Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=NN(C)C)[C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:20]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[CH:4][CH:3]=1
Reactant: CN(C)N=C(C(=O)C(F)(F)F)c1ccc(Br)cc1
Reactant: O=S(=O)(O)O
Product: O=C(C(=O)C(F)(F)F)c1ccc(Br)cc1
Temperature: 45 °C
Yield: 92 %

Procedure:
3-(4-bromophenyl)-3-(2,2-dimethylhydrazono)-1,1,1-trifluoropropan-2-one (2.0 g, 6.2 mmol) was suspended in 5N sulfuric acid (60 mL) and heated at 45° C. for 6 h. The temperature was raised to 85° C. for 2 h, and upon cooling a precipitate formed. This material which was isolated by filtration to give 1-(4-bromophenyl)-3,3,3-trifluoropropane-1,2-dione 1.6 g (92%) as a yellow solid. The dione (1.6 g, 5.7 mmol) was taken up in methanol (30 mL), N-(tert-butoxycarbonyl)-L-prolinal (1 g, 5.0 mmol) was added, followed by addition of 28% ammonium hydroxide solution (10 mL). The reaction was stirred at room temperature for 18 h, poured onto dichloromethane (200 mL), washed with water and dried with MgSO4. Filtration, concentration and application to a 40 M Biotage cartridge, gradient elution with 5%-30% ethyl acetate/Hexanes, gave J32.a 1.3 g (50%). 1H NMR (300 MHz, DMSO-d6) δ 12.88 (br.s, 1H), 7.72 (d, J=8.4 Hz, 2H), 7.39 (d, J=8.0 Hz, 2H), 4.84-4.70 (m, 1H), 3.57-3.49 (m, 1H), 3.39-3.29 (m, 1H), 2.31-2.20 (m, 1H), 1.98-1.78 (m, 3H), 1.39/1.13 (m, 9H). LRMS: Anal. Calcd. for C19H20BrF3N3O2 458.07; found: 458.06 and 460.06 (M−H)−. HRMS: Anal. Calcd. for C19H22BrF3N3O2 460.0847; found: 460.0866 and 462.0840 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.[C:9]1([C:15]#[CH:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:9]1([C:15]#[C:16][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1ccc(I)cn1
Reactant: C#Cc1ccccc1
Product: Nc1ccc(C#Cc2ccccc2)cn1

Procedure:
The title compound, light yellow solid, MS: m/e=195.2 (M+H+), can be prepared in accordance with the general method of example 1 from 2-amino-5-iodopyridine and phenylacetylene.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1.[C:17]([C:21]1[O:25][N:24]=[C:23]([N:26]=[C:27]=[O:28])[CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:27]([NH:26][C:23]2[CH:22]=[C:21]([C:17]([CH3:20])([CH3:19])[CH3:18])[O:25][N:24]=2)=[O:28])=[CH:8][CH:7]=1
Reactant: CC(C)(C)c1cc(N=C=O)no1
Reactant: Nc1ccc(OCc2ccccc2F)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(OCc3ccccc3F)cc2)no1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
4-(2-Fluoro-benzyloxy)-phenylamine (0.12 g, 1 eq) was mixed with 5-tert-Butyl-3-isocyanato-isoxazole (0.9 g 1 eq) and dissolved in dry toluene. The reaction stirred at 80° C. overnight. The solvent was removed and purified by HPLC. Yield: 85 mg (31%), LC/MS [MH+] 384.
Reaction SMILES: C(N1[C:12](=[O:13])[C:11](=C2N(C)C3C=C(O)C=CC=3S2)SC1=NC1C=C(C=CC=1NCC)C#N)C1C=CC=CC=1.[CH2:37]([N:44]1[C:48](=[O:49])[C:47](=[C:50]2[N:54]([CH3:55])[C:53]3[CH:56]=[CH:57][C:58]([OH:60])=[CH:59][C:52]=3[S:51]2)[S:46][C:45]1=[N:61][C:62]1[CH:63]=[C:64]([CH:67]=[CH:68][C:69]=1[NH:70][CH2:71][CH3:72])[C:65]#[N:66])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[CH2:37]([N:44]1[C:48](=[O:49])[C:47](=[C:50]2[N:54]([CH3:55])[C:53]3[CH:56]=[CH:57][C:58]([O:60][CH2:11][CH2:12][OH:13])=[CH:59][C:52]=3[S:51]2)[S:46][C:45]1=[N:61][C:62]1[CH:63]=[C:64]([CH:67]=[CH:68][C:69]=1[NH:70][CH2:71][CH3:72])[C:65]#[N:66])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CCNc1ccc(C#N)cc1N=C1SC(=C2Sc3cc(O)ccc3N2C)C(=O)N1Cc1ccccc1
Reactant: CCNc1ccc(C#N)cc1N=C1SC(=C2Sc3ccc(O)cc3N2C)C(=O)N1Cc1ccccc1
Product: CCNc1ccc(C#N)cc1N=C1SC(=C2Sc3cc(OCCO)ccc3N2C)C(=O)N1Cc1ccccc1

Procedure:
The title compound was prepared in a manner similar to that described in Example 59 by replacing the product of Example 57 with the product of Example 249. MS(ESI): 558 (MH+).
Reaction SMILES: [C:1]([O:9][CH2:10][C@:11]1([O:44][CH2:43][C@@H:33]([O:34][C:35](=[O:42])[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C@@H:23]([O:24][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:13]1[O:14][C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[OH:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:45]C(C)=O.C(=O)([O-])[O-].[K+].[K+]>>[C:1]([O:9][CH2:10][C@:11]1([O:44][CH2:43][C@@H:33]([O:34][C:35](=[O:42])[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C@@H:23]([O:24][C:25](=[O:32])[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@@H:13]1[O:14][C:15](=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[O:12][CH3:45])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)=O
Reactant: O=C(OC[C@@]1(O)OC[C@@H](OC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CO[C@]1(COC(=O)c2ccccc2)OC[C@@H](OC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Temperature: 50 °C
Reaction time: 18 h
Yield: 97.5 %

Procedure:
To a solution of 1,3,4,5-tetra-O-benzoyl-β-D-fructopyranose (10.00 g, 16.8 mmol) in acetone (40 mL) dimethyl sulfate (2.4 ml, 25.16 mmoles, 1.5 eq.) was added followed by potassium carbonate (3.48 g, 25.16 mmoles) and the reaction mixture was stirred at 50° C. under nitrogen for 18 hours. Solvents were removed under vacuo and the resulting residue was dissolved in ethyl acetate (150 ml), washed with 5% citric acid, water, brine, dried over sodium sulfate, filtered and concentrated to an oily solid. Purification on a silica gel column (hexane:ethyl acetate, 4:1) afforded 10.0 g (98%) of title compound as white foam.
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][CH:20]([NH:23][C:24](=[O:27])[CH2:25]Br)[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH:28]1([OH:33])[CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH:1]1[C:14]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][CH:20]([NH:23][C:24](=[O:27])[CH2:25][O:33][CH:28]5[CH2:32][CH2:31][CH2:30][CH2:29]5)[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: OC1CCCC1
Reactant: O=C(CBr)NC1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Product: O=C(COC1CCCC1)NC1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1

Procedure:
Using a procedure similar to that described in Example 21 except starting with N-(1-[9,10-dihydro-9,10-methanoanthracen-9-ylmethyl]-4-piperidyl)-2-bromoacetamide (described in Example 38a) and cyclopentanol, the title compound was obtained as a white solid (63%) mp 127.0°-8.0° C.; MS(CI): 431 (M+H); NMR (300 MHz,DMSO-d6): 1.48 (br m, 4H), 1.62(br m, 8H), 2.8(br m, 2H), 2.45(s, 2H), 2.94(br m, 2H), 3.34(s, submerged, 2H), 3.60(br m, 1H), 3,74(2, 2H), 3.89(sextet, 1H, J=3.9 Hz), 4.30(s, 1H), 6.91(br m, 4H), 7.18(d, 2H, J=6.2 Hz), 7.26(d, 2H, J=6.2 Hz), 7.33(d, 1H, J=8.3 Hz).
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[H-].[Na+].F[C:9]1[CH:17]=[C:16]([CH3:18])[C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=1.Cl>C1COCC1>[CH:1]1([CH2:4][O:5][C:9]2[CH:17]=[C:16]([CH3:18])[C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=2)[CH2:3][CH2:2]1
Reactant: OCC1CC1
Reactant: Cc1cc(F)ncc1C(=O)O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(OCC2CC2)ncc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Cyclopropylmethanol (3.92 mL) was added to a suspension of sodium hydride (60% oil, 1.93 g) in THF (30 mL) by small portions at 0° C., and the obtained mixture was stirred at room temperature for 1 hr. To the reaction mixture was added 6-fluoro-4-methylnicotinic acid, and the mixture was stirred at room temperature for 20 hr. The reaction mixture was neutralized with 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained solid was recrystallized (hexane/ethyl acetate) to give the title compound (1.14 g).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C:14](=[O:15])[O:13][CH2:12][CH2:11][N:10]2[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:5][CH:4]=1.COC(=O)C(N)C1C=CC(F)=CC=1>>[CH2:16]([N:10]1[CH:11]=[CH:12][O:13][C:14](=[O:15])[C@@H:9]1[C:6]1[CH:5]=[CH:4][C:3]([F:2])=[CH:8][CH:7]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C1OCCN(Cc2ccccc2)[C@H]1c1ccc(F)cc1
Agent: COC(=O)C(N)c1ccc(F)cc1
Agent: Cl
Product: O=C1OC=CN(Cc2ccccc2)[C@H]1c1ccc(F)cc1
Temperature: 65 °C
Reaction time: 72 h

Procedure:
To a solution of 3-(4-fluorophenyl)-4-phenylmethyl-2-morpholinone (i.e. N-benzyl-4-fluorophenyl-l,4-oxazin-2-one) (10g) in isopropyl acetate (110 ml) at room temperature was added a solution of (-)-3-bromocamphor-8-sulphonic acid ((-)-3BCS) (12g) in acetonitrile (24 ml). Crystallisation began after 2-3 min. The slurry was stirred for 1 h at room temperature. Trifluoroacetic acid (7 ml) was added and the mixture stirred at 65° C. for 3 days. The mixture was cooled to 0°-5° C., aged for 1 h. and the solid collected, washed with isopropyl acetate and dried in vacuo at 40° C., to give the N-benzyl-3-(S)-(4-fluorophenyl)-1,4-oxazin-2-one (-)-3BCS salt: yield 17.24 g, ee 98.6% (S) isomer. The chiral composition of the remaining liquors was determined as 79% (R), 21% (S). The liquors were stirred at 65° C. for 3 days, then cooled to 0°-5° C. The solid was collected, washed with isopropyl acetate and dried in vacuo to give a further batch of the N-benzyl-3-(S)-(4-fluorophenyl)-1,4-oxazin-2-one (-)-3BCS salt: yield 0.84 g, ee 98.6% (S) isomer. The chiral composition of the remaining liquors was determined as 64% (R), 36% (S). The liquors were stripped in vacuo and the residue was dissolved in isopropyl acetate (20 ml) containing trifluoroacetic acid (1 ml) and stirred at 65° C. for 20 h. The mixture was cooled to 0°-5° C. for 1 h and the solid collected, washed with isopropyl acetate and dried in vacuo to give a further batch of the N-benzyl-3-(S)-(4-fluorophenyl)-1,4-oxazin-2-one (-)-3BCS salt: yield 2.2 g, ee 99.2% (S) isomer. Total weight of (-)-3BCS salt: 20.28 g, 97% yield. A sample (0.5 g) of the (-)-3BCS salt was retained and the remainder converted back to free base. The salt was partitioned between isopropyl acetate (50 ml) and water (100 ml) containing 0.88 ammonia soln. (3 ml). The layers were separated and the aqueous phase extracted with isopropyl acetate (25 ml). The combined organic phases were washed with water (25 ml). The organic phase was concentrated to residue and flushed with isopropyl acetate to give the 3-(S)-(4-fluorophenyl)-4-phenylmethyl-2-morpholinone (i.e. N-benzyl-3-(S)-(4-fluorophenyl)-l,4-oxazin-2-one) as the free base: yield 8.7 g, 93% recovery, ee 98.4% (S) isomer.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]2[OH:15])=[CH:5][CH:4]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].O.S(=O)(=O)(O)O>C(OCC)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=[O:15])=[CH:7][CH:8]=1
Reactant: COc1ccc(C2CCCCC2O)cc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: COc1ccc(C2CCCCC2=O)cc1

Procedure:
146 g (0.71 mole) of 2-(4-methoxyphenyl)-cyclohexanol from the 1st stage were dissolved in 600 ml of diethyl ether. A solution consisting of 69.9 g (0.23 mole) of sodium dichromate (as dihydrate), 355 ml of water and 53.2 ml of conc. sulfuric acid was added dropwise while stirring vigorously and cooling in an ice bath so that the internal temperature did not exceed 10° C. After completion of the addition the reaction mixture was stirred overnight at room temperature. After separating the phases the aqueous phase was then extracted twice with 200 ml of diethyl ether. The combined organic phases were washed twice with 200 ml of saturated sodium hydrogen carbonate solution and dried over sodium sulfate. After removing the solvent by distillation the remaining oil was distilled and the fraction passing over at 128–134° C./0.05 bar was collected. After crystallisation from n-hexane 130 g of colourless crystals with a melting point of 90° C. were obtained (90% of theory).
Reaction SMILES: C1([NH:7][C:8]([C:10]2[C:11](=[O:31])[N:12]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[C:13]3[C:18]([C:19]=2O)=[CH:17][C:16]([Cl:21])=[CH:15][N:14]=3)=O)CCCCC1.C(N(CC)CC)C.O=P(Cl)(Cl)[Cl:41]>>[Cl:41][C:19]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([Cl:21])[CH:17]=2)[N:12]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:11](=[O:31])[C:10]=1[C:8]#[N:7]
Reactant: COc1ccc(Cn2c(=O)c(C(=O)NC3CCCCC3)c(O)c3cc(Cl)cnc32)cc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(Cn2c(=O)c(C#N)c(Cl)c3cc(Cl)cnc32)cc1
Yield: 95 %

Procedure:
A solution of 6-chloro-4-hydroxy-1-(4-methoxy-benzyl)-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid cyclohexylamide (93) (10.6 g, 24 mmol) and triethylamine (8.33 mL, 60 mmol) was heated in neat POCl3 overnight at 90° C. The solution was cooled and the excess POCl3 was distilled under vacuum. The residue was suspended in saturated NaHCO3 solution, sonicated briefly and filtered. The solids were dissolved in dichloromethane, washed subsequently by saturated NaHCO3 solution, water and brine. The organic phase was dried over MgSO4 and evaporated to yield 8.2 g (95%) of 4,6-dichloro-1-(4-methoxybenzyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (95) as white solids. MP 208° C. 1H-NMR (DMSO-d6): δ 3.69 (s, 3H), 5.50 (s, 2H), 6.82 (m, 2H), 7.87 (m, 2H), 8.59 (d, J=2.8 Hz, 1H), 8.94 (d, J=2.8 Hz, 1H); EIMS m/z 362 (M+2).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[H-].[Na+].[CH3:14][Si:15]([CH3:22])([CH3:21])[CH2:16][CH2:17][O:18][CH2:19]Cl.O>CN(C=O)C>[Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([CH2:19][O:18][CH2:17][CH2:16][Si:15]([CH3:22])([CH3:21])[CH3:14])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Clc1ncnc2[nH]cc(I)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)ncnc21
Reaction time: 2 h

Procedure:
A solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (20.0 g) in DMF (50 ml) was slowly added to a solution of sodium hydride (3.4 g) in DMF (190 ml) under ice cooling. Thereafter, 2-(trimethylsilyl)ethoxymethyl chloride (13.3 ml) was added thereto, and stirred at the same temperature for 2 hours. 2-(Trimethylsilyl)ethoxymethyl chloride (1.3 ml) was additionally added to the reaction mixture, and stirred at room temperature for 1 hour. The reaction mixture was poured into water (600 ml), and stirred at room temperature for 15 minutes. The resulting precipitate was collected by filtration and washed with water and diisopropyl ether, followed by dissolution with ethyl acetate again. Insoluble matter was then filtered off by filtration. The solvent of the filtrate was distilled off under reduced pressure. Heptane was added to the resulting residue to collect the precipitate by filtration. The precipitate was washed with heptane, and dried under reduced pressure to obtain the title compound (21.2 g) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].C([O-])([O-])=O.[K+].[K+].Br[CH:18]([CH2:24]Br)[C:19]([O:21][CH2:22]C)=[O:20]>CC(C)=O.CO>[C:5]([C:4]1[CH:7]=[CH:8][C:9]2[O:10][CH:18]([C:19]([O:21][CH3:22])=[O:20])[CH2:24][NH:1][C:2]=2[CH:3]=1)#[N:6]
Reactant: CCOC(=O)C(Br)CBr
Reactant: N#Cc1ccc(O)c(N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(C)=O
Product: COC(=O)C1CNc2cc(C#N)ccc2O1
Temperature: 25 °C
Yield: 50.7 %

Procedure:
3-Amino-4-hydroxy-benzonitrile (180 mg, 1.34 mmol) was dissolved in acetone (1.4 mL). To the solution was added K2CO3 (555 mg, 4.02 mmol) and ethyl 2, 3-dibromopropanoate (380 mg, 1.46 mmol). The mixture was heated to reflux for 16 h. After cooling to room temperature the reaction mixture was filtered and concentrated in vacuo to give an oil. The oil was dissolved in methanol and was purified by silica gel chromatography (0-10% dichloromethane/hexanes) to afford methyl 6-cyano-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylate (148 mg, 0.68 mmol). The methyl ester was isolated as methanol was used for loading the compound on silica resulting in transesterification. 1H NMR (400.0 MHz, DMSO-d6) δ 6.98 (dd, J=2.0, 8.2 Hz, 1H), 6.93-6.90 (m, 2H), 6.34 (s, 1H), 5.13 (t, J=3.3 Hz, 1H), 3.66 (s, 3H), 3.50-3.41 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17]3[C:13]([N:14]=[CH:15][N:16]=3)=[C:12](SC)[N:11]3[CH2:20][CH2:21][N:22]=[C:10]23)=[CH:4][CH:3]=1.[NH3:23]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17]3[NH:16][CH:15]=[N:14][C:13]=3[C:12](=[NH:23])[N:11]3[CH2:20][CH2:21][N:22]=[C:10]23)=[CH:4][CH:3]=1
Reactant: CSC1=C2N=CN=C2N(Cc2ccc(Cl)cc2)C2=NCCN21
Reactant: N
Solvent: CCO
Product: N=C1c2nc[nH]c2N(Cc2ccc(Cl)cc2)C2=NCCN12
Temperature: 25 °C

Procedure:
The product of Procedure 76, 2.26 g. is suspended in a solution of about 6 g. of ammonia in 100 ml. of ethanol. Further anhydrous ammonia was added to yield a substantially saturated solution. The mixture was then placed in a pressure apparatus and heated at 100° overnight with agitation. The container was cooled to room temperature, opened, and the supernatent liquid decanted from the yellow solid. The precipitated solid and the residue obtained on evaporation of the supernatant liquid proved to be identical by infrared and thin-layer chromatography. They were combined and recrystallized from DMF, recovered as the hydrate containing 1/4 mole water of hydration, m.p. 296°-299°.
Reaction SMILES: F[B-](F)(F)F.[O:6]=[N+:7]=[O:8].[Br:9][C:10]1[N:15]2[N:16]=[C:17]([CH2:19][CH3:20])[CH:18]=[C:14]2[C:13]([O:21][CH3:22])=[CH:12][CH:11]=1.O>C(#N)C>[Br:9][C:10]1[N:15]2[N:16]=[C:17]([CH2:19][CH3:20])[C:18]([N+:7]([O-:8])=[O:6])=[C:14]2[C:13]([O:21][CH3:22])=[CH:12][CH:11]=1
Reactant: O=[N+]=O
Reactant: CCc1cc2c(OC)ccc(Br)n2n1
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CC#N
Product: CCc1nn2c(Br)ccc(OC)c2c1[N+](=O)[O-]
Reaction time: 0.33 h
Yield: 47.9 %

Procedure:
After adding nitronium tetrafluoroborate (176 mg) to a solution of 7-bromo-2-ethyl-4-methoxypyrazolo[1,5-a]pyridine (282 mg) in acetonitrile (20 mL) at 0° C., the mixture was stirred for 20 minutes. Upon completion of the reaction, water was added, extraction was performed with ethyl acetate, the extract was washed with saturated aqueous sodium hydrogencarbonate and brine and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (20 g), and the title compound (159 mg) was obtained from the n-hexane:ethyl acetate (3:1) fraction as yellow crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH3:13])[N:9]=[C:10]([CH3:12])[CH2:11][C:3]=12.[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O>[CH3:13][N:8]1[C:4]2=[N:5][CH:6]=[N:7][C:2]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:3]2[CH2:11][C:10]([CH3:12])=[N:9]1
Reactant: CC1=NN(C)c2ncnc(Cl)c2C1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC1=NN(C)c2ncnc(-c3ccccc3)c2C1
Temperature: 100 °C
Yield: 37.5 %

Procedure:
The 5-chloro-1,3-dimethyl-1,4-dihydropyridazino[3,4-d]pyrimidine (1.1 g), phenyl boronic acid (682 mg) and potassium carbonate (771 mg) were dissolved in toluene (15 mL) and water (1.5 mL). After the reaction mixture was degassed with nitrogen for 30 minute, Pd(PPh3)4 (323 mg) was added. The reaction mixture was again degassed with nitrogen for 20 minutes and then heated to 100° C. for 3 hours in a sealed tube. The reaction mixture was filtered through a celite pad and washed with ethyl acetate (2×20 mL). The combined filtrate was washed with water (10 mL) and brine (10 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography using MeOH/CHCl3 (0.8:9.2) as eluent to afford 1,3-dimethyl-5-phenyl-1,4-dihydropyridazino[3,4-d]pyrimidine (500 mg) as colorless viscous liquid. 1H NMR (DMSO-d6): δ 1.89 (s, 3H), 3.37 (s, 3H), 3.52 (s, 2H), 7.47-7.57 (m, 5H), 8.60 (s, 1H).
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([O:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][C:22]([OH:24])=O)=[CH:15][CH:14]=1)=[O:11])([CH3:8])([CH3:7])[CH3:6].C[N:26](C=O)C>>[C:5]([O:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][C:22]([NH2:26])=[O:24])=[CH:15][CH:14]=1)=[O:11])([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)OC(=O)Nc1ccc(CCCC(=O)O)cc1
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CC(C)(C)OC(=O)Nc1ccc(CCCC(N)=O)cc1
Temperature: -5 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
Thionyl chloride (0.22 mL, 3.01 mmol) was added slowly to a solution of 4-[4-(t-Butoxycarbonylamino)phenyl]butanoic acid (100) (0.70 g, 2.51 mmol) in DMF (5 mL) cooled at −5° C. The mixture was stirred for an additional 1 h at −5° C. Excess ammonia (freshly distilled from its aqueous solution) was added to the reaction medium. The second mixture was stirred for an additional 1 h. Ethyl acetate (50 mL) was added to the mixture, which was washed with brine (2×50 mL). The organic layer was dried over MgSO4, concentrated and the residue was purified by silica gel column chromatography (dichloromethane:acetone, 9:1) to give 4-[4-(t-Butoxycarbonylamino)phenyl]butanamide (99) (0.57 g, 82%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[NH2:12].[Br:13][CH2:14][CH2:15][CH2:16][C:17](Cl)=[O:18]>ClCCCl.ClCCl>[Br:13][CH2:14][CH2:15][CH2:16][C:17]([NH:12][C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[Cl:1])=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:18]
Reactant: O=C(Cl)CCCBr
Reactant: Nc1cnc2ccccc2c1Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(CCCBr)Nc1cnc2ccccc2c1Cl
Temperature: 25 °C
Yield: 53.7 %

Procedure:
A solution of 4-chloroquinolin-3-amine (3.70 g, 20.74 mmol) and 4-bromobutyryl chloride (11.54 g, 62.22 mmol) dissolved in 100 mL of 1,2-dichloroethane was heated to reflux. After 17 hours the reaction was cooled to room temperature, diluted with dichloromethane, washed with saturated aqueous K2CO3, H2O and brine, dried over Na2SO4, and concentrated under reduced pressure to give a brown solid. The solid was triturated with a mixture of hexane and ether, filtered and dried to give 4-bromo-N-(4-chloroquinolin-3-yl)butanamide (3.65 g) as a brown solid.