Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC[N:3]1[C:7]2[N:8]=[CH:9][N:10]=[C:11]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:6]=2[C:5]([C:18]2[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=2)[C:21]#[N:22])=[C:4]1[CH3:26].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:26][C:4]1[NH:3][C:7]2[N:8]=[CH:9][N:10]=[C:11]([N:12]3[CH2:13][CH2:14][O:15][CH2:16][CH2:17]3)[C:6]=2[C:5]=1[C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[C:21]#[N:22]
Reactant: Cc1c(-c2cccc(C#N)c2)c2c(N3CCOCC3)ncnc2n1CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1[nH]c2ncnc(N3CCOCC3)c2c1-c1cccc(C#N)c1

Procedure:
A solution of 3-[7-(hydroxymethyl)-6-methyl-4-(morpholin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]benzonitrile (C9) (from the previous step, 125 mg, ≦0.278 mmol) in acetonitrile (5 mL) was adjusted to a pH of >11 by addition of solid potassium carbonate. The mixture was filtered and concentrated in vacuo; purification via preparative HPLC (Column: Boston Symmetrix ODS-H, 5 μm; Mobile phase A: 0.225% formic acid in water; Mobile phase B: acetonitrile; Gradient: 19% to 39% B) afforded the product as a yellow solid. Yield: 54 mg, 0.17 mmol, 61% over two steps. LCMS m/z 319.9 [M+H+]. 1H NMR (400 MHz, DMSO-d6) δ 12.17 (br s, 1H), 8.34 (s, 1H), 7.77-7.83 (m, 2H), 7.65-7.74 (m, 2H), 3.27-3.33 (m, 4H), 2.98-3.06 (m, 4H), 2.36 (s, 3H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[N:10]1[CH2:31][CH2:30][C:13]2([C:17](=[O:18])[N:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)[CH2:12][CH2:11]1.B(Br)(Br)Br>>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[N:10]1[CH2:31][CH2:30][C:13]2([C:17](=[O:18])[N:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:28])([F:29])[F:27])=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)[CH2:12][CH2:11]1
Reactant: COc1ccc(C)cc1N1CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O
Agent: BrB(Br)Br
Product: Cc1ccc(O)c(N2CCC3(CC2)CCN(c2ccc(OC(F)(F)F)cc2)C3=O)c1

Procedure:
The title compound was prepared in analogy to example 13 from a mixture of 8-(2-methoxy-5-methyl-phenyl)-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 8) and boron tribromide. Light yellow solid. MS (ESI): 421.1 (MH+)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.Cl[C:16]1[N:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[N:17]=1>>[CH3:23][C:18]1[CH:19]=[C:20]([CH3:22])[N:21]=[C:16]([NH:14][C:11]2[CH:12]=[CH:13][C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=3)=[CH:9][CH:10]=2)[N:17]=1
Reactant: Cc1cc(-c2ccc(N)cc2)ccn1
Reactant: Cc1cc(C)nc(Cl)n1
Product: Cc1cc(-c2ccc(Nc3nc(C)cc(C)n3)cc2)ccn1

Procedure:
The title compound was prepared in analogy to example 62 from 4-(2-methyl-pyridin-4-yl)-phenylamine and 2-chloro-4,6-dimethylpyrimidine. Obtained as a yellowish solid (Yield=33%). MS ISP (m/e): 291.1 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=9.73 (s, 1H), 8.43 (d, 1H), 7.97 (d, 2H), 7.73 (d, 2H), 7.55 (s, 1H); 7.47 (d, 1H), 6.67 (s, 1H), 2.50 (s, 3H hidden in DMSO-peak), 2.34 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]([C@@H:23]3[CH2:27][CH2:26][NH:25][CH2:24]3)[C:7]([CH2:9][N:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]([S:19]([CH3:22])(=[O:21])=[O:20])=[N:11]3)=[N:8][C:4]=2[CH:3]=1.[C:30](O)(=[O:33])[CH2:31][CH3:32].C(OC(=O)C)(=O)C>>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]([C@@H:23]3[CH2:27][CH2:26][N:25]([C:30](=[O:33])[CH2:31][CH3:32])[CH2:24]3)[C:7]([CH2:9][N:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]([S:19]([CH3:22])(=[O:21])=[O:20])=[N:11]3)=[N:8][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2[C@@H]2CCNC2)c2ccccc12
Reactant: CCC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CCC(=O)N1CC[C@@H](n2c(Cn3nc(S(C)(=O)=O)c4ccccc43)nc3cc(Cl)ccc32)C1

Procedure:
The title compound was prepared in analogy to Example 2-17 by using 1-({5-chloro-1-[(3R)-(pyrrolidin-3-yl)]-1H-benzo[d]imidazol-2-yl}methyl)-3-(methylsulfonyl)-1H-indazole and propionic acid instead of 1-{[5-chloro-1-(pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl]methyl}-3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine and acetic anhydride.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:28]([OH:31])[C:29]#[CH:30].C(N(C(C)C)CC)(C)C>[Cu]I.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].O.O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:30]#[C:29][CH2:28][OH:31])=[CH:4][CH:3]=1
Reactant: C#CCO
Reactant: Brc1ccc(I)cc1
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: OCC#Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
A mixture of 4-bromoiodobenzene (8.00 g), copper(I) iodide (108 mg), triphenylphosphine (372 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (586 mg), propargyl alcohol (1.84 ml), diisopropylethylamine (19.7 ml) and tetrahydrofuran (100 ml) was stirred at room temperature for 13 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=98:2-90:10) to give the object product (4.34 g) as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[C@H:4]([CH3:7])[CH2:5][OH:6].C(Cl)(Cl)(Cl)Cl.ClC(Cl)(Cl)C(=N)O[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>FC(F)(F)S(O)(=O)=O.C1CCCCC1>[CH2:18]([O:6][CH2:5][C@H:4]([CH3:7])[C:3]([O:2][CH3:1])=[O:8])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)[C@H](C)CO
Reactant: N=C(OCc1ccccc1)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: C1CCCCC1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)[C@@H](C)COCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.9 %

Procedure:
An oven dried 1 L single-necked round bottom flask was equipped with a magnetic stir bar and then charged sequentially with 15.948 g (0.135 mol) of (R)-(-)-methyl-3-hydroxy-2-methylpropanoate, carbon tetrachloride (150 mL), cyclohexane (300 mL), and 35.796 g (0.142 mol) of benzyl 2,2,2-trichloroacetimidate. Trifluoromethanesulfonic acid (0.8 mL; 9.0 mmol) was added to the solution and the resulting mixture was stirred for 16 h at room temperature under an N2 atmosphere. The reaction mixture was then filtered and the filtrate concentrated in vacuo. The residue was redissolved in 150 mL EtOAc and extracted with saturated aqueous NaHCO3 (lxlOO mL). The organic layer was washed with saturated NaCl, dried (MgSO4), filtered and evaporated. The residual oil was purified on a silica gel flash chromatography column eluted with 10% EtOAc-hexane. The purified fractions were combined and evaporated in vacuo to afford 20.787g of the title compound as an oil. MS (CI): m/e=209 (M+1).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[C:11]([CH3:17])[CH:10]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br.O>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[C:11]([CH3:17])[CH:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2ccc(C#N)c(C)c2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Cc1cc(-c2ccc(O)cc2)ccc1C#N
Temperature: 25 °C
Reaction time: 14 h
Yield: 94.8 %

Procedure:
The product from Example 164A (5.60 g, 25.4 mmol) in CH2Cl2 (120 mL) at 78° C. was treated with 1.0 M BBr3 (in CH2Cl2, 76 mL, 76.0 mmol) dropwise over 1 hour. After stirring for 14 hours at room temperature, the mixture was warmed to 0° C. (ice bath) and treated with water (0.5 mL). After 10 minutes, additional water was added (2.0 mL), ice bath was removed, and 5.0 mL of water was added. The mixture was then treated with another 20 mL of water and allowed to stir for 45 minutes. The mixture was filtered and the filtrate extracted with CH2Cl2. The CH2Cl2 layers were combined, dried over sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to provide the title compound as an off-white powder (5.04 g, 94% yield). 1HNMR (300 MHz, CDCl3) δ2.35 (s, 3H), 5.0 (s, 1H), 6.79-7.50 (m, 7H); MS (DCI) m/z 210 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:15])[C:12]([NH2:14])=O)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].C(Cl)(Cl)=O.C1(C)C=CC=CC=1>C1(C)C=CC=CC=1.ClC(Cl)Cl>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([CH3:15])[C:12]#[N:14])=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1ccc(C(C)C(N)=O)cc1
Agent: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CC(C)Cc1ccc(C(C)C#N)cc1
Reaction time: 12 h
Yield: 80 %

Procedure:
4-isobutyl-α-methylphenylacetamide (2 g; 9.7 mmol), prepared according the procedure described in WO 00/24710, is dissolved in a solution (2:1) toluene/trichloromethane (30 mL). 20% in toluene phosgene (15.5 mL, 30 mmol) is added and the resulting mixture is left stirring 12 h under inert atmosphere until the complete disappearance of the starting reagent. After solvents evaporation under reduced pressure, the crude is dissolved in ethyl acetate (20 mL), the organic phase is washed with a saturated solution of NaHCO3 (2×20 mL) and with a saturated solution of NaCl (2×15 mL), dried over Na2SO4 and evaporated under vacuum to give 2-(4-isobutylphenyl)propionitrile as colourless oil (1.45 g; 7.76 mmol). Yield 80%. 1H-NMR (CDCl3): δ 7.42 (d, 2H, J=7 Hz); 7.28 (d, 2H, J=7 Hz); 4.05 (q, 1H, J=8 Hz); 2.65 (d, 2H, J=8 Hz); 1.95 (m, 1H); 1.80 (d, 3H, J=8 Hz); 1.05 (d, 6H, J=8 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[CH3:10][S:11]([NH:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1)(=[O:13])=[O:12].CC([O-])=O.[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:8][N:6]1[C:5](=[O:9])[CH:4]=[CH:3][C:2]([C:19]2[CH:20]=[C:15]([NH:14][S:11]([CH3:10])(=[O:12])=[O:13])[CH:16]=[CH:17][CH:18]=2)=[CH:7]1
Reactant: CS(=O)(=O)Nc1cccc(B(O)O)c1
Reactant: Cn1cc(Br)ccc1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2cccc(NS(C)(=O)=O)c2)ccc1=O
Temperature: 90 °C
Reaction time: 0.33 h
Yield: 20.3 %

Procedure:
A mixture of 5-bromo-1-methylpyridin-2-one (100 mg, 0.532 mmol), [3-(methanesulfonamido)phenyl]boronic acid (171.1 mg, 0.798 mmol), KOAc (130.0 mg, 1.326 mmol) and Pd(dppf)Cl2 (38.9 mg, 0.05 mmol) in dioxane/H2O (2 mL/0.5 mL) was stirred at 90° C. for 20 min. The mixture was concentrated and the residue was purified by column chromatography on silica gel (PE:EA=1:1) to give the title compound (30.0 mg, 20%) as a brown solid. 1H NMR (CDCl3, 400 MHz) δ 7.65-7.60 (dd, J1=7.6 Hz, J2=2.4 Hz, 1H), 7.54 (d, J=2.4 Hz, 1H), 7.41 (t, J=8.0 Hz, 1H), 7.33 (s, 1H), 7.24 (d, J=7.6 Hz, 1H), 7.17 (d, J=7.6 Hz, 1H), 6.86 (brs, 1H), 6.67 (d, J=9.2 Hz, 1H), 3.65 (s, 3H), 3.05 (s, 3H). LCMS (M+H)+ 279.
Reaction SMILES: [F:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH:13]=[CH:12][C:11]=2[F:23])=[C:6]([CH3:24])[CH:5]=[CH:4][C:3]=1[OH:25].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]>CN(C=O)C>[F:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH:13]=[CH:12][C:11]=2[F:23])=[C:6]([CH3:24])[CH:5]=[CH:4][C:3]=1[O:25][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]
Reactant: CCOC(=O)CBr
Reactant: Cc1ccc(O)c(F)c1NCc1cc(-c2cccc(F)c2)ccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(C)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.6 %

Procedure:
To a solution of 2-fluoro-3-[[2-fluoro-5-(3-fluorophenyl)phenyl]methylamino]-4-methyl-phenol (300 mg, 0.87 mmol, 1 eq) in DMF (6 mL) was added Cs2CO3 (425 mg, 1.31 mmol, 1.5 eq). The reaction mixture was stirred at room temperature for 1 h, then ethyl 2-bromoacetate (174 mg, 1.04 mmol, 1.2 eq) was added. The reaction mixture was stirred for 1 h then the reaction quenched by pouring into water. The mixture was extracted with EtOAc and the organic extract washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (EtOAc:petroleum ether, 0:1 to 1:10) to give the title compound as an oil (260 mg, 70%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]([CH3:40])([CH3:39])[CH2:9][N:10]1[CH:14]=[C:13]([C:15]2[CH:38]=[CH:37][C:18]3[C:19]4[N:20]=[C:21]([C:27]5[N:28]([CH2:32][C:33]([F:36])([F:35])[F:34])[N:29]=[CH:30][N:31]=5)[S:22][C:23]=4[CH2:24][CH2:25][O:26][C:17]=3[CH:16]=2)[CH:12]=[N:11]1)(C)(C)C.C(Cl)Cl.FC(F)(F)C(O)=O.C(=O)=O>>[CH3:40][C:8]([NH2:7])([CH3:39])[CH2:9][N:10]1[CH:14]=[C:13]([C:15]2[CH:38]=[CH:37][C:18]3[C:19]4[N:20]=[C:21]([C:27]5[N:28]([CH2:32][C:33]([F:36])([F:35])[F:34])[N:29]=[CH:30][N:31]=5)[S:22][C:23]=4[CH2:24][CH2:25][O:26][C:17]=3[CH:16]=2)[CH:12]=[N:11]1
Reactant: CC(C)(Cn1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4CC(F)(F)F)nc2-3)cn1)NC(=O)OC(C)(C)C
Agent: O=C=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(N)Cn1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4CC(F)(F)F)nc2-3)cn1
Yield: 15 %

Procedure:
To a round bottom flask containing [1,1-Dimethyl-2-(4-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol-1-yl)-ethyl]-carbamic acid tert-butyl ester (0.175 g, 0.000297 mol) in methylene chloride (1.1 mL, 0.017 mol) was added trifluoroacetic acid (1.3 mL, 0.017 mol). The solution was stirred at room temperature until CO2 evolution stopped (30 minutes). The solvent was removed in vacuo and purified by reverse-phase HPLC to give 393 (21.8 mg) as a white solid. MS(ESI+) 490.1. 1H NMR (400 MHz, DMSO) δ 8.37 (d, J=9.7, 1H), 8.29 (s, 1H), 8.26 (d, J=8.3, 1H), 7.98 (s, 1H), 7.49 (dd, J=8.3, 1.7, 1H), 7.37 (d, J=1.7, 1H), 5.86 (q, J=8.7, 2H), 4.39 (t, J=5.0, 2H), 3.47 (t, J=5.0, 2H), 2.86 (s, 2H), 1.50 (s, 6H).
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]2[CH:11]=[C:10]([CH2:12][N:13]3[C:17](=[O:18])[C:16]4([CH2:23][CH2:22][N:21](C(O)=O)[CH2:20][CH2:19]4)[N:15]([CH3:27])[C:14]3=[O:28])[N:9]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:7]=2[N:8]=1)#[N:2].C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:31][C:30]([CH3:33])([CH3:32])[CH2:29][N:9]1[C:7]2[N:8]=[C:3]([C:1]#[N:2])[N:4]=[CH:5][C:6]=2[CH:11]=[C:10]1[CH2:12][N:13]1[C:17](=[O:18])[C:16]2([CH2:19][CH2:20][NH:21][CH2:22][CH2:23]2)[N:15]([CH3:27])[C:14]1=[O:28]
Reactant: CN1C(=O)N(Cc2cc3cnc(C#N)nc3n2CC(C)(C)C)C(=O)C12CCN(C(=O)O)CC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1C(=O)N(Cc2cc3cnc(C#N)nc3n2CC(C)(C)C)C(=O)C12CCNCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 7.62 g (0.015 moles) of 3-[2-cyano-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidin-6-ylmethyl]-1-methyl-2,4-dioxo-1,3,8-triaza-spiro[4.5]decane-8-carboxylic acid .tert.-butyl ester in 30 ml of CH2Cl2, 30 ml (389 mmoles) of TFA is added at 0° C. After bing stirred for 1 hour at ambient temperature, sat. NaHCO3 is added at 0° C. to the reaction mixture and the mixture is extracted with CH2Cl2. The combined extracts are dried over MgSO4 and concentrated under reduced pressure to give desired 7-(2,2-dimethyl-propyl)-6-(1-methyl-2,4-dioxo-1,3,8-triaza-spiro[4.5]dec-3-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile in quantitative yield. The crude product is used for the next step without purification.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][NH:9][CH2:10][C:11]#[CH:12].[CH3:13][S:14](Cl)(=[O:16])=[O:15]>C(Cl)Cl>[CH3:8][N:9]([CH2:10][C:11]#[CH:12])[S:14]([CH3:13])(=[O:16])=[O:15]
Reactant: C#CCNC
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCN(C)S(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Triethylamine (6.55 ml) was added to an ice-cooled solution of N-methyl-N-(2-propynyl)amine (2603 mg) in methylene chloride (25 ml). Methanesulfonyl chloride (3.50 ml) was further added dropwise, the reaction mixture was stirred at that temperature for 1 hour, and then stirred further at room temperature for 2 hours. After ice was added, the reaction mixture was extracted with ethyl acetate, washed successively with 1 N hydrochloric acid, a saturated aqueous sodium hydrogencarbonate solution, and saturated brine, dried over anhydrous magnesium sulfate, and then filtered through silica gel. The filtrate was concentrated under reduced pressure to give the title compound (4522 mg). The obtained compound was used in the following reaction without further purification.
Reaction SMILES: [C:1](=[NH:23])([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:14]=[N:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=2)=[CH:8][CH:7]=1)[NH2:2].[CH:24]([CH:26]([CH2:31][C:32]1[CH:33]=[N:34][C:35]([O:38][CH3:39])=[N:36][CH:37]=1)[C:27](OC)=O)=[O:25].C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[CH3:39][O:38][C:35]1[N:34]=[CH:33][C:32]([CH2:31][C:26]2[C:24](=[O:25])[N:23]=[C:1]([O:3][CH2:4][CH2:5][C:6]3[CH:7]=[CH:8][C:9]([O:12][C:13]4[CH:14]=[N:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=4)=[CH:10][CH:11]=3)[NH:2][CH:27]=2)=[CH:37][N:36]=1
Reactant: COC(=O)C(C=O)Cc1cnc(OC)nc1
Reactant: N=C(N)OCCc1ccc(Oc2ccc(C(F)(F)F)nc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1ncc(Cc2c[nH]c(OCCc3ccc(Oc4ccc(C(F)(F)F)nc4)cc3)nc2=O)cn1
Temperature: 130 °C
Yield: 9.6 %

Procedure:
To the solution of 2-(4-{[6-(trifluoromethyl)-3-pyridinyl]oxy}phenyl)ethyl imidocarbamate (400 mg, 0.913 mmol) and methyl 2-formyl-3-[2-(methyloxy)-5-pyrimidinyl]propanoate (246 mg, 1.095 mmol) in NMP (3 mL) was added K2CO3 (505 mg, 3.65 mmol). The mixture was heated with a microwave reactor at 130° C. for 1 h. Purification via MDAP then afforded the title compound (44 mg, 9.65% yield). LCMS: rt=3.10 min, [M+H+]=500
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:21][C:6]2=[C:7]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[S:8][C:9]([S:10]([CH3:13])(=O)=O)=[C:5]2[C:4](=[O:22])[CH2:3]1.[Na].[C:25]1(S)[CH:30]=[CH:29]C=[CH:27][CH:26]=1>CCO>[CH3:1][C:2]1([CH3:23])[CH2:21][C:6]2=[C:7]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[S:8][C:9]([S:10][C:13]3[CH:29]=[CH:30][CH:25]=[CH:26][CH:27]=3)=[C:5]2[C:4](=[O:22])[CH2:3]1
Reactant: Sc1ccccc1
Reactant: CC1(C)CC(=O)c2c(S(C)(=O)=O)sc(C(=O)N3CCCC3)c2C1
Agent: [Na]
Solvent: CCO
Product: CC1(C)CC(=O)c2c(Sc3ccccc3)sc(C(=O)N3CCCC3)c2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of the 6,6-dimethyl-3-methanesulphonyl-1-(pyrrolidin-1-ylcarbonyl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one (400 mg, 1.1 mmol) in EtOH (15 mL) was added thiophenol sodium salt (297 mg, 2.2 mmol). The mixture was stirred at room temperature for 3 h then the solvent evaporated. The residue was partitioned between EtOAc (20 mL) and water (30 mL). The organic phase was separated, dried (Na2SO4) and evaporated. The resultant oil was triturated with ether/hexane and the colourless solid (330 mg, 76%) collected by filtration. mp 140° C. C21H23NO2S2 requires: C, 65.42; H, 6.01; N, 3.63%. Found: C, 65.55; H, 5.77; N, 3.980%,. 1H NMR (360 MHz, CDCl3) δ1.07 (6H, s), 1.86-1.90 (4H, m), 2.43 (2H, s), 2.78 (2H, s), 3.36-3.60 (4H, m), 7.43-7.51 (3H, m), 7.67-7.70 (2H, m). MS (ES+) 386 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][N:9]=[CH:10][C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=2)=[CH:4][C:3]=1[CH:19]1[CH2:22][CH2:21][CH2:20]1>C(O)C>[Cl:1][C:2]1[C:3]([CH:19]2[CH2:20][CH2:21][CH2:22]2)=[CH:4][C:5]2[N:6]([C:10]([C:11]3[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=3)=[N:9][N:8]=2)[N:7]=1
Reactant: Fc1cc(F)cc(C=NNc2cc(C3CCC3)c(Cl)nn2)c1
Solvent: CCO
Product: Fc1cc(F)cc(-c2nnc3cc(C4CCC4)c(Cl)nn23)c1
Temperature: 70 °C

Procedure:
Ferric chloride (3.423 g, 12.66 mmol) in ethanol (15 ml) was added dropwise to a solution of N-(6-chloro-5-cyclobutylpyridazin-3-yl)-N′-(3,5-difluorobenzylidene)hydrazine (0.816 g, 2.53 mmol) in ethanol (35 ml) and heated at 70° C. After 3 hours the reaction mixture was partitioned between dichloromethane (250 ml) and brine (250 ml). The organic phase was dried (MgSO4), filtered and evaporated. The residue was purified by chromatography on silica gel, eluting with ethyl acetate-hexane mixtures to afford the title pyridazite (0.51 g, 63%). 1H NMR (250 MHz, CDCl3) 1.84-2.08 (1H, m), 2.08-2.36 (3H, m), 2.42-2.68 (2H, m), 3.65-3.87 (1H, m), 6.88-7.06 (1H, m), 8.01 (1H, s), 8.04-8.21 (2H, m). MS (ES+) 321 [MH]+, 323 [MH]+.
Reaction SMILES: Br[C:2]1[C:11]2[O:10][C@@H:9]([CH3:12])[CH2:8][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][C:5]=2[S:4][CH:3]=1.[CH:20](/B(O)O)=[CH:21]/[CH3:22].C(=O)([O-])[O-].[K+].[K+].O>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:12][C@H:9]1[CH2:8][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][C:5]2[S:4][CH:3]=[C:2](/[CH:20]=[CH:21]\[CH3:22])[C:11]=2[O:10]1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)Cc2scc(Br)c2O1
Reactant: C/C=C\B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: C/C=C\c1csc2c1O[C@@H](C)CN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Yield: 75 %

Procedure:
A mixed solution of tert-butyl (2S)-8-bromo-2-methyl-2,3-dihydrothieno[2,3-f][1,4]oxazepine-4(5H)-carboxylate (599 mg) obtained in Example 12, steps 1-4, cis-propenylboronic acid (192 mg), dichlorobis(triphenylphosphine)palladium (60 mg) and potassium carbonate (713 mg) in DME-water (1:1, 20 mL) was stirred at 85° C. for 4 hr under a nitrogen stream. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 5→15% ethyl acetate/hexane) to give the title compound (399 mg, 75%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[N:6]=[C:5]([Br:7])[NH:4][N:3]=1.[H-].[Na+].CS(O[CH2:15][CH3:16])(=O)=O>CN(C)C=O.O>[Br:1][C:2]1[N:6]=[C:5]([Br:7])[N:4]([CH2:15][CH3:16])[N:3]=1
Reactant: Brc1n[nH]c(Br)n1
Reactant: CCOS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1nc(Br)nc1Br
Temperature: 100 °C
Yield: 90.6 %

Procedure:
3,5-Dibromo-1H-1,2,4-triazole (2.5 g, 11.0 mmol, Eq: 1.00) was dissolved in dimethylformamide (31.8 ml) and sodium hydride (529 mg, 60% dispersion in mineral oil, 13.2 mmol, Eq: 1.2) was added slowly. Ethyl methanesulfonate (2.74 g, 2.27 ml, 22.0 mmol, Eq: 2) was added to the reaction and the mixture was heated in a microwave oven for 60 minutes at 100° C. The mixture was diluted with water and extracted 3× with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and the solvent was evaporated to give 3,5-dibromo-1-ethyl-1H-[1,2,4]triazole (2.54 g, 90.4%) as a white powder. MS: m/z=255.9 (M+H+)