Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][NH:11][CH:12]=2)[CH:5]=[CH:4][C:3]=1[C:13]1[N:18]=[N:17][C:16]([N:19]2[CH2:23][C@@H:22]3[CH2:24][N:25](C(OC(C)(C)C)=O)[CH2:26][C@@H:21]3[CH2:20]2)=[CH:15][CH:14]=1.Cl.N>O1CCOCC1.CO>[CH2:20]1[C@@H:21]2[CH2:26][NH:25][CH2:24][C@@H:22]2[CH2:23][N:19]1[C:16]1[N:17]=[N:18][C:13]([C:3]2[CH:4]=[CH:5][C:6]([C:8]3[CH:9]=[N:10][NH:11][CH:12]=3)=[CH:7][C:2]=2[OH:1])=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3ccc(-c4ccc(-c5cn[nH]c5)cc4O)nn3)C[C@@H]2C1
Agent: Cl
Agent: N
Solvent: CO
Solvent: C1COCCO1
Product: Oc1cc(-c2cn[nH]c2)ccc1-c1ccc(N2C[C@H]3CNC[C@H]3C2)nn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.4 %

Procedure:
To a solution of (3aR,6aS)-tert-butyl 5-(6-(2-hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (75 mg, 0.167 mmol) in 1 mL of dioxane was added 4N HCl in dioxane (1 mL, 4.00 mmol). The reaction mixture was stirred at RT overnight, and then basified with 2N NH3 in MeOH to form a precipitate which was separated via centrifugation to provide a dark solid, 2-(6-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridazin 3-yl)-5-(1H-pyrazol-4-yl)phenol (50 mg, 0.136 mmol, 82% yield) MS (M+1)=349.1.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][O:9][C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)=[O:5])C.[OH-].[Li+].C(Cl)Cl>CO.O>[Br:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]2[O:9][CH:8]=[N:7][C:6]=2[C:4]([OH:5])=[O:3])=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1ncoc1-c1ccc(Br)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: O=C(O)c1ncoc1-c1ccc(Br)cc1
Temperature: 60 °C

Procedure:
5-(4-Bromo-phenyl)-oxazole-4-carboxylic acid ethyl ester (1.0 g, 3.4 mmol) was dissolved in MeOH:H2O (5:1, 60 mL) and then lithium hydroxide (1.0 g, 41.8 mmol) was added. The reaction was heated to 60° C. for 10 minutes then allowed to cool. The reaction was submitted to acidic aqueous/CH2Cl2 workup then concentrated to afford the title compound.
Reaction SMILES: N#N.[C:3]1([CH:9]=[CH:10][C:11]([NH2:13])=[O:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([O-])(O)=O.[Na+].[CH2:19]([O:21][C:22](=[O:27])[C:23](=O)[CH2:24]Br)[CH3:20].FC(F)(F)C(OC(=O)C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[CH2:19]([O:21][C:22]([C:23]1[N:13]=[C:11](/[CH:10]=[CH:9]/[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[O:12][CH:24]=1)=[O:27])[CH3:20]
Reactant: CCOC(=O)C(=O)CBr
Reactant: NC(=O)C=Cc1ccccc1
Agent: N#N
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: CCOC(=O)c1coc(/C=C/c2ccccc2)n1

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a suspension of 3-phenyl-acrylamide (10.31 g, 67.95 mmol) and NaHCO3 (28.47 g, 339.73 mmol) in THF (260 mL) was treated with 3-bromo-2-oxo-propionic acid ethyl ester (13.04 mL, 88.33 mmol) and the reaction mixture was heated at reflux for 15 h. 3-Bromo-2-oxo-propionic acid ethyl ester (13.04 mL, 88.33 mmol) was added again and the reaction mixture was stirred at reflux for 15 h. The reaction mixture was then filtered over celite and the solvents were evaporated under reduced pressure. The residue was dissolved in THF (30 mL) and treated at 0° C., dropwise, with trifluoroacetic anhydride (30.0 mL, 215.83 mmol). The reaction mixture was then stirred at rt overnight. Sat. aq. Na2CO3 was added and the mixture was extracted with EA (3×150 mL), dried over MgSO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (1:9 EA-Hept) gave the title compound as a yellow solid. TLC:rf (1:9 EA-Hept)=0.1. LC-MS-conditions 02: tR=1.01 min; [M+H]+=244.48.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[NH:8][C:9](=[O:12])[CH2:10][O:11][C:6]=2[CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:19][CH2:20][CH2:21][CH2:22]I>CCCCCCC.CCOC(C)=O>[Cl:19][CH2:20][CH2:21][CH2:22][N:8]1[C:7]2[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]=2[O:11][CH2:10][C:9]1=[O:12]
Reactant: ClCCCI
Reactant: Cc1cccc2c1NC(=O)CO2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: Cc1cccc2c1N(CCCCl)C(=O)CO2
Yield: 48.1 %

Procedure:
5-Methyl-4H-benzo[1,4]oxazin-3-one (81MF941a) (1.514 g, 9.28 mmol), Cs2CO3 (4.53 g, 13.9 mmol) and 3-chloro-1-iodopropane (2.09 g, 10.21 mmol) were mixed according to GP6. CC (SiO2; Heptane/EtOAc 10:1-5) gave the title compound (81MF941b) (1.07 g, 48%). 1H NMR (CDCl3) δ 6.99-6.87 (m, 3H), 4.42 (s, 2H), 4.17 (t, J=7.2 Hz, 2H), 3.45 (t, J=6.4 Hz, 2H), 2.41 (s, 3H), 2.04-1.97 (m, 2H); 13C NMR (CDCl3) δ 168.3, 149.9, 129.1, 128.7, 126.9, 125.1, 115.0, 69.4, 42.2, 42.1, 30.6, 20.9.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:15]([N+:16]([O-])=O)=[CH:14][CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]>O1CCCC1.[Pd]>[NH2:16][C:15]1[C:6]([NH:5][CH2:4][CH2:3][CH2:2][OH:1])=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1NCCCO
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)c1cccc(N)c1NCCCO
Temperature: 25 °C
Reaction time: 23 h
Yield: 78.3 %

Procedure:
To a solution of methyl 2-[(3-hydroxypropyl)amino]-3-nitrobenzoate (86.6 g, 0.341 mol) in tetrahydrofuran (1000 mL) was added 10% palladium on carbon (50% wet; 8.70 g), and the mixture was purged with hydrogen and stirred under balloon pressure hydrogen at room temperature for 23 hr. The catalyst was removed by filtration, and the filtrate was concentrated in vacuo to give the title compound as a brown oil (59.8 g, 0.267 mol, 78%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[NH:23][C:24]([NH:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1[F:34])=[O:25])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17](O)=[O:18])[CH:13]=2)[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.[CH3:69][O:70][C:71](=[O:75])[CH2:72][CH2:73][NH2:74].Cl>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[NH:23][C:24]([NH:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1[F:34])=[O:25])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17]([NH:74][CH2:73][CH2:72][C:71]([O:70][CH3:69])=[O:75])=[O:18])[CH:13]=2)[CH:7]=1
Reactant: COC(=O)CCN
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)cc2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCNC(=O)c1c[nH]c(-c2cc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)c(F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (Example 96) (200 mg, 0.43 mmol), HATU (179 mg, 0.47 mmol) and N,N-diisopropylethylamine (166 mg, 1.29 mmol) in anhydrous DMF (10 ml) was stirred at room temperature for 10 minutes, followed by addition of β-alanine methyl ester hydrochloride (91 mg, 0.65 mmol). The mixture was stirred for another 10 minutes and poured into 100 ml of water with vigorous stirring. 2M HCl was added dropwise until pH=4. The precipitates were filtered, washed with water and dried in vacuo to give methyl 3-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}propanoate as brown solid. Yield: 180 mg, 76%.
Reaction SMILES: CO[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]=1.[CH2:10]([C:17]#[N:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.N12CCCCC1C=NCCC2>>[C:17]([C:10](=[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)#[N:18]
Reactant: COC1=NCCCCC1
Reactant: N#CCc1ccccc1
Agent: C1=NCCCN2CCCCC12
Product: N#CC(=C1CCCCCN1)c1ccccc1
Yield: 41.7 %

Procedure:
Stir 8.1 g of caprolactim methyl ether and 5.0 g of benzyl cyanide with 0.6 g of 1,5-diazabicyclo [5.4.0]undec-5-ene under nitrogen for 48 hours at 130°; distil off any excess benzyl cyanide under a high vacuum, and rub down the thus-produced residue with a little methyl alcohol before filtering to obtain 3.78 g of the title compound. Recrystallize from methyl alcohol to obtain a purer product, MP 108° to 113°.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][CH3:14])(=[O:12])=[O:11])=[CH:6][CH:5]=1.Br[CH2:16][C:17]1[C:18]([Cl:26])=[C:19]([C:22]([O:24][CH3:25])=[O:23])[S:20][CH:21]=1.S([O-])(O)(=O)=O.[K+]>CN(C=O)C>[Cl:26][C:18]1[C:17]([CH2:16][N:13]([S:10]([C:7]2[CH:8]=[CH:9][C:4]([Cl:3])=[CH:5][CH:6]=2)(=[O:12])=[O:11])[CH3:14])=[CH:21][S:20][C:19]=1[C:22]([O:24][CH3:25])=[O:23]
Reactant: CNS(=O)(=O)c1ccc(Cl)cc1
Reactant: COC(=O)c1scc(CBr)c1Cl
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1scc(CN(C)S(=O)(=O)c2ccc(Cl)cc2)c1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 102.3 %

Procedure:
Sodium hydride (60% dispersion, 150 mg, 3.8 mmol) was added to a solution of 4-chloro-N-methylbenzenesulfonamide (640 mg, 3.1 mmol) in DMF (12 ml) while cooling in an ice/water bath. After stirring for 15 min the mixture was allowed to warm to room temperature and stirred for a further 30 min. Methyl 4-bromomethyl-3-chlorothiophene-2-carboxylate (1.08 g, 4.0 mmol) was added and the mixture was stirred for 18 h. 0.3N Potassium hydrogen sulphate solution was added and the mixture evaporated. The mixture was extracted with ethyl acetate and the organic extract was washed with brine, dried and reduced. Chromatography (25% EtOAc/75% 60-80 pet ether) yielded methyl 3-chloro(N-(4-chlorobenzenesulphonyl)-N-methylaminomethyl)thiophene-2-carboxylate (1.25 g, 79%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([OH:10])=[O:9])[NH:5][C:6]=1[CH3:7].CC1NC(C(OCC)=O)=CC=1>>[CH3:7][C:6]1[NH:5][C:4]([C:8]([OH:10])=[O:9])=[CH:3][CH:2]=1
Reactant: Cc1[nH]c(C(=O)O)cc1Br
Agent: CCOC(=O)c1ccc(C)[nH]1
Product: Cc1ccc(C(=O)O)[nH]1

Procedure:
The title compound was synthesized by an analogous method to Intermediate 18 starting from ethyl 5-methyl-1H-pyrrole-2-carboxylate (Intermediate 20).
Reaction SMILES: Cl[C:2]1[CH2:7][CH:6]2[CH:4]([CH2:5]2)[C:3]=1/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11].[N-:15]=[N+]=[N-].[Na+]>>[CH2:13]([O:12][C:10]([C:9]1[NH:15][C:2]2[CH2:7][C@@H:6]3[CH2:5][C@@H:4]3[C:3]=2[CH:8]=1)=[O:11])[CH3:14]
Reactant: CCOC(=O)/C=C/C1=C(Cl)CC2CC12
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: CCOC(=O)c1cc2c([nH]1)C[C@@H]1C[C@H]21

Procedure:
(E)-Ethyl 3-(3-chlorobicyclo[3.1.0]hex-2-en-2-yl)acrylate (142 mg, 0.67 mmol) was reacted with sodium azide (65 mg, 1.00 mmol) according to General Procedure 1.1.C. The product was purified by chromatography eluting with heptane-EtOAc, gradient 0 to 10% EtOAc to afford the title compound. 38 mg. 1H NMR (CHLOROFORM-d) δ: 8.67 (br. s., 1H), 6.71 (d, J=1.7 Hz, 1H), 4.28 (q, J=7.1 Hz, 2H), 2.95 (dd, J=16.6, 6.6 Hz, 1H), 2.73 (d, J=16.6 Hz, 1H), 1.87-2.07 (m, 2H), 1.34 (t, J=7.1 Hz, 3H), 1.02 (td, J=7.6, 4.7 Hz, 1H), 0.17 (q, J=4.2 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:12]([OH:13])=[CH:11][C:5]2[CH2:6][O:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.[C:14]1([S:20]([CH2:22][CH2:23][CH2:24][CH2:25]Cl)=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[Cl:1][C:2]1[C:12]([O:13][CH2:25][CH2:24][CH2:23][CH2:22][S:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:21])=[CH:11][C:5]2[CH2:6][O:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1
Reactant: O=C1Nc2cc(Cl)c(O)cc2CO1
Reactant: O=S(CCCCCl)c1ccccc1
Product: O=C1Nc2cc(Cl)c(OCCCCS(=O)c3ccccc3)cc2CO1

Procedure:
Prepared analogously to Example 4 from 7-chloro-6-hydroxy-4H-3,1-benzoxazin-2-one and 4-phenylsulfinyl-butylchloride.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[N:6][C:5]=1Cl.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>C(O)C.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[N:6][C:5]=1[C:18]1[CH:19]=[CH:20][C:15]([C:14]([F:25])([F:24])[F:13])=[CH:16][CH:17]=1
Reactant: COC(=O)c1ccc(C)nc1Cl
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C)nc1-c1ccc(C(F)(F)F)cc1
Temperature: 120 °C
Reaction time: 3 h
Yield: 87.2 %

Procedure:
2-Chloro-6-methylnicotinic acid methyl ester (18.6 g) and 4-trifluoromethylphenylboronic acid (22.0 g) were dissolved in a mixed solvent of ethanol (100 mL) and toluene (100 mL), and to this solution were added 2M sodium carbonate (100 mL) and tetrakis(triphenylphosphine)palladium(0) (2.90 g). The mixture was stirred at 120° C. for 3 hours under heating. Ethyl acetate (200 mL) was added to the reaction solution. The aqueous layer was separated off. The organic layer was washed successively with 0.1N sodium hydroxide, water, and saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel with (hexane:ethyl acetate=1:4, v/v) to give the title compound (25.8 g) as a colorless oil.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=3)[N:9]=2)[NH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Cl[Si:34]([CH:41]([CH3:43])[CH3:42])([CH:38]([CH3:40])[CH3:39])[CH:35]([CH3:37])[CH3:36]>O1CCCC1>[I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=3)[N:9]=2)[N:4]([Si:34]([CH:41]([CH3:43])[CH3:42])([CH:38]([CH3:40])[CH3:39])[CH:35]([CH3:37])[CH3:36])[CH:3]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: COc1cc(-c2cnc3[nH]cc(I)c3n2)cc(OC)c1OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: COc1cc(-c2cnc3c(n2)c(I)cn3[Si](C(C)C)(C(C)C)C(C)C)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
A solution of 7-iodo-2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine (6.7 g, 16.29 mmol) in anhydrous tetrahydrofuran (150 ml) was cooled to 0° C. and treated with potassium bis(trimethylsilyl)amide (0.5M in toluene, 35.85 ml, 17.9 mmol) dropwise. After complete addition, the reaction mixture was stirred at room temperature for 1 hour, treated dropwise with chloro-triisopropyl-silane (3.9 ml, 18.4 mmol), and allowed to stir at room temperature for 16 hours. Chloro-triisopropyl-silane (1.0 ml, 4.7 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours, and then at 60° C. for 16 hours. The reaction mixture was partitioned between EtOAc/saturated aqueous NH4Cl. The organic layers were collected, dried over MgSO4, filtered, and concentrated giving a dark solid. The residue was purified by silica gel chromatography using 3-100% EtOAc in hexanes as eluant to provide 7.4 g (80%) of 7-iodo-5-triisopropylsilanyl-2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine as a white solid. MP 156.5-157.2, M+H=568.
Reaction SMILES: [C:1]1([CH2:7][CH:8]([OH:10])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]1([CH2:7][C:8](=[O:10])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(O)Cc1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 1-phenyl-2-propanol (2.18 g, 16.0 mmol) in CH2Cl2 (100 mL) is added Dess-Martin periodinane (50 mL, 15 wt % solution in methylene chloride) at 0° C. After stirring at 0° C. for 1 h, the mixture is warmed to RT and stirred for 1.5 h. To the reaction mixture is added saturated NaHCO3 (200 mL) and stirred at RT for 20 min. The mixture is filtered through Celite and the organic phase is washed with water and brine then dried over MgSO4. The solvent is removed under reduced pressure and the crude material is purified by flash chromatography to afford the title compound as a colorless oil: (M+1)+=135.
Reaction SMILES: BrC1C=CC(C(=O)CC)=CC=1.C(O)(=O)C=O.[OH-].[Na+].[Br:19][C:20]1[CH:33]=[CH:32][C:23]([C:24](/[C:26](/[CH3:31])=[CH:27]\[C:28]([OH:30])=O)=[O:25])=[CH:22][CH:21]=1.[NH:34]1[CH2:41][CH2:40][CH2:39][C@H:35]1[C:36]([OH:38])=[O:37].C1N=CN(C(N2C=NC=C2)=O)C=1>O1CCCC1.O.C(O)C.O>[Br:19][C:20]1[CH:21]=[CH:22][C:23]([C:24](/[C:26](/[CH3:31])=[CH:27]\[C:28]([N:34]2[CH2:41][CH2:40][CH2:39][C@H:35]2[C:36]([OH:38])=[O:37])=[O:30])=[O:25])=[CH:32][CH:33]=1
Reactant: C/C(=C/C(=O)O)C(=O)c1ccc(Br)cc1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: CCC(=O)c1ccc(Br)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=CC(=O)O
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: C/C(=C/C(=O)N1CCC[C@H]1C(=O)O)C(=O)c1ccc(Br)cc1
Reaction time: 20 h

Procedure:
To a slurry of 16.0 g. of p-bromopropiophenone and 8.0 g. of glyoxylic acid in 90 ml. of water is added (with cooling) a mixture of 20 g. of 50% sodium hydroxide in 280 ml. of ethanol-water (1:1). The mixture is allowed to stand at room temperature for 20 hours and then heated to the boiling point for 30 minutes. The mixture is diluted with 800 ml. of ice and water, stirred several minutes and filtered. The filtrate is acidified with 5 N HCl and filtered to give 12.5 g. of β-(4-bromobenzoyl)crotonic acid as tan crystals, m.p. 137°-144° C. The preceding compound (5.0 g.) is coupled with L-proline with N,N-carbonyldiimidazole in tetrahydrofuran to give 1-[β-(4-bromobenzoyl)crotonyl]-L-proline. A mixture of the preceding compound with thiolacetic acid in acetonitrile gives the product of the example as a glass.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:17]([CH2:18][CH2:19][CH3:20])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][NH:29][CH2:30][C:31]4[C:36]([CH3:37])=[CH:35][C:34]([CH3:38])=[CH:33][C:32]=4[CH3:39])[CH:23]=3)[CH:14]=2)[N:9]=1)(C)(C)C>FC(F)(F)C(O)=O.C(Cl)Cl>[CH2:18]([N:17]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][NH:29][CH2:30][C:31]4[C:36]([CH3:37])=[CH:35][C:34]([CH3:38])=[CH:33][C:32]=4[CH3:39])[CH:23]=3)[CH:14]=2)[N:9]=[C:8]1[NH2:7])[CH2:19][CH3:20]
Reactant: CCCN1Cc2cc(Oc3cccc(CNCc4c(C)cc(C)cc4C)c3)ccc2N=C1NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCN1Cc2cc(Oc3cccc(CNCc4c(C)cc(C)cc4C)c3)ccc2N=C1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (3-propyl-6-{3-[(2,4,6-trimethyl-benzylamino)-methyl]-phenoxy}-3,4-dihydro-quinazolin-2-yl)-carbamic acid tert-butyl ester (0.00041 mol) in trifluoroacetic acid (1 mL) and DCM (10 mL) was stirred overnight at room temperature and the solvent was evaporated. The obtained residue was decomposed in diisopropyl ether/CH3CN, then the desired product was filtered off and dried to yield the title compound as a solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:6]1[CH:27]=[CH:26][C:9]([C:10]([NH:12][CH2:13][CH2:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][CH:19]=[C:18]3[C:24]#[N:25])=[O:11])=[CH:8][CH:7]=1)([CH3:5])[CH3:4].N1C=CC=CC=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[C:24]([C:18]1[C:17]2[C:21](=[CH:22][CH:23]=[C:15]([CH2:14][CH2:13][NH:12][C:10](=[O:11])[C:9]3[CH:8]=[CH:7][C:6]([C:3]([CH3:5])([CH3:4])[CH2:2][NH:1][S:35]([CH3:34])(=[O:37])=[O:36])=[CH:27][CH:26]=3)[CH:16]=2)[NH:20][CH:19]=1)#[N:25]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(CN)c1ccc(C(=O)NCCc2ccc3[nH]cc(C#N)c3c2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(CNS(C)(=O)=O)c1ccc(C(=O)NCCc2ccc3[nH]cc(C#N)c3c2)cc1
Reaction time: 0.08 h
Yield: 80.2 %

Procedure:
To a solution of 4-[2-amino-1,1-dimethyl-ethyl]-N-[2-(3-cyano-1H-indol-5-yl)-ethyl]-benzamide (97 mg, 0.27 mmol) (reference example 105) in CH2Cl2 (1 ml) was added pyridine (24 μL, 0.30 mmol) and methanesulfonyl chloride (23 μL, 0.30 mmol). The reaction was stirred for 5 min then concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with 8% 7M NH3 in CH3OH/CH2Cl2 to give 95 mg of product. MS (ion spray) m/z 439 (M+H)+.
Reaction SMILES: BrC1C(N2CCN(CC3C=NC=CC=3)CC2)=C2N=C(C3C=CC(CN)=CC=3)NC2=NC=1.[CH2:32]([CH:39]1[CH2:44][CH2:43][N:42]([C:45]2[C:50]([Br:51])=[CH:49][N:48]=[C:47]3[NH:52][C:53]([C:55]4[CH:69]=[CH:68][C:58]([CH2:59][NH:60]C(=O)OC(C)(C)C)=[CH:57][CH:56]=4)=[N:54][C:46]=23)[CH2:41][CH2:40]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:32]([CH:39]1[CH2:40][CH2:41][N:42]([C:45]2[C:50]([Br:51])=[CH:49][N:48]=[C:47]3[NH:52][C:53]([C:55]4[CH:69]=[CH:68][C:58]([CH2:59][NH2:60])=[CH:57][CH:56]=4)=[N:54][C:46]=23)[CH2:43][CH2:44]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2nc3c(N4CCC(Cc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: NCc1ccc(-c2nc3c(N4CCN(Cc5cccnc5)CC4)c(Br)cnc3[nH]2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1ccc(-c2nc3c(N4CCC(Cc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Yield: 96.9 %

Procedure:
This was prepared using the same procedure as for (4-(6-bromo-7-(4-(pyridin-3-ylmethyl)piperazin-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)phenyl)methanamine, but here using tert-butyl 4-(7-(4-benzylpiperidin-1-yl)-6-bromo-3H-imidazo[4,5-b]pyridin-2-yl)benzylcarbamate (15 mg, 0.026 mmol), TFA (0.2 mL) and CH2Cl2 (1 mL). The same purification procedure gave the desired product (12 mg, 97%) as a colourless solid; δH (500 MHz, DMSO-d6) 1.40-1.48 (m, 2H, 2× piperidine CHAHB), 1.73 (d, br, J=11.7 Hz, 2H, 2× piperidine CHAHB), 1.79-1.85 (m, 1H, piperidine CH), 2.61 (app d, J=7.1 Hz, 2H, PhCH2), 3.31-3.36 (m, 2H, 2× piperidine NCHAHA), 3.79 (s, 2H, CH2NH2), 3.85 (app d, J=12.0 Hz, 2H, 2× piperidine NCHAHA), 7.20 (t, J=7.2 Hz, 1H, phenyl H-4), 7.23 (d, J=7.0 Hz, 2H, phenyl H-2 & H-6), 7.31 (t, J=7.5 Hz, 2H, phenyl H-3 & H-5), 7.48 (d, J=8.2 Hz, 2H, phenyl H-3′ & H-5′), 8.10 (d, J=8.2 Hz, 2H, phenyl H-2′ & H-6′), 8.21 (s, 1H, (s, 1H, imidazo[4,5-b]pyridine H-5).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[Cl:23][C:24]1[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=1[N:31]=[C:32]=[O:33]>C1(C)C=CC=CC=1>[Cl:23][C:24]1[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=1[NH:31][C:32]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:21][CH:20]=1)=[O:33]
Reactant: Cc1cccc(N=C=O)c1Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4cccc(C)c4Cl)cc3)c2cc1OC
Yield: 37 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (52 mg) was dissolved in toluene (5 ml) with heat, 2-chloro-3-methylphenyl isocyanate (0.2 ml) was added, and the admixture was refluxed with heat for 12 minutes. The reaction solution was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 30 mg of the title compound (yield: 37%).