Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]1=[O:14])=[O:5].[C:20](OCC)(OCC)(OCC)[CH2:21][CH3:22].O>CN(C=O)C.CO>[CH2:21]([C:22]1[N:6]([CH:7]2[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]2=[O:14])[C:4](=[O:5])[C:3]2[C:2](=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:19])[N:1]=1)[CH3:20]
Reactant: Cc1cccc(N)c1C(=O)NC1CCC(=O)NC1=O
Reactant: CCOC(CC)(OCC)OCC
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nc2cccc(C)c2c(=O)n1C1CCC(=O)NC1=O
Yield: 22.9 %

Procedure:
A solution of 2-amino-N-(2,6-dioxo-piperidin-3-yl)-6-methyl-benzamide (0.5 g, 1.9 mmol) and triethyl orthopropionate (0.42 mL, 2.1 mmol) in DMF (5 mL) was heated at 150° C. in a microwave oven for 1.5 hours. To the mixture, was added water (30 mL). The mixture was cooled in an ice-water bath. The suspension was filtered to give a solid, which was stirred in methanol (15 mL) overnight. The suspension was filtered and washed with methanol (10 mL) and ethyl acetate (10 mL) to give 3-(2-ethyl-5-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as a white solid (0.13 g, 22% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 grad 90/10 in 5 min CH3CN/0.1% H3PO4, 5.74 min (98.9%); mp: 228-230° C.; 1H NMR (DMSO-d6) δ 1.27 (t, J=7 Hz, 3H, CH3), 2.07-2.13 (m, 1H, CHH), 2.50 (s, 3H, CH3), 2.51-2.65 (m, 2H, 2CHH), 2.82-2.92 (m, 3H, CH2, CHH), 5.21 (dd, J=6, 11 Hz, 1H, NCH), 7.25 (d, J=8 Hz, 1H, Ar), 7.46 (d, J=8 Hz, 1H, Ar), 7.64 (t, J=8 Hz, 1H, Ar), 10.98 (s, 1H, NH); 13C NMR (DMSO-d6) δ 11.18, 21.05, 22.48, 28.02, 35.51, 55.26, 118.64, 125.00, 128.86, 133.70, 139.82, 148.27, 157.69, 161.14, 169.75, 172.63; LCMS: MH=300; Anal Calcd for C16H17N3O3: C, 64.20; H, 5.72; N, 14.04. Found: C, 61.30; H, 5.34; N, 13.28.
Reaction SMILES: [CH3:1][CH:2]1[CH2:4][CH:3]1[CH2:5][O:6][C:7]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[C:8]=1[C:9]#[N:10]>CCOC(C)=O.CCO.[Pd]>[NH2:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:7]([O:6][CH2:5][CH:3]2[CH2:4][CH:2]2[CH3:1])[C:8]=1[C:9]#[N:10]
Reactant: CC1CC1COc1cccc([N+](=O)[O-])c1C#N
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC1CC1COc1cccc(N)c1C#N
Yield: 79.1 %

Procedure:
A solution of 2-((2-methylcyclopropyl)methoxy)-6-nitrobenzonitrile (example 235c) (0.29 g, 1.25 mmol) in EtOAc/EtOH 1:1 (30 mL) was hydrogenated in an H-cube apparatus using 10% Pd/C as catalyst. The solution was evaporated to give 2-amino-6-((2-methylcyclopropyl)methoxy)benzonitrile (0.20 g, 79%) as a yellow oil. MS 203 (MH+).
Reaction SMILES: [C:1]([O:9][CH:10]1[CH:17]2[CH:13]([C:14](=[O:18])[NH:15][CH2:16]2)[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([O:27][CH:28]1[CH:35]2[CH:31]([NH:32][C:33](=[O:36])[CH2:34]2)[CH2:30][CH2:29]1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[Cl:45][C:46]1[C:53]([CH3:54])=[C:52](I)[CH:51]=[CH:50][C:47]=1[C:48]#[N:49]>O1CCOCC1.[Cu]I>[C:1]([O:9][CH:10]1[CH:17]2[CH:13]([C:14](=[O:18])[N:15]([C:52]3[CH:51]=[CH:50][C:47]([C:48]#[N:49])=[C:46]([Cl:45])[C:53]=3[CH3:54])[CH2:16]2)[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([O:27][CH:28]1[CH:35]2[CH:31]([N:32]([C:52]3[CH:51]=[CH:50][C:47]([C:48]#[N:49])=[C:46]([Cl:45])[C:53]=3[CH3:54])[C:33](=[O:36])[CH2:34]2)[CH2:30][CH2:29]1)(=[O:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C1CC2C(CCC2OC(=O)c2ccccc2)N1
Reactant: O=C(OC1CCC2C(=O)NCC12)c1ccccc1
Reactant: Cc1c(I)ccc(C#N)c1Cl
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1c(N2C(=O)CC3C(OC(=O)c4ccccc4)CCC32)ccc(C#N)c1Cl
Product: Cc1c(N2CC3C(OC(=O)c4ccccc4)CCC3C2=O)ccc(C#N)c1Cl
Temperature: 110 °C

Procedure:
To a vial containing mixtures of compound 1I and 1J (100 mg, 0.4 mmol) obtained from previous step in dioxane (1 mL) were added CuI (15.6 mg, 0.08 mmol), K3PO4 (174 mg, 0.82 mmol), 1,2-cyclohexyldiamine (4.7 mg, 0.08 mmol) and compound 1E (136 mg, 0.49 mmol). The vial was sealed, and heated at 110° C. for 14 hr, cooled to RT. The solid was filtered off, and filtrate was concentrated. Purification by silica gel chromatography (5% to 100% EtOAc in hexanes, then 10% methanol in EtOAc) provide the mixtures of title compounds 1K and 1L (total 98 mg) as a yellow oil. MS (ES) m/z 395 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6](O)[C:5]2=[CH:9][CH:10]=[CH:11][N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=3)[C:4]2=[N:3]1.[OH-].[Na+].P(Cl)(Cl)([Cl:25])=O>>[CH3:1][N:2]1[CH:7]=[C:6]([Cl:25])[C:5]2=[CH:9][CH:10]=[CH:11][N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=3)[C:4]2=[N:3]1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN1C=C(O)C2=CC=CN(c3ccc(Cl)c(Cl)c3)C2=N1
Agent: [Na+]
Agent: [OH-]
Product: CN1C=C(Cl)C2=CC=CN(c3ccc(Cl)c(Cl)c3)C2=N1

Procedure:
Reflux a mixture of 2-methyl-4-hydroxy-8-(3,4-dichlorophenyl)pyrido[2,3-c]pyridazine (3) (3.0 g, 10 mmol) in phosphorous oxychloride (10 mL) for 2 hrs. Cool the reaction mixture, pour onto cracked ice and neutralize the solution with 1N NaOH. Extract the solution with ethyl acetate (2×100 mL) and wash the combined organic layers with brine. Dry the solution (Na2SO4) and evaporate in vacuo to obtain 4.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[N:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18](=[O:22])[CH:19]([OH:21])[CH3:20])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.[NH2:29][C:30]1[N:35]=[CH:34][C:33](B(O)O)=[CH:32][N:31]=1>>[NH2:29][C:30]1[N:35]=[CH:34][C:33]([C:2]2[N:3]=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:5]3[N:10]=[C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([C:18](=[O:22])[C@@H:19]([OH:21])[CH3:20])[CH2:14][CH2:13]4)[S:8][C:6]=3[N:7]=2)=[CH:32][N:31]=1
Reactant: Nc1ncc(B(O)O)cn1
Reactant: CC(O)C(=O)N1CCN(Cc2nc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Product: C[C@H](O)C(=O)N1CCN(Cc2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3s2)CC1
Yield: 24.6 %

Procedure:
1-[4-(5-Chloro-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidin-2-ylmethyl)-piperazin-1-yl]-2-hydroxy-propan-1-one (100 mg) was reacted with 62 mg of 2-aminopyrimidine-5-boronic acid, pinacol ester via General Procedure A. The product was purified by reverse phase HPLC to yield 28 mg of 108. MS (Q1) 486.2 (M)+.
Reaction SMILES: [F:1][C:2]([F:23])([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]OS(C)(=O)=O)[C:3]([F:6])([F:5])[F:4].[NH2:24][C:25]1[CH:35]=[CH:34][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:27][CH:26]=1.C(O)C>CN(C)P(N(C)C)(N(C)C)=O.C(O)C.O>[F:1][C:2]([F:23])([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:24][C:25]1[CH:26]=[CH:27][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:34][CH:35]=1)[C:3]([F:6])([F:5])[F:4]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CS(=O)(=O)OCCCCCCCCCCCC(F)(F)C(F)(F)F
Solvent: O
Solvent: CCO
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1ccc(NCCCCCCCCCCCC(F)(F)C(F)(F)F)cc1

Procedure:
A solution of 18.1 g. of 11-(pentafluoroethyl)-1-(methanesulfonyloxy)undecane and 19.8 g. of ethyl p-aminobenzoate in hexamethylphosphoramide is heated at 120° C. for 20 hours. After cooling, the reaction mixture is diluted with ethanol:water (1:1) (30 ml.) and chilled. More ethanol is added, the mixture is filtered and the solid residue is recrystallized from ethanol to yield the product as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:12]=[C:11]([N:13]=[C:14](SC)SC)[S:10][C:5]=2[N:6]=[C:7]([CH3:9])[N:8]=1.Cl.Cl.[NH2:21][CH2:22][C@@:23]1([OH:31])[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:1][O:2][C:3]1[C:4]2[N:12]=[C:11]([NH:13][C:14]3[O:31][C@:23]4([CH2:22][N:21]=3)[CH:28]3[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]3)[CH2:24]4)[S:10][C:5]=2[N:6]=[C:7]([CH3:9])[N:8]=1
Reactant: COc1nc(C)nc2sc(N=C(SC)SC)nc12
Reactant: NC[C@]1(O)CN2CCC1CC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1nc(C)nc2sc(NC3=NC[C@@]4(CN5CCC4CC5)O3)nc12
Temperature: 100 °C
Yield: 49.6 %

Procedure:
A mixture of dimethyl 7-methoxy-5-methylthiazolo[5,4-d]pyrimidin-2-ylcarbonimidodithioate (56 mg, 0.19 mmol), (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (51 mg, 0.22 mmol) and cesium carbonate (175 mg, 0.54 mmol) in DMF (0.5 mL) was heated to 100° C. for 2 hours. The reaction mixture was cooled to ambient temperature, poured into water and extracted with chloroform (4×). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The mixture was purified by silica gel chromatography (2-40% [9:1 methanol:ammonium hydroxide]-chloroform). The product fractions were combined and concentrated in vacuo to afford (R)—N-(7-methoxy-5-methylthiazolo[5,4-d]pyrimidin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (34 mg, 50% yield). 1H NMR (400 MHz, CDCl3) δ ppm 9.10 (br. s., 1 H) 4.14 (s, 3 H) 4.03 (d, J=9.54 Hz, 1 H) 3.68 (d, J=9.54 Hz, 1 H) 3.39 (dd, J=14.93, 1.63 Hz, 1 H) 2.74-3.07 (m, 5 H) 2.68 (s, 3 H) 2.04-2.28 (m, 2 H) 1.70-1.86 (m, 1 H) 1.44-1.67 (m, 2 H). MS (LC/MS) R.T.=1.10; [M+H]+=361.32.
Reaction SMILES: [CH2:1]([Sn:5]([CH2:18][CH2:19][CH2:20][CH3:21])([CH:12]1CC[CH2:15][CH2:14][CH2:13]1)[CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[CH2:2][CH2:3][CH3:4].[CH:22]1([Mg]Cl)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.[CH2:30]([Sn:34]([Cl:43])(CCCC)[CH2:35][CH2:36][CH2:37][CH3:38])[CH2:31][CH2:32][CH3:33].C([Sn](CCCC)(CCCC)C1CCCCC1)CCC>[Hg].CCCCC>[CH2:18]([Sn:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:12][CH2:13][CH2:14][CH3:15])[CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[CH2:19][CH2:20][CH3:21].[CH2:30]([Sn:34]([Cl:43])([CH2:35][CH2:36][CH2:37][CH3:38])[CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[CH2:31][CH2:32][CH3:33]
Reactant: CCCC[Sn](CCCC)(C1CCCCC1)C1CCCCC1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cl[Mg]C1CCCCC1
Agent: CCCC[Sn](CCCC)(CCCC)C1CCCCC1
Agent: [Hg]
Solvent: CCCCC
Product: CCCC[Sn](Cl)(CCCC)C1CCCCC1
Temperature: 36 °C
Yield: 93.2 %

Procedure:
Tributylcyclohexyl stannane was prepared using a procedure similar to that described in Example 1 for dibutyldicyclohexyl stannane, with the exception that a 25% molar excess of cyclohexylmagnesium chloride was reacted with tributyltin chloride. The boiling point of the product was 123° C. under a pressure of 0.7 mm. of mercury. A solution containing 37.3 grams (0.1 mole) of tributylcyclohexyl stannane in 50 cc. of pentane was placed in a reaction vessel equipped with a thermometer, mechanically driven stirrer, addition funnel, watercooled reflux condenser, and nitrogen inlet. To this was gradually added over a 25 minute period a solution containing 6.1 grams (0.1 mole) of stannic chloride in 50 cc. of pentane. During the addition, the temperature of the reaction mixture rose from 25° to 36° C. and the initially clear, colorless solution turned cloudy and yellow. After heating the solution to reflux temperature (36° C.) for 15 minutes, it was allowed to cool to ambient temperature. The product was extracted using 55 cc. of a 1.2 molar aqueous hydrochloric acid solution. The resultant two-phase mixture was transferred to a separatory funnel and the lower aqueous layer drawn off and discarded. The organic layer was extracted with two-50 cc. portions of 1.2 molar aqueous hydrochloric acid solution followed by two-50 cc. portions of water. The organic layer was then dried over anhydrous sodium sulfate, which was subsequently removed by filtration. The filtrate was concentrated using a rotary evaporator to yield 32.8 grams (93.2% yield) of dibutylcyclohexyltin chloride, a hazy, colorless liquid exhibiting an index of refraction (nD25) of 1.5079. The crude product was distilled under reduced pressure to yield 29.3 grams of dibutylcyclohexyltin chloride boiling between 139° and 140° C. at a pressure between 0.8 and 0.9 millimeter of mercury.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9]Cl)[CH:2]=1.NC(N)=[S:13].[OH-].[Na+]>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][SH:13])[CH:2]=1
Reactant: ClCCCc1cccnc1
Reactant: NC(N)=S
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: SCCCc1cccnc1
Temperature: 25 °C

Procedure:
A mixture of 3-(3-pyridyl)-1-propylchloride (3 g; 19.4 mmol) and thiourea (1.48 g; 19.4 mmol) in ethanol (10 mL) was refluxed for 24 hours. Aqueous sodium hydroxide, 15 mL of a 0.75 N solution, was added, and the mixture was refluxed for an additional 2 hours. After cooling to room temperature, the solvent was removed in vacuo. Chromatographic purification of the crude thiol on a silica gel column eluting with 50% ethyl acetate in hexane delivered 1.2 g of 3-(3-Pyridyl)-1-propylmercaptan as a clear liquid. 1H NMR (300 MHz, CDCl3): δ1.34 (m, 1H); 1.90 (m, 2H); 2.52 (m, 2H); 2.71 (m, 2H); 7.81 (m, 1H); 7.47 (m, 1H); 8.42 (m, 2H).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][C:6]2([C:16]([O:18][CH3:19])=[O:17])[N:8]([C:9]([O:11][C:12]([CH3:15])(C)C)=[O:10])[CH:3]1[CH2:4][CH2:5]2.C(O)(C(F)(F)F)=O.C(Cl)(OC[C:31]1[CH:36]=[CH:35]C=[CH:33][CH:32]=1)=O>C(Cl)Cl>[O:1]=[C:2]1[CH2:7][C:6]2([C:16]([O:18][CH3:19])=[O:17])[N:8]([C:9]([O:11][CH2:12][C:15]3[CH:35]=[CH:36][CH:31]=[CH:32][CH:33]=3)=[O:10])[CH:3]1[CH2:4][CH2:5]2
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)C12CCC(C(=O)C1)N2C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C12CCC(C(=O)C1)N2C(=O)OCc1ccccc1
Reaction time: 12 h
Yield: 30 %

Procedure:
A mixture of O7-tert-butyl O4-methyl 2-oxo-7-azabicyclo[2.2.1]heptane-4,7-dicarboxylate (prepared according to the literature: Org. Lett., Vol. 9, No. 7, 2007 p 1235-p 1238) (0.34 g, 1.27 mmol), TFA (1.5 ml) in DCM was stirred for 2 hours. After removal of solvent and TFA under reduced pressure, the residue was dissolved into DCM (5 mL). To it was added TEA (0.51 g, 5.08 mmol) and CbzCl (0.43 g, 2.54 mmol). After 12 hours, the mixture was concentrated under reduced pressure. The residue was purified by flash chromatography to give O7-benzyl O4-methyl 2-oxo-7-azabicyclo[2.2.1]heptane-4,7-dicarboxylate 148b. Yield:30%. MS: calc'd (MH +) 304, measured (MH +) 304.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C1(=O)O[CH2:12][CH2:11][O:10]1.N1C=CN=C1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:12][CH2:11][OH:10])=[CH:4][CH:3]=1
Reactant: O=C1OCCO1
Reactant: Oc1ccc(Br)cc1
Agent: c1c[nH]cn1
Product: OCCOc1ccc(Br)cc1
Temperature: 150 °C

Procedure:
4-Bromophenol (1 eq.), ethylene carbonate (1 eq.) and imidazole (0.5% loading) were combined and heated at 150° C. for 2 h to afford the title compound as a brown oil.
Reaction SMILES: [C:1]1([C:7]2[O:8][N:9]=[C:10]3[CH:15]=[CH:14][C:13]([CH2:16][C:17]#N)=[CH:12][C:11]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)C.[OH-:22].[Na+].[OH2:24]>>[C:1]1([C:7]2[O:8][N:9]=[C:10]3[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:24])=[O:22])=[CH:12][C:11]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [OH-]
Reactant: O
Reactant: N#CCc1ccc2noc(-c3ccccc3)c2c1
Agent: [Na+]
Solvent: CCO
Product: O=C(O)Cc1ccc2noc(-c3ccccc3)c2c1
Reaction time: 0.5 h
Yield: 54 %

Procedure:
A solution of 5.0 g (0.021 mole) of 3-phenyl-2,1-benzisoxazole-5-acetonitrile, 100 ml of ethanol, and 10 ml of 20% sodium hydroxide was heated at reflux under a nitrogen atmosphere for 20 hr. The solution was poured into 800 ml of water, let stand for 0.5 hr and filtered. The filtrate was treated with charcoal, filtered, and the filtrate made acidic with concentrated hydrochloric acid. The mixture was allowed to stand at ambient temperature overnight and then filtered. The filter cake was washed with water, air dried, and recrystallized from 2-propanol to yield 2.9 g (54%) of gray powder, m.p. 173°-174° C. with decomposition.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[F:20][C:21]1[CH:22]=[C:23]([N:31]=[C:32]=[O:33])[CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1>>[F:20][C:21]1[CH:22]=[C:23]([NH:31][C:32](=[O:33])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:16]4[C:11](=[N:12][CH:13]=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=2)[CH:24]=[C:25]([C:27]([F:29])([F:30])[F:28])[CH:26]=1
Reactant: O=C=Nc1cc(F)cc(C(F)(F)F)c1
Reactant: NC(=O)c1[nH]c2ncccc2c1-c1ccc(N)cc1
Product: NC(=O)c1[nH]c2ncccc2c1-c1ccc(NC(=O)Nc2cc(F)cc(C(F)(F)F)c2)cc1

Procedure:
78.1 mg of solid beige-coloured 3-{4-[3-(3-fluoro-5-trifluoromethylphenyl)-ureido]phenyl}-1H-pyrrolo[2,3-b]pyridine-2-carboxamide are prepared as described in Example 7 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-b]-pyridine-2-carboxamide and 3-fluoro-5-trifluoromethylphenyl isocyanate.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].[H-].[Na+].[CH3:14][OH:15]>CN(C=O)C.C(Cl)(Cl)Cl.[Cu]I>[O:15]1[CH:4]=[CH:2][O:3][CH:14]1[C:6]1[CH:11]=[CH:10][C:9]([N:1]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4](=[O:5])[C:2]2=[O:3])=[CH:8][CH:7]=1
Reactant: CO
Reactant: O=C1Nc2ccccc2C1=O
Agent: [Cu]I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=C1C(=O)N(c2ccc(C3OC=CO3)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Isatin (1.88 g, 0.0128 mol) in anhydrous DMF (100 mL) was cooled in an ice-bath under nitrogen and treated with sodium hydride (0.3 g, 1 equivalent). The reaction was warmed to room temperature and stirred for 1 hour. It was then treated with 2-(4-bromophenyl)-1,3-dioxalane (2.83 g, 0.0124 mol) followed by CuI (4.71 g, 2 equivalents). This suspension was heated in an oil-bath at 135° C. under nitrogen for 16 hours. It was then cooled to room temperature and diluted with an equal volume of chloroform. The resulting suspension was filtered and the filtrate was concentrated under reduced pressure. The residue was suspended in xylenes (100 mL) and evaporated to dryness. A thick, viscous oil was recovered which was used as such for the next reaction. TLC (5% methanol in chloroform) showed clean conversion, Rf (product)=0.91.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][NH:6][C:5]2=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:33].[C:37]([C:39]1[CH:40]=[C:41]([CH:43]=[CH:44][CH:45]=1)[NH2:42])#[CH:38]>ClCCCl>[ClH:33].[C:37]([C:39]1[CH:40]=[C:41]([NH:42][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([CH3:1])[CH:3]=3)[N:8]=[CH:7][N:6]=2)[CH:43]=[CH:44][CH:45]=1)#[CH:38]
Reactant: Cc1ccc2nc[nH]c(=O)c2c1
Reactant: ClC(Cl)(Cl)Cl
Reactant: C#Cc1cccc(N)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCCl
Product: C#Cc1cccc(Nc2ncnc3ccc(C)cc23)c1
Product: Cl
Temperature: 60 °C

Procedure:
6-Methyl-quinazolin-4-one (350 mg, 2.18 mmol) was added to a suspension of polymer-supported triphenylphosphine (from Fluka, 3.63 g of about 3 mmol P/g resin; 10.9 mmol) in a mixture of CCl4 (3.35 g, 21.80 mmol) and 1,2 dichloroethane (10 mL). The mixture was heated to 60° C. for 2 hours and then the polymer was removed by filtration and washed with dichloroethane. The filtrate was collected in a flask containing 3-ethynyl-aniline (0.644 g, 2.18 mmol) and concentrated to 5 mL by evaporation. After 4 hours reflux under N2, followed by cooling to 20° C., the title product was collected by filtration (551 mg; 86%; M.P. 256°-257° C.; LC-MS: 260 (MH+); anal. RP-HPLC RT: 4.41 min).
Reaction SMILES: [CH:1]([C:3]1[NH:4][C:5]([CH3:11])=[CH:6][C:7]=1[C:8]([OH:10])=O)=[O:2].[N:12]1([CH2:17][CH2:18][NH2:19])[CH:16]=[CH:15][N:14]=[N:13]1>>[N:12]1([CH2:17][CH2:18][NH:19][C:8]([C:7]2[CH:6]=[C:5]([CH3:11])[NH:4][C:3]=2[CH:1]=[O:2])=[O:10])[CH:16]=[CH:15][N:14]=[N:13]1
Reactant: Cc1cc(C(=O)O)c(C=O)[nH]1
Reactant: NCCn1ccnn1
Product: Cc1cc(C(=O)NCCn2ccnn2)c(C=O)[nH]1
Yield: 79 %

Procedure:
2-Formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2.0 g, 13.06 mmol) reacted with 2-[1,2,3]triazol-1-yl-ethylamine (1.76 g, 15.67 mmol) to give 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)amide (2.55 g, 79%).
Reaction SMILES: CN1CCN(C2C=CC(NC3C4N(N=CN=4)C(C4C=C(C(N)=O)SC=4)=CN=3)=CC=2)CC1.[Br:32][C:33]1[N:38]2[N:39]=[CH:40][N:41]=[C:37]2[C:36](Br)=[N:35][CH:34]=1.[F:43][C:44]1[CH:45]=[C:46]([NH2:56])[CH:47]=[CH:48][C:49]=1[N:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1.CCN(C(C)C)C(C)C>CC(O)C>[Br:32][C:33]1[N:38]2[N:39]=[CH:40][N:41]=[C:37]2[C:36]([NH:56][C:46]2[CH:47]=[CH:48][C:49]([N:50]3[CH2:51][CH2:52][O:53][CH2:54][CH2:55]3)=[C:44]([F:43])[CH:45]=2)=[N:35][CH:34]=1
Reactant: Brc1ncc(Br)n2ncnc12
Reactant: Nc1ccc(N2CCOCC2)c(F)c1
Agent: CN1CCN(c2ccc(Nc3ncc(-c4csc(C(N)=O)c4)n4ncnc34)cc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Fc1cc(Nc2ncc(Br)n3ncnc23)ccc1N1CCOCC1
Yield: 98.5 %

Procedure:
This compound may be prepared using methods as described for Compound 6, step 1 using 5,8-dibromo-[1,2,4]triazolo[1,5-a]pyrazine (0.5 g, 1.799 mmol), 3-fluoro-4-morpholin-4-yl-phenylamine (0.53 g, 2.70 mmol), and DIPEA (0.470 mL, 2.70 mmol) in 2-propanol (6 mL). The reaction mixture is partitioned between 10% citric acid aqueous solution and DCM. The organic phase is separated and washed with water and brine, dried over MgSO4, filtered and concentrated under vacuum to afford the title compound (697 mg, 98%) which is used in the next step without further purification. LCMS: Rt 3.52 min (98.2%).
Reaction SMILES: [Cl:1][S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[C:8]([OH:12])([CH3:11])([CH3:10])[CH3:9]>ClCCl>[C:8]([O:12][C:6](=[O:7])[NH:5][S:2]([Cl:1])(=[O:4])=[O:3])([CH3:11])([CH3:10])[CH3:9]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(C)(C)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NS(=O)(=O)Cl
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A 5 L round bottom flask was charged with chlorosulfonyl isocyanate [Aldrich, product # 142662] (149 mL, 1.72 mol) and dichloromethane (1.5 L) and cooled using an ice bath to 2° C. tert-Butanol (162 mL, 1.73 mol) in dichloromethane (200 mL) was added dropwise at a rate so that the temperature did not exceed 10° C. The resulting solution was stirred at room temperature for 30-60 min to provide tert-butyl[chlorosulfonyl]carbamate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]=[CH:6][C:7]1[CH:8]=[N:9][C:10]([N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH3:14])=[CH:11][CH:12]=1)[CH3:2].[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH:6]([NH:30][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:7]1[CH:8]=[N:9][C:10]([N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH3:14])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1ccc(N(C)C(=O)OC(C)(C)C)nc1
Reactant: NCc1ccccc1
Product: CCOC(=O)CC(NCc1ccccc1)c1ccc(N(C)C(=O)OC(C)(C)C)nc1
Temperature: 95 °C

Procedure:
A mixture of 12-4 (1.7 g, 5.6 mmol) and benzylamine (8 mL, 73.2 mmol) was heated in a sealed-tube at 95° C. for 24 hr. The crude reaction mixture was purified using silica gel flash chromatography (EtOAc/hexanes 1:3 to 1:1) to afford the desired product 12-5 as an oil. Rf (silica, EtOAc/hexanes 1:1)=0.63.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([C:23]([CH3:25])=[CH2:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:33][CH2:32][CH:31]([CH2:34][CH:35]=O)[CH2:30][CH2:29]1)=[O:27])C1C=CC=CC=1.S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH:48]1([O:53][C:54](=[O:64])[C@H:55]([CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[NH2:56])[CH2:52][CH2:51][CH2:50][CH2:49]1>>[OH:8][C:9]1[CH:14]=[C:13]([OH:15])[C:12]([CH:23]([CH3:24])[CH3:25])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:33][CH2:32][CH:31]([CH2:34][CH2:35][NH:56][C@H:55]([C:54]([O:53][CH:48]2[CH2:52][CH2:51][CH2:50][CH2:49]2)=[O:64])[CH2:57][C:58]2[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=2)[CH2:30][CH2:29]1)=[O:27]
Reactant: C=C(C)c1cc(C(=O)N2CCC(CC=O)CC2)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: N[C@@H](Cc1ccccc1)C(=O)OC1CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)c1cc(C(=O)N2CCC(CCN[C@@H](Cc3ccccc3)C(=O)OC3CCCC3)CC2)c(O)cc1O

Procedure:
Prepared from Intermediate D and L-phenylalanine cyclopentyl ester tosylate. 1H NMR (300 MHz, d3-MeOD) 7.44-7.17 (5H, m), 6.95 (1H, s), 6.34 (1H, s), 5.17, (1H, m), 4.35-4.12 (4H, m), 3.46-3.35 (1H, m), 3.27-2.85 (6H, m), 1.93-1.21, (13H, m), 1.19 (6H, d, J=7.0 Hz). LC/MS: purity 98.4%, m/z 523 [M+H]+