Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH3:13])[CH2:9][CH2:10][C:11]#[N:12])(C)(C)C.[C:15]([OH:21])([C:17]([F:20])([F:19])[F:18])=[O:16]>ClCCl>[F:18][C:17]([F:20])([F:19])[C:15]([OH:21])=[O:16].[NH2:7][C@H:8]([CH3:13])[CH2:9][CH2:10][C:11]#[N:12]
Reactant: C[C@H](CCC#N)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](N)CCC#N
Temperature: 25 °C
Reaction time: 15 h
Yield: 68 %

Procedure:
In a 100 mL round-bottomed flask, ((R)-3-cyano-1-methyl-propyl)-carbamic acid tert-butyl ester (158 mg, 0.80 mmol) was combined with TFA (2 ml) and dichloromethane (8 mL) to give a colorless solution. The reaction mixture was stirred at 25° C. for 15 h. The solvent was evaporated to provide 53 mg (68%) of (R)-4-aminopentanenitrile trifluoroacetate which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([C:3]1[C:14]([CH:15]([CH3:18])[C:16]#[N:17])=[C:6]2[C:7]3[CH2:13][CH2:12][O:11][C:8]=3[CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2].N.C(O)C>[Co]>[CH2:1]([C:3]1[C:14]([CH:15]([CH3:18])[CH2:16][NH2:17])=[C:6]2[C:7]3[CH2:13][CH2:12][O:11][C:8]=3[CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nn2ccc3c(c2c1C(C)C#N)CCO3
Agent: [Co]
Agent: N
Solvent: CCO
Product: CCc1nn2ccc3c(c2c1C(C)CN)CCO3
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.3 %

Procedure:
A mixture of 2-(2-ethyl-8,9-dihydrofuro[3,2-c]pyrazolo[1,5-a]pyridin-1-yl)propanenitrile (185 mg, 0.767 mmol), Raney cobalt (1.9 g) and 2M ammonia/ethanol solution (15 mL) was stirred at room temperature for 12 hr under a hydrogen atmosphere, and further stirred at 40° C. for 3 hr. The catalyst was filtered through celite, and the filtrate was concentrated under reduced pressure to give the title compound (185 mg, yield 98%).
Reaction SMILES: [BrH:1].[N+:2]([C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][CH:11]=1)N)([O-:4])=[O:3].CC1(C)N([O])C(C)(C)CCC1.N([O-])=O.[Na+].[OH-].[Na+]>O.C(#N)C>[Br:1][C:7]1[CH:6]=[C:5]([N+:2]([O-:4])=[O:3])[CH:11]=[CH:10][CH:9]=1
Reactant: Br
Reactant: Nc1cccc([N+](=O)[O-])c1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=[N+]([O-])c1cccc(Br)c1
Temperature: 10 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
Water (45 ml), acetonitrile (6 ml), and 48% hydrobromic acid (27 ml) were added to 3-nitroaniline (2c) (2.76 g, 20 mmol) at room temperature. To the mixed solution, 2,2,6,6-tetramethylpiperidine 1-oxyl (0.31 g, 2 mmol) was added at room temperature, and the mixture was cooled to 10° C. or lower. Then, sodium nitrite (2.07 g) dissolved in water (15 ml) was added thereto. After stirring at room temperature for approximately 2 hours, a 10 mol/L aqueous sodium hydroxide solution (30 ml) was added thereto, and the precipitated crystals were collected by filtration, washed with water (40 ml), and then dried under reduced pressure to obtain 3-bromonitrobenzene (1c) (3.75 g, 93.0%). The instrumental spectrum data and HPLC retention time (Rt) of the obtained compound (1c) were completely consistent with those of the commercially available compound (1c).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:16]=[C:15]([C:17]#[N:18])[CH:14]=[C:13]([Cl:19])[N:12]=2)[C:6]([Cl:9])=[CH:7][CH:8]=1.[Cl:21][C:22]1[N:23]=[C:24]([CH3:30])[NH:25][C:26]=1[C:27](O)=[O:28]>>[Cl:21][C:22]1[N:23]=[C:24]([CH3:30])[NH:25][C:26]=1[C:27]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]2[CH:16]=[C:15]([C:17]#[N:18])[CH:14]=[C:13]([Cl:19])[N:12]=2)[C:4]=1[F:20])=[O:28]
Reactant: Cc1nc(Cl)c(C(=O)O)[nH]1
Reactant: N#Cc1cc(Cl)nc(Oc2c(Cl)ccc(CN)c2F)c1
Product: Cc1nc(Cl)c(C(=O)NCc2ccc(Cl)c(Oc3cc(C#N)cc(Cl)n3)c2F)[nH]1
Yield: 62.6 %

Procedure:
The previously described 2-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-6-chloro-4-pyridinecarbonitrile (0.040 g, 0.13 mmol) and 4-chloro-2-methyl-1H-imidazole-5-carboxylic acid (0.023 g, 0.14 mmol) were employed in a similar process described herein to prepare the title compound (0.037 g, 64%) as a white solid after purification by Reverse-Phase HPLC (water:acetonitrile with 0.1% TFA) followed by neutralization. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 11.92 (br. s., 1H) 7.13-7.34 (m, 5H) 4.72 (d, J=5.91 Hz, 2H) 2.36 (s, 3H). ES-LCMS: m/z 453.9, 456.0 (M+1).
Reaction SMILES: CCC([O-])(C)C.[Na+].[C:8](OC)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:18]1(=[O:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.S(=O)(=O)(O)O>C1(C(C)C)C=CC=CC=1>[C:8]([CH:19]1[CH2:20][CH2:21][CH2:22][CH2:23][C:18]1=[O:24])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COC(=O)c1ccccc1
Reactant: O=C1CCCCC1
Agent: CCC(C)(C)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(C)c1ccccc1
Product: O=C1CCCCC1C(=O)c1ccccc1
Temperature: 100 °C
Yield: 76 %

Procedure:
Cumene (dry, 180 mL), sodium tert-pentoxide (35.8 g; 0.326 mol), and methyl benzoate (68.1 g; 0.50 mol) were placed into a four-necked, round bottom, half-liter flask equipped with a stirrer, a thermometer, and a reflux condenser. The mixture was heated to 100° C. and kept at that temperature under a blanket of nitrogen. Cyclohexanone (24.5 g; 0.250 mol) was added slowly over a period of 15 minutes by means of a syringe pump. After 20 minutes from the beginning of the addition of the ketone, the mixture was cooled with an ice water bath to room temperature. Aqueous sulfuric acid (10%) was added with stirring, keeping the temperature below 25° C., until the pH of the aqueous layer was acidic. The organic layer was washed in a one liter separation funnel with aqueous sodium bicarbonate and then with water. The solvents were evaporated on a Rotovap and the residue was crystallized from heptane, affording BCH (38.43 g, 76% yield) having a purity of 99% (GC).
Reaction SMILES: [CH3:1][CH:2]([CH3:12])[C:3]#[C:4][C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[NH2:7]>CN(C=O)C.[Cu]I>[CH:2]([C:3]1[NH:7][C:6]2[C:5]([CH:4]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([CH3:12])[CH3:1]
Reactant: CC(C)C#Cc1ccccc1N
Agent: [Cu]I
Solvent: CN(C)C=O
Product: CC(C)c1cc2ccccc2[nH]1
Temperature: 160 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(3-methylbut-1-ynyl)aniline (Compound 37, 3.47 g, 21.8 mmol) in DMF (100 ml) was added copper (I) iodide (41 mg, 0.22 mmol). The mixture was stirred at 160° C. for 2 h and was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with 5% EtOAc-hexanes to yield 2-isopropyl-1H-indole (Compound 38) as an off-white solid.
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:44])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=5)[N:24]([CH2:32][CH2:33][O:34][CH3:35])[N:23]=4)[N:20]=3)[N:15](COCC[Si](C)(C)C)[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].FC(F)(F)C(O)=O.C(N)CN>ClCCl>[C:1]([CH:3]1[CH2:4][N:5]([C:7](=[O:44])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=5)[N:24]([CH2:32][CH2:33][O:34][CH3:35])[N:23]=4)[N:20]=3)[NH:15][CH:14]=2)=[O:12])[CH3:9])[CH2:6]1)#[N:2]
Reactant: COCCn1nc(-c2cnc3c(n2)c(C(=O)N[C@H](C)C(=O)N2CC(C#N)C2)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: NCCN
Solvent: ClCCl
Product: COCCn1nc(-c2cnc3[nH]cc(C(=O)N[C@H](C)C(=O)N4CC(C#N)C4)c3n2)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.4 %

Procedure:
In a round-bottomed flask, 2-[6-chloro-1-(2-methoxy-ethyl)-1H-indazol-3-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (50 mg, 0.079 mmol) was dissolved in dichloromethane (0.5 ml) and trifluoroacetic acid (0.25 ml, 3.24 mmol) was added. The reaction mixture was stirred at room temperature for 2 h then concentrated. The residue was dissolved in dichloromethane (0.5 ml) and ethylenediamine (0.32 ml, 4.74 mmol) was added. The reaction was stirred at room temperature for 1.5 h then quenched with water and diluted with ethyl acetate. The resultant suspension was filtered, washed with hot water and ethyl acetate and dried under high vacuum to provide 19 mg (48%) of 2-[6-chloro-1-(2-methoxy-ethyl)-1H-indazol-3-yl]-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as a light yellow powder. MS: (M+H)+=507; 1H NMR (DMSO-d6, 400 MHz): δ (ppm) 12.88 (br. s., 1H), 9.16 (s, 1H), 8.72 (dd, J=8.6, 3.0 Hz, 1H), 8.49 (dd, J=8.6, 4.8 Hz, 2H), 8.00 (s, 1H), 7.23-7.30 (m, 1H), 4.52-4.79 (m, 5H), 4.19-4.28 (m, 1H), 4.08-4.16 (m, 1H), 3.85 (t, J=5.3 Hz, 3H), 3.24 (s, 3H), 1.41 (t, J=6.6 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[CH:11][NH:12]2)=[CH:8][C:7]=1[OH:15].Cl[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=[O:26])[CH3:25])[CH:18]=1.CC(C)([O-])C.[K+].O>CS(C)=O.C(OCC)(=O)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[CH:11][NH:12]2)=[CH:8][C:7]=1[O:15][C:17]1[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=[O:26])[CH3:25])[CH:18]=1
Reactant: CC(=O)Nc1cc(Cl)ccn1
Reactant: COCCOc1cc2[nH]ccc2cc1O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COCCOc1cc2[nH]ccc2cc1Oc1ccnc(NC(C)=O)c1
Temperature: 150 °C
Reaction time: 13 h
Yield: 53 %

Procedure:
6-(2-Methoxyethoxy)-1H-indol-5-ol described in Production Example 20-4 (3.94 g, 19.0 mmol) and N-(4-chloropyridin-2-yl)acetamide described in Production Example 1-5 (3.25 g, 19.0 mmol) were dissolved in dimethylsulfoxide (25 mL), then 97% potassium tert-butoxide (2.20 g, 19.0 mmol) was added at room temperature, and the mixture was heated and stirred at 150° C. for 13 hours. Water and ethyl acetate were added to the reaction liquid at mom temperature for partition. The aqueous layer was extracted with ethyl acetate three times and the combined organic layer was washed with water. The organic layer was dried over anhydrous sodium sulfate. The drying agent was filtered off and the filtrate was concentrated under vacuum, and then the resultant was purified with NH silica gel column chromatography (n-heptane:ethyl acetate=2:3-0:1-ethyl acetate:methanol=49:1-9:1). The target fraction was concentrated under vacuum to obtain the title compound (3.45 g, 53%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH:6]([OH:9])[C:7]#[CH:8])=[CH:2]1.[CH3:10][CH2:11]CCCC.[OH-].[Na+].C(OS(OCC)(=O)=O)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>[O:1]1[CH:5]=[CH:4][C:3]([CH:6]([O:9][CH2:10][CH3:11])[C:7]#[CH:8])=[CH:2]1
Reactant: CCCCCC
Reactant: C#CC(O)c1ccoc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCOS(=O)(=O)OCC
Agent: [Br-]
Solvent: C1CCOC1
Product: C#CC(OCC)c1ccoc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 1-(3-furyl)-1-hydroxy-2-propyne (20.0 g, 0.163 mol), hexane (200 mL) and THF (25 mL) was added tetrabutylammonium bromide (1.05 g, 0.0032 mol), 50% NaOH (150 mL) and then diethylsulfate (30.0 g, 0.195 mol) at 0° C. The mixture was stirred for 3 hours at room temperature, poured into ice, and extracted with ethyl acetate. The combined organic layers were wasted with brine, dried over Na2SO4 and concentrated in vacuo. The residue was distilled at 70°-84° C. and (10 mmHg) to afford 1-(3-furyl)-1-ethoxy-2-propyne.
Reaction SMILES: O.[N-:2]=[N+:3]=[N-:4].[Na+].[CH2:6]([Sn:10](Cl)([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7][CH2:8][CH3:9]>COC(C)(C)C>[CH2:15]([Sn:10]([N:2]=[N+:3]=[N-:4])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:11][CH2:12][CH2:13][CH3:14])[CH2:16][CH2:17][CH3:18]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Yield: 64.3 %

Procedure:
Into 40 ml of distilled water was added 9.99 g of sodium azide (0.154 mol, 10.0 equiv), 30 ml tert-butyl methyl ether, and 5.0 g (0.0154 mol, 1.0 equiv) tributyltin chloride. The resultant mixture was stirred at room temperature for one hour. Carbon 13 NMR of an aliquot taken at this point showed absence of the starting tributyltin chloride. Therefore, the organic layer, after being separated from the aqueous layer, was dried over anhydrous sodium sulfate, filtered, concentrated, and distilled to afford 3.29 g (65%) of the desired product (bp.=115°-117° C./0.4 mm): 13C NMR δ27.8, 27.0, 15.2, 13.6.
Reaction SMILES: [CH2:1]([O:8][NH:9][C@H:10]1[CH2:15][NH:14][C@H:13]([C:16]([NH:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])[CH2:21][CH2:20]2)=[O:17])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[C:46]([O-])(O)=[O:47].[Na+].CCN(C(C)C)C(C)C.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.P(=O)(O)(O)O>ClCCl>[CH2:1]([O:8][N:9]1[C:46](=[O:47])[N:14]2[CH2:15][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:16]([NH:18][CH:19]1[CH2:20][CH2:21][N:22]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:23][CH2:24]1)=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC1CCN(C(=O)OCc2ccccc2)CC1)[C@@H]1CC[C@@H](NOCc2ccccc2)CN1
Reactant: O=C([O-])O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=P(O)(O)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CCN(C(=O)OCc2ccccc2)CC1)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
Benzyl 4-[({(2S,5R)-5-[(benzyloxy)amino]piperidin-2-yl}carbonyl)amino]piperidine-1-carboxylate in the form of a tosylate salt (8.1 kg, 12.68 mol) was slurried in dichloromethane (108 kg), after which 5 wt % NaHCO3 (42 kg, 25.36 mol) was added and the resulting biphasic mixture was stirred vigorously for 30 minutes. The phases were separated, and the organic phase was washed with water (40.5 kg). The organic phase was then distilled at atmospheric pressure to ˜20 L, followed by the addition of DCM (108 kg). DIPEA (5.25 kg, 40.58 mol) was then added and the batch cooled to 0-5° C. Triphosgene (3.01 kg, 10.14 mol) was added in four portions, while keeping the temperature at <10° C. After 30 minutes, a dilute phosphoric acid solution (4.97 kg 85 wt % phosphoric acid in 32 kg water) was added, and the batch aged at 20° C. overnight. The phases were separated and the organic phase was washed with 5 wt % NaHCO3 (26 kg) and water (25 kg). The organic phase was then distilled at atmospheric pressure to 30 L. Ethanol (77 kg) was then added, followed by the addition of seed (10 g). (Note: Crystallization will occur without the use of seed, but the use of seed is preferred as it typically provides a more consistent product and a better yield.) The slurry was distilled in vacuo to a volume of 33 L, then heptane (55 kg) was added dropwise. The slurry was then cooled to 0° C., filtered, washed with 3:1 heptane:ethanol (30 L), and dried on the filter under nitrogen stream to give the title product (5.90 kg, 94%). 1H NMR (CDCl3) 7.35 (10H, m), 6.57 (1H, d), 5.14 (2H, s), 5.07 (1H, d), 4.92 (1H, d), 4.13 (2H, m), 3.95 (1H, m), 3.89 (1H, d), 3.31 (1H, s), 2.99 (3H, m), 2.65 (1H, d), 2.38 (1H, m), 1.94 (4H, m), 1.62 (2H, m) and 1.34 (2H, m).
Reaction SMILES: [C:1]([C:3]1[CH:33]=[CH:32][C:6]2[N:7]([C:10]3[CH:11]=[C:12]4[C:16](=[CH:17][CH:18]=3)[NH:15][CH:14]=[C:13]4[C:19]3[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH:20]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1)#[N:2]>C(Cl)Cl>[C:1]([C:3]1[CH:33]=[CH:32][C:6]2[N:7]([C:10]3[CH:11]=[C:12]4[C:16](=[CH:17][CH:18]=3)[NH:15][CH:14]=[C:13]4[C:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH:20]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3ccc(-n4cnc5cc(C#N)ccc54)cc23)CC1
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)ncn2-c1ccc2[nH]cc(C3=CCNCC3)c2c1
Yield: 75 %

Procedure:
5-Cyano-1-[3-(N-t-butoxycarbonyl-1,2,5,6-tetrahydropyrid-4-yl)indol-5-yl]-1H-benzimidazole was used, and methylene chloride was used as solvent. Filtration afforded the title compound (75%) as a yellow solid: mp, decomposes at 240° C.; IR (KBr) 2228 cm-1 ; 13C NMR (CD3OD) δ 144.4, 137.9, 133.6, 131.1, 129.9, 126.0, 125.3, 125.2, 120.1, 118.4, 118.3, 117.5, 117.3, 116.1, 114.8, 113.2, 112.9, 110.4, 66.7, 42.0, 40.9. Anal. calcd. for C21H17N5.1.1 C4H8O2 [dioxane].1.1 HCl: C, 64.03; H, 5.69; N, 14.70. Found: C, 64.20; H, 5.54; N, 14.47.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:12]=2)[N:7]=[CH:6][N:5]=1.[CH2:21]([OH:23])[CH3:22]>>[CH2:21]([O:23][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:12]=2)[N:7]=[CH:6][N:5]=1)[CH3:22]
Reactant: CCO
Reactant: Fc1ccc(-c2ccc3ncnc(Cl)c3c2)cc1
Agent: [H-]
Agent: [Na+]
Product: CCOc1ncnc2ccc(-c3ccc(F)cc3)cc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88 %

Procedure:
To absolute ethanol (10 ml) was added NaH (80 mg of a 60% dispersion in mineral oil, 2.0 mmol). The mixture was stirred at room temperature for 10 minutes. Then, 4-chloro-6-(4-fluorophenyl)-quinazoline (52 mg, 0.2 mmol) was added to this solution. The resulting mixture was stirred at room temperature for another 30 minutes. The solvents were evaporated in vacuo and the crude residue was purified by silica gel flash chromatography, the mobile phase being a mixture of ethanol and dichloromethane in a volume ratio of 1:100), yielding the title compound as a white solid (46 mg, yield: 88%) was characterized by its mass spectrum as follows: MS (m/z): 269 ([M+H]+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:12]=[N:11][CH:10]=[C:9]3[S:13][C:14]([C:16](OC)=[O:17])=[CH:15][C:8]=23)=[CH:4][CH:3]=1.[Cl-].[Cl-].[Ca+2].[BH4-].[Na+].O>C(O)C>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:12]=[N:11][CH:10]=[C:9]3[S:13][C:14]([CH2:16][OH:17])=[CH:15][C:8]=23)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc2c(Oc3ccc(Cl)cc3)cncc2s1
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: OCc1cc2c(Oc3ccc(Cl)cc3)cncc2s1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of Example 61A (254 mg, 0.793 mmol) in absolute ethanol (4 mL) was treated with anhydrous CaCl2 (177 mg, 1.59 mmol), stirred for 1 hour, cooled to 0° C., treated with NaBH4 (123 mg, 3.25 mmol), stirred at 0° C. for 4 hours and at room temperature for 18 hours, treated with water and extracted with dichloromethane. The extract was washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified on silica gel with 30% ethyl acetate/hexane to provided the title compound.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][CH:8]=1)OC)#[N:2].[C:15]1([CH2:21][CH2:22][NH2:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(OCC)C>CO>[C:1]([NH:3][C:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][CH:8]=1)=[N:23][CH2:22][CH2:21][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)#[N:2]
Reactant: NCCc1ccccc1
Reactant: COC(=NC#N)c1ccc(C#N)cc1
Solvent: CCOCC
Solvent: CO
Product: N#CNC(=NCCc1ccccc1)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.5 %

Procedure:
Methyl N-cyano-4-cyanobenzenecarboximidate (0.37 g, 2.0 mmol) was suspended in methanol (4 ml), and 2-phenylethylamine (0.25 g, 2.1 mmol) was added. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, methanol (6 ml) and diethyl ether (10 ml) were added to the reaction solution, and deposited crystals were collected by filtration to give the title compound (0.51 g, 1.87 mmol, yield: 94%) as colorless crystals.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH3:9][N:10]1[N:14]=[N:13][C:12]([C:15]2[CH:20]=[CH:19][N:18]3[CH:21]=[CH:22][N:23]=[C:17]3[CH:16]=2)=[N:11]1>CN(C=O)C>[I:1][C:21]1[N:18]2[CH:19]=[CH:20][C:15]([C:12]3[N:13]=[N:14][N:10]([CH3:9])[N:11]=3)=[CH:16][C:17]2=[N:23][CH:22]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Cn1nnc(-c2ccn3ccnc3c2)n1
Solvent: CN(C)C=O
Product: Cn1nnc(-c2ccn3c(I)cnc3c2)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 92 %

Procedure:
N-Iodo succinimide (300 mg, 1.3 mmol) was added in one portion to a stirred suspension of 7-(2-methyl-2H-tetrazol-5-yl)-imidazo[1,2-a]pyridine (240 mg, 1.2 mmol) in dry DMF (2 ml) at RT under N2. After 5 hours, the reaction was quenched with saturated aqueous sodium thiosulphate/saturated aqueous NaHCO3 (1:1, 2 ml). Water (2 ml) was then added and the mixture was stirred at RT for 15 minutes. The solid was collected by filtration and dried in vacuo to give the title compound (360 mg) as a cream solid. 1H NMR (400 MHz, DMSO-d6): 8.51 (1H, dd), 8.20 (1H, dd), 7.86 (1H, s), 7.65 (1H, dd), 4.47 (3H, s).
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]2[NH:20][C:21](=[O:32])[C:22]3[N:27]([CH3:28])[N:26]=[C:25]([CH2:29][CH2:30][CH3:31])[C:23]=3[N:24]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:4]([O:6]C)=O.[NH3:33]>>[OH:1][CH2:2][C@H:3]([NH:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([CH2:18][C:19]2[NH:20][C:21](=[O:32])[C:22]3[N:27]([CH3:28])[N:26]=[C:25]([CH2:29][CH2:30][CH3:31])[C:23]=3[N:24]=2)=[CH:16][CH:17]=1)(=[O:10])=[O:11])[C:4]([NH2:33])=[O:6]
Reactant: CCCc1nn(C)c2c(=O)[nH]c(Cc3ccc(S(=O)(=O)N[C@@H](CO)C(=O)OC)cc3)nc12
Reactant: N
Product: CCCc1nn(C)c2c(=O)[nH]c(Cc3ccc(S(=O)(=O)N[C@@H](CO)C(N)=O)cc3)nc12
Temperature: 25 °C
Reaction time: 60 h

Procedure:
Methyl (2S)-3-hydroxy-2-({4-[(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)methyl]phenyl}sulfonamido)propanoate (280 mg, 0.0006 mol) was dissolved in 0.880 aqueous ammonia solution (10 ml), and stirred at room temperature for 60 hours. The reaction mixture was then concentrated under reduced pressure, suspended in water (10 ml), then re-concentrated under reduced pressure. Crystallisation from ethanol gave the title compound (192 mg), m.p.226-229° C.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([OH:19])=[C:7]([CH:16]=[CH:17][CH:18]=1)[C:8]([CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[O:9])(=[O:3])[CH3:2].[C:20](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[C:1]([O:4][C:5]1[C:6]([O:19][CH3:20])=[C:7]([CH:16]=[CH:17][CH:18]=1)[C:8]([CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[O:9])(=[O:3])[CH3:2]
Reactant: COC(=O)CCC(=O)c1cccc(OC(C)=O)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)CCC(=O)c1cccc(OC(C)=O)c1OC

Procedure:
A stirred mixture of methyl 3-(3-acetoxy-2-hydroxybenzoyl)-propionate, potassium carbonate, methyl iodide, and dry acetone, was heated under reflux for 24 hours. Evaporation of the filtered solution gave methyl 3-(3-acetoxy-2-methoxybenzoyl)-propionate.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[F:15][C:16]1[C:17]([OH:35])=[C:18]([CH:29]=[C:30]([N+:32]([O-])=O)[CH:31]=1)[CH2:19][N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24].[CH3:36][O:37][CH2:38][CH2:39][CH2:40]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl-].[NH4+]>C1COCC1.CO.[Zn]>[NH2:32][C:30]1[CH:31]=[C:16]([F:15])[C:17]([O:35][CH2:40][CH2:39][CH2:38][O:37][CH3:36])=[C:18]([CH:29]=1)[CH2:19][N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: CN(Cc1cc([N+](=O)[O-])cc(F)c1O)C(=O)OC(C)(C)C
Reactant: COCCCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: COCCCOc1c(F)cc(N)cc1CN(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 105.2 %

Procedure:
DIAD was added to a solution of 17D (751 mg, 2.5 mmol), 3-methoxypropan-1-ol (496 mg, 5.50 mmol), triphenylphosphine (1443 mg, 5.50 mmol) in THF (5 mL) at 0° C. The reaction mixture was stirred at 0° C. for 30 min, and rt for 16 h. The mixture was concentrated and purified by flash chromatography (0-50% EtOAc in hexanes) to give a light yellow solid. The obtained solid was dissolved in MeOH (20 mL) and THF (5 mL). Zinc (1635 mg, 25.00 mmol) and ammonium chloride (2.64 mL, 75 mmol) was added. The reaction mixture was stirred rt for 2 h. After aqueous work up and extraction, the crude product was purified by flash chromatography to give 28A (900 mg, 2.63 mmol, 105% yield). MS (ESI) m/z: 343.1 (M+H)+.