Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH:7]2[CH2:30][NH:29][C:10]3=[N:11][C:12]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[C:13]([C:15]4[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=4)[N:14]=[C:9]3[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O=[CH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[N:1]1([CH:7]2[CH2:30][N:29]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[C:10]3=[N:11][C:12]([C:22]4[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=4)=[C:13]([C:15]4[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=4)[N:14]=[C:9]3[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCCCCC=O
Reactant: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)NCC(N2CCCCC2)C3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: CCOC(=O)CCCCCCN1CC(N2CCCCC2)Cc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 7-(piperidin-1-yl)-2,3-di-p-tolyl-5,6,7,8-tetrahydropyrido[2,3-b]pyrazine (step 7) (62 mg, 0.156 mmol) in DCE (5 ml) under nitrogen, was treated with ethyl 7-oxoheptanoate (53.6 mg, 0.311 mmol) and stirred at room temperature for 15 minutes. Sodium triacetoxyborohydride (132 mg, 0.622 mmol) was added and the resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM (20 ml) and washed with water. The organic portion was passed through a phase separating column and concentrated under reduced pressure. Purification of the crude material by chromatography on silica eluting with 0-100% EtOAc in iso-hexane afforded the titled compound;
Reaction SMILES: Cl.[CH2:2]([NH:4][C:5](=[O:92])[C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11](=[O:91])[C@H:12]([CH2:84][CH2:85][CH2:86][NH:87][C:88](=[NH:90])[NH2:89])[NH:13][C:14](=[O:83])[C@H:15]([CH2:79][CH:80]([CH3:82])[CH3:81])[NH:16][C:17](=[O:78])[C@@H:18]([CH2:71][C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1)[NH:19][C:20](=[O:70])[C@H:21]([CH2:62][C:63]1[CH:68]=[CH:67][C:66]([OH:69])=[CH:65][CH:64]=1)[NH:22][C:23](=[O:61])[C@H:24]([CH2:59][OH:60])[NH:25][C:26](=[O:58])[C@H:27]([CH2:48][C:49]1[C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[NH:51][CH:50]=1)[NH:28][C:29](=[O:47])[C@H:30]([CH2:42][CH2:43][C:44](=[O:46])[NH2:45])[NH:31][C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[CH3:3].[C:93]([O-:96])(=[O:95])[CH3:94]>CO>[C:93]([OH:96])(=[O:95])[CH3:94].[CH2:2]([NH:4][C:5](=[O:92])[C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11](=[O:91])[C@H:12]([CH2:84][CH2:85][CH2:86][NH:87][C:88](=[NH:89])[NH2:90])[NH:13][C:14](=[O:83])[C@H:15]([CH2:79][CH:80]([CH3:81])[CH3:82])[NH:16][C:17](=[O:78])[C@@H:18]([CH2:71][C:72]1[CH:73]=[CH:74][CH:75]=[CH:76][CH:77]=1)[NH:19][C:20](=[O:70])[C@H:21]([CH2:62][C:63]1[CH:64]=[CH:65][C:66]([OH:69])=[CH:67][CH:68]=1)[NH:22][C:23](=[O:61])[C@H:24]([CH2:59][OH:60])[NH:25][C:26](=[O:58])[C@H:27]([CH2:48][C:49]1[C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[NH:51][CH:50]=1)[NH:28][C:29](=[O:47])[C@H:30]([CH2:42][CH2:43][C:44](=[O:46])[NH2:45])[NH:31][C:32]([O:34][CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:33])[CH3:3]
Reactant: CC(=O)[O-]
Agent: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](CCC(N)=O)NC(=O)OCc1ccccc1
Agent: Cl
Solvent: CO
Product: CC(=O)O

Procedure:
A solution of 300 mg. of Nα -benzyloxycarbonyl-L-glutaminyl-L-tryptophyl-L-seryl-L-tyrosyl-D-phenylalanyl-L-leucyl-L-arginyl-L-proline N-ethylamide hydrochloride in 100 ml. of methanol is put on a column of Dowex 1 × 2 (acetate form) resin 1.8 by 23 cm. and the material is eluted with methanol, collecting 40 ml. fractions. Fractions 2 to 5 on standing give an insoluble product. They are combined and filtered and the filtrate is concentrated to 30 ml. and diluted with ether (150 ml.). The product which precipitates is filtered off, washed with ether and dried at 50° C. under reduced pressure to give Nα -benzyloxycarbonyl-L-glutaminyl-L-tryptophyl-L-seryl-L-tyrosyl-D-phenylalanyl-L-leucyl-L-arginyl-L-proline N-ethylamide acetate salt [α]D23 -29° (c 1.00, DMF); λmax 289.5 E11 41.7 λmax 280 E11 54.3.
Reaction SMILES: [CH3:1][N:2](S(C1C=CC(C)=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].[Cl:24][C:25]1[C:32]([N+:33]([O-:35])=[O:34])=[CH:31][CH:30]=[CH:29][C:26]=1[C:27]#[N:28].[Cl-].[Al+3].[Cl-].[Cl-].ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl>[Cl:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:5]=1[C:4]1[N:28]=[C:27]([C:26]2[CH:29]=[CH:30][CH:31]=[C:32]([N+:33]([O-:35])=[O:34])[C:25]=2[Cl:24])[N:2]([CH3:1])[N:3]=1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=C(Cl)c2c(F)cccc2Cl)cc1
Reactant: N#Cc1cccc([N+](=O)[O-])c1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Solvent: ClC(Cl)Cl
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1cccc([N+](=O)[O-])c1Cl
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
A mixture of N-methyl-N-(p-toluenesulfonyl)-2-chloro-6-fluorobenzohydrazonoyl chloride (1.90 g), 2-chloro-3-nitrobenzonitrile (1.19 g), anhydrous aluminum chloride (0.70 g) and o-dichlorobenzene (20 ml) is stirred at an oil bath temperature of 140° C. for 30 minutes. After cooling, the reaction mixture is dissolved in chloroform (100 ml), washed with dilute hydrochloric acid, dilute aqueous solution of sodium hydroxide and saline in this order, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexane-ethyl acetate as eluent to give 1.19 g of desired compound (melting point: 112.0°-114.0° C.).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6](Br)=[CH:5][CH:4]=1)[CH3:2].C([Li])(C)(C)C.[F:15][C:16]1[CH:26]=[C:25]([C:27]#[C:28][C:29]2[CH:30]=[C:31]3[C:36](=[CH:37][CH:38]=2)[O:35][C:34]([CH3:40])([CH3:39])[CH:33]=[C:32]3OS(C(F)(F)F)(=O)=O)[CH:24]=[CH:23][C:17]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C1COCC1.CCCCC.[Cl-].[Cl-].[Zn+2].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>[F:15][C:16]1[CH:26]=[C:25]([C:27]#[C:28][C:29]2[CH:30]=[C:31]3[C:36](=[CH:37][CH:38]=2)[O:35][C:34]([CH3:40])([CH3:39])[CH:33]=[C:32]3[C:6]2[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)[CH:24]=[CH:23][C:17]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCc1ccc(Br)cc1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(OS(=O)(=O)C(F)(F)F)=CC(C)(C)O3)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(CC)cc2)=CC(C)(C)O3)cc1F
Temperature: 25 °C

Procedure:
A solution of 4-ethylbromobenzene (150.0 mg, 0.80 mmol) in 3.0 mL of THF was cooled to -78° C. and tert-butyllithium (102.5 mg, 1.60 mmol, 0.94 ml of a 1.7M solution in pentane) was added to give a yellow solution. After 30 minutes a solution of ZnCl2 (218.0 mg, 1.60 mmol) in 5.0 mL THF was slowly added via cannula. The resulting solution was warmed to room temperature and transferred via cannula to a solution of ethyl 2-fluoro-4-(2,2-dimethyl-4-trifluoromethanesulfonyloxy-(2H)-chromen-6-ylethynyl)-benzoate (Compound 271, 160.0 mg, 0.32 mmol) and tetrakis(triphenylphosphine)palladium(0) (20.0 mg, 0.02 mmol) in 2.0 mL THF. This solution was heated to 50° C. for 2 hours, cooled to room temperature, and the reaction quenched by the addition of saturated aqueous NH4Cl. This solution was extracted with EtOAc and the combined organic layers were washed with H2O and saturated aqueous NaCl before being dried (MgSO4) and concentrated under reduced pressure. The title compound, 115.0 mg (79%), was isolated by column chromatography (5% EtOAc/hexanes) as a colorless solid. 1H NMR (300 MHz, CDCl3) δ: 7.88 (1H, d, J=7.8 Hz), 7.35 (1H, dd, J=2.0, 8.3 Hz), 7.28-7.20 (7H, m), 6.88 (1H, d, J=8.3 Hz), 5.65 (1H, s), 4.39 (2H, q, J=7.1 Hz), 2.73 (2H, q, J=7.6 Hz), 1.52 (6H, s), 1.40 (3H, t, J=7.1 Hz), 1.31 (3H, t, J=7.6 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([C:11](=O)[CH3:12])[CH:10]=1.[CH3:25][NH2:26]>C(O)C>[CH3:25][N:26]=[C:11]([C:9]1[CH:10]=[C:5]([O:4][C:3]2[CH:17]=[CH:18][C:19]([C:21]([F:24])([F:23])[F:22])=[CH:20][C:2]=2[Cl:1])[CH:6]=[CH:7][C:8]=1[N+:14]([O-:16])=[O:15])[CH3:12]
Reactant: CN
Reactant: CC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Solvent: CCO
Product: CN=C(C)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of 5-[2-chloro-4-(trifluoromethyl)phenoxy]-2-nitrophenyl ethanone (3.3 g., 0.0092 mole) in absolute ethanol (30 ml) was bubbled methylamine for 0.5 hour as the temperature rose to about 40° C. The solution was stirred for 12 hours at room temperature and then heated to reflux for 4 hours. The solvent was stripped to give 3.0 g of a brown oil. Recrystallization from methanol/water gave a brown solid (1.2 g., mp. 133°-7° C.).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH:3]([CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[O:4][Si:5]([CH2:10][CH3:11])([CH2:8][CH3:9])[CH2:6][CH3:7].C(N(CC)CC)C.[C:27](Cl)(=[O:30])[CH2:28][CH3:29].C(=O)(O)[O-].[Na+]>ClCCl>[C:27]([N:15]1[CH2:16][CH2:17][CH:12]([CH:3]([O:4][Si:5]([CH2:8][CH3:9])([CH2:6][CH3:7])[CH2:10][CH3:11])[C:2]([F:18])([F:1])[F:19])[CH2:13][CH2:14]1)(=[O:30])[CH2:28][CH3:29]
Reactant: CCC(=O)Cl
Reactant: CC[Si](CC)(CC)OC(C1CCNCC1)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)N1CCC(C(O[Si](CC)(CC)CC)C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.7 %

Procedure:
4-[2,2,2-Trifluoro-1-(triethylsiloxy)ethyl]piperidine (250 mg, 0.841 mmol) was dissolved in dichloromethane (5.0 mL). To this, triethylamine (0.176 mL, 1.26 mmol) and propionyl chloride (0.110 mL, 1.26 mmol) were added at 0° C. and the mixture was stirred at room temperature for 2 hours. The reaction was stopped by addition of a saturated aqueous sodium bicarbonate solution to the reaction mixture, and extraction with dichloromethane was performed, followed by drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=7/3) to give 1-propionyl-4-[2,2,2-trifluoro-1-(triethylsiloxy)ethyl]-piperidine (231 mg, yield: 78%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:25]=[CH:24][C:8]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[O:10])=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+]>CO.C1COCC1>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([N:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:15][CH2:16]2)=[O:10])=[CH:24][CH:25]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1ccc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(C(=O)O)cc2)CC1
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
7.08 g (20.3 mmol) of t-butyl 4-(4-methoxycarbonylbenzoyl)piperazine-1-carboxylate was stirred in 40 ml of methanol and 40 ml of THF. 51 ml (51 mmol) of 1 N aqueous sodium hydroxide solution was added to the resultant solution, and they were stirred at 80° C. for 20 minutes. The reaction liquid was evaporated under reduced pressure and 1 N hydrochloric acid was added to the residue. After the extraction with ethyl acetate followed with the treatment in an ordinary manner, the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:14]=3[C:15]([O:17]C)=[O:16])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[OH-].[Na+].O>CO>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:14]=3[C:15]([OH:17])=[O:16])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(F)ccc1Nc1ccnc2cc(Cl)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc(F)ccc1Nc1ccnc2cc(Cl)ccc12
Yield: 99.5 %

Procedure:
A solution of 1.8 g of the ester of Example 1, 25 ml of N sodium hydroxide solution, 25 ml of water and 100 ml of methanol was heated at 70°-75° C. for 90 minutes and the methanol was then evaporated. 100 ml of water and 10 ml of dimethylformamide were added to the mixture which was then heated to reflux. 4 ml of acetic acid were added thereto and the mixture was held in an ice bath for an hour and was then vacuum filtered. The recovered crystals were washed with water and dried to obtain 1.715 g of 2-(7-chloro-4-quinolinylamino)-5-fluoro-benzoic acid melting at 341°-342° C.
Reaction SMILES: [Cl:1]Cl.[CH:3]1([C:6]2[NH:7][C:8]([CH:13]([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])=[CH:9][C:10](=[O:12])[N:11]=2)[CH2:5][CH2:4]1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[Cl:1][C:9]1[C:10](=[O:12])[N:11]=[C:6]([CH:3]2[CH2:4][CH2:5]2)[NH:7][C:8]=1[CH:13]([O:14][CH2:15][CH3:16])[O:17][CH2:18][CH3:19]
Reactant: ClCl
Reactant: CCOC(OCC)c1cc(=O)nc(C2CC2)[nH]1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(OCC)c1[nH]c(C2CC2)nc(=O)c1Cl
Temperature: 29 °C
Yield: 98 %

Procedure:
Chlorine was carefully passed through 2-cyclopropyl-6-(diethoxymethyl)-4(1H)-pyrimidinone (i.e. the product of Example 3) (46.0 g, 0.193 mol) and sodium acetate (18.8 g, 0.229 mol) in acetic acid (185 mL). The temperature was maintained in the range of about 28-30° C. When the starting material had been consumed, the flow of chlorine was stopped immediately. Toluene (185 mL) was added, and the mixture was evaporated under reduced pressure. The process was repeated. The mixture was partitioned between ethyl acetate (450 mL) and water (50 mL). The organic layer was further washed with water (4×50 mL), dried and evaporated to leave the product as an off-white solid (51.75 g, 98% yield). Product recrystallized from hexanes had a melting point of 109-111° C.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:10]2[S:18][CH:17]=[C:16]([C:19]#[CH:20])[C:11]=2[N:12]=[C:13](Cl)[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][CH2:22][C@@H:23]([OH:25])[CH3:24].C(OCC)(=O)C>O1CCOCC1>[CH2:1]([NH:8][C:9]1[C:10]2[S:18][CH:17]=[C:16]([C:19]#[CH:20])[C:11]=2[N:12]=[C:13]([NH:21][CH2:22][C@@H:23]([OH:25])[CH3:24])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#Cc1csc2c(NCc3ccccc3)nc(Cl)nc12
Reactant: C[C@H](O)CN
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C#Cc1csc2c(NCc3ccccc3)nc(NC[C@H](C)O)nc12
Temperature: 120 °C
Reaction time: 24 h
Yield: 52.3 %

Procedure:
N-Benzyl-2-chloro-7-ethynylthieno[3,2-d]pyrimidin-4-amine (30 mg, 0.096 mmol) was dissolved in anhydrous dioxane (0.5 mL) and (S)-1-aminopropan-2-ol (23 μL, 0.288 mmol) was added. The reaction mixture was stirred at 120° C. for 24 hours. After adding ethyl acetate (3 mL), the reaction mixture was washed with brine. After drying with MgSO4 and concentrating by filtration, purification by silica gel chromatography (ethyl acetate/hexane:1/3→1/1) yielded the target compound of Example 44 (17 mg, 50% yield).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]1=[O:16].[H-].[Na+]>CN(C=O)C>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]2=[O:16])=[CH:4][CH:3]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: O=C1CCCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCCCN1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-fluorobenzyl bromide (15 g, 79 mmol) and 2-piperidinone (8.4 g, 85 mmol) in DMF (150 mL) was added sodium hydride (3.6 g of a 60% suspension in mineral oil, 90 mmol) in portions over a period of 20 min. The mixture was stirred at ambient temperature for 18 hours. The solvent was removed under vacuum and the residue was partitioned between EtOAc and water. The organic extract was washed with brine, dried over MgSO4, filtered, and concentrated under vacuum. The residual oil was purified using silica gel column chromatography eluting with 50%-70% ethyl acetate in hexanes. The appropriate fractions were combined and concentrated to afford the title compound as white solid. 1H NMR (400 MHz, CDCl3) δ 7.23 (dd, J=8.7; 5.4 Hz, 2H), 7.00 (t, J=8.7 Hz, 2H), 4.56 (s, 2H), 3.18 (t, J=6 Hz, 2H), 2.46 (t, J=6 Hz, 2H), 1.79 (m, 4H).
Reaction SMILES: [Mg].[C:2](Br)([CH3:5])([CH3:4])[CH3:3].[CH:7]([C:10]1[C:18]([CH:19]=[O:20])=[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][N:12]2[N:11]=1)([CH3:9])[CH3:8].[Cl-].[NH4+]>CCOCC.C1C=CC=CC=1>[CH:7]([C:10]1[C:18]([CH:19]([OH:20])[C:2]([CH3:5])([CH3:4])[CH3:3])=[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][N:12]2[N:11]=1)([CH3:9])[CH3:8]
Reactant: CC(C)(C)Br
Reactant: CC(C)c1nn2ccccc2c1C=O
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Solvent: c1ccccc1
Product: CC(C)c1nn2ccccc2c1C(O)C(C)(C)C
Yield: 52 %

Procedure:
To a suspension of 1.6 g of magnesium in 10 ml of dry ether was added a solution of 9.3 g of tert. butylbromide in 15 ml of dry ether under stirring. After the addition was completed, the stirring was continued for an hour at room temperature. To the Grignard reagent were added 2.5 g of 2-isopropyl-3-formylpyrazolo[1,5-a]pyridine in 5 ml of dry benzene under stirring. The mixture was stirred for an hour at room temperature and 11 hours at reflux temperature. The reaction mixture was treated with 100 ml of aqueous 20% ammonium chloride solution and extracted with ether. The ether layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was subjected to silica gel column chromatography, eluted with dichloromethane, to give 1.7 g (52%) of pale yellow crystals, mp 95° C.
Reaction SMILES: [OH:1]O.[C:3]([O:11][CH3:12])(=[O:10])[C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1>C(O)(=O)C>[C:3]([O:11][CH3:12])(=[O:10])[C:4]1[CH:9]=[CH:8][N+:7]([O-:1])=[CH:6][CH:5]=1
Reactant: OO
Reactant: COC(=O)c1ccncc1
Solvent: CC(=O)O
Product: COC(=O)c1cc[n+]([O-])cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
To a solution of hydrogen peroxide (43 mL) in 250 mL of acetic acid was added methyl isonicotinate. The reaction mixture was stirred at 80° C. overnight (about eighteen hours). The solution was concentrated to about 50 mL, water was added and the mixture was saturated with sodium carbonate. The aqueous phase was extracted with methylene chloride. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and trituated with hexane. The resulting precipitate was filtered and air-dried to give 24.5 g (65% yield) of product as a white solid: mp: 118-120° C.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[CH2:3][N:4]([CH2:19][C:20]([F:23])([F:22])[F:21])[C:5]1[CH:6]=[CH:7][C:8]([C:16](O)=[O:17])=[N:9][C:10]=1[O:11][CH2:12][CH:13]1[CH2:15][CH2:14]1.[NH2:26][C@@H:27]([CH2:31][CH:32]1[CH2:34][CH2:33]1)[C:28]([NH2:30])=[O:29]>>[C:28]([C@@H:27]([NH:26][C:16]([C:8]1[CH:7]=[CH:6][C:5]([N:4]([CH2:19][C:20]([F:21])([F:22])[F:23])[CH2:3][C:2]([F:24])([F:1])[F:25])=[C:10]([O:11][CH2:12][CH:13]2[CH2:14][CH2:15]2)[N:9]=1)=[O:17])[CH2:31][CH:32]1[CH2:34][CH2:33]1)(=[O:29])[NH2:30]
Reactant: O=C(O)c1ccc(N(CC(F)(F)F)CC(F)(F)F)c(OCC2CC2)n1
Reactant: NC(=O)[C@@H](N)CC1CC1
Product: NC(=O)[C@H](CC1CC1)NC(=O)c1ccc(N(CC(F)(F)F)CC(F)(F)F)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-[bis-(2,2,2-trifluoro-ethyl)-amino]-6-cyclopropylmethoxy-pyridine-2-carboxylic acid and (S)-2-amino-3-cyclopropyl-propionamide (CAN 156077-93-9) as starting materials, MS (EI): m/e=483.1 [M+H]+.
Reaction SMILES: [CH3:1][CH2:2][N:3]1[C:9]2[N:10]=[C:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:12]=[CH:13][C:8]=2[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4]1.[F:23][C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[S:32])[CH:27]=[CH:28][CH:29]=1>>[F:23][C:24]1[CH:25]=[C:26]([NH:30][C:31]([N:17]2[CH2:18][CH2:19][N:14]([C:11]3[N:12]=[CH:13][C:8]4[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4][N:3]([CH2:2][CH3:1])[C:9]=4[N:10]=3)[CH2:15][CH2:16]2)=[S:32])[CH:27]=[CH:28][CH:29]=1
Reactant: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCNCC3)nc21
Reactant: Fc1cccc(N=C=S)c1
Product: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCN(C(=S)Nc4cccc(F)c4)CC3)nc21

Procedure:
Pipemidic acid (25 mg, 0.0824 mmol) and 3-fluorophenyl isothiocyanate (9.9 μL, 0.0824 mmol) were used. Purification on silica yielded compound 25 in Table 1, below (22 mg, 59%). 1H NMR (300 MHz, CDCl3) δ 9.32 (s, 1H), 8.66 (s, 1H), 7.41 (s, 1H), 7.37-7.27 (m, 1H), 6.96 (t, J=7.39, 2H), 6.88 (t, J=7.67 Hz, 1H), 4.38-4.27 (m, 2H), 4.27-3.91 (m, 8H), 1.54-1.43 (m, 3H) ppm.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:4]=1[C:5]([OH:7])=O)[CH3:2].CCN=C=NCCCN(C)C.Cl.[CH:27]1([CH2:30][NH2:31])[CH2:29][CH2:28]1.OC1C2N=NNC=2C=CC=1>CN(C)C=O>[CH:27]1([CH2:30][NH:31][C:5](=[O:7])[C:4]2[CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=[CH:11][C:3]=2[CH2:1][CH3:2])[CH2:29][CH2:28]1
Reactant: CCc1ccc([N+](=O)[O-])cc1C(=O)O
Reactant: NCC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: CCc1ccc([N+](=O)[O-])cc1C(=O)NCC1CC1
Reaction time: 18 h
Yield: 78.6 %

Procedure:
2-Ethyl-5-nitrobenzoic acid (0.40 g), EDC.HCl (0.45 g), cyclopropylmethylamine (0.17 g) and hydroxybenzotriazole (0.04 g) were combined in dimethylformamide (10 ml) and stirred for 18 h. Solvent was removed at reduced pressure, the residue dissolved in dichloromethane and washed with 2N HCl and water. The organic phase was dried (MgSO4) and solvent removed at reduced pressure to give the title compound (0.4 g). 1H NMR (CDCl3) δ: 0.31 (2H, m), 0.59 (2H, m), 1.09 (1H, m), 1.28(3H, t, J=7.6Hz), 2.92 (2H, m), 3.33 (2H, m), 5.97 (1H, brs), 7.45 (1H, d, J=8.4 Hz), 8.20 (2H, m).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:5]([Cl:24])=[C:6]([C:20]([Cl:23])=[CH:21][CH:22]=1)[CH2:7][O:8][C:9]1[C:10]2[N:11]([C:15]([Br:19])=[C:16]([CH3:18])[N:17]=2)[CH:12]=[CH:13][CH:14]=1.[CH3:25][C:26]([CH3:28])=O.C([BH3-])#N.[Na+]>Cl.C(O)C>[Br:19][C:15]1[N:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:7][C:6]3[C:20]([Cl:23])=[CH:21][CH:22]=[C:4]([NH:3][CH:26]([CH3:28])[CH3:25])[C:5]=3[Cl:24])[C:10]2=[N:17][C:16]=1[CH3:18]
Reactant: Cc1nc2c(OCc3c(Cl)ccc(N)c3Cl)cccn2c1Br
Reactant: CC(C)=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: Cc1nc2c(OCc3c(Cl)ccc(NC(C)C)c3Cl)cccn2c1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.5 %

Procedure:
To a mixture of 8-(3-amino-2,6-dichlorobenzyloxy)-3-bromo-2-methylimidazo[1,2-a]pyridine dihydrochloride (100 mg) and acetone (116 mg) in 3M HCl solution in ethanol (2 ml) was added sodium cyanoborohydride (25 mg) in one portion. The mixture was stirred for 2 hours at ambient temperature and then concentrated in vacuo. The residue was partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The organic layer was dried and concentrated in vacuo to give an oil, which was purified by preparative thin-layer chromatography on silica gel (ethyl acetate:n-hexane =1:2, V/V), to give 3-bromo-8-(2,6-dichloro-3-isopropylaminobenzyloxy)-2-methylimidazo[1,2-a]pyridine as a white solid (50 mg).