Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=C(NC2C3C(=C(C)C=C(S(C4C=CC=C(C(=O)NCCCCCCCC=O)C=4)(=O)=O)C=3)N=CC=2C(N)=O)C=CC=1.[OH:45][CH2:46][CH2:47][CH2:48][CH2:49][C:50]#[C:51][C:52]1[CH:57]=[CH:56][C:55]([NH:58][C:59]([C:61]2[CH:62]=[C:63]([S:67]([C:70]3[CH:71]=[C:72]4[C:77](=[C:78]([CH3:80])[CH:79]=3)[N:76]=[CH:75][C:74]([C:81]([NH2:83])=[O:82])=[C:73]4[NH:84][C:85]3[CH:90]=[CH:89][CH:88]=[C:87]([O:91][CH3:92])[CH:86]=3)(=[O:69])=[O:68])[CH:64]=[CH:65][CH:66]=2)=[O:60])=[CH:54][CH:53]=1>>[CH3:92][O:91][C:87]1[CH:86]=[C:85]([NH:84][C:73]2[C:72]3[C:77](=[C:78]([CH3:80])[CH:79]=[C:70]([S:67]([C:63]4[CH:64]=[CH:65][CH:66]=[C:61]([C:59](=[O:60])[NH:58][C:55]5[CH:56]=[CH:57][C:52]([C:51]#[C:50][CH2:49][CH2:48][CH2:47][CH:46]=[O:45])=[CH:53][CH:54]=5)[CH:62]=4)(=[O:69])=[O:68])[CH:71]=3)[N:76]=[CH:75][C:74]=2[C:81]([NH2:83])=[O:82])[CH:90]=[CH:89][CH:88]=1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(C#CCCCCO)cc5)c4)cc23)c1
Agent: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)NCCCCCCCC=O)c4)cc23)c1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(C#CCCCC=O)cc5)c4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 112, using instead Intermediate 76 as substrate. ES/MS calcd. for C37H33N4O6S+ 661.2. Found m/z=663.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N:15]([CH2:23][CH:24]3[CH2:29][CH2:28][O:27][C:26]([CH3:31])([CH3:30])[CH2:25]3)C(=O)OC(C)(C)C)[N:10]=2)=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.Cl.O1CCOCC1>CO>[Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH2:23][CH:24]3[CH2:29][CH2:28][O:27][C:26]([CH3:31])([CH3:30])[CH2:25]3)[N:10]=2)=[CH:4][C:5]([F:8])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N(CC1CCOC(C)(C)C1)c1cccc(-c2cc(F)ncc2Cl)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC1(C)CC(CNc2cccc(-c3cc(F)ncc3Cl)n2)CCO1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of tert-butyl 5′-chloro-2′-fluoro-2,4′-bipyridin-6-yl((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)carbamate (950 mg, 2.111 mmol) in methanol (5 mL) was added 4M HCl/dioxane (15 mL, 494 mmol). The resulting mixture was stirred for ˜45 min at ambient temperature. The mixture then was concentrated in vacuo and the resulting residue was dissolved in EtOAc (˜50 mL) and saturated aqueous NaHCO3 solution (˜50 mL). The separated organic layer was washed with saturated aqueous NaHCO3 solution (1×), brine (1×), dried over Na2SO4, filtered off and concentrated in vacuo providing crude (R/S)-5′-chloro-N-((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)-2′-fluoro-2,4′-bipyridin-6-amine as a colorless oil, which was directly used in the next reaction without further purification. Yield: 740 mg. LCMS (m/z): 350.1 [M+H]+; Retention time=0.69 min.
Reaction SMILES: C([O:5][C:6](=[O:42])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][O:16]/[N:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:21][CH:20]=2)=[CH:9][C:8]=1[O:29][C:30](=[O:41])[C:31]1[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.[Cl-].[Na+].O>[C:25]([C:22]1[CH:23]=[CH:24][C:19](/[CH:18]=[N:17]/[O:16][CH2:15][CH2:14][O:13][C:10]2[CH:11]=[CH:12][C:7]([C:6]([OH:42])=[O:5])=[C:8]([O:29][C:30](=[O:41])[C:31]3[CH:32]=[CH:33][C:34]([C:37]([F:39])([F:40])[F:38])=[CH:35][CH:36]=3)[CH:9]=2)=[CH:20][CH:21]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)c1ccc(OCCO/N=C/c2ccc(C(C)(C)C)cc2)cc1OC(=O)c1ccc(C(F)(F)F)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1ccc(/C=N/OCCOc2ccc(C(=O)O)c(OC(=O)c3ccc(C(F)(F)F)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.8 %

Procedure:
To a solution of 4-{2-[({(E)-[4-(tert-butyl)phenyl]methylidene}amino)oxy]ethoxy}-2-{[4-(trifluoromethyl)benzoyl]oxy}benzoic acid tert-butyl ester (0.387 g, 0.66 mmol) in methylene chloride (15 mL) was added trifluoroacetic acid (0.400 mL, 2.83 mmol). The reaction was stirred at room temperature overnight, poured into brine and the aqueous layer extracted with ethyl acetate. The combined organics dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography using ethyl acetate/hexanes (20/80)+1% formic acid to afford the title compound (0.300 g, 86%) as a white solid. mp=146.3-147.9° C.; mass spectrum (+APCI, M+H) m/z 530. 1H NMR (400 MHz, DMSO-d6); δ 12.70 (bs, 1H), 8.28 (d, 2H), 8.24 (s, 1H), 7.95 (m, 3H), 7.52 (d, 2H), 7.40 (d, 2H), 7.03 (m, 2H), 4.44 (t, 2H), 4.38 (t, 2H), 1.26 (s, 9H). Elemental analysis: Calcd. for C28H26F3NO6: C, 63.51; H, 4.95; N, 2.65, Found: C, 63.15; H, 4.90; N, 2.64.
Reaction SMILES: COC(C1C(C)=CC(C2C=CC=C(C(F)(F)F)C=2)=CN=1)=O.ClC1C=C([C:30]2[CH:31]=[C:32]([CH3:49])[C:33]([C:36]([N:38]3[CH2:43][CH2:42][CH:41]([N:44]4[CH2:48][CH2:47][CH2:46][CH2:45]4)[CH2:40][CH2:39]3)=[O:37])=[N:34][CH:35]=2)C=CC=1Cl.[CH3:50][O:51][C:52]1[CH:57]=[CH:56][C:55](B(O)O)=[CH:54][C:53]=1[C:61]([F:64])([F:63])[F:62].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.[Pd](Cl)Cl>[CH3:50][O:51][C:52]1[CH:57]=[CH:56][C:55]([C:30]2[CH:31]=[C:32]([CH3:49])[C:33]([C:36]([N:38]3[CH2:39][CH2:40][CH:41]([N:44]4[CH2:48][CH2:47][CH2:46][CH2:45]4)[CH2:42][CH2:43]3)=[O:37])=[N:34][CH:35]=2)=[CH:54][C:53]=1[C:61]([F:64])([F:63])[F:62]
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)cnc1C(=O)N1CCC(N2CCCC2)CC1
Reactant: COc1ccc(B(O)O)cc1C(F)(F)F
Agent: Cl[Pd]Cl
Agent: COC(=O)c1ncc(-c2cccc(C(F)(F)F)c2)cc1C
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(-c2cnc(C(=O)N3CCC(N4CCCC4)CC3)c(C)c2)cc1C(F)(F)F

Procedure:
In analogy to the procedure described for the preparation of intermediate 1A, (5-bromo-3-methyl-pyridin-2-yl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (see example 28) was reacted with 4-methoxy-3-trifluoromethyl-phenyl-boronic acid, (1,1′-bis-diphenylphosphino)-ferrocene)palladium-(II)dichloride (1:1 complex with CH2Cl2) and sodium carbonate in dioxane/water to give the title compound as brown amorphous solid. MS: 448.2 (MH+).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:14][CH3:15])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.[CH2:16]([N:19]=[C:20]=[O:21])[CH:17]=[CH2:18].[N-]=C=O>C1C=CC=CC=1.C(N(CC)CC)C>[CH2:16]([NH:19][C:20](=[O:21])[O:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][CH2:4][CH:3]([O:2][CH3:1])[O:14][CH3:15])=[CH:8][CH:9]=1)[CH:17]=[CH2:18]
Reactant: C=CCN=C=O
Reactant: COC(CCOc1ccc(O)cc1)OC
Agent: [N-]=C=O
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: C=CCNC(=O)Oc1ccc(OCCC(OC)OC)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
4-(3,3-Dimethoxypropoxy)phenol (0.05 mole) dissolved in benzene (10 ml) is charged into a glass reaction flask equipped with a mechanical stirrer. Allyl isocyanate (0.06 mole) and triethylamine (3 drops) are then added, and the resulting mixture is stirred at room temperature for a period of about 6 hours. The dried solution is stirpped of solvent and unreacted isocyanate to yield the desired product O-[4-(3,3-dimethoxypropoxy)phenyl] N-allylcarbamate as the residue.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[N:34]1[CH:35]=[CH:36][N:37]2[C:42]([CH2:43][CH2:44]O)=[CH:41][CH:40]=[CH:39][C:38]=12.[C:46]([OH:49])(=[S:48])[CH3:47]>O1CCCC1.CN(C)C=O>[C:46]([S:48][CH2:44][CH2:43][C:42]1[N:37]2[CH:36]=[CH:35][N:34]=[C:38]2[CH:39]=[CH:40][CH:41]=1)(=[O:49])[CH3:47]
Reactant: OCCc1cccc2nccn12
Reactant: CC(O)=S
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(=O)SCCc1cccc2nccn12
Reaction time: 0.17 h

Procedure:
To a solution of triphenyl phosphine (4.20 g) in tetrahydrofuran (30 ml) was added dropwise, at −15° C., diisopropyl azodicarboxylate (3.16 ml). The mixture was stirred for 10 minutes at the same temperature. To the reaction mixture were, then, added a solution of 2-(imidazo[1,2-a]pyridin-5-yl)ethanol (1.00 g) in dimethylformamide (20 ml) and thioacetic acid (1.14 ml). The reaction mixture was stirred for 0.5 hour at −15° C. and, then, for 20 hours at room temperature. The reaction mixture was concentrated, which was diluted with ethyl acetate and washed with water, a saturated aqueous solution of sodium hydrogencarbonate and, then, with a saturated aqueous saline solution, followed by drying over anhydrous magnesium sulfate and concentration. The concentrate was purified by means of a column chromatography (carrier: silica gel, developing solvent: ethyl acetate-hexane, 1:1) to afford the title compound (0.52 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]2[CH2:23][CH2:22][N:21]([CH2:24][C:25]([O:27]CC)=[O:26])[CH2:20][CH2:19][N:18]([CH2:30][C:31]([O:33]CC)=[O:32])[CH2:17][CH2:16][N:15]([CH2:36][C:37]([O:39]CC)=[O:38])[CH2:14][CH2:13]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[Na+]>O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]2[CH2:13][CH2:14][N:15]([CH2:36][C:37]([OH:39])=[O:38])[CH2:16][CH2:17][N:18]([CH2:30][C:31]([OH:33])=[O:32])[CH2:19][CH2:20][N:21]([CH2:24][C:25]([OH:27])=[O:26])[CH2:22][CH2:23]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)CN1CCN(CCc2ccc([N+](=O)[O-])cc2)CCN(CC(=O)OCC)CCN(CC(=O)OCC)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CN1CCN(CCc2ccc([N+](=O)[O-])cc2)CCN(CC(=O)O)CCN(CC(=O)O)CC1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
To a suspension of 200 mg (0.35 mmole) of 1-[2-(4-nitrophenyl)ethyl]-1,4,7,10-tetraazacyclododecane-4,7,10-triacetic acid, triethyl ester (prepared by the procedure of Example 19) in 15 ml of water was added 59 μl of NaOH (50% wt/wt, 3 eq). The mixture was stirred at 80° C. for 6 hours. The resulting homogeneous orange solution was then cooled to room temperature and freeze-dried to yield a brown solid which was purified by HPLC (Q-Sepharose™, HPLC System III) using a linear gradient of 0-10% aqueous HOAc over 60 minutes to yield (50%) of the hydrolyzed product 1-[2-(4-nitrophenyl)ethyl]-1,4,7,10-tetraazacyclododecane-4,7,10-triactic acid, and characterized by:
Reaction SMILES: [C:1](Br)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH2:9][CH:10]([CH:14]([CH3:17])[CH2:15][CH3:16])[C:11]([O-:13])=[O:12].[Na+]>>[C:1]([O:12][C:11](=[O:13])[CH:10]([NH2:9])[CH:14]([CH3:17])[CH2:15][CH3:16])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCC(C)C(N)C(=O)[O-]
Reactant: CCCCCC(=O)Br
Agent: [Na+]
Product: CCCCCC(=O)OC(=O)C(N)C(C)CC
Temperature: 0 °C

Procedure:
Finally, in a dry 2-necked, round bottomed flask, fixed with a separatory funnel, containing 10.81 g (60 mmol) of the prepared hexanoyl bromide, and side arm water condenser fixed with a dry receiving flask, is placed 11.03 g (72 mmol) of sodium 2-amino-3-methylpentanoate. The round bottomed flask is placed in an ice bath and the hexanoyl bromide is added drop wise. After addition is completed the mixture is shaken and the ice bath is replaced by a heating mantle. The flask is then heated until no more solution is dropping into the receiving flask. This crude distillate is then further fractionally distilled to yield 2-amino-3-methylpentanoic hexanoic anhydride.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[C:13]([CH:15](C#N)[C:16]2[CH:17]=[C:18]([CH:21]=[C:22]([CH3:24])[CH:23]=2)[C:19]#[N:20])[C:12]([CH:27]([CH3:29])[CH3:28])=[C:11]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CN(C=[O:44])C>>[CH2:1]([O:8][C:9]1[N:14]=[C:13]([C:15]([C:16]2[CH:17]=[C:18]([CH:21]=[C:22]([CH3:24])[CH:23]=2)[C:19]#[N:20])=[O:44])[C:12]([CH:27]([CH3:29])[CH3:28])=[C:11]([O:30][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C#N)cc(C(C#N)c2nc(OCc3ccccc3)nc(OCc3ccccc3)c2C(C)C)c1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: Cc1cc(C#N)cc(C(=O)c2nc(OCc3ccccc3)nc(OCc3ccccc3)c2C(C)C)c1
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a stirred solution of 3-((2,6-bis(benzyloxy)-5-isopropylpyrimidin-4-yl)(cyano)methyl)-5-methylbenzonitrile (53.46 g, 0.0195M) in anhydrous DMF (400 mL) in a water bath under nitrogen atmosphere, was added 60% sodium hydride (4.87 g, 0.1205M) portionwise. After 30 min., oxygen gas was bubbled into the reaction mixture using oxygen balloon. After 3 hr., sat. aqueous ammonium chloride solution was added and the product was extracted with ether. Ether layer was washed with water twice, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo to give a crude product as a light yellow solid. The crude product was purified by silica gel column chromatography (eluent, EA:hexane (1:9)) to afford 45.7 g (88%) of 3-(2,6-bis(benzyloxy)-5-isopropylpyrimidine-4-carbonyl)-5-methylbenzonitrile as a light yellow solid. m.p. 129-130° C. 1H NMR (300 MHz, CDCl3) δ 1.20 (3H, d, J=7.0 Hz), 1.22 (3H, d, J=7.0 Hz), 2.43 (3H, s), 2.84 (1H, m), 5.34 (2H, s), 5.51 (2H, s), 7.29-7.46 (10H, m), 7.66 (1H, s), 7.83 (1H, s), 7.90 (1H, s).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([P:9]2(=[O:16])[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[CH3:15][N:12]1[CH2:13][CH2:14][P:9]([C:6]2[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=2)(=[O:16])[CH2:10][CH2:11]1
Reactant: COc1ccc(P2(=O)CCN(C)CC2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CN1CCP(=O)(c2ccc(O)cc2)CC1
Temperature: -78 °C

Procedure:
4-(4-Methoxyphenyl)-1-methyl-1,4-azaphosphinane 4-oxide (1.05 g, 4.39 mmol) was made 0.16 M in DCM and stirred at −78° C. To this stirring solution was added BBr3 (2.09 g, 8.34 mmol) dropwise. The reaction mixture was slowly warmed to ambient temperature over 16 h. The precipitate was filtered off then dissolved in water. The pH was adjusted to pH=7 with 2N aq HCl. A precipitate was filtered off and the filtrate was concentrated in vacuo. The residue was suspended in 4:1 DCM:MeOH and stirred for 20 mins. The solids were filtered off and the filtrate was concentrated in vacuo to afford the requisite product. MS: cal'd 226 (MH+), exp 226 (MH+)
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)=[N:4][CH:5]=[CH:6][N:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[CH3:45][C:46]1[CH:47]=[CH:48][C:49]([NH:52][C@H:53]2[CH2:58][CH2:57][C@@H:56]([NH2:59])[CH2:55][CH2:54]2)=[N:50][CH:51]=1>C(Cl)Cl>[Cl:1][C:2]1[C:3]([C:8]([CH3:13])([CH3:12])[C:9]([NH:59][C@H:56]2[CH2:55][CH2:54][C@@H:53]([NH:52][C:49]3[CH:48]=[CH:47][C:46]([CH3:45])=[CH:51][N:50]=3)[CH2:58][CH2:57]2)=[O:11])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: CC(C)(C(=O)O)c1nccnc1Cl
Reactant: Cc1ccc(N[C@H]2CC[C@@H](N)CC2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(N[C@H]2CC[C@@H](NC(=O)C(C)(C)c3nccnc3Cl)CC2)nc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a round bottomed flask was added 2-(3-chloropyrazin-2-yl)-2-methylpropanoic acid (0.267 g, 1.333 mmol, 00388), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.659 g, 1.733 mmol, GenScript) and triethylamine (0.743 ml, 5.33 mmol, Sigma-Aldrich Chemical Company, Inc.) in DCM (4.44 ml). cis-N1-(5-Methylpyridin-2-yl)cyclohexane-1,4-diamine (0.3709 g, 1.333 mmol) was added and the reaction was allowed to stir at room temperature for 4 h. Solvent was evaporated in vacuo. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage SNAP HP-silica gel column (50 g), eluting with a gradient of 10% to 100% EtOAc in hexane to give the title compound (105.0 mg, 0.271 mmol, 20.3% yield). Product peak was found at 1.438 min (m+1=388.0). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.45-1.67 (m, 12 H) 1.75 (d, J=4.89 Hz, 2 H) 2.08 (s, 3 H) 3.68 (br. s., 1 H) 3.76 (br. s., 1 H) 6.50 (d, J=8.41 Hz, 1 H) 7.14-7.28 (m, 2 H) 7.76 (s, 1 H) 8.42 (d, J=2.54 Hz, 1 H) 8.65 (d, J=2.54 Hz, 1 H)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:16][C:17](=[O:19])[CH3:18])[CH:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.CCN(C(C)C)C(C)C.[CH3:29][C:30]([CH3:35])([CH3:34])[C:31](Cl)=[O:32]>C(Cl)Cl>[C:17]([NH:16][C:4]1[CH:5]=[CH:6][C:7]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)=[C:2]([NH:1][C:31](=[O:32])[C:30]([CH3:35])([CH3:34])[CH3:29])[CH:3]=1)(=[O:19])[CH3:18]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(=O)Nc1ccc(NCC2CCOCC2)c(N)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)Nc1ccc(NCC2CCOCC2)c(NC(=O)C(C)(C)C)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
N-{3-Amino-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}acetamide (25.9 g, 98.6 mmol) and DIPEA (20.6 mL, 15.4 g, 118 mmol) were dissolved in 500 mL of DCM. Trimethylacetyl chloride (12.7 mL, 12.5 g, 103 mmol) was added dropwise at 0° C. and the solution was stirred for 3 h at 0° C. and 1 h at room temperature. The pink solid was collected by filtration, washed with H2O and dried in vacuo. Yield: 33.1 g (97%); MS (ESI) (M+H)+=348.05.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1.[C:13]1([SH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:13]1([S:19][C:2]2[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)c1sc(Br)nc1C
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc(Sc2ccccc2)nc1C
Reaction time: 4 h
Yield: 98.5 %

Procedure:
A suspension of ethyl 2-bromo-4-methyl-5-thiazole-carboxylate (22 g), thiophenol (10.75 g) and potassium carbonate powder (24.3 g) in dimethylformamide (100 ml) is stirred. for 4 hours at 80° C. The reaction mixture is treated in the same manner as in Example 1 to give ethyl 2-phenylthio-4-methyl-5-thiazolecarboxylate (24.2 g) boiling at 160°-161° C. at 1 mmHg.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([N:12]1[C:16]2[C:17](=[O:22])[N:18]([CH3:21])[N:19]=[CH:20][C:15]=2[N:14]=[C:13]1[N:23]1[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]1)[C:9]#[C:10][CH3:11]>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([N:12]1[C:16]2[C:17](=[O:22])[N:18]([CH3:21])[N:19]=[CH:20][C:15]=2[N:14]=[C:13]1[N:23]1[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]1)[C:9]#[C:10][CH3:11]
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2cnn(C)c(=O)c21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC#CCn1c(N2CCNCC2)nc2cnn(C)c(=O)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.4 ml of trifluoroacetic acid was added to a 0.4-ml dichloromethane solution of 0.0351 g of t-butyl 4-[1-(2-butynyl)-6-methyl-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl]piperazine-1-carboxylate, and the mixture was stirred at room temperature for one hour. The solvent was concentrated. The residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 0.0295 g of the title compound.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[CH:15][S:16][CH:17]=2)=[C:9]([CH3:18])[CH:8]=1)(=O)=O.C([Sn](CCCC)(CCCC)[C:26]([O:28]CC)=[CH2:27])CCC.[Cl-].[Li+]>O1CCOCC1.C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:18][C:9]1[CH:8]=[C:7]([C:26](=[O:28])[CH3:27])[CH:12]=[CH:11][C:10]=1[C:13]1[N:14]=[CH:15][S:16][CH:17]=1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1cc(OS(=O)(=O)C(F)(F)F)ccc1-c1cscn1
Agent: [Pd]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(-c2cscn2)c(C)c1
Temperature: 25 °C
Yield: 40.8 %

Procedure:
To a stirred solution of 3-methyl-4-(1,3-thiazol-4-yl)phenyl trifluoromethanesulfonate from step 3 (2.60 g, 8.05 mmol) in dioxane (75 ml) was added tributyl(1-ethoxyvinyl)tin (3.5 g, 9.66 mmol), tetrakis(triphenylphosphine) palladium (930 mg, 0.805 mmol), lithium chloride (850 mg, 20.0 mmol), and the mixture was heated at reflux temperature for 8 hours. The reaction mixture was cooled down to room temperature, and diluted with ethyl acetate. The whole was washed with saturated potassium fluoride aqueous solution, and the precipitate was removed by filteration through celite. The resulting solution was extracted with ethyl acetate. The organic layer was concentrated in vacuo. To the residue was added THF (50 ml), 2N HCl aqueous solution (50 ml), and the mixture was heated at reflux temperature for 8 hours. The reaction mixture was cooled down to room temperature, made neutral by addition of NaHCO3, and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate-hexane (1:5) to give title compound (714 mg, 41% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]1[C:10]3[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=3[O:8][CH2:7][C:6]2=1.[O:20](C(C)(C)C)[K].O=O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]1[C:10]3[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=3[O:8][CH:7]([OH:20])[C:6]2=1
Reactant: CC(C)(C)O[K]
Reactant: COc1ccc2[nH]c3c(c2c1)COc1ccccc1-3
Agent: O=O
Solvent: CN(C)C=O
Product: COc1ccc2[nH]c3c(c2c1)C(O)Oc1ccccc1-3

Procedure:
8-methoxy-6,11-dihydro-5-oxa-11-aza-benzo[a]fluorene (300 mg, 1.194 mmoL) in DMF (5 mL) was treated with KO-t-Bu (1.0 M in THF, 2.0 mL, 2.0 mmoL) under a flow of O2 for 6 hours. The reaction mixture was then partitioned between water and EtOAc. The EtOAc layer was washed with saturated NH4Cl, water, brine, dried over anhydrous Na2SO4, filtered and concentrated to yield a brown oil. The crude material was then purified by column chromatography (silica gel, hexanes:EtOAc 9:1 as eluent) to yield the title compound as a white solid.
Reaction SMILES: Br[C:2]#[N:3].CC#N.[F:7][C:8]1[C:13]([F:14])=[CH:12][C:11]([NH2:15])=[C:10]([NH2:16])[CH:9]=1>O.CO>[NH2:3][C:2]1[NH:16][C:10]2[CH:9]=[C:8]([F:7])[C:13]([F:14])=[CH:12][C:11]=2[N:15]=1
Reactant: N#CBr
Reactant: Nc1cc(F)c(F)cc1N
Solvent: CO
Solvent: CC#N
Solvent: O
Product: Nc1nc2cc(F)c(F)cc2[nH]1
Reaction time: 2 h

Procedure:
To a stirred solution of 4.9 mL of 5M BrCN/MeCN in 50 mL of H2O, was added dropwise a solution of 3.515 g (24.389 mmole) of 10 in 50 mL of MeOH over 20 min. After the addition, stirring was continued at room temperature for 2 h. The reaction mixture was concentrated to ~50 mL arid was extracted with EtOAc (50 mL×3). The combined EtOAc solution was back washed with 100 mL of H2O and then discarded. The combined H2O phase was basified with sat. NaHCO3 solution (precipitation occurred) and was extracted again with EtOAc (70 mL×3). The EtOAc solution was dried (Na2SO4) and evaporated to dryness. The residue was suspended in 50 mL of CHCl3 and filtered. The yellowish solid was washed with portions of CHCl3 to give 3.40 g of 11. The filtrate and washings were evaporated to dryness and the procedure was repeated to give an additional 0.355 g of 11. The total yield of 11 was 3.755 g (91%). 1H NMR DMSO-d6) d 10.79 (br. s, 1, 1-NH). 7.06 (dd, 2, 4-H and 7-H, 3JF-H =11.0 Hz, 4JF-H =7.5 Hz), 6.30 (br. s, 2, 2-NH2).