Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([CH:12]([NH2:14])[CH3:13])[C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[N:7]2.[NH2:22][C:23]1[N:31]=[C:30]2[C:26]([NH:27][CH:28]=[N:29]2)=[C:25](Br)[N:24]=1.C(O)CCC.C(N(CC)C(C)C)(C)C>>[F:1][C:2]1[CH:11]=[C:10]([CH:12]([NH:14][C:25]2[N:24]=[C:23]([NH2:22])[N:31]=[C:30]3[C:26]=2[N:27]=[CH:28][NH:29]3)[CH3:13])[C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[N:7]2
Reactant: CC(N)c1cc(F)c2ccnnc2c1-c1cccc(F)c1
Reactant: Nc1nc(Br)c2[nH]cnc2n1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1nc(N)nc2[nH]cnc12)c1cc(F)c2ccnnc2c1-c1cccc(F)c1
Temperature: 120 °C
Reaction time: 18 h

Procedure:
A solution of 1-[5-fluoro-8-(3-fluorophenyl)cinnolin-7-yl]ethanamine (73 mg, 0.26 mmol) [from peak 1 of Examples 20 and 21, step B] and 2-amino-6-bromopurine (82 mg, 0.38 mmol) in 1-butanol (0.51 mL, 5.6 mmol) was treated with N,N-diisopropylethylamine (67 μL, 0.38 mmol), degassed with nitrogen for 5 minutes and stirred at 120° C. for 18 hours. The reaction mixture was diluted with methanol (10 mL), stirred and filtered. The filtrate was purified first by RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.05% TFA, at flow rate of 60 mL/minute) and then by RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/minute) to give the desired product in 26%. LCMS for C21H17F2N8 (M+H)+: m/z=419.2; Found: 418.9. 1H NMR (300 MHz, DMSO-d6): δ 12.1 (br s, 1H), 9.44 (d, J=5.9 Hz, 1H), 8.25-8.22 (m, 1H), 8.13-8.01 (m, 1H), 7.94-7.83 (m, 1H), 7.72-7.53 (m, 3H), 7.40-7.29 (m, 1H), 7.28-7.22 (m, 1H), 5.45-5.21 (m, 3H), 1.42-1.38 (m, 3H).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([OH:10])=O)=[C:6]([F:11])[C:5]([F:12])=[C:4]([F:13])[C:3]=1[F:14].S(Cl)(Cl)=O.[Mg].C(OCC)(=O)[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOCC.C1C=CC=CC=1.O.C(Cl)(Cl)(Cl)Cl.C(O)C>[F:11][C:6]1[C:5]([F:12])=[C:4]([F:13])[C:3]([F:14])=[C:2]([F:1])[C:7]=1[C:8]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:10]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C(O)c1c(F)c(F)c(F)c(F)c1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Mg]
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)CC(=O)c1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.6 %

Procedure:
A mixture consisting of 100 g (0.47 mol) of pentafluorobenzoic acid, 900 ml of benzene and 350 ml (4.80 mol) of thionyl chloride was heated under reflux for 40 hours. After completion of the reaction, the reaction solution was concentrated under a reduced pressure. After repetition of evaporation with benzene (900 ml×2), the resulting residue was dissolved in 500 ml of ether. A mixture consisting of 11.5 g (0.47 mol) of magnesium, 450 ml of ethanol and 20 ml of carbon tetrachloride was stirred at room temperature for 1 hour, and 71.6 ml (0.47 mol) of diethyl malonate dissolved in 900 ml of ether was added dropwise thereto. After 17 hours of stirring at the same temperature, the reaction solution was evaporated to dryness under a reduced pressure, and the residue was dissolved in 1,500 ml of ether. To this was added dropwise the above acid chloride at room temperature, followed by 63 hours of stirring at the same temperature. After completion of the reaction, the reaction solution was washed with 10% citric acid and water in that order, and then dried over anhydrous sodium sulfate, subsequently evaporating the solvent. The residue was mixed with 300 ml of water and 1.00 g (5.81 mol) of p-toluenesulfonic acid, heated under reflux for 6 hours, mixed with 2,500 ml of benzene and then washed with water. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The resulting residue was purified by distillation under a reduced pressure (10 mmHg, 118°-120° C.) to yield 89.7 g (67%) of the title compound.
Reaction SMILES: C([O:3][C:4](=O)[NH:5][N:6]=[CH:7][C:8]1[N:9]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[NH:11][CH:12]=1)C.C1(OC2C=CC=CC=2)C=CC=CC=1>>[C:13]1([C:10]2[N:9]3[C:4](=[O:3])[NH:5][N:6]=[CH:7][C:8]3=[CH:12][N:11]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)NN=Cc1c[nH]c(-c2ccccc2)n1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=c1[nH]ncc2cnc(-c3ccccc3)n12

Procedure:
A 7.76 gm. portion of 3-(2-phenyl-4-imidazolylmethylene)carbazic acid ethyl ester in 50 ml. of diphenyl ether is reacted as described in Example 70 giving the desired product m.p. 245°-248° C.
Reaction SMILES: [CH3:1]/[C:2](=[CH:6]\[CH3:7])/[C:3](O)=[O:4].CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[CH3:24][O:25][C:26](=[O:29])[CH2:27][NH2:28]>C(Cl)Cl>[CH3:24][O:25][C:26](=[O:29])[CH2:27][NH:28][C:3](=[O:4])/[C:2](/[CH3:1])=[CH:6]/[CH3:7]
Reactant: COC(=O)CN
Reactant: C/C=C(\C)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C/C=C(\C)C(=O)NCC(=O)OC
Temperature: -15 °C
Reaction time: 0.25 h
Yield: 42.6 %

Procedure:
(E)-2-methyl-2-butenoic acid (300 mg, 3.00 mmol) was dissolved in CH2Cl2 (6 mL) and N-methyl morpholine (396 μL, 3.60 mmol) was added to the solution. The reaction mixture was cooled to −15° C. Isobutyl chloroformate (389 μL, 3.00 mmol) was added and stirred at −15° C. for 15 min. Glycine methyl ester hydrochloride (377 mg, 3.00 mmol), CH2Cl2 (4 mL), and N-methyl morpholine (330 μL, 3.00 mmol) were added to the solution. After stirring at −15° C. for 15 min, the reaction mixture was warmed to 24° C. and stirred for 16 h. CH2Cl2 (60 mL) was added to the reaction mixture and the organic layer was washed with 1 N aq HCl (3×20 mL) and 5% aq NaHCO3 (3×20 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was evaporated. The crude product was purified by silica gel column chromatography using 30% and 40% EtOAc/CH2Cl2 to give 11 (219 mg, 43% yield). 1H-NMR (400 MHz, CDCl3) δ 6.47 (m, 1H), 6.37 (bs, 1H), 4.05 (d, J=4.8 Hz, 2H), 3.73 (s, 3H), 1.83 (m, 3H), 1.73 (m, 3H); 13C-NMR (100 MHz, CDCl3) δ 170.8, 169.4, 131.8, 131.2, 52.4, 41.6, 14.0, 12.3; HRMS (ESI) calcd for C8H14NO3 [M+H]+172.0974, found 172.0974.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:10][C:11]([C:13]1[C:14](=[O:31])[N:15]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:16]2[C:21]([C:22]=1[OH:23])=[CH:20][CH:19]=[CH:18][N:17]=2)=O)C>C1(C)C(C)=CC=CC=1>[CH:1]1([NH:7][C:11]([C:13]2[C:14](=[O:31])[N:15]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:16]3[C:21]([C:22]=2[OH:23])=[CH:20][CH:19]=[CH:18][N:17]=3)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: CCOC(=O)c1c(O)c2cccnc2n(Cc2ccccc2)c1=O
Solvent: Cc1ccccc1C
Product: O=C(NC1CCCCC1)c1c(O)c2cccnc2n(Cc2ccccc2)c1=O
Temperature: 140 °C
Yield: 82 %

Procedure:
Cyclohexylamine (1.18 mL, 10.35 mmol) was added to a stirred solution of 1-benzyl-4-hydroxy-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester (3) (1.68 g, 5.17 mmol) in xylene and heated at 140° C. for 3 h. The solution was cooled and the solvent was evaporated under vacuum. The residue was suspended in water and extracted by dichloromethane. The combined organic phase washed by water and brine, then dried over Na2SO4 and evaporated to yield 1.6 g (82%) of 1-benzyl-4-hydroxy-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid cyclohexylamide (7) as white solids. MP: 143° C.; 1H-NMR (DMSO-d6): δ 1.22-1.87 (m, 10H), 3.87 (m, 1H), 5.62 (s, 2H), 7.20-7.32 (m, 5H), 7.43 (dd, J=4.6, 8.0 Hz, 1H), 8.48 (dd, J=1.5, 7.5 Hz, 1H), 8.77 (dd, J=1.5, 7.5 Hz, 1H), 10.20 (s, 1H); EIMS: 378 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:9](Cl)[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[CH2:29][NH:30][NH2:31].C([O-])([O-])=O.[Cs+].[Cs+]>>[C:1]([O:5][C:6]([C:7]1[CH:12]=[CH:11][C:10]2[C:9]([CH:8]=1)=[N:31][N:30]([CH2:29][C:25]1[S:24][CH:28]=[CH:27][CH:26]=1)[C:13]=2[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:22])([CH3:4])([CH3:3])[CH3:2]
Reactant: NNCc1cccs1
Reactant: CC(C)(C)OC(=O)c1ccc(C#Cc2ccccc2)c(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(C)(C)OC(=O)c1ccc2c(Cc3ccccc3)n(Cc3cccs3)nc2c1
Yield: 36 %

Procedure:
The reaction was performed according to example 1 using 156.4 mg 3-chloro-4-phenylethynyl-benzoic acid tert-butyl ester, 164.7 mg thiophen-2-ylmethyl-hydrazine hydrochloride (2.0 equiv.) and 488.7 mg Cs2CO3 (3.0 equiv.) with a reaction time of 5 hours at 110° C. This afforded 72.8 mg (36%) of the title compound. 1H-NMR (DMSO-d6) δ 1.56 (s, 9H), 4.58 (s, 2H), 5.86 (s, 2H), 6.93 (dd, 1H, J=5.1, 3.5 Hz), 7.04 (dd, 1H, J=3.5, 1.0 Hz), 7.16 (d, 2H, J=7.4 Hz), 7.20-7.29 (m, 3H), 7.42 (dd, 1H, J=8.8, 1.2 Hz), 7.44 (dd, 1H, J=5.0, 1.2 Hz), 7.55 (dd, 1H, J=8.7, 0.7 Hz), 8.20 (s, 1H).
Reaction SMILES: [NH2:1][CH:2]([CH3:11])[C:3]([CH3:10])([CH3:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[CH:13]=[CH2:14]>>[CH2:17]([O:16][C:12]([CH2:13][CH2:14][NH:1][CH:2]([CH3:11])[C:3]([CH3:9])([CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:15])[CH3:18]
Reactant: C=CC(=O)OCC
Reactant: CCOC(=O)C(C)(C)C(C)N
Product: CCOC(=O)CCNC(C)C(C)(C)C(=O)OCC

Procedure:
In the second stage of the reaction, the ethyl 3-amino-2,2-dimethylbutanoate derivative 4 is reacted with ethyl acrylate to obtain the corresponding ethyl 3-(2-ethoxycarbonylethyl)amino-2,2-dimethylbutanoate derivative 5--which in the case of the preparation of BIII 277 might be, for example: ethyl 3-(2-ethoxycarbonylethyl)amino-4-(3-methoxyphenyl)-2,2-dimethylbutanoate (R2 =CH3O): ##STR4##
Reaction SMILES: [CH3:1][N:2]([CH3:10])[CH:3]=[CH:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].C(N(CC)CC)C.[F:18][C:19]1[C:27]([CH3:28])=[C:26]([F:29])[C:25]([F:30])=[C:24]([N+:31]([O-:33])=[O:32])[C:20]=1[C:21](Cl)=[O:22]>C(OCC)(=O)C>[CH3:1][N:2]([CH3:10])[CH:3]=[C:4]([C:21](=[O:22])[C:20]1[C:24]([N+:31]([O-:33])=[O:32])=[C:25]([F:30])[C:26]([F:29])=[C:27]([CH3:28])[C:19]=1[F:18])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C=CN(C)C
Reactant: Cc1c(F)c(F)c([N+](=O)[O-])c(C(=O)Cl)c1F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=CN(C)C)C(=O)c1c(F)c(C)c(F)c(F)c1[N+](=O)[O-]
Temperature: 5 °C
Reaction time: 1 h

Procedure:
1.4 g (0.01 mol) of ethyl 3-dimethylaminoacrylate, 15 ml of ethyl acetate and 1.4 ml (0.01 mol) of triethylamine were loaded and cooled to 5° C., and a liquid mixture of 3.5 g (0.011 mol) of 2,4,5-trifluoro-3-methyl-6-nitrobenzoyl chloride and 5 ml of ethyl acetate was added dropwise while the temperature was maintained at 0 to 5° C. The resulting mixture was stirred at 5° C. for 1 hour and then stirred at room temperature (25° C.) for 2 hours. The precipitated triethylamine hydrochloride was filtered off, and the filtrate was concentrated under reduced pressure to give ethyl 3-dimethylamino-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate with a 43.6% purity as the residue.
Reaction SMILES: C=CC=C.O=O.C(O[CH:11]=[CH:12][CH2:13][CH2:14][O:15][C:16](=[O:18])[CH3:17])(=O)C.[C:19]([OH:22])(=[O:21])[CH3:20]>>[C:19]([O:22][CH:13]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[CH:12]=[CH2:11])(=[O:21])[CH3:20]
Reactant: CC(=O)O
Reactant: CC(=O)OC=CCCOC(C)=O
Agent: C=CC=C
Agent: O=O
Product: C=CC(COC(C)=O)OC(C)=O
Yield: 1.15 %

Procedure:
From the upper part of the reactor, which was the same reactor as used in the acetoxylation process in Example 1 and temperature of heating medium in the jacket was kept at 87° C., were fed butadiene at 1.7 kg/h, acetic acid at 19.1 kg/h and nitrogen gas containing 5 mol % oxygen at 40 Nm3 /h and reacted under the same reaction conditions as in the acetoxylation process in Example 1. As the result, 2100 kg of reaction products of a composition containing 13.10% of 1,4-diacetoxybutene, and 1.15% of 3,4-diacetoxybutene were produced.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([NH2:11])[CH2:5]2.[C@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@H:6]([NH2:11])[CH2:5]2
Reactant: NC1Cc2ccc(Br)cc2C1
Agent: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Product: N[C@H]1Cc2ccc(Br)cc2C1

Procedure:
resolving 5-bromo-2-aminoindane with either (R) or (S)-10-camphorsulfonic acid to obtain either chiral (R)- or (S)-5-bromo-2-aminoindane;
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.[CH3:9][CH:10]1C(=O)CCCC1=O>>[OH:7][CH:3]([CH3:2])[CH2:4][CH2:5][CH2:6][C:1](=[O:8])[CH:9]=[CH2:10]
Reactant: O=C1CCCC(=O)C1
Reactant: CC1C(=O)CCCC1=O
Product: C=CC(=O)CCCC(C)O

Procedure:
Employing procedures similar to those described in Example 1, except that cyclohexane-1,3-dione is substituted for 2-methylcyclohexane-1,3-dione, 7-hydroxyoct-1-en-3-one is produced.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)[CH2:4][C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:34](=[O:35])[C:33]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]2[C:31]1=[O:40])(OCC)=O.CCOCC>CC#N.O>[C:31]1(=[O:40])[N:2]([CH:3]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=2)[CH2:4][C:5]([O:7][CH3:8])=[O:6])[C:34](=[O:35])[C:33]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]12
Reactant: COC(=O)CC(N)c1ccc(OC)c(OC)c1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CC#N
Product: COC(=O)CC(c1ccc(OC)c(OC)c1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.5 %

Procedure:
A mixture of methy 3-amino-3-(3',4'-dimethoxyphenyl)propionate hydrochloride (1.38 g, 5.00 mmol), sodium carbonate (0.53 g, 5.00 mmol), and N-carboethoxyphthalimide (1.10 g, 5.0 mmol) in 40 mL of CH3CN/H2O (1/1) was stirred for 1 hour at room temperature. The reaction solution was then partially concentrated under reduced pressure to remove the acetonitrile. This afforded a white gum in water. To the mixture was then added 5 mL of ether and the mixture was stirred for 2 hours. The resulting slurry was filtered, the solid was washed with a copious amount of water and air-dried overnight to afford 1.69 g (92%) of methyl 3-phthalimido-3-(3',4'-dimethoxyphenyl)propionate as a white solid: mp 114.1°-115.6° C.; 1H NMR (DMSO-d6, 250 MHz) δ 7.80-7.95 (m, 4 H, Ar), 6.80-7.10 (m, 3 H, At), 5.65 (dd, 1 H, J1 =7 Hz, J2 =9 Hz), 3.74 (s, 3 H, OCH3), 3.72 (s, 3 H, OCH3), 3.55 (s, 3 H, OCH3), 3.30-3.67 (m, 2 H); 13C NMR (DMSO-d6) δ 170.8, 167.6, 148.6, 148.4, 134.7, 131.1, 131.0, 123.2, 119.3, 111.7, 111.0, 55.5, 51.6, 49.9, 35.6. Anal. Calcd for C20H19NO6. Theoretical C, 65.03; H, 5.18; N, 3.79. Found C, 65.17; H, 5.14; N, 3.75. HPLC 99%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:27](=[O:28])[N:26]([CH3:29])[C:12]2[N:13]([CH3:25])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[NH:21][N:22]=[CH:23][CH:24]=1)=[CH:16][CH:15]=3.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:27](=[O:28])[N:26]([CH3:29])[C:12]2[N:13]([CH3:25])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[CH:24]=[CH:23][N:22]([S:31]([CH3:30])(=[O:33])=[O:32])[N:21]=1)=[CH:16][CH:15]=3
Reactant: CS(=O)(=O)Cl
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4ccn[nH]4)ccc3n(C)c21
Product: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4ccn(S(C)(=O)=O)n4)ccc3n(C)c21

Procedure:
The process is carried out as indicated in Example 99 above with the compound from Example 39, 3-(2,4-dichlorophenyl)-1,9-dimethyl-6-(2H-pyrazol-3-yl)-1,9-dihydro-pyrido[2,3-b]indol-2-one, and methanesulphonyl chloride.
Reaction SMILES: [C:1]([C:3]1[O:4][C:5]2[CH:13]=[C:12]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]4[CH:33]=[CH:32][C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:25]=4)[CH:17]=3)[CH:11]=[CH:10][C:6]=2[C:7](=[O:9])[CH:8]=1)#[N:2].[N-:34]=[N+:35]=[N-:36].[Na+].[Cl-].[NH+]1C=CC=CC=1.O>CN(C)C=O>[N:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:32]=[CH:33][C:24]=1[CH2:23][O:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[O:15][CH2:14][C:12]1[CH:11]=[CH:10][C:6]2[C:7](=[O:9])[CH:8]=[C:3]([C:1]3[NH:36][N:35]=[N:34][N:2]=3)[O:4][C:5]=2[CH:13]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cc(=O)c2ccc(COc3cccc(OCc4ccc5ccccc5n4)c3)cc2o1
Agent: [Cl-]
Agent: [Na+]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CN(C)C=O
Product: O=c1cc(-c2nnn[nH]2)oc2cc(COc3cccc(OCc4ccc5ccccc5n4)c3)ccc12
Temperature: 100 °C

Procedure:
0.72 g of 2-cyano-7-(3-(quinolin-2-ylmethoxy)phenoxymethyl)-4-oxo-4H-1-benzopyran, 0.54 g of sodium azide and 0.96 g pyridinium chloride are combined in 20 ml of dimethylformamide and heated for 3 hours at 100° C. The mixture is poured into water and the precipitate filtered off. This crude product is recrystallized from dimethylformamide to give 5-(7-(3-(quinolin-2-ylmethoxy)-phenoxymethyl)-4-oxo-4H-1-benzopyran-2-yl)tetrazole; m.p. 246° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([CH2:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[F:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[CH2:22][CH2:23][O:24][CH2:25][C:26]([NH2:28])=[NH:27].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[Cl:1][C:2]1[N:10]=[CH:9][C:8]([CH2:11][CH3:12])=[CH:7][C:3]=1[C:4]([NH:28][C:26](=[NH:27])[CH2:25][O:24][CH2:23][CH2:22][C:16]1[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=1[F:14])=[O:6]
Reactant: N=C(N)COCCc1cc(F)ccc1F
Reactant: CCc1cnc(Cl)c(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cnc(Cl)c(C(=O)NC(=N)COCCc2cc(F)ccc2F)c1

Procedure:
In analogy to the procedure described in example 78.3, 2-chloro-5-ethyl-nicotinic acid was reacted with 2-[2-(2,5-difluoro-phenyl)-ethoxy]-acetamidine hydrochloride (example 78.2) in the presence of TBTU and DIPEA to give 2-chloro-N-{2-[2-(2,5-difluoro-phenyl)-ethoxy]-1-imino-ethyl}-5-ethyl-nicotinamide as yellow oil. MS: m/e=382.3 [M+H+].
Reaction SMILES: [C:1]([O:9]C)(=O)[C:2]#[C:3][C:4]([O:6][CH3:7])=[O:5].[F:11][C:12]([F:22])([F:21])[C:13]1[CH:18]=[CH:17][C:16]([NH:19][NH2:20])=[CH:15][CH:14]=1.C[O-].[Na+]>CCOCC>[O:9]=[C:1]1[N:19]([C:16]2[CH:17]=[CH:18][C:13]([C:12]([F:11])([F:22])[F:21])=[CH:14][CH:15]=2)[N:20]=[C:3]([C:4]([O:6][CH3:7])=[O:5])[CH2:2]1
Reactant: COC(=O)C#CC(=O)OC
Reactant: NNc1ccc(C(F)(F)F)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Product: COC(=O)C1=NN(c2ccc(C(F)(F)F)cc2)C(=O)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 500 mL round-bottomed flask was charged with dimethyl but-2-ynedioate 70 (6.0 g, 42 mmol) and 50 mL of ether. To this solution was added a solution of 1-(4-(trifluoromethyl)phenyl)hydrazine 69 (7.6 g, 43 mmol) in 100 mL of ether over 30 min. After stirring at room temperature for 30 min, the reaction was concentrated and redissolved in MeOH (200 mL). The solution was added dropwise over 1 h to a NaOMe solution (made from sodium metal (3.9 g, 169 mmol) in 200 mL of MeOH). This mixture was stirred at room temperature for 1.5 h, the MeOH was removed, 100 mL of 5 N HCl was added, and the precipitate was collected by filtration. The solid was triturated with CH2Cl2 to give methyl 5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-pyrazole-3-carboxylate 71.
Reaction SMILES: [C:1]([N:8]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([O:26]C)=[O:25])=[CH:19][CH:18]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([N:8]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:23][C:24]([OH:26])=[O:25])=[CH:21][CH:22]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: COC(=O)Cc1ccc(CN(Cc2ccccn2)C(=O)OC(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(Cc1ccc(CC(=O)O)cc1)Cc1ccccn1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 98.3 %

Procedure:
The compound obtained in Example 8-3 (83.2 mg) was dissolved in THF (0.8 ml) and methanol (0.8 ml). After the addition of 1 N aqueous solution of sodium hydroxide (0.8 ml), the mixture was stirred for 35 minutes at room temperature. After the reaction, the solvent was removed by distillation and the residue was dissolved in distilled water. Aqueous solution of hydrochloric acid (1 mol/l) was added to the solution to adjust the pH to 3-4. The settled-down oily product was extracted with chloroform, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed by distillation and the residue was dried under vacuum to obtain the title compound (78.7 mg) as colorless oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:9]=[C:10]([CH2:16][CH3:17])[C:11](=[O:15])[NH:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24](Cl)=[O:25]>>[CH2:16]([C:10]1[C:11](=[O:15])[NH:12][C:13]([CH3:14])=[C:8]([C:6]2[O:7][C:3]([CH2:2][NH:1][C:24]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=3)=[O:25])=[CH:4][CH:5]=2)[CH:9]=1)[CH3:17]
Reactant: O=C(Cl)c1ccccn1
Reactant: CCc1cc(-c2ccc(CN)o2)c(C)[nH]c1=O
Product: CCc1cc(-c2ccc(CNC(=O)c3ccccn3)o2)c(C)[nH]c1=O

Procedure:
Example 269 is substantially repeated except for utilizing 5-(5-aminomethylfuran-2-yl)-3-ethyl-6-methyl-1H-pyridin-2-one and pyridine-2-carboxylic acid chloride to afford the title compound. MS: m/e=338 (M+H).
Reaction SMILES: C(O)(C(F)(F)F)=O.[OH:8][C:9]([CH3:31])([CH3:30])[CH2:10][C@@:11]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:16][C:15](=[O:17])[N:14]([C@H:18]2[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]2)[CH2:13][CH2:12]1.Cl[C:33]1[CH:34]=[CH:35][C:36]2[N:37]([CH:39]=[CH:40][N:41]=2)[N:38]=1.CCN(C(C)C)C(C)C>C(O)(C)C>[OH:8][C:9]([CH3:31])([CH3:30])[CH2:10][C@@:11]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[O:16][C:15](=[O:17])[N:14]([C@H:18]2[CH2:23][CH2:22][CH2:21][N:20]([C:33]3[CH:34]=[CH:35][C:36]4[N:37]([CH:39]=[CH:40][N:41]=4)[N:38]=3)[CH2:19]2)[CH2:13][CH2:12]1
Reactant: CC(C)(O)C[C@]1(c2ccccc2)CCN([C@H]2CCCNC2)C(=O)O1
Reactant: Clc1ccc2nccn2n1
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(O)C[C@]1(c2ccccc2)CCN([C@H]2CCCN(c3ccc4nccn4n3)C2)C(=O)O1
Temperature: 160 °C
Yield: 10.1 %

Procedure:
The TFA salt of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-piperidin-3-yl)-1,3-oxazinan-2-one (6 mg, 0.018 mmol), 6-chloroimidazo[1,2-b]pyridazine (6 mg, 2.15 equiv.), and i-Pr2NEt (30 μL, excess) were mixed with isopropanol (1 mL). The mixture was heated in a microwave oven at 160° C. for 2.5 h. After being cooled to rt, the mixture was filtered and purified by prep HPLC to afford the title compound (0.82 mg) as brown oil. LC-MS Method 1 tR=1.07 min., m/z=450 (M+1).
Reaction SMILES: C([BH3-])#N.[Na+].[CH3:5][O:6][N:7]=[C:8]([CH2:10][CH2:11][CH2:12][N:13]1[C:25]2[C:24]3[CH:23]=[CH:22][C:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:20][C:19]=3[N:18]=[C:17]([NH2:32])[C:16]=2[N:15]=[C:14]1[CH2:33][CH2:34][CH3:35])[CH3:9]>C(O)C.C(O)(=O)C>[NH2:32][C:17]1[C:16]2[N:15]=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]([CH2:12][CH2:11][CH2:10][CH:8]([NH:7][O:6][CH3:5])[CH3:9])[C:25]=2[C:24]2[CH:23]=[CH:22][C:21]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[CH:20][C:19]=2[N:18]=1
Reactant: CCCc1nc2c(N)nc3cc(-c4ccccc4)ccc3c2n1CCCC(C)=NOC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCCc1nc2c(N)nc3cc(-c4ccccc4)ccc3c2n1CCCC(C)NOC
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
Sodium cyanoborohydride (2.26 g, 36.1 mmol) was added to a solution of 5-(4-amino-7-phenyl-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)pentan-2-one O-methyloxime (3.0 g, 7.22 mmol) in ethanol (50 mL) and acetic acid (3 mL) and stirred at ambient temperature overnight. Another portion of sodium cyanoborohydride was added (1.0 g) and the reaction was stirred for an additional 4 hours. The reaction mixture was concentrated under reduced pressure and the residue was diluted in water and neutralized to pH ˜8 with 10% sodium hydroxide solution. The product was extracted into dichloromethane, washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, and concentrated under reduced pressure to provide 2.73 g of N-[4-(4-amino-7-phenyl-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)-1-methylbutyl]-O-methylhydroxylamine.