.81 (m, 2H); LC/MS (ESI+): 537 (M+H).
Reaction SMILES: Br.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[O:19][C:18]([NH2:20])=[N:17][N:16]=3)=[CH:11][CH:10]=2)[CH:3]=1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27]>N1C=CC=CC=1.CO>[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[O:19][C:18]([NH:20][C:26](=[O:27])[C:25]4[CH:29]=[CH:30][CH:31]=[C:23]([C:22]([F:21])([F:32])[F:33])[CH:24]=4)=[N:17][N:16]=3)=[CH:13][CH:14]=2)[CH:3]=1
Reactant: Nc1nnc(-c2ccc(Oc3cccnc3)cc2)o1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Agent: Br
Solvent: c1ccncc1
Solvent: CO
Product: O=C(Nc1nnc(-c2ccc(Oc3cccnc3)cc2)o1)c1cccc(C(F)(F)F)c1
Reaction time: 3 h
Yield: 23.5 %

Procedure:
5-[4-(Pyridin-3-yloxy)phenyl]-1,3,4-oxadiazol-2-amine hydrobromide salt (167.5 mg, 0.5 mmol) was suspended in 2 mL of anhydrous pyridine. 3-Trifluoromethylbenzoyl chloride (156.4 mg, 0.75 mmol) was added to the solution. The reaction mixture formed an orange-red solution with a small amount of white precipitate. It was left to stir for 3 hours. Then it was diluted with ca. 1 mL of MeOH, filtered through 0.22 u syringe filter and purified by reverse phase preparative HPLC using acetonitrile/water mixture containing 0.01% of TFA. Fractions, containing the product, were combined and partitioned between ca. 40 mL of EtOAc and ca. 40 mL of saturated aqueous NaHCO3. The EtOAc layer was washed with brine, dried over anhydrous sodium sulfate and filtered. Solvent was removed in vacuo to give the title product as a yellow solid (50.0 mg). Yield 23.4%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([CH:19]3[CH2:24][CH2:23][N:22]([C:25](=[O:27])[CH3:26])[CH2:21][CH2:20]3)=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2[nH]c(C3CCNCC3)cc2-c2ccncc2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)N1CCC(c2cc(-c3ccncc3)c(-c3ccc(F)cc3)[nH]2)CC1
Reaction time: 8 h

Procedure:
A solution of 10.0 mg of the product of Example 4 was dissolved in 0.5 ml of pyridine and treated with 2.6 μL of acetic anhydride. The solution was stirred overnight and diluted with 5 ml water and was extracted with ethyl acetate (2×5 ml). The combined organic phase was dried over MgSO4, filtered and concentrated in vacuo to give the title compound.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24](Cl)=[N:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>CS(C)=O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[N:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11]
Reactant: O=C(c1ccc(Oc2nccnc2Cl)cc1)c1nc2ccccc2s1
Reactant: C1COCCN1
Solvent: CS(C)=O
Product: O=C(c1ccc(Oc2nccnc2N2CCOCC2)cc1)c1nc2ccccc2s1
Temperature: 100 °C

Procedure:
To a solution of benzo[d]thiazol-2-yl(4-(3-chloropyrazin-2-yloxy)phenyl)methanone (185 mg, 0.503 mmol) in DMSO (2 mL) was added morpholine (219 μl, 2.52 mmol). The reaction mixture was heated at 100° C. for 2 h. The reaction mixture was partitioned between EtOAc and brine. The precipitate formed was collected by filtration, washed with EtOAc and water, dried to provide benzo[d]thiazol-2-yl(4-(3-morpholinopyrazin-2-yloxy)phenyl)methanone as light-yellow solid. MS (ESI, pos. ion) m/z: 419.0. IC50 (uM) ++.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:6][N:7]1[C:11]([C:12](=[O:29])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[N:18]([N:20]=[C:21]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)[N:22]=3)[CH:19]=2)=[C:10]([C:30](O)=[O:31])[CH:9]=[N:8]1>>[CH3:6][N:7]1[C:11]([C:12]([NH:13][C:14]2[CH:15]=[CH:16][C:17]3[N:18]([N:20]=[C:21]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)[N:22]=3)[CH:19]=2)=[O:29])=[C:10]([C:30]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:31])[CH:9]=[N:8]1
Reactant: C1CCNC1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccc2nc(-c3cccnc3)nn2c1
Product: Cn1ncc(C(=O)N2CCCC2)c1C(=O)Nc1ccc2nc(-c3cccnc3)nn2c1

Procedure:
Using pyrrolidine and 1-methyl-5-(2-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid, the title compound was prepared in the same manner as described for example 2. White solid (53 mg, 33%). Mp.: 251° C. MS: m/z=417.3 (M+H+).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:11]=[C:10]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH:19]([CH3:21])[CH3:20])[CH2:15][CH2:14]2)[CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].CC[N:24]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:25]C.C=CC1C=CC=CC=1.C=CC1C=CC(C=C)=CC=1.C1C2C(=CC=CC=2)CN1>C(Cl)Cl>[ClH:2].[Cl:2][C:3]1[CH:11]=[C:10]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH:19]([CH3:21])[CH3:20])[CH2:15][CH2:14]2)[CH:9]=[CH:8][C:4]=1[C:5]([N:24]1[CH2:25][C:29]2[C:28](=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:27]1)=[O:6]
Reactant: CC(C)N1CCC(Oc2ccc(C(=O)Cl)c(Cl)c2)CC1
Reactant: CCN(CC)Cc1ccccc1
Agent: C=Cc1ccc(C=C)cc1
Agent: Cl
Agent: c1ccc2c(c1)CNC2
Solvent: ClCCl
Solvent: C=Cc1ccccc1
Product: CC(C)N1CCC(Oc2ccc(C(=O)N3Cc4ccccc4C3)c(Cl)c2)CC1
Reaction time: 16 h
Yield: 72.9 %

Procedure:
A stirred mixture of 2-chloro-4-[(1-isopropyl-4-piperidinyl)oxy]benzoyl chloride hydrochloride (D33) (0.20 g) and diethylaminomethyl polystyrene (3.2 mmol/g, 1.0 g) in DCM (10 ml) at rt was treated with isoindoline (0.08 g) and stirred for 16 h. The reaction mixture was chromatographed directly [silica gel, step gradient 0-10% MeOH (containing 10% 0.880 ammonia solution) in DCM]. Fractions containing the required product were evaporated, redissolved in DCM, treated with excess hydrogen chloride (1M solution in diethyl ether) and then concentrated. The residue was crystallised from acetone to yield the title compound (E62) as a white solid (0.09 g). MS electrospray (+ion) 399/401 (MH+). 1H NMR δ (DMSO-d6): 10.90 (1H, s), 7.33-7.10 (6H, m), 6.96 (1H, m), 4.82-4.51 (3H, m), 4.39 (3H, m), 3.35 (2H, m), 3.00 (2H, m), 2.11-1.80 (4H, m), 1.17 (6H, m).
Reaction SMILES: C(OP([CH2:9][C:10]#[N:11])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:22]([O:24][C:25]1[CH:26]=[C:27]([C:33]([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:37]([OH:43])[CH:36]=2)=O)[CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH3:23].O>C1COCC1>[CH2:22]([O:24][C:25]1[CH:26]=[C:27](/[C:33](/[C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:37]([OH:43])[CH:36]=2)=[CH:9]\[C:10]#[N:11])[CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH3:23]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CCOc1cc(C(=O)c2ccc(OC)c(O)c2)ccc1OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1cc(/C(=C\C#N)c2ccc(OC)c(O)c2)ccc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
To a solution of cyanomethylphosphonic acid diethyl ester (8.1 mL, 51.6 mmol) in anhydrous THF (50 mL) was added lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 51.6 mL, 51.6 mmol) at 0° C. and stirred for 30 min at room temperature followed by addition of (3-ethoxy-4-methoxy-phenyl)-(3-hydroxy-4-methoxy-phenyl)-methanone (5.20 g, 17.2 mmol) in THF (40 mL) and refluxed overnight. The reaction mixture was poured into water (50 mL), extracted with CH2Cl2 (2×60 mL). The combined organic phases were washed with brine (60 mL), dried over MgSO4, and purified via flash column chromatography (EtOAc/Hexane) to give E/Z-3-(3-ethoxy-4-methoxy-phenyl) -3-(3-hydroxy-4-methoxy-phenyl)-acrylonitrile as an off-white solid (5.26 g, 94% yield). The product was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].[O:14]1[CH2:19][CH2:18][CH2:17][O:16][CH:15]1[CH2:20][CH2:21][CH:22]1[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29]O)[CH2:24][CH2:23]1.Cl.C(O)CCO>CCOCC>[O:14]1[CH2:19][CH2:18][CH2:17][O:16][CH:15]1[CH2:20][CH2:21][CH:22]1[CH2:23][CH2:24][CH:25]([CH:28]=[CH:29][C:4]2[CH:5]=[CH:6][C:7]([O:8][C:9]([F:12])([F:11])[F:10])=[C:2]([F:1])[CH:3]=2)[CH2:26][CH2:27]1
Reactant: OCCC1CCC(CCC2OCCCO2)CC1
Reactant: Fc1cc(Br)ccc1OC(F)(F)F
Agent: Cl
Solvent: OCCCO
Solvent: CCOCC
Product: Fc1cc(C=CC2CCC(CCC3OCCCO3)CC2)ccc1OC(F)(F)F
Temperature: 0 °C
Reaction time: 3 h
Yield: 52.3 %

Procedure:
A Grignard reagent prepared from 3-fluoro-4-trifluoromethoxybromobenzene (9.3 g, 38.7 mmol) and dried Mg (0.97 g 39.9 mmol) in a 50 ml ether solvent, was cooled down 0° C., followed by dropwise adding thereto, a 40 ml ether solution of the above 2-(4-(1,3-dioxan-2-ylethyl)cyclohexyl)ethanol (6.3 g, 26.2 mmol), heating the mixture up to room temperature, stirring it for 3 hours, adding this reaction solution to 6N HCl (100 ml), extracting the resulting product with ethyl acetate, washing the extraction solution successively with a saturated aqueous solution of sodium bicarbonate and water, drying over MgSO4, distilling off the solvent, adding toluene (150 ml) and Amberlist (3.0 g) to the residue, refluxing for 5 hours, while removing water formed by the reaction by means of Dean-Stark, adding trimethylene glycol (1.0 g, 13.1 mmol), further refluxing for one hour, filtering off Amberlist, distilling off the solvent, purifying the residue according to column chromatography treatment using ethyl acetate/toluene (1/2) as a developing solvent, on silica gel, and distilling off the solvent, to isolate 1-(2-(4-(1,3-dioxan-2-ylethyl)cyclohexyl)vinyl-3-fluoro-4-trifluoromethoxybenzene (5.5 g, 13.7 mmol). The yield of this product from 2-(4-(1,3-dioxan-2-ylethyl)cyclohexyl)ethanol was 52.3%.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9]O[C:6]=2[CH2:5][CH2:4][CH2:3]1.C([O-])(=O)C.[NH4+:20]>CN(C)C=O>[O:1]=[C:2]1[CH2:3][CH2:4][CH2:5][C:6]2[NH:20][CH:9]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:7]1=2
Reactant: CCOC(=O)c1coc2c1C(=O)CCC2
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c[nH]c2c1C(=O)CCC2
Temperature: 100 °C

Procedure:
To a stirred suspension of 4-oxo-4,5,6,7-tetrahydrobenzofuran-3-carboxylic acid (28.2 g, 157 mmol) in ethyl alcohol (500 mL) under nitrogen at ambient temperature was added acetyl chloride(56 mL, 783 mmol) dropwise. After stirring 1 h, the solution was then heated at reflux for 1 h. The solution was cooled and concentrated in vacuo. The residue was taken up into dichloromethane, washed with aqueous sodium bicarbonate, washed quickly with 1N sodium hydroxide, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford ethyl 4-oxo-4,5,6,7-tetrahydrobenzofuran-3-carboxylate as an oil. A mixture of this ester (24.46 g, 117 mmol) and ammonium acetate (15.85 g, 206 mmol) in N,N-dimethylformamide (225 mL) was heated at 100° C. under Nitrogen for 1.25 h. The mixture was cooled, poured into ice water, and extracted two times with dichloromethane. The combined organic extracts were washed with water, dried over magnesium sulfate, filtered, concentrated in vacuo, and the residue triturated with ether to give ethyl 4-oxo-4,5,6,7-tetrahydroindole-3-carboxylate. A mixture of this ester (11.31 g, 55 mmol) in 5N sodium hydroxide (200 mL) and ethanol (20 mL) was heated at reflux for 1h. After cooling in an ice bath, the mixture was acidified with concentrated hydrochloric acid, the precipitate filtered, rinsed with ice water, and dried in vacuo to afford 4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid. m.p. 269°-270° C.