Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]2[N:14]=[C:15]([SH:17])[N:16]=[C:4]2[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:24][C:25](I)([F:27])[F:26].C(=O)=O>CN(C)C=O.C(Cl)Cl.C(OCC)(=O)C.C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]2[N:14]=[C:15]([S:17][C:25]([F:27])([F:26])[F:24])[N:16]=[C:4]2[N:3]=1
Reactant: Cc1cc(-c2ccccc2)n2nc(S)nc2n1
Reactant: FC(F)(F)I
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccccc2)n2nc(SC(F)(F)F)nc2n1
Temperature: 30 °C

Procedure:
To 1.5 g (6.2 mmol) of 5-methyl-7-phenyl-1,2,4-triazolo[1,5-a]pyrimidin-2-thiol and 1.5 g (10.9 mmol) of powdered potassium carbonate stirring in 20 ml of dimethylformamide, 3 ml of condensed trifluoromethyl iodide was added dropwise at ambient temperature. Keeping the dry ice condenser on from the addition, the stirred mixture was warmed to 30° C. At three separate times during a 2 h period, 2.0 ml portions of trifluoromethyliodide were added. Excess water was added and the aqueous mixture was extracted with a 1:1 mixture of ethyl acetate/diethyl ether (200 ml) and the organic layer was washed with water, saturated sodium bicarbonate, brine, dried over magnesium sulfate and evaporated in vacuo to give an oil. Silica gel column chromatography (methylene chloride followed by 1:1 methylene chloride/ethyl acetate) afforded 0.4 g of the title compound (main component present), m.p. 91°-93° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:8]([O:13][C:14]3[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=3)=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.Cl[C:22]1[NH:26][C:25]2[C:27]([O:31][CH3:32])=[CH:28][CH:29]=[CH:30][C:24]=2[N:23]=1>CC(O)C.O>[CH3:32][O:31][C:27]1[C:25]2[NH:26][C:22]([NH:18][C:17]3[CH:16]=[CH:15][C:14]([O:13][C:8]4[C:7]([CH:4]5[CH2:3][CH2:2][O:1][CH2:6][CH2:5]5)=[CH:12][CH:11]=[CH:10][N:9]=4)=[CH:20][CH:19]=3)=[N:23][C:24]=2[CH:30]=[CH:29][CH:28]=1
Reactant: Nc1ccc(Oc2ncccc2C2CCOCC2)cc1
Reactant: COc1cccc2nc(Cl)[nH]c12
Solvent: CC(C)O
Solvent: O
Product: COc1cccc2nc(Nc3ccc(Oc4ncccc4C4CCOCC4)cc3)[nH]c12
Temperature: 170 °C

Procedure:
A glass microwave reaction vessel was charged with 4-(3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yloxy)aniline (0.1130 g, 0.418 mmol) and 2-chloro-7-methoxy-1H-benzo[d]imidazole (0.092 g, 0.502 mmol) in IPA. The reaction mixture was stirred and heated in a Biotage Initiator microwave reactor at 170° C. for 30 min. The reaction mixture was diluted with water and extracted with DCM. The organic extract was washed with water, brine, dried with magnesium sulfate, filtered, and concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage pre-packed silica gel column (40S), eluting with a gradient of 1% to 5% MeOH in DCM, to provide 7-methoxy-N-(4-(3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amine. MS (ESI, pos. ion) m/z: 417.0 (M+1). IC50 (uM) +++++.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([OH:31])=[O:30])[C:26]([CH2:32][CH2:33][CH2:34][O:35][C:36]3[CH:41]=[CH:40][CH:39]=[C:38](N4CCN(C)CC4)[CH:37]=3)=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12].[N:49]1([CH2:54][CH2:55][O:56]C2C=CC(O)=CC=2)[CH2:53][CH2:52][CH2:51][CH2:50]1>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([OH:31])=[O:30])[C:26]([CH2:32][CH2:33][CH2:34][O:35][C:36]3[CH:41]=[CH:40][C:39]([O:56][CH2:55][CH2:54][N:49]4[CH2:53][CH2:52][CH2:51][CH2:50]4)=[CH:38][CH:37]=3)=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: Oc1ccc(OCCN2CCCC2)cc1
Reactant: CN1CCN(c2cccc(OCCCc3ccc(N4CCc5cccc(C(=O)Nc6nc7ccccc7s6)c5C4)nc3C(=O)O)c2)CC1
Product: O=C(Nc1nc2ccccc2s1)c1cccc2c1CN(c1ccc(CCCOc3ccc(OCCN4CCCC4)cc3)c(C(=O)O)n1)CC2

Procedure:
The title compound 106 was prepared in a similar manner to the synthesis of compound 105 by substituting compound 87C with compound 106B: 1H NMR (DMSO-d6): δ 12.84 (s, 1H), 9.68 (s, 1H), 8.04 (d, J=7.93 Hz, 1H), 7.79 (d, J=8.24 Hz, 7.60 (d, J=7.32 Hz, 1H), 7.56 (d, J=8.54 Hz, 1H), 7.34-7.50 (m, 4H), 6.86-6.97 (m, 6H), 4.92 (s, 2H), 4.19-4.21 (m, 2H), 3.86-3.89 (m, 6H), 3.08-3.13 (m, 4H), 2.98 (t, J=5.8 Hz, 1H), 2.79-2.82 (m, 2H), 1.87-2.05 (m, 6H) ESI (+)/MS: 678 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([NH:14][CH3:15])=[O:13])[CH:3]=1.CCN(C(C)C)C(C)C.[F:28][C:29]1[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:30]=1[O:31][CH:32]1[CH2:35][NH:34][CH2:33]1>C(O)(C)C>[Cl:40][C:38]1[CH:37]=[CH:36][C:30]([O:31][CH:32]2[CH2:35][N:34]([C:2]3[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]4[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=4)[C:12]([NH:14][CH3:15])=[O:13])[CH:3]=3)[CH2:33]2)=[C:29]([F:28])[CH:39]=1
Reactant: Fc1cc(Cl)ccc1OC1CNC1
Reactant: CNC(=O)c1cccc(Nc2cc(Cl)ccn2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CNC(=O)c1cccc(Nc2cc(N3CC(Oc4ccc(Cl)cc4F)C3)ccn2)c1
Temperature: 80 °C
Yield: 20.5 %

Procedure:
To a solution of 3-((4-chloropyridin-2-yl)amino)-N-methylbenzamide (0.300 g, 1.14 mmol) in Isopropanol (4 mL) was added DIPEA (0.3 mL, 1.71 mmol) and 3-(2-fluoro-4-chlorophenoxy)azetidine (0.230 g, 1.14 mmol) [prepared as described in Example AAA] and the reaction mixture was heated at 80° C. for 7 h. The mixture was concentrated under reduced pressure and extracted with EtOAc (2×20 mL). The organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by silica gel column chromatography provided 3-((4-(3-(4-chloro-2-fluorophenoxy)azetidin-1-yl)pyridin-2-yl)amino)-N-methylbenzamide (0.10 g, 3%) as a solid. Observed mass (M+1): 427.1
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:38])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]2[CH:15]=[N:16][C:17]([O:20][CH2:21][C:22]3[C:23]([C:30]4[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][C:31]=4[Cl:37])=[N:24][O:25][C:26]=3[CH:27]([CH3:29])[CH3:28])=[CH:18][CH:19]=2)[CH:8]=1)C>O.C(O)C>[Cl:36][C:35]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:37])[C:30]=1[C:23]1[C:22]([CH2:21][O:20][C:17]2[N:16]=[CH:15][C:14]([O:13][C:9]3[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=3)[C:6]([OH:38])=[O:5])=[CH:19][CH:18]=2)=[C:26]([CH:27]([CH3:29])[CH3:28])[O:25][N:24]=1
Reactant: CCOC(=O)c1cccc(Oc2ccc(OCc3c(-c4c(Cl)cccc4Cl)noc3C(C)C)nc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(Oc2cccc(C(=O)O)c2)cn1
Temperature: 25 °C
Reaction time: 50 h

Procedure:
NaOH (0.228 g, 5.7 mmol) in water (0.25 ml) was added to a solution of 3-{6-[3-(2,6-dichloro-phenyl)-5-isopropyl-isoxazol-4-ylmethoxy]-pyridin-3-yloxy}-benzoic acid ethyl ester (0.157 g, 0.3 mmol) in ethanol (5 ml) and the reaction mixture was stirred at room temperature for 50 h. The solvent was removed under reduced pressure and the residue diluted with water (1.5 ml) and acidified to pH 6. The resulting solution was extracted with ethyl acetate and the extract was dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to afford 3-{6-[3-(2,6-dichloro-phenyl)-5-isopropyl-isoxazol-4-ylmethoxy]-pyridin-3-yloxy}-benzoic acid as colorless oil. Yield 0.14 g (33%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][CH2:11][NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:18][CH:17]=1)(=[O:15])=[O:14].NC1C=C(C=CC=1O)[C:31]([OH:33])=[O:32]>>[CH2:22]([C:19]1[CH:18]=[CH:17][C:16]([S:13]([NH:12][CH2:11][CH2:10][C:2]2[O:1][C:5]3[CH:6]=[CH:7][C:8]([C:31]([OH:33])=[O:32])=[CH:9][C:4]=3[N:3]=2)(=[O:14])=[O:15])=[CH:21][CH:20]=1)[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: Nc1cc(C(=O)O)ccc1O
Reactant: CCCCCc1ccc(S(=O)(=O)NCCc2nc3ccccc3o2)cc1
Product: CCCCCc1ccc(S(=O)(=O)NCCc2nc3cc(C(=O)O)ccc3o2)cc1

Procedure:
The title compound of Step 1 was prepared following the procedure described above for the preparation of the product of Step 3 of Example 1, substituting 3-amino-4-hydroxybenzoic acid in place of o-aminophenol. MS m/e 417; HPLC retention time 3.50 min.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH2:11][N:12]2[C:16]([CH3:17])=[C:15]([Br:18])[CH:14]=[N:13]2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[CH:2]=C.N1C(C)=CC=CC=1C.[OH2:27].ClCCl>O1CCOCC1.O.O=[Os](=O)(=O)=O>[Br:18][C:15]1[CH:14]=[N:13][N:12]([CH2:11][C:5]2([O:4][CH2:1][CH:2]=[O:27])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[C:16]=1[CH3:17]
Reactant: O
Reactant: C=CCOC1(Cn2ncc(Br)c2C)CCCCC1
Agent: O=[Os](=O)(=O)=O
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: Cc1c(Br)cnn1CC1(OCC=O)CCCCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of EXAMPLE 167B (3.13 g) in dioxane/water (3:1, 40 mL) was added 2,6-lutidine (2.5 mL), OsO4 (2.5% in tert-butanol, 2.75 mL), and NaIO4 (8.55 g) under argon. The reaction mixture was stirred at room temperature for 4 hours, then water (50 mL) and dichloromethane (200 mL) were added. The organic layer was separated, and the water phase was extracted by dichloromethane (3×200 mL). The combined organic layers were washed with brine (200 mL) and dried over Na2SO4. After filtration, the solvent was removed to give the crude product which was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6]([OH:14])[C:7]2[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH:17]([N:30]1[CH2:33][CH:32](OC(C2C=CC(Cl)=CC=2)C2C=CC=CC=2Cl)[CH2:31]1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH:17]([N:30]1[CH2:33][CH:32]([O:14][CH:6]([C:7]2[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=2)[C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:16][CH:15]=2)[CH2:31]1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: OC(c1ccc(Br)cc1)c1ccc(Br)cc1
Reactant: Clc1ccc(C(OC2CN(C(c3ccccc3)c3ccccc3)C2)c2ccccc2Cl)cc1
Product: Brc1ccc(C(OC2CN(C(c3ccccc3)c3ccccc3)C2)c2ccc(Br)cc2)cc1

Procedure:
This material was prepared from 4,4′-dibromobenzhydrol (84) using the procedure described for compound (8) (6.15 g, 66%).
Reaction SMILES: [O:1]([CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[NH:15][C:14]2[CH:18]=[C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:20]=[CH:21][C:13]=2[O:12]1)[Si](C(C)(C)C)(C)C.[Cl:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32]Br.[K+].[Br-]>>[Cl:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32][N:15]1[C:14]2[CH:18]=[C:19]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:20]=[CH:21][C:13]=2[O:12][CH:11]([CH2:10][CH2:9][OH:1])[C:16]1=[O:17]
Reactant: Clc1cccc(CBr)c1
Reactant: CC(C)(C)[Si](C)(C)OCCC1Oc2ccc(-c3ccccc3)cc2NC1=O
Agent: [Br-]
Agent: [K+]
Product: O=C1C(CCO)Oc2ccc(-c3ccccc3)cc2N1Cc1cccc(Cl)c1

Procedure:
Prepared from 2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-3-oxo-6-phenyl-2H-1,4-benzoxazine by Methods F and G, alkylating with 3-chlorobenzyl bromide, to afford a white crystalline solid in 27% overall yield, mp 119°-121° C.; IR (KBr) 3517, 1659, 1487, 1435, 1387, 1282, 1260, 1060, 760 cm-1 ; 1H NMR (CDCl3) δ 2.22-2.38 (m, 3H), 3.95 (v br s, 2H), 4.90 (dd, J=7.6, 5.5 Hz, 1H), 5.18 (ABq, JAB =17.1 Hz, 2H), 7.04 (d, J=1.9 Hz, 1H), 7.08 (d, J=8.3 Hz, 1H), 7.15-7.42 (m, 10H); MH+ at m/z=394; Anal. Calc'd for C23 H20ClNO3 : C, 70.14; H, 5.12; N, 3.56. Found: C, 70.10; H, 5.11; N, 3.51.
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.CC([O-])=O.[Na+].[Br:14]Br.[OH-].[Na+]>CC(O)=O>[Br:14][C:4]1[N:3]=[C:2]([F:1])[C:7]([OH:8])=[CH:6][CH:5]=1
Reactant: BrBr
Reactant: Oc1cccnc1F
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Oc1ccc(Br)nc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 10.7 %

Procedure:
A stirred solution of 2-fluoro-3-pyridinol (1.10 g, 9.73 mmol) and NaOAc (0.80 g, 9.73 mmol) in HOAc (10 mL) was treated with Br2 (1.56 g, 9.73 mmol) at 5° C., and the reaction mixture was allowed to warm to ambient temperature, and stirred at ambient temperature for 4 h. The mixture was poured onto ice and neutralized with 2N NaOH to pH about 7, and then extracted with EtOAc. The combined organic extract was washed with water, brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give a yellow oil. The crude material was purified by flash chromatography on a silica gel column eluted with 1:20 EtOAc/CH2Cl2 to give a colorless oil, which solidified after standing. The solid was recrystallized from hexanes to give 0.2 g (11%) of 6-bromo-2-fluoro-3-pyridinol as a white solid. The filtrate was concentrated to a solid, which was recrystallized from 2:1 hexanes/benzene to give additional 0.57 g (31%) of 6-bromo-2-fluoro-3-pyridinol as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.77 (s, 1H), 7.40-7.30 (m, 2H); LRMS (ESI), m/z 192/194 (M+H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:16][C:17]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:18]=1[NH2:19]>CN(C=O)C>[N:5]1([CH2:4][CH2:3][CH2:2][NH:19][C:18]2[CH:20]=[CH:21][C:22]([N+:24]([O-:26])=[O:25])=[CH:23][C:17]=2[F:16])[CH:9]=[CH:8][N:7]=[CH:6]1
Reactant: Nc1ccc([N+](=O)[O-])cc1F
Reactant: ClCCCn1ccnc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(NCCCn2ccnc2)c(F)c1
Temperature: 25 °C
Reaction time: 36 h
Yield: 122 %

Procedure:
To a solution of 1-(3-chloropropyl)-1H-imidazole (1.90 g, 13.14 mmol), cesium carbonate (4.28 g, 13.14 mmol) and a catalytic amount of KI in DMF (30 mL) cooled in an ice-bath was added 2-fluoro-4-nitroaniline (1.38 g, 8.84 mmol) in one portion. At the end of addition, the mixture was refluxed and stirred further for 36 h. The reaction mixture was cooled to rt and filtered. The filtrate was concentrated in vacuo. To the residue was added water (50 mL) and the resulting mixture was extracted with DCM (20 mL×2). The combined organic layers were washed with brine (20 mL×2) and concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (V/V)=15:1) to give the title compound as yellow oil (2.85 g, 82%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][OH:9].C([Li])CCC.[CH2:15]([N:22]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCCCCC.C1COCC1>[CH2:15]([N:22]1[CH2:26][CH2:25][C:24]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][OH:9])([OH:27])[CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: OCc1ccccc1I
Reactant: O=C1CCN(Cc2ccccc2)C1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OCc1ccccc1C1(O)CCN(Cc2ccccc2)C1
Temperature: -4 °C
Reaction time: 1 h
Yield: 54.2 %

Procedure:
To a solution of (2-iodophenyl)methanol (5.88 g, 0.0251 mol) in tetrahydrofuran (40 mL, 0.5 mol) at −78 Celsius was added 1.600 M of n-butyllithium in hexane (31.7 mL). The mixture was stirred at −4 celsius for 1 hour, then cooled to −78 Celsius. A solution of 1-benzylpyrrolidin-3-one (3.67 mL, 0.0228 mol) in THF (2 mL) was added to the above mixture, and the resulting mixture was stirred at −78 Celsius for 2 hours. The reaction was quenched with small amount of brine, then extracted with ethyl acetate. The organic phase was dried over MgSO4 and concentrated. The residue was purified by flash chromatography on silica gel column with 70% AcOEt in hexanes to give the desired compound (3.5 g, 54% yield). MS (ESI): 284.1 (M+H+).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11][CH:12]3[CH2:20][C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH2:13]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.CC([O-])(C)C.[K+].C([N:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH:35]1[CH2:40][CH2:41]OS(C(F)(F)F)(=O)=O)C1C=CC=CC=1.[C:50]1([CH3:56])[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>C(OCC)(=O)C>[CH2:56]([CH:40]([CH:35]1[CH2:36][CH2:37][CH2:38][CH2:39][NH:34]1)[CH2:41][N:11]([C:9]1[CH:8]=[CH:7][C:6]2[O:1][CH2:2][CH2:3][O:4][C:5]=2[CH:10]=1)[CH:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: Cc1ccccc1
Reactant: c1ccc2c(c1)CC(Nc1ccc3c(c1)OCCO3)C2
Reactant: O=S(=O)(OCCC1CCCCN1Cc1ccccc1)C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: c1ccc(CC(CN(c2ccc3c(c2)OCCO3)C2Cc3ccccc3C2)C2CCCCN2)cc1
Temperature: 50 °C

Procedure:
To a stirred solution of compound 57 (1 g, 3.74 mmol) in dry toluene (25 mL) was added KOtBu (0.63 g, 5.61 mmol) at 0° C. and the solution was heated at 50° C. for 5 hours. A solution of trifluoromethanesulfonic acid 2-(1-benzyl-piperidin-2-yl)-ethyl ester (58) (1.4 g, 4.11 mmol) in dry toluene (5 mL) was then added at 0° C. and refluxed for 16 hours. TLC showed incomplete conversion of the starting material, hence another 0.5 eq of compound 58 was added and refluxed for 16 hours. The reaction mixture was diluted with ethyl acetate and the organic layer was washed with water and brine. The solution was dried over anhydrous Na2SO4, filtered and concentrated. The crude material was purified by Combiflash® chromatrography eluting with 7-8% methanol-DCM to get compound 59.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]([O:15]C)=O)=[C:10](/[N:17]=[CH:18]/[N:19]([CH3:21])C)[CH:9]=2)=[CH:4][CH:3]=1.[CH3:22][N:23]1[CH2:27][CH2:26][CH:25]([CH2:28][O:29][C:30]2[CH:31]=[C:32](CN)[CH:33]=[CH:34][CH:35]=2)[CH2:24]1>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]3[C:13](=[O:15])[N:19]([CH2:21][C:34]4[CH:33]=[CH:32][CH:31]=[C:30]([O:29][CH2:28][CH:25]5[CH2:26][CH2:27][N:23]([CH3:22])[CH2:24]5)[CH:35]=4)[CH:18]=[N:17][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CN1CCC(COc2cccc(CN)c2)C1
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1/N=C/N(C)C
Solvent: CO
Product: CN1CCC(COc2cccc(Cn3cnc4cc(-c5ccc(Cl)cc5)sc4c3=O)c2)C1

Procedure:
The title compound was synthesized according to Example 13c from methyl 5-(4-chlorophenyl)-3-{[(1E)-(dimethylamino)methylene]amino}thiophene-2-carboxylate (0.352 g, 1.09 mmol) and 1-{3-[(1-methylpyrrolidin-3-yl)methoxy]phenyl}methanamine (0.200 g, 0.91 mmol) in MeOH (2 mL) to give the title compound. Yield: 0.225 g (44%). 1H NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 7.59-7.62 (m, 2H), 7.45 (s, 1H), 7.39-7.42 (m, 2H), 7.22-7.26 (m, 1H), 6.81-6.91 (m, 3H), 5.17 (s, 2H), 3.83 (d, 2H, J=6.9 Hz), 2.60-2.66 (m, 2H), 2.38-2.57 (m, 3H), 2.32 (s, 3H), 1.97-2.08 (m, 1H), 1.51-1.60 (m, 1H). MS (ESI+) 465.99 (M+1H+)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:18][CH3:19])=[C:6]([CH:8]2[C:14](=[O:15])[CH:13]3[CH2:16][CH:10]([CH2:11][CH2:12]3)[C:9]2=[O:17])[CH:7]=1.[CH3:20][C:21]1[N:22]=[CH:23][S:24][CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(=O)([O-])[O-].[Ag+2].C(#N)C.O>[CH2:18]([C:5]1[CH:4]=[CH:3][C:2]([C:23]2[S:24][CH:25]=[C:21]([CH3:20])[N:22]=2)=[CH:7][C:6]=1[CH:8]1[C:14](=[O:15])[CH:13]2[CH2:16][CH:10]([CH2:11][CH2:12]2)[C:9]1=[O:17])[CH3:19]
Reactant: Cc1cscn1
Reactant: CCc1ccc(Br)cc1C1C(=O)C2CCC(C2)C1=O
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC#N
Product: CCc1ccc(-c2nc(C)cs2)cc1C1C(=O)C2CCC(C2)C1=O

Procedure:
3-(5-Bromo-2-ethylphenyl)bicyclo[3.2.1]octane-2,4-dione (200 mg, 0.62 mmol), 4-methylthiazole (74 mg, 0.75 mmol), silver carbonate (860 mg, 3.1 mmol), triphenylphosphine (16.3 mg, 62.2 umol) and [1,1-bis(diphenylphosphino)ferrocene]palladium(II)chloride (26 mg, 31.1 umol) are added to a scintillation vial and shaken with a degassed solvent mixture of acetonitrile:water 1:1 (1.5 ml) at 65° C. for 22 hours. The mixture is concentrated under reduced pressure, taken up in DMSO (1.5 ml), filtered and purified by preparative reverse-phase HPLC to give 3-[2-ethyl-5-(4-methyl-thiazol-2-yl)phenyl]bicyclo[3.2.1]octane-2,4-dione.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:6][CH:5]=[CH:4][N:3]=1.[Cl:14]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:7]([N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[N:6][CH:5]=[C:4]([Cl:14])[N:3]=1
Reactant: Clc1nccnc1N1CCNCC1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)Cl
Product: Clc1cnc(N2CCNCC2)c(Cl)n1
Temperature: 25 °C
Yield: 44.7 %

Procedure:
To a suspension of 2-chloro-3-(1-piperazinyl)pyrazine (11.7 g, 58.7 mmol; from Example 90, Step 1) in CHCl3 (50 mL) was N-chlorosuccinimid (14.4 g, 108 mmol) added and the mixture was heated at reflux for 30 minutes. The reaction mixture was cooled to ambient temperature and extracted twice with water. The combined aqueous phases were made alkaline (11M NaOH), saturated with NaCl, cooled, and extracted with EtOAc (×3). Concentration of the combined, dried (MgSO4), organic phases afforded 6.12 g (45%) of the title compound as a brown oil which crystallized upon standing: mp 89-97° C. Anal. (C8H10Cl2N4.1/3H2O) C, H, N.
Reaction SMILES: CN(C)C=O.[C:6]([O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[O:20][CH3:21])[N:16]=[CH:15][NH:14][C:13]2=O)(=[O:8])[CH3:7].S(Cl)([Cl:25])=O>>[ClH:25].[Cl:25][C:13]1[C:12]2[C:17](=[CH:18][C:19]([O:20][CH3:21])=[C:10]([O:9][C:6](=[O:8])[CH3:7])[CH:11]=2)[N:16]=[CH:15][N:14]=1
Reactant: COc1cc2nc[nH]c(=O)c2cc1OC(C)=O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Cl)c2cc1OC(C)=O
Product: Cl
Yield: 87 %

Procedure:
Dimethylformamide (0.25 ml) was added dropwise to a solution of 6-acetoxy-7-methoxy-3,4-dihydro-quinazolin-4-one (13.8 g, 59.0 mmol) in thionyl chloride (150 ml) and the reaction was heated at reflux for 1.5 hours. The reaction was cooled, excess thionyl chloride was removed in vacuo and the residue was azeotroped with toluene (2×50 ml) to remove the last of the thionyl chloride. Drying in vacuo yielded 4-chloro-6-acetoxy-7-methoxyquinazoline hydrochloride (14.7 g, 87% yield) as a beige solid, which was used without further purification:
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[CH:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]([NH:13][O:14][CH2:15][CH2:16][O:17]C=C)=[O:12])[C:3]=1[NH:20][C:21]1[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=1[F:28].Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[C:7]2[N:8]=[CH:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]([NH:13][O:14][CH2:15][CH2:16][OH:17])=[O:12])[C:3]=1[NH:20][C:21]1[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=1[F:28]
Reactant: C=COCCONC(=O)c1cc2scnc2c(F)c1Nc1ccc(I)cc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(NOCCO)c1cc2scnc2c(F)c1Nc1ccc(I)cc1F
Reaction time: 1 h

Procedure:
To a solution of 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzo[d]thiazole-6-carboxamide (410 mg, 0.8 mmol) in CH2Cl2 (5 mL) was added 1.0 N HCl (aq., 5 mL, 5 mmol) dropwise. After stirring for 1 h, the reaction mixture was neutralized with saturated NaHCO3 (aq.). The organic layer was separated, washed with water (30 mL×2) and brine (30 mL) sequentially, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (CH2Cl2/MeOH, 15:1, v/v) and the desired product was obtained as a white solid (290 mg, 52% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.83 (s, 1H), 8.92 (s, 1H), 8.03 (s, 1H), 7.90 (s, 1H), 7.56 (d, J=9.4 Hz, 1H), 7.30 (d, J=8.7 Hz, 1H), 6.41 (m, 1H), 4.72 (m, 1H), 3.85 (m, 2H), 3.59 (m, 2H). MS (ES+): m/z 492.35 [MH+].