Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([C:26]5[O:30][C:29]([CH:31]=O)=[CH:28][CH:27]=5)[CH:24]=4)[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH3:36][P:37]([CH3:42])([CH2:39][CH2:40][NH2:41])=[O:38].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C>[CH3:36][P:37]([CH3:42])([CH2:39][CH2:40][NH:41][CH2:31][C:29]1[O:30][C:26]([C:23]2[CH:24]=[C:25]3[C:20](=[CH:21][CH:22]=2)[N:19]=[CH:18][N:17]=[C:16]3[NH:15][C:11]2[CH:10]=[C:9]3[C:14](=[CH:13][CH:12]=2)[N:6]([CH2:5][C:4]2[CH:33]=[CH:34][CH:35]=[C:2]([F:1])[CH:3]=2)[N:7]=[CH:8]3)=[CH:27][CH:28]=1)=[O:38]
Reactant: CP(C)(=O)CCN
Reactant: O=Cc1ccc(-c2ccc3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c3c2)o1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CP(C)(=O)CCNCc1ccc(-c2ccc3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c3c2)o1
Temperature: 25 °C
Yield: 43 %

Procedure:
5-(4-(1-(3-fluorobenzyl)-1H-indazol-5-ylamino)quinazolin-6-yl)furan-2-carbaldehyde and 2-(dimethylphosphinoyl)ethanamine (compound 2.2, 82 mg) were suspended in dichloromethane (20 mL). Sequentially, acetic acid (3 drops) and sodium triacetoxyborohydride (237 mg) were added at room temperature. The mixture was stirred at room temperature until the starting material disappeared. The reaction was quenched with 2N NaOH aqueous solution and extracted with dichloromethane. The combined organic layer and extracts were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography, eluting with 20% methanol in dichloromethane to give the desired product as yellow crystalline solid (138 mg). LCMS ESI(+) m/z: 569 (M+1). Yield: 43%. 1H NMR (300 MHz, CD3OD) δ 8.75 (d, 1H), 8.40 (s, 1H), 8.18 (m, 1H), 8.12 (m, 2H), 7.76 (m, 1H), 7.68 (m, 1H), 7.61 (m, 1H), 7.30 (m, 2H), 7.03 (m, 2H), 6.92 (m, 3H), 6.46 (d, 1H), 5.69 (s, 2H), 3.91 (s, 2H), 2.99 (m, 2H), 2.10 (m, 2H), 1.52 (d, 3H).
Reaction SMILES: C(O[C@@H:5]1[O:27][C@H:26]([CH2:28][O:29][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@@H:16]([O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:6]1[O:7][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)C.ClCCCl.[C:42]([Si](C)(C)C)#[N:43].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[C:8]([O:7][C@@H:6]1[C@H:16]([O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:26]([CH2:28][O:29][C:30](=[O:37])[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[O:27][C@H:5]1[C:42]#[N:43])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(=O)O[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Reactant: C[Si](C)(C)C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Product: N#C[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Reaction time: 0.03 h

Procedure:
A stirred solution of 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose (50.3 g, 80 mmol), 1,2-dichloroethane (100 ml), and cyanotrimethylsilane (15.84 g, 160 mmol) was treated in one portion via a syringe with anhydrous stannic chloride (20.8 g, 9.33 ml, 80 mmol). The darkening solution was stirred for two minutes then poured into saturated sodium hydrogen carbonate (800 ml), and stirred five minutes (pH 7). Chloroform (1 liter) was added and the emulsion was filtered through Celite®. The chloroform layer was separated, dried (MgSO4) and evaporated under reduced pressure (15 torr, 40° ) to a light orange syrup which was crystallized from ethanol (charcoal to afford 2 (30 g from two crops, 80%) as long white needles; mp 77°-78° after drying at 0.05 torr, 60° for two hours; [α]D25 +24.4° (0.5 CHCl3).
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:5]([CH2:6]O[Si](C)(C)C)=[C:4]([CH3:14])[CH:3]=1.[CH3:15][Si:16]([C:19]#[CH:20])([CH3:18])[CH3:17]>C(N(CC)CC)C.[Cu]I.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>[CH3:14][C:4]1[CH:3]=[C:2]([C:20]#[C:19][Si:16]([CH3:18])([CH3:17])[CH3:15])[CH:13]=[CH:12][C:5]=1[C:6]#[C:15][Si:16]([CH3:19])([CH3:18])[CH3:17]
Reactant: C#C[Si](C)(C)C
Reactant: Cc1cc(Br)ccc1CO[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: Cc1cc(C#C[Si](C)(C)C)ccc1C#C[Si](C)(C)C
Temperature: 70 °C
Yield: 66.4 %

Procedure:
Using General Procedure D; (4-bromo-2-methyl-benzyloxy)-trimethylsilane (Intermediate 134, 550.0 mg, 2.01 mmol) in triethylamine (8 mL) was treated with copper(I)iodide (38.0 mg, 0.20 mmol) and then sparged with argon for 5 minutes. Trimethylsilyl acetylene (1.05 g, 10.6 mmols) was then added followed by dichlorobis(triphenylphosphine)palladium(II) (142.0 mg, 0.20 mmol). The resulting reaction mixture was heated to 70° C. for 5 days. The title compound (380.0 mg, 65%) was isolated by chromatography (0-2% EtOAc-hexanes) as an orange oil.
Reaction SMILES: CO.[CH3:3][NH:4][CH3:5].[C:6]([NH:9][CH2:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[S:18](Cl)(=[O:20])=[O:19])(=[O:8])[CH3:7]>CO.O1CCCC1>[Cl:17][C:15]1[CH:14]=[CH:13][C:12]([S:18](=[O:20])(=[O:19])[N:4]([CH3:5])[CH3:3])=[C:11]([CH:16]=1)[CH2:10][NH:9][C:6](=[O:8])[CH3:7]
Reactant: CNC
Reactant: CC(=O)NCc1cc(Cl)ccc1S(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)NCc1cc(Cl)ccc1S(=O)(=O)N(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(Step 1) To a solution of 2N dimethylamine methanol solution (7.51 ml) in methanol (15 ml) was added dropwise a suspension of 2-[(acetylamino)methyl]-4-chlorobenzenesulfonyl chloride (2.12 g) in tetrahydrofuran (5 ml) under ice-cooling. The mixture was allowed to warm to room temperature, and stirred for 3 hr. The reaction mixture was quenched with water, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give N-[5-chloro-2-(dimethylsulfamoyl)benzyl]acetamide (1.77 g) as a white solid.
Reaction SMILES: [Br:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:17])([F:16])[F:15])[CH:8]=2)[N:4]([CH3:18])[C:3]=1[C:19]([OH:21])=[O:20].[C:22](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH3:22][O:20][C:19]([C:3]1[N:4]([CH3:18])[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:17])([F:16])[F:15])[CH:8]=2)=[N:6][C:2]=1[Br:1])=[O:21]
Reactant: Cn1c(-c2cccc(OC(F)(F)F)c2)nc(Br)c1C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1c(Br)nc(-c2cccc(OC(F)(F)F)c2)n1C
Reaction time: 70 h
Yield: 93.4 %

Procedure:
A stirred solution of 1.826 g (5.0 mmol) of 5-bromo-3-methyl-2-(3-trifluoromethoxy-phenyl)-3H-imidazole-4-carboxylic acid (example 72) in 20 ml of DMF was treated at RT with 2.073 g (15.0 mmol) of potassium carbonate, followed by addition of 0.62 ml=1.42 g (10.0 mmol) of iodomethane. After 70 hours, the reaction mixture was poured into crashed ice and extracted twice with Et2O; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (n-heptane/CH2Cl2 1:0 to 0:1) to give 1.77 g (93%) of the title compound as light yellow oil. MS: 379.0 (MH+, 1Br).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH3:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:25][O:26][C:27]1[C:32]2[N:33]=[C:34]([NH:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[CH3:43])[O:35][C:31]=2[CH:30]=[C:29]([CH2:44][C:45](O)=[O:46])[CH:28]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[CH3:25][O:26][C:27]1[C:32]2[N:33]=[C:34]([NH:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[CH3:43])[O:35][C:31]=2[CH:30]=[C:29]([CH2:44][C:45]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C@H:8]([CH3:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=2)=[O:46])[CH:28]=1
Reactant: CCOC(=O)C[C@@H](C)c1ccc(N)cc1
Reactant: COc1cc(CC(=O)O)cc2oc(Nc3ccccc3C)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C[C@@H](C)c1ccc(NC(=O)Cc2cc(OC)c3nc(Nc4ccccc4C)oc3c2)cc1
Reaction time: 20 h
Yield: 100.8 %

Procedure:
A stirred solution of with ethyl (R) 3-(4-aminophenyl)butanoate (0.107 g, Reference Example 1) in dimethylformamide (10 mL) was treated with diisopropylethylamine (0.4 g), 2-(4-methoxy-2-o-tolylaminobenzoxazol-6-yl)acetic acid [0.105 g, Reference Example 9(a)] and then with O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.14 g). The mixture was left to stand for 20 hours and then partitioned between ethyl acetate and hydrochloric acid (1M). The organic phase was washed with water, then with aqueous bicarbonate solution (5%), then with water, then with brine, then dried and then evaporated to give the title compound (0.17 g) as a cream coloured solid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([NH:9][CH2:10][C:11]([OH:13])=[O:12])[CH:6]=[CH:7][CH:8]=1.O1CCOCC1.[C:22](OC([O-])=O)([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].Cl>C(=O)([O-])O.[Na+].C(#N)C>[C:25]([O:24][C:22]([N:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:14])([F:15])[F:1])[CH:4]=1)[CH2:10][C:11]([OH:13])=[O:12])=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: O=C(O)CNc1cccc(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N(CC(=O)O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
226 mg (1.03 mmol) of DL-[3-(trifluoromethyl)phenyl]-glycine are dissolved in 10 ml of an aqueous 5% sodium hydrogen carbonate solution and treated with 4 ml dioxan. 261 μl (1.13 mmol) of tert.-butyl dicarbonate are added and the mixture stirred overnight at RT. For the workup, the solution is carefully acidified to pH 2 with 1 N hydrochloric acid. The precipitated product is redissolved by addition of acetonitrile, and purified by preparative HPLC (Method 20). 135 mg (41% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24]O)=[CH:20][CH:19]=2)=[CH2:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.CS(Cl)(=O)=O.[CH3:31][N:32]1[C:38]([CH3:40])([CH3:39])[C:36](=[O:37])[NH:35][C:33]1=[O:34].[H-].[Na+]>CCN(CC)CC>[CH3:31][N:32]1[C:38]([CH3:40])([CH3:39])[C:36](=[O:37])[N:35]([CH2:24][C:21]2[CH:22]=[CH:23][C:18]([C:16]([C:3]3[C:2]([CH3:1])=[CH:11][C:10]4[C:9]([CH3:13])([CH3:12])[CH2:8][CH2:7][C:6]([CH3:15])([CH3:14])[C:5]=4[CH:4]=3)=[CH2:17])=[CH:19][CH:20]=2)[C:33]1=[O:34]
Reactant: C=C(c1ccc(CO)cc1)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Reactant: CN1C(=O)NC(=O)C1(C)C
Agent: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Product: C=C(c1ccc(CN2C(=O)N(C)C(C)(C)C2=O)cc1)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Yield: 38.2 %

Procedure:
Adopting the procedure outlined for example 9 using 40.0 mg (0.12 mmol) of {4-[1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-vinyl]-phenyl}-methanol, 0.05 mL of Methanesulfonyl chloride, 0.10 mL of NEt3, 300 mg of 1,5,5-trimethyl-hydantoin, and 51 mg of NaH, 21.0 mg of the product was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Br:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:13]1(=O)[CH2:18][CH2:17][CH2:16][C:15](=[O:19])[CH2:14]1>C(O)(=O)C>[Br:12][C:3]1[C:2]([NH:1][C:13]2[CH2:18][CH2:17][CH2:16][C:15](=[O:19])[CH:14]=2)=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cccc(N)c1Br
Reactant: O=C1CCCC(=O)C1
Solvent: CC(=O)O
Product: COC(=O)c1cccc(NC2=CC(=O)CCC2)c1Br
Temperature: 80 °C
Reaction time: 8 h
Yield: 75.9 %

Procedure:
Methyl 3-amino-2-bromobenzoate (2.39 g, 10.0 mmol) and cyclohexane-1,3-dione (1.12 g, 10.0 mmol) were dissolved in 10 mL of acetic acid at 25° C., under nitrogen. The mixture was stirred at 80° C. for 8 hours. The resultant solid was purified by chromatography column on silica gel (elution with hexane/ethyl acetate) to afford 2.46 g (76%) of methyl 2-bromo-3-((3-oxocyclohex-1-en-1-yl)amino)benzoate as a tan foam. 1H NMR (CDCl3-d1) δ 7.53-7.55 (m, 2H), 7.37 (dd, 1H, J=7.2, 8.4 Hz), 6.34 (br s, 1H), 5.57 (s, 1H), 3.95 (s, 3H), 2.56-2.59 (m, 2H), 2.40-2.42 (m, 2H), and 2.08-2.11 (m, 2H). MS (ESI) m/e [M+1]+ 324.0.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1.[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].CO>C(OCC)(=O)C>[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:26]3[CH2:27][CH2:28][CH:23]([C:20]4[CH:19]=[CH:18][C:17]([O:16][CH3:15])=[CH:22][CH:21]=4)[CH2:24][CH2:25]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: COc1ccc(C2CCNCC2)cc1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc(C2CCN(C[C@H](O)COc3cccc4[nH]ccc34)CC2)cc1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-(4-methoxyphenyl)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 66% overall yield. FDMS m/e=380 (M+ of free base). α[D]589=−11.77 (c=0.61, methanol).
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.[CH:9]1([CH2:12][N:13]([CH3:23])[S:14]([N:17]2[CH:21]=[CH:20][N+](C)=C2)(=[O:16])=[O:15])[CH2:11][CH2:10]1.[C@H:24]1([NH:33][C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=C(N)C=3)[N:35]=2)[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1>>[CH:9]1([CH2:12][N:13]([CH3:23])[S:14]([NH:17][C:21]2[CH:20]=[C:41]3[C:36](=[CH:37][CH:38]=2)[N:35]=[C:34]([NH:33][C@H:24]2[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:26][CH2:25]2)[CH:43]=[CH:42]3)(=[O:15])=[O:16])[CH2:10][CH2:11]1
Reactant: CN(CC1CC1)S(=O)(=O)n1cc[n+](C)c1
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Agent: O=S(=O)([O-])C(F)(F)F
Product: CN(CC1CC1)S(=O)(=O)Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1

Procedure:
The title compound was prepared in accordance with step C of the general method described in example 76 from 3-(cyclopropylmethyl-methyl-sulfamoyl)-1-methyl-3-H-imidazol-1-ium trifluoromethanesulfonate and (R)—N2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=423.7 (M+H+).
Reaction SMILES: [C:1]([O:7][CH2:8]Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[I-:10].[K+]>CC(C)=O.N#N>[C:1]([O:7][CH2:8][I:10])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: [I-]
Agent: N#N
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)C(=O)OCI
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Chloromethyl pivalate (6 mL) was dissolved in dry acetone (500 mL) in an atmosphere of N2. To the mixture was added dry potassium iodide (15.33 g), and the mixture was stirred at room temperature for two days. After this time the mixture was filtered to yield a clear solution of iodomethyl pivalate.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:17][C:16]3[C:11](=[N:12][CH:13]=[CH:14][C:15]=3[O:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:20]=3[F:28])[CH:10]=2)=[N:7][CH:8]=1.[NH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35]CC)=O.CCN(C(C)C)C(C)C>C(#N)C>[F:28][C:20]1[CH:21]=[C:22]([N+:25]([O-:27])=[O:26])[CH:23]=[CH:24][C:19]=1[O:18][C:15]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:10]=[C:9]([C:6]3[N:7]=[CH:8][C:3]([CH2:2][N:29]4[CH2:30][CH2:31][CH2:32][C:33]4=[O:35])=[CH:4][CH:5]=3)[S:17][C:16]=12
Reactant: CCOC(=O)CCCN
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4ccc(CCl)cn4)sc23)c(F)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCCN1Cc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)nc1
Temperature: 25 °C
Yield: 48.3 %

Procedure:
A mixture of 102 (500 mg, 1.202 mmol), ethyl 4-aminobutanoate (403 mg, 2.405 mmol) and DIPEA (0.630 mL, 3.61 mmol) under nitrogen in acetonitrile (12 mL) was heated to reflux for 3 days, then cooled to RT. The reaction mixture was then concentrated. The crude product was purified by Biotage (25M column; MeOH/DCM: 0/100 to 20/80 over 20 CV). The desired fractions were collected, concentrated and dried under high vacuum to afford the title compound 103 (270 mg, 0.58 mmol, 48% yield). MS (m/z): 465.5 (M+H).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:14]=2)[CH:9]=[C:8]1[C:21]([O:23][CH2:24][CH3:25])=[O:22].Br[CH:27]([CH3:30])[C:28]#[N:29]>CN(C=O)C>[C:28]([CH:27]([N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:14]=2)[CH:9]=[C:8]1[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH3:30])#[N:29]
Reactant: CC(Br)C#N
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2cc(C(=O)OCC)n(C(C)C#N)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
A mixture of K2CO3 (7.9 g, 57.4 mmol) and diethyl 1H-indole-2,6-dicarboxylate (Intermediate A, 5.0 g, 19.1 mmol) in DMF (30 mL) is stirred at room temperature for 30 min. A solution of 2-bromo-propionitrile (3.4 mL, 38.3 mmol) in DMF (10 mL) is added. The reaction mixture is warmed to 80° C. for 6 h and then cooled to room temperature and stirred for another 16 h. Solvent is removed and the residue is partitioned between EtOAc and water. The organic layer is separated, dried and concentrated to afford crude compound which is purified by flash column chromatography using EtOAc in hexanes followed by trituration with acetonitrile to afford the title compound (5.5 g, 91%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]1([S:18](Cl)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>N1C=CC=CC=1>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][S:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:20])=[O:19])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Agent: Cl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cc(NS(=O)(=O)c2ccccc2)ccc1F
Temperature: 10 °C
Reaction time: 0.33 h

Procedure:
4-fluoro-3-nitro-aniline (7.8 g, 50 mmol) is taken up in 50 mL pyridine and cooled to 10° C. The benzenesulphonic acid chloride (7.0 mL, about 55 mmol) is added dropwise with stirring within about 20 min at 10-20° C. The mixture is stirred for about 0.5 h at ambient temperature and poured onto ice water. After acidifying with conc. hydrochloric acid the mixture is extracted with 150 mL ethyl acetate, washed with water, dried and concentrated by evaporation. The residue is dissolved in diethylether, diluted with petroleum ether and cooled. The crystals formed are filtered off, washed with diethylether/petroleum ether and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:25])[C:7]=1[CH2:8][C:9]([C:11]1[C:16]2[CH:17]=[C:18]([C:20]([OH:22])=O)[O:19][C:15]=2[C:14]([O:23][CH3:24])=[CH:13][CH:12]=1)=[O:10].O.ON1C2C=CC=CC=2N=N1.[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:25])[C:7]=1[CH2:8][C:9]([C:11]1[C:16]2[CH:17]=[C:18]([C:20]([N:41]3[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]3)=[O:22])[O:19][C:15]=2[C:14]([O:23][CH3:24])=[CH:13][CH:12]=1)=[O:10]
Reactant: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)c2cc(C(=O)O)oc12
Reactant: CN1CCNCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)c2cc(C(=O)N3CCN(C)CC3)oc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 79 %

Procedure:
4-[2-(3,5-Dichloro-4-pyridyl)-1-oxoethyl]-7-methoxybenzofuran-2-carboxylic acid (Compound M, 5.8 g) obtained in Reference Example 3 was dissolved in DMF (700 ml), and 1-hydroxybenzotriazole monohydrate (8.4 g), N-ethyl-N′-3-dimethylaminopropylcarbodiimide monohydrochloride (11.6 g) and 1-methylpiperazine (6.8 ml) were added thereto, and the mixture was stirred at room temperature for 5 hours. After the solvent was distilled off under reduced pressure, the residue was extracted with chloroform, washed with a saturated aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform:methanol 80:1 to 20:1) and then recrystallized from ethanol to give Compound 13 (5.5 g, 79%) as colorless crystals.
Reaction SMILES: [NH:1]([C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[CH2:6][CH2:7][NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[NH2:2].[C:18]([CH2:24][C:25]#[N:26])(=O)[C:19]([CH3:22])([CH3:21])[CH3:20].Cl.CCO>CCO>[NH2:26][C:25]1[N:1]([C:3]2[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=2)[CH2:6][CH2:7][NH:8][C:9](=[O:14])[C:10]([F:11])([F:12])[F:13])[N:2]=[C:18]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:24]=1
Reactant: NNc1cccc(CCNC(=O)C(F)(F)F)c1
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Solvent: CCO
Product: CC(C)(C)c1cc(N)n(-c2cccc(CCNC(=O)C(F)(F)F)c2)n1
Temperature: 77.5 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
To a stirring solution of N-(3-hydrazinophenethyl)-2,2,2-trifluoroacetamide (0.18 g, 0.73 mmol) in absolute EtOH (5 ml) at RT was added pivaloylacetonitrile (0.11 g, 0.87 mmol) and saturated HCl/EtOH (3 drops from a pipet). The resulting solution was stirred at 75-80° C. overnight, then cooled to RT and concentrated. The residue was dissolved in Et2O and washed with saturated. NaHCO3. The aqueous was extracted with Et2O (1×). The combined organics were washed with brine (1×), dried (MgSO4), filtered, concentrated and purified via flash chromatography to provide N-[3-(5-amino-3-t-butyl-1H-pyrazol-1-yl)phenethyl]-2,2,2-trifluoroacetamide as an orange glass (0.18 g, 70% yield). 1H NMR (300 MHz, CDCl3): δ 7.47-7.46 (m, 2H), 7.43-7.39 (m, 1H), 7.14-7.12 (m, 1H), 5.51 (s, 1H), 3.67 (q, J=6.6 Hz, 2H), 2.95 (t, J=6.6 Hz, 2H), 1.33 (s, 9H); MS (ESI) m/z: 355.2 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([OH:17])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:18][C:19]1[S:20][CH:21]=[C:22]([CH3:24])[N:23]=1.C(N(C(C)C)CC)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>ClCCl>[CH3:24][C:22]1[N:23]=[C:19]([NH:18][C:15](=[O:17])[CH2:14][N:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)[S:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CC(=O)O)CC1
Reactant: Cc1csc(N)n1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1csc(NC(=O)CN2CCN(C(=O)OC(C)(C)C)CC2)n1
Reaction time: 20 h

Procedure:
To a round-bottomed flask containing 2-(1-tert-butoxycarbonyl-piperazin-4-yl)-acetic acid×2HCl (0.100 g, 0.36 mmol) was added 2-amino-4-methylthiazole (0.045 g, 0.39 mmol) and anhydrous dichloromethane (4 ml). The reaction mixture was cooled into an ice-bath under argon, and then diisopropylethylamine (0.139 g, 1.08 mmol) was added followed by PyBOP (0.187 g, 0.36 mmol). The ice-bath was removed and the reaction mixture was allowed to stir for 20 h under argon. The solvent was removed in vacuo, the residue was absorbed on silica gel and the free running powder was placed on a 20 g isolute silica column which was eluted with 30% ethyl acetate in dichloromethane and then 60% ethyl acetate in dichloromethane. The title compound was obtained as a gummy material (0.076 g, 62%). 1H-NMR (500 MHz, DMSO-d6) 1.39 (s, 9H, C(CH3)3), 2.25 (s, 3H, CH3), 2.45 (br s, 4H, piperazine N(CH2)2), 3.27 (s, 2H, NCH2CO), 6.76 (s, 1H, thiazole 5-H), 11.78 (s, 1H, CONH);