Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:23][C@H:24]([C:35]([O:37][CH3:38])=[O:36])[CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1.ClC(OCC(C)C)=O.C(N(CC)CC)C>O1CCCC1>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([NH:23][C@H:24]([C:35]([O:37][CH3:38])=[O:36])[CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 85.9 %

Procedure:
Condensation of Z-Phe-OH (15.0 g.) and H-Trp-OCH3 (12.8 g.) by the mixed anhydride method using isobutyl chloroformate (6.52 ml.) and triethylamine (10.1 g.) in tetrahydrofuran for a few minutes at -20° C. and then for about 1 hr. at room temperature, isolation of the crude product by ethyl acetate extraction, and purification by crystallization from ether-hexane gave Z-Phe-Trp-OCH3 (21.5 g., 8670 yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.FC(F)(F)S(O)(=O)=O.[C:18]([N:23]1[CH2:27][CH2:26][O:25][C:24]1=[O:28])(=[O:22])/[CH:19]=[CH:20]/[CH3:21].[Cl-].[NH4+]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:20]([CH3:21])[CH2:19][C:18]([N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])=[O:22])=[CH:5][CH:4]=1
Reactant: COc1ccc(N)cc1
Reactant: C/C=C/C(=O)N1CCOC1=O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: COc1ccc(NC(C)CC(=O)N2CCOC2=O)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 79.6 %

Procedure:
A solution of anisidine (55.4 mg, 0.45 mmol) in toluene (1.5 ml) was cooled to 0° C., and trifluoromethanesulfonic acid (40 μL, 0.45 mmol) was added dropwise. The mixture was stirred for 10 minutes, and to this solution were added Pd((R)-binap)(OH2)2(OTf)2 (8 mg, 0.00752 mmol) and 3-crotonoyl-1,3-oxazolidin-2-one (47 mg, 0.3 mmol). The ice-cooling bath was removed and the mixture was reacted at room temperature for 20 hours. A saturated aqueous solution of ammonium chloride was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The organic layer was concentrated and purified by a silica gel column chromatography (hexane:ethyl acetate=4:1) to give the objective 3-[3-(4-methoxyphenylamino)butyryl]-1,3-oxazolidin-2-one (66.5 mg, 96% yield). The enantiomeric excess was determined by a liquid chromatography with an optical isomer separating column (column: AD-H) to be 94% e.e.
Reaction SMILES: [SH:1][C:2]1[N:7]2[N:8]=[C:9]([CH2:11][NH:12][C:13]([C:15]3[CH:35]=[CH:34][C:18]4[O:19]C(C5C=CC=CC=5)(C5C=CC=CC=5)[O:21][C:17]=4[CH:16]=3)=[O:14])[N:10]=[C:6]2[N:5]=[C:4]([CH3:36])[CH:3]=1>FC(F)(F)C(O)=O.O>[OH:21][C:17]1[CH:16]=[C:15]([CH:35]=[CH:34][C:18]=1[OH:19])[C:13]([NH:12][CH2:11][C:9]1[N:10]=[C:6]2[N:5]=[C:4]([CH3:36])[CH:3]=[C:2]([SH:1])[N:7]2[N:8]=1)=[O:14]
Reactant: Cc1cc(S)n2nc(CNC(=O)c3ccc4c(c3)OC(c3ccccc3)(c3ccccc3)O4)nc2n1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(S)n2nc(CNC(=O)c3ccc(O)c(O)c3)nc2n1
Reaction time: 1 h
Yield: 94.9 %

Procedure:
N-[(7-Mercapto-5-methyl-s-triazolo[1,5-a]-pyrimidin-2-yl)methyl]-2,2-diphenyl-1,3-benzodioxol-5-carboxamide (22.7 g) are stirred for 1 hour in 210 ml of trifluoroacetic acid and 5 ml of water. A small amount of insoluble material is filtered off and the mother liquor is evaporated to dryness. The yellow residue is treated with 900 ml of ethyl acetate, stirred in an ultrasound bath for 1 hour and subsequently cooled in an ice bath. The yellow solid is filtered off and dried in a vacuum at 40° C. There are obtained 14.4 g of 3,4-dihydroxy-N-(7-mercapto-5-methyl[1.2.4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-benzamide as a yellow powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:11]2[C:19]3[NH:18][C:17](=[O:20])[NH:16][C:15]=3[CH:14]=[C:13]([C:21]3[C:22]([CH3:27])=[N:23][O:24][C:25]=3[CH3:26])[CH:12]=2)[C:5]([CH:8]2[CH2:10][CH2:9]2)=[N:6][CH:7]=1.N([O:30][C:31](C)(C)[CH3:32])=O>C(#N)C.CCOC(C)=O>[CH:8]1([C:5]2[N:6]=[CH:7][C:2]([NH:1][C:31](=[O:30])[CH3:32])=[CH:3][C:4]=2[C:11]2[C:19]3[NH:18][C:17](=[O:20])[NH:16][C:15]=3[CH:14]=[C:13]([C:21]3[C:22]([CH3:27])=[N:23][O:24][C:25]=3[CH3:26])[CH:12]=2)[CH2:9][CH2:10]1
Reactant: Cc1noc(C)c1-c1cc(-c2cc(N)cnc2C2CC2)c2[nH]c(=O)[nH]c2c1
Reactant: CC(C)(C)ON=O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cnc(C2CC2)c(-c2cc(-c3c(C)noc3C)cc3[nH]c(=O)[nH]c23)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.9 %

Procedure:
4-(5-Amino-2-cyclopropylpyridin-3-yl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one (75 mg, 0.21 mmol) was dissolved in acetonitrile (2 mL), at room temperature added tert-butyl nitrite (32 mg, 0.31 mmol) and CuBr2 (56 mg, 0.25 mmol), stirred at room temperature for 1 h. The reaction mixture was diluted with EtOAc, washed with brine, evaporated organic solvent, purified with Prep HPLC. (0-100% CH3CN/H2O) to afford 16 mg of N-(6-cyclopropyl-5-(6-(3,5-dimethylisoxazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)pyridin-3-yl)acetamide.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:6]=1)[OH:4].O.C(=O)(O)[O-].[Na+].[Cl:22][CH2:23][C:24](Cl)=[O:25]>ClCCl>[Cl:22][CH2:23][C:24]([NH:1][CH2:2][C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([C:12]([F:15])([F:13])[F:14])[CH:6]=1)[OH:4])=[O:25]
Reactant: NC[C@H](O)c1ccc(F)c(C(F)(F)F)c1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C(CCl)NC[C@H](O)c1ccc(F)c(C(F)(F)F)c1

Procedure:
(R)-2-amino-1-(4-fluoro-3-(trifluoromethyl)phenyl)ethanol (2.27 g, 10.2 mmol) was dissolved in 50 mL of dichloromethane. Water (50 mL) containing sodium bicarbonate (1.11 g, 13.2 mmol) was added. The mixture was stirred under ice bath and 2-chloroacetyl chloride (1.38 g, 12.2 mmol) in dichloromethane (10 mL) was added dropwise. The mixture was stirred for 20 min. The pH value was checked and concentrated sodium bicarbonate solution was added (15 mL) to adjust pH to basic. The ice bath was removed and the mixture was stirred for 15 min. TLC indicated consumption of the starting material. The mixture was extracted with dichloromethane and sodium bicarbonate solution. The organic layer was washed with brine and dried. Solvents were evaporated and the resulting material was purified through ISCO flash column chromatography (40 g silica gel, 20% to 90% ethyl acetate in hexanes gradient) to give 2-chloro-N—[(R)-2-(4-fluoro-3-trifluoromethylphenyl)-2-hydroxy-ethyl]-acetamide as an oily material, which gradually solidified (2.64 g). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.18 (br. s., 1H) 3.40 (ddd, J=14.07, 8.21, 5.29 Hz, 1H) 3.72 (ddd, J=14.16, 6.99, 3.40 Hz, 1H) 4.09 (s, 2H) 4.95 (dd, J=7.93, 3.02 Hz, 1H) 7.03 (br. s., 1H) 7.16-7.26 (m, 1H) 7.54-7.62 (m, 1H) 7.66 (dd, J=6.61, 2.08 Hz, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=3)[C:16]3([CH:31]=[CH:30][C:29](=[O:32])[CH:28]=[CH:27]3)[N:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br>C(O)(=O)C.C(Cl)(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=3)[C:16]3([CH:31]=[CH:30][C:29](=[O:32])[CH:28]=[CH:27]3)[N:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C2=CC(N3CCN(Cc4ccccc4)CC3)=NC23C=CC(=O)C=C3)cc1
Agent: Br
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: O=C1C=CC2(C=C1)N=C(N1CCN(Cc3ccccc3)CC1)C=C2c1ccc(O)cc1
Temperature: 20 °C
Yield: 62.4 %

Procedure:
2-(4-Benzyl-1-piperazinyl)-4-(4-hydroxyphenyl)-1-azaspiro[4.5]deca-1,3,6,9-tetraen-8-one can be obtained in the following manner: 2-(4-benzyl-1-piperazinyl)-4-(4-methoxyphenyl)-1-azaspiro[4.5]deca-1,3,6,9-tetraen-8-one (6.3 g) dissolved in acetic acid (150 cc) and a 48% strength solution of hydrobromic acid (100 cc) are heated for 12 hours to a temperature of about 100° C. After being cooled to a temperature of about 20° C., the solution is evaporated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. Crushed ice (200 g) is added to the residue, followed by 11N aqueous ammonia solution (500 cc). The aqueous solution is washed with chloroform (2×300 cc). The organic fractions are combined, washed with distilled water (200 cc), dried over anhydrous sodium sulphate, filtered and evaporated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The residue obtained is dissolved in chloroform (200 cc) and the solution is poured into silica (120 g) contained in a column 3.2 cm in diameter. Elution is performed first with chloroform (1 liter) and the corresponding eluate is rejected. Elution is then performed with a mixture of chloroform and methanol (95:5 volume) (1 liter) and the corresponding eluate is evaporated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. 2-(4-Benzyl-1-piperazinyl)-4-(4-hydroxyphenyl)-1-azaspiro[4.5]deca-1,3,6,9-tetraen-8-one (3.8 g) is thereby obtained in the form of a brown cake.
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10](=[O:22])(=[O:21])[NH:11][CH2:12][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:5]=1.[I-].[Li+]>N1C=CC=CC=1>[C:17]([O:16][C:14]([CH2:13][CH2:12][NH:11][S:10]([C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([OH:23])=[O:2])(=[O:22])=[O:21])=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: COC(=O)c1cccc(S(=O)(=O)NCCC(=O)OC(C)(C)C)c1
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)CCNS(=O)(=O)c1cccc(C(=O)O)c1

Procedure:
A solution of 3-(2-tert-Butoxycarbonyl-ethylsulfamoyl)-benzoic acid methyl ester (step 1) (5.0 g, 14.56 mmol) and lithium iodide (2.53 g, 18.93 mmol) in pyridine (60 ml) was heated at reflux for 16 h. The reaction mixture was concentrated in vacuo, diluted with DCM (60 ml) and poured into 1.5N HCl (60 ml). The aqueous phase was separated and extracted with DCM (6×60 ml). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. The crude residue was purified using an Isolute® PE-AX 10 g cartridge (anion exchange column), eluting with MeOH (200 ml) and then a 1:1 mixture of MeOH/AcOH (200 ml) to afford the title compound as white crystals; 1H NMR (400 MHz, CDCl3) δ 8.63 (1H, s), 8.32(1H, d), 8.14(1H, d), 7.68 (1H, t), 5.63 (1H, t), 3.22 (2H, m), 2.51(2H, t), 1.43 (9H, s).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]1([CH2:16]C(O)=O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N1CCCCC1.C(=O)([O-])[O-].[Na+].[Na+]>O>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCNCC1
Solvent: O
Product: Oc1ccc(C=Cc2ccccc2)cc1
Temperature: 90 °C
Reaction time: 0.2 h

Procedure:
A portion (244.24 grams, 2.0 moles) of 4-hydroxybenzaldehyde, phenylacetic acid (272.30 grams, 2.0 moles) and piperidine (51.6 milliliters) are added to a reactor equipped with a reflux condenser and stirred under a nitrogen atmosphere. Heating commences and after 12 minutes and at 93° C., a solution forms. After a total of 27 minutes, the reaction temperature reaches 150° C. and is held therein. After 2 hours at the 150° C. temperature, a solution of sodium carbonate (40.0 grams) in deionized water (800 milliliters) is added to the reactor over a 3 minute period while stirring and heating are maintained. After 10 minutes of mixing with heating, stirring ceases and the aqueous layer is decanted from the reactor. The solid product remaining in the reactor is recovered and dissolved in a solution of sodium hydroxide (100.0 grams) in deionized water (2400 milliliters) which has been heated to 90° C. The resultant solution is held for 16 hours at 4° C. and the resultant crystalline precipitate which forms is recovered by filtration. The crystals are suspended in deionized water (1600 milliliters) which is stirred and then acidified to a pH of one by addition of aqueous concentrated hydrochloric acid. The resultant crystalline product is recovered by filtration, then washed on the filter with deionized water (two 250 milliliter portions). The product recovered on the filter is dried at 80° C. under a vacuum of 2 mm Hg to a constant weight of 87.1 grams of white crystalline powder. Fourier transform infrared spectrophotometric analysis of a potassium chloride pellet of the product reveals the presence of the expected hydroxyl group O--H stretching absorbance centered at 3416 cm-1 (broad), the ethylene C--H out-of-plane deformation at 965 cm-1, the C--H out-of-plane vibration at 819 cm-1 for the para substituted aromatic ring and the C--H out-of-plane vibration at 746 and 686 cm-1 for the monosubstituted aromatic ring. High pressure liquid chromatographic analysis of the 4-hydroxystilbene product using a uv detector set at 254 nm reveals a single sharp peak. Proton magnetic resonance spectroscopy further confirms the product structure.
Reaction SMILES: [C:1]([S:5][CH2:6][C:7]1[CH:8]=[C:9]([NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[CH:10]=[CH:11][C:12]=1[CH2:13][N:14]1[CH:18]=[C:17]([CH2:19][C:20]#[N:21])[CH:16]=[N:15]1)([CH3:4])([CH3:3])[CH3:2].C[Si]([N:33]=[N+:34]=[N-:35])(C)C.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[C:1]([S:5][CH2:6][C:7]1[CH:8]=[C:9]([NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[CH:10]=[CH:11][C:12]=1[CH2:13][N:14]1[CH:18]=[C:17]([CH2:19][C:20]2[N:33]=[N:34][NH:35][N:21]=2)[CH:16]=[N:15]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)SCc1cc(NC(=O)C(C)(C)C)ccc1Cn1cc(CC#N)cn1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)SCc1cc(NC(=O)C(C)(C)C)ccc1Cn1cc(Cc2nn[nH]n2)cn1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To N-[3-tert-butylsulfanylmethyl-4-(4-cyanomethyl-pyrazol-1-ylmethyl)-phenyl]-2,2-dimethyl-propionamide (0.015 g, 0.04 mmol) in toluene (1 mL) was added trimethylsilyl azide (0.02 mL, 0.1 mmol), followed by dibutyltin oxide (0.001 g, 0.004 mmol), and the reaction was stirred at 80° C. overnight. Starting material was still present, so additional trimethylsilyl azide (0.20 mL, 1.1 mmol) and dibutyltin oxide (0.005 g, 0.02 mmol) were added, and the reaction was stirred for 6 hours at 100° C. After work-up, the crude material was purified by preparative HPLC to give the title compound.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:9][NH:10]2)=[CH:6][CH:5]=1.I[CH3:20].O>C1COCC1>[Cl:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:9][N:10]2[CH3:20])=[CH:6][CH:5]=1
Reactant: CI
Reactant: CCOC(=O)Cc1n[nH]c2cc(Cl)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)Cc1nn(C)c2cc(Cl)ccc12
Reaction time: 0.5 h
Yield: 100 %

Procedure:
Sodium hydride (24 mg, 0.602 mmol, 60% in oil) was added to ethyl (6-chloro-1H-indazol-3-yl)acetate (Preparation 168, 120 mg, 0.502 mmol) in THF (4 mL) at 0° C. and the mixture was stirred for 30 minutes. Then iodomethane (0.09 mL, 1.508 mmol) was added. The mixture was stirred at room temperature for 30 mins then water (4 mL) was added. The mixture was evaporated in vacuo and the aqueous residue was acidified with aqueous HCl (6 M). This was extracted with ethyl acetate (10 mL) and the organic phase was dried over sodium sulphate and evaporated in vacuo to afford the title compound as a white solid in 100% yield, 150 mg.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][S:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2([C:26]#[N:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1>ClCCl>[CH3:12][S:13]([C:14]1[CH:15]=[CH:16][C:17]([C:20]2([C:26]#[N:27])[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)=[CH:18][CH:19]=1)=[O:9]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(C2(C#N)CCOCC2)cc1
Solvent: ClCCl
Product: CS(=O)c1ccc(C2(C#N)CCOCC2)cc1
Temperature: 25 °C
Yield: 88.6 %

Procedure:
A solution of meta-chloroperbenzoic acid (5.08 g, 22.66 mmol) in dichloromethane (30 ml) was added dropwise over 15 minutes at 0° C. to a solution of 4-[4-(methylthio)phenyl]tetrahydro-2H-pyran-4-carbonitrile (4.8 g, 20.6 mmol) in dichloromethane (40 ml). The reaction mixture was warmed to room temperature over 4 hours. The mixture was then diluted with dichloromethane (180 ml), washed with sodium sulphite solution and 10% aqueous sodium carbonate. The organic layer was separated, dried over sodium sulphate and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (100:0:0 to 95:5:0.5 by volume) to provide the title compound (4.55 g, 89%) as an off-white solid. LRMS APCI+ m/z 250 [MH]+.
Reaction SMILES: C([NH:6][C:7]1[N:12]=[C:11]2[N:13]=[C:14]([CH2:16][CH2:17][CH3:18])[NH:15][C:10]2=[CH:9][CH:8]=1)(=O)CCC.Cl>CO>[NH2:6][C:7]1[N:12]=[C:11]2[N:13]=[C:14]([CH2:16][CH2:17][CH3:18])[NH:15][C:10]2=[CH:9][CH:8]=1
Reactant: CCCC(=O)Nc1ccc2[nH]c(CCC)nc2n1
Agent: Cl
Solvent: CO
Product: CCCc1nc2nc(N)ccc2[nH]1
Temperature: 45 °C
Yield: 79.6 %

Procedure:
A mixture of 5-butyramido-2-propylimidazo[4,5-b]pyridine (250 mg, 1.07 mmol), MeOH (20 mL), and concentrated aqueous HCl (2 mL) was heated to 45° C. for 16 hours. Concentration and neutralization with NaHCO3 gave 150 mg of the title compound as a glass. 1H NMR (300 MHz, CD3OD) δ7.57 (d, 1H, J=8.5 Hz), 6.46 (d, 1H, J=8.5 Hz), 2.76 (t, 2H, J=7.5 Hz), 1.85-1.70 (m, 2H), 0.93 (t, 3H, J=7.5 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[NH:8][C:9](=O)[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Li+].[OH-].Cl.[C:15](O)(=O)C>C(O)C.O>[Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:15])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: O=c1[nH]c2c(Cl)cccc2o1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1nc2c(Cl)cccc2o1

Procedure:
To a solution of the 4-chloro-2-benzooxazolinone (0.10 mol) in 200 mL ethanol is added LiOH (0.20 mol) in 100 mL of water. The solution is refluxed for 8 hr and cooled. The solution is neutralized with 1N HCl and extracted with ethyl acetate followed by drying over MgSO4. The solution is concentrated and taken up in 200 mL of toluene and 0.10 mol of acetic acid. The solution is refluxed in a Dean Stark trap for 12 hours, concentrated and purified by flash chromatography.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:13]([NH2:17])[CH2:14][CH2:15][CH3:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:18]([O:21][C:22]1[CH:23]=[C:24]([CH2:34][C:35](O)=[O:36])[CH:25]=[CH:26][C:27]=1[C:28]([O:30][CH2:31][CH2:32][CH3:33])=[O:29])[CH2:19][CH3:20]>>[CH2:18]([O:21][C:22]1[CH:23]=[C:24]([CH2:34][C:35]([NH:17][CH:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:14][CH2:15][CH3:16])=[O:36])[CH:25]=[CH:26][C:27]=1[C:28]([O:30][CH2:31][CH2:32][CH3:33])=[O:29])[CH2:19][CH3:20]
Reactant: CCCOC(=O)c1ccc(CC(=O)O)cc1OCCC
Reactant: CCCC(N)c1ccccc1N1CCCCC1
Product: CCCOC(=O)c1ccc(CC(=O)NC(CCC)c2ccccc2N2CCCCC2)cc1OCCC

Procedure:
Prepared from 1-(2-piperidino-phenyl)-1-butylamine and 3-n-propoxy-4-n-propoxycarbonyl-phenylacetic acid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[Cu][C:17]#[N:18].Cl>CN1CCCC1=O>[CH3:8][C:6]1[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]([N+:13]([O-:15])=[O:14])=[C:2]([CH:7]=1)[C:17]#[N:18]
Reactant: Cc1cc(Br)c([N+](=O)[O-])cc1C(F)(F)F
Reactant: N#C[Cu]
Agent: Cl
Solvent: CN1CCCC1=O
Product: Cc1cc(C#N)c([N+](=O)[O-])cc1C(F)(F)F
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 88.1 %

Procedure:
A mixture of 1-bromo-5-methyl-2-nitro-4-trifluoromethyl-benzene from step 2 (49.80 g, 175 mmol) and copper(I) cyanide (16.5 g, 184 mmol) in 1-methyl-2-pyrrolidone (NMP) (180 mL) was heated up to 150° C. and stirred for 30 min under nitrogen atmosphere. The mixture was cooled to 23° C. and poured into 1 N HCl, extracted with TBME, washed with brine and dried over Na2SO4. Removal of the solvent in vacuum left a brown oil, which was purified by silica gel column chromatography with heptane/ethyl acetate 4:1->2:1 to give the title compound as a light yellow solid (35.48 g, 88%). MS (EI) 230.1 [M].
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[C:12]3[C:13]([Br:21])=[CH:14][N:15]=[CH:16][C:17]=3[CH:18]=[CH:19][CH:20]=2)(=[O:10])=[O:9])[CH2:4]1.Cl.N[C@H:24]1[CH2:28]CN(S(C2C3C(Br)=CN=CC=3C=CC=2)(=O)=O)[CH2:25]1>>[CH2:28]([NH:2][C@@H:3]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[C:12]3[C:13]([Br:21])=[CH:14][N:15]=[CH:16][C:17]=3[CH:18]=[CH:19][CH:20]=2)(=[O:10])=[O:9])[CH2:4]1)[CH:24]=[CH2:25]
Reactant: N[C@H]1CCN(S(=O)(=O)c2cccc3cncc(Br)c23)C1
Reactant: N[C@@H]1CCN(S(=O)(=O)c2cccc3cncc(Br)c23)C1
Agent: Cl
Product: C=CCN[C@@H]1CCN(S(=O)(=O)c2cccc3cncc(Br)c23)C1

Procedure:
(R)-3-Amino-1-(4-bromo-5-isoquinolinesulfonyl)pyrrolidine hydrochloride can be used in the method of Example 5-1 instead of (S)-3-amino-1-(4-bromo-5-isoquinolinesulfonyl)pyrrolidine hydrochloride to obtain the title compound.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH3:31])[C:14]=2[C@H:15]2[O:21][CH2:20][C@@H:19]([F:22])[C@H:18]([NH:23]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[O:8])[N:6]=1.[CH2:32]([O:34][C:35]1[C:36]([F:45])=[C:37](B(O)O)[C:38]([F:41])=[CH:39][CH:40]=1)[CH3:33]>>[NH2:23][C@H:18]1[C@H:19]([F:22])[CH2:20][O:21][C@H:15]([C:14]2[N:13]([CH3:31])[N:12]=[CH:11][C:10]=2[NH:9][C:7]([C:5]2[N:6]=[C:2]([C:37]3[C:38]([F:41])=[CH:39][CH:40]=[C:35]([O:34][CH2:32][CH3:33])[C:36]=3[F:45])[S:3][CH:4]=2)=[O:8])[CH2:16][CH2:17]1
Reactant: CCOc1ccc(F)c(B(O)O)c1F
Reactant: Cn1ncc(NC(=O)c2csc(Br)n2)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Product: CCOc1ccc(F)c(-c2nc(C(=O)Nc3cnn(C)c3[C@@H]3CC[C@@H](N)[C@H](F)CO3)cs2)c1F

Procedure:
Following the procedure for Example 101 starting from tert-butyl ((3S,4R,7S)-7-(4-(2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-3-fluorooxepan-4-yl)carbamate (Intermediate 99), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (3-ethoxy-2,6-difluorophenyl)boronic acid gave 285. 1H NMR (400 MHz, DMSO-d6) δ 9.87 (s, 1H), 8.63 (s, 1H), 7.79 (s, 1H), 7.39 (td, J=9.3, 5.2 Hz, 1H), 7.24 (td, J=9.6, 1.9 Hz, 1H), 4.80 (dd, J=11.0, 3.6 Hz, 1H), 4.49-4.25 (m, 1H), 4.16 (q, J=6.9 Hz, 3H), 4.08-3.90 (m, 1H), 3.78 (s, 3H), 3.29-3.18 (m, 1H), 2.10-2.02 (m, 1H), 1.91-1.77 (m, 1H), 1.74-1.64 (m, 2H), 1.36 (t, J=6.9 Hz, 3H). LCMS (ES+) m/z 496 (M+1).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][O:9][C:10](=[O:35])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][N:18]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:19](=[O:28])[C:20]#[C:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:12]=1>>[CH3:8][O:9][C:10](=[O:35])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][N:18]2[C:29]3[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:20](=[C:21]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:19]2=[O:28])[CH:12]=1
Reactant: Ic1ccccc1
Reactant: COC(=O)c1cccc(CN(C(=O)C#Cc2ccccc2)c2ccccc2)c1
Product: COC(=O)c1cccc(CN2C(=O)C(=C(c3ccccc3)c3ccccc3)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 5 starting from iodo-benzene (commercially available) and 3-{[phenyl-(3-phenyl propynoyl)-amino]-methyl}-benzoic acid methyl ester. 1H NMR (CDCl3, 300 MHz) δppm 8.01 (s, 1H), 8.00 (d, 1H), 7.93 (d, 1H), 7.33-7.52 (m, 12H), 7.05 (dt, 1H), 6.66 (m, 2H), 6.43 (d, 2H), 4.96 (s, 2H), 3.91 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7](Cl)=[N:8]2.[CH3:14][O:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][NH2:19]>>[CH3:14][O:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][NH:19][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[CH:12][C:3]=2[O:2][CH3:1])[N:8]=1
Reactant: COc1cccc2nc(Cl)ccc12
Reactant: COc1ccccc1CN
Product: COc1ccccc1CNc1ccc2c(OC)cccc2n1

Procedure:
The title compound, MS: m/e=295.4 (M+H+), was prepared in accordance with the general method of example 1 from 5-methoxy-2-chloroquinoline (CAS-RN: 160893-07-2) and 2-methoxybenzylamine.