Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:26])[N:5]([CH:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=2)[CH2:7][C:8]([OH:10])=O)[C:4](=[O:21])[C:3]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:2]12.[CH2:27]([NH2:32])[CH2:28][CH2:29][CH2:30][CH3:31].CCOCC>C(OCC)(=O)C>[CH2:27]([NH:32][C:8](=[O:10])[CH2:7][CH:6]([N:5]1[C:1](=[O:26])[C:2]2=[CH:25][CH:24]=[CH:23][CH:22]=[C:3]2[C:4]1=[O:21])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)[CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCN
Reactant: COc1ccc(C(CC(=O)O)N2C(=O)c3ccccc3C2=O)cc1OC
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCCCCNC(=O)CC(c1ccc(OC)c(OC)c1)N1C(=O)c2ccccc2C1=O
Reaction time: 1 h

Procedure:
By following the procedure of Example 46 utilizing 3-phthalimido-3-(3,4'-dimethoxyphenyl)propionic acid and amylamine (1.0 equiv) to afford 2.15 g (84%) of crude product. The crude product was dissolved in 150 mL of ethyl acetate and then 50 mL of ether was added and the mixture stirred for 1 hour. The resulting slurry was filtered and the solid dried in vacuo to afford 1.28 g (50%) yield of 3-phthalimido-3-(3',4'-dimethoxyphenyl)propionic amylamide as a white powder: mp 140.5°-142.1° C.; 1H NMR (DMSO-d6, 250 MHz), d 8.05 (t, 1 H, J=5 Hz), 7.85 (m, 4 H), 7.03 (br s, 1 H), 6.90 (m, 3 H), 5.68 (t, 1 H, J=8 Hz), 3.73 (s, 3 H), 3.71 (s, 3 H), 3.19 (d, 2 H, J=8 Hz), 2.8-3.1 (m, 2 H), 0.9-1.3 (m, 6 H), 0.74 (m, 3 H); 13C NMR (DMSO-d6) δ 168.8, 167.7, 148.5, 148.3, 134.5, 131.5, 131.2, 123.1, 119.5, 111.6, 111.1, 55.4, 50.6, 38.2, 37.4, 28.7, 28.3, 21.7, 13.7; Anal. Calcd. for C24H28N2O5. Theoretical: C, 67.9; H, 6.65; N, 6.60. Found: C, 67.84; H, 6.70; N, 6.57.
Reaction SMILES: C1(N(C(=O)C2C=CC([N+]([O-])=O)=CC=2)N)C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl.Cl.C1(O)C=CC=CC=1.ClP([N:38]([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[N:39]=[C:40]([Cl:50])[C:41]1[CH:46]=[CH:45][C:44]([N+:47]([O-:49])=[O:48])=[CH:43][CH:42]=1)(Cl)=O>C(Cl)(Cl)(Cl)Cl>[C:51]1([NH:38][N:39]=[C:40]([Cl:50])[C:41]2[CH:46]=[CH:45][C:44]([N+:47]([O-:49])=[O:48])=[CH:43][CH:42]=2)[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1
Reactant: O=[N+]([O-])c1ccc(C(Cl)=NN(c2ccccc2)P(=O)(Cl)Cl)cc1
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: NN(C(=O)c1ccc([N+](=O)[O-])cc1)c1ccccc1
Solvent: Oc1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc(C(Cl)=NNc2ccccc2)cc1
Temperature: 25 °C

Procedure:
A quantity (12.86 g., 0.05 mole) of p-nitrobenzoic acid phenylhydrazide, prepared according to the method described by J. Hausknecht, Chem. Ber. 22, p. 324 (1889), was added to a suspension of 10.41 g. (0.05 mole) phosphorus pentachloride in 75 ml. carbon tetrachloride, and the resulting suspension was heated to the reflux temperature. Heating at the reflux temperature was continued until evolution of hydrogen chloride gas ceased. After cooling the reaction mixture to about 25° C., it was poured into an ice-cold suspension of 15.5 g. (0.17 mole) of phenol in 50 ml. carbon tetrachloride. When the reaction between the phenol and the p-nitrobenzoyl chloride (dichlorophosphinyl)phenylhydrazone intermediate was completed, the carbon tetrachloride solvent and other volatile components were removed by evaporation under reduced pressure at 30° C. The resulting suspension of p-nitrobenzoyl chloride phenylhydrazone in triphenyl phosphate was filtered and the filter cake comprising the p-nitrobenzoyl chloride phenylhydrazone was washed with 100 ml. carbon tetrachloride, 50 ml. methanol, and 50 ml. ether. The solid on the filter was recrystallized from a solvent mixture consisting of 100 ml. benzene and 300 ml. naphtha (boiling range 203° to 212° F.). There was thus obtained 4.10 g. of p-nitrobenzoyl chloride phenylhydrazone having a melting point of 156° to 157.5° C. A second recrystallization from a mixture of benzene and Skellysolve C gave the compound melting at 157° to 158.5°C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([O:24][Si](C(C)(C)C)(C)C)[CH:22]=3)[CH:17]=[CH:16][CH:15]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-].C([O-])(O)=O.[Na+].C(Cl)Cl>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([OH:24])[CH:22]=3)[CH:17]=[CH:16][CH:15]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2cccc3ccc(O[Si](C)(C)C(C)(C)C)cc23)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(c2cccc3ccc(O)cc23)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of (R)-3-(tert-butoxycarbonylamino)-1-[7-(tert-butyldimethylsilyloxy)naphthalen-1-yl]pyrrolidine, as described above in Step H, (970 mg, 2.19 mmol) in THF (15 mL) was added TBAF (2.40 mL of a 1 M solution in THF, 2.40 mmol), dropwise. The mixture was stirred at ambient temperature for 30 min, then poured into saturated aqueous NaHCO3 (50 mL) and CH2Cl2 (100 mL). The aqueous layer was extracted further with CH2Cl2 (2×50 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting with a gradient of CH2C2—0% to 20% EtOAc to yield the desired phenol.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C@@H:8]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:9][C:10](OC)=[O:11].S([O-])([O-])(=O)=O.[Na+].[Na+].Cl>O1CCCC1>[F:7][C@@H:8]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:9][CH2:10][OH:11]
Reactant: CCCCCC[C@H](F)CC(=O)OC
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Solvent: C1CCOC1
Product: CCCCCC[C@H](F)CCO
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.2 %

Procedure:
Under nitrogen atmosphere, 1 ml of dry tetrahydrofuran (THF) and 88 mg (2.3 mM) of lithium aluminum hydride were placed in a two-necked round-bottomed flask and cooled on an ice path. To the mixture, a solution of 400 mg (2.1 mM) of methyl (S)-3-fluorononanoate in 1 ml of dry THF was added dropwise. The ice bath was removed and the resultant mixture was stirred for 2 hours at room temperature. After the reaction, the reaction vessel (flask) was cooled on an ice bath. To the resultant reaction mixture, 0.5 ml of saturated sodium sulfate was added, followed by stirring for 30 minutes. To the resultant mixture, 4 ml of 3M-hydrochloric acid (HCl) was added, followed by extraction with Et2O. The organic layer was washed with 5 wt. %-sodium hydrogencarbonate aqueous solution and dried with anhydrous magnesium sulfate, followed by distilling-off of the solvent under reduced pressure to obtain 270 mg (1.66 mM) of (S)-3-fluorononanol.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[O:15][CH3:16])[C:5]([F:17])=[CH:4][N:3]=1.[CH2:18]([S:20][CH2:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25])[CH3:19].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.CN1C(=O)CCC1.C(OCC)(=O)C>[CH2:18]([S:20][CH2:21][C:22]1[CH:23]=[C:24]([NH:25][C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=3[O:15][CH3:16])[C:5]([F:17])=[CH:4][N:3]=2)[CH:26]=[CH:27][CH:28]=1)[CH3:19]
Reactant: CCSCc1cccc(N)c1
Reactant: COc1cc(F)ccc1-c1nc(Cl)ncc1F
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCSCc1cccc(Nc2ncc(F)c(-c3ccc(F)cc3OC)n2)c1
Temperature: 130 °C
Reaction time: 3 h

Procedure:
A mixture of 2-chloro-5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidine (750 mg; 2.92 mmol), 3-[(ethylsulfanyl)methyl]aniline (376 mg; 2.24 mmol), chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) methyl-tert-butylether adduct (139 mg; 0.17 mmol; ABCR GmbH & CO. KG) and 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (80 mg; 0.17 mmol; Aldrich Chemical Company Inc.) and potassium phosphate (2.39 g; 11.24 mmol) in toluene (15 ml) and NMP (3 mL) was stirred at 130° C. for 3 hours. After cooling, the batch was diluted with ethyl acetate and washed with aqueous sodium chloride solution. The organic phase was filtered using a Whatman filter and concentrated. The residue was purified by chromatography (hexane/ethyl acetate 2:1) to give the pure product (536 mg; 1.38 mmol).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[N:5]([OH:10])[C:4]([CH3:12])([CH3:11])[CH2:3]1.OO.S(=O)(=O)(O)O.N=O.S([O-])([O-])=O.[Na+].[Na+].[OH-:28].[Na+].[BH4-].[Na+]>O.C(O)(C)(C)C>[OH:1][CH:2]1[CH2:7][C:6]([CH3:8])([CH3:9])[N:5]([O:10][CH2:3][C:4]([OH:28])([CH3:12])[CH3:11])[C:4]([CH3:12])([CH3:11])[CH2:3]1
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Reactant: [OH-]
Agent: N=O
Agent: O=S(=O)(O)O
Agent: O=S([O-])[O-]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(O)CON1C(C)(C)CC(O)CC1(C)C
Temperature: 40 °C
Reaction time: 1.3 h
Yield: 84 %

Procedure:
A solution of 17.2 g (100 mmol) of 4-hydroxy-1-oxyl-2,2,6,6-tetramethylpiperidine dissolved in 40 mL of water and three-fourths of a solution of 25.0 g (0.37 mol) of 50% aqueous hydrogen peroxide are added simultaneously over three hours at 40° C. to a mixture of 1.12 g (4.0 mmol) of ferrous sulfate heptahydrate, 25 mL of water, 0.5 mL of 98% sulfuric acid and 200 mL of tert-butyl alcohol. At the conclusion of the nitroxyl addition, 0.145 g (0.5 mmol) of ferrous sulfate heptahydrate, 0.1 mL of 98% sulfuric acid, and 1-2 mL of water are added to the reaction mixture. The remainding one-fourth of the peroxide solution is added over one hour at 40° C. One hour later, a solution of 2.9 g. (40 mmol) of 50% aqueous hydrogen peroxide is added dropwise to the reaction mixture. After another 1.3 hours, a solution of 0.14 g (0.5 mmol) of ferrous sulfate heptahydrate, 0.15 mL of 98% sulfuric acid and 1-2 mL of water are added in one portion. The reaction mixture is stirred an additional 40 minutes at 40° C. After the peroxides are decomposed with sodium sulfite, the reaction mixture is treated with sodium hydroxide and sodium borohydride and concentrated. The residue is dissolved in ethyl acetate and passed through silica gel to afford 20.5 g (84% yield) of the title compound as a white solid.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][CH2:26][C:27]1[C:28]([F:44])=[C:29]([O:34][C:35]2[CH:36]=[C:37]([CH:40]=[C:41]([Cl:43])[CH:42]=2)[C:38]#[N:39])[C:30]([Cl:33])=[CH:31][CH:32]=1.[Cl:45][C:46]1[CH:47]=[C:48]2[C:52](=[CH:53][CH:54]=1)[NH:51][C:50]([C:55](O)=[O:56])=[CH:49]2.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C.O>[Cl:45][C:46]1[CH:47]=[C:48]2[C:52](=[CH:53][CH:54]=1)[NH:51][C:50]([C:55]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([O:34][C:35]3[CH:36]=[C:37]([C:38]#[N:39])[CH:40]=[C:41]([Cl:43])[CH:42]=3)[C:28]=1[F:44])=[O:56])=[CH:49]2
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3cc4cc(Cl)ccc4[nH]3)c2F)c1
Reaction time: 1 h
Yield: 57.5 %

Procedure:
HATU (91 mg, 0.24 mmol) was added to a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (50 mg, 0.16 mmol), 5-chloro-1H-indole-2-carboxylic acid (50 mg, 0.24 mmol) and DIPEA (0.042 ml, 0.24 mmol) in DMF (1.5 mL). After 1 h, the reaction mixture was diluted with ethyl acetate and water. A solid precipitated which was filtered, triturated with methanol and dried under vacuum to give the title compound (0.045 g, 57%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.82 (s, 1H), 9.10 (s, 1H), 7.80 (s, 1H), 7.69 (s, 1H), 7.45-7.55 (m, 3H), 7.35-7.44 (m, 2H), 7.11-7.21 (m, 2H), 4.56 (d, 2H). MS: m/z 488 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[Cl-].[Al+3].[Cl-].[Cl-].[C:14](Cl)(=[O:16])[CH3:15]>ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([C:14](=[O:16])[CH3:15])[CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9]
Reactant: Cc1cccc(C)c1O
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1cc(C)c(O)c(C)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To an ice-cooled solution of 2,6-dimethylphenol (12.2 g, 0.1 mmol) in dichloromethane, anhydrous aluminum chloride (14.4 g) was slowly added with stirring, followed by slow addition of acetyl chloride (9.4 g) . The reaction mixture was stirred at 10° C. or below for 1 h, then at room temperature for 3 h. Thereafter, the mixture was poured into ice water. Then, the reaction product was extracted with dichloromethane and the extracted layer was washed with water. Further, the extracted layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was recrystallized with benzene, giving the desired compound, 2,6-dimethyl-4-acetylphenol in an amount of 1.9 g.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:7]2[CH:12]=[C:11]([CH3:13])[N:10]3N=N[N:16]=[C:9]3[C:8]=2[N:17]=1)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.[ClH:48]>CC(O)C.C(OCC)C>[ClH:48].[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH:19]([CH3:20])[CH3:21])[C:7]2[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([NH2:16])[C:8]=2[N:17]=1)[CH3:2]
Reactant: CCOCc1nc2c(cc(C)n3nnnc23)n1CC(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)O
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCOCc1nc2c(N)nc(C)cc2n1CC(C)C
Reaction time: 72 h

Procedure:
A mixture of 8-(ethoxymethyl)-7-(2-methylpropyl)-5-methyl-7H-imidazo[4,5-c]tetraazolo[1,5-a]pyridine (6.5 g, 22.5 mmol), triphenylphosphine (6.5 g, 24.8 mmol), and toluene (130 mL) was stirred and heated at reflux under nitrogen for 24 hours. Additional triphenylphosphine (3.0 g, 11.4 mmol) was added to the cloudy mixture, and the reaction was continued for three days. The solvent was removed under reduced pressure, and the resulting brown oil was dissolved in methanol (100 mL). Following the addition of a 1.0 M solution of hydrochloric acid in diethyl ether (45 mL) to the methanol solution, the reaction was heated at reflux overnight. The solvents were removed under reduced pressure, and water (200 mL) was added to the resulting brown oil, forming a white precipitate that was removed by filtration. Solid sodium carbonate (6.5 g) was added to the aqueous solution, followed by extraction with dichloromethane (2×200 mL). The combined extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide a brown oil, which was dissolved in 2-propanol (45 mL). A 1.0 M solution of hydrochloric acid in diethyl ether (22.5 mL) was added to the solution of crude product, and a white solid formed. After one hour the solid was isolated by filtration, washed with cold 2-propanol and diethyl ether, and dried in a vacuum oven at 90° C. for two days to yield 4.3 g of 2-(ethoxymethyl)-1-(2-methylpropyl)-6-methyl-1H-imidazo[4,5-c]pyridin-4-amine hydrochloride as a white solid, m.p. 181-183° C. Analysis: Calculated for C14H22N4O.HCl: % C, 56.27; % H, 7.76; % N, 18.75. Found: % C, 56.33; % H, 7.67; % N, 18.90.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][OH:8].[H-].[Na+].O1CCCC1.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>ClCCl.O>[CH2:28]([O:8][CH2:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH3:17]
Reactant: OCCc1cccs1
Reactant: CCCCCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCCCCCOCCc1cccs1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 53.8 %

Procedure:
13 g of 2-thiopheneethanol was cooled to 0° C., and to this, a suspension formed by adding 5.8 g of sodium hydride (60% in oil) to 100 ml of tetrahydrofuran was added dropwise. The solution was stirred at 0° C. for 20 minutes under a nitrogen atmosphere, and to this, 25 g of 1-bromododecane was added dropwise. The resulting solution was heated to 90° C. and stirred for 11.5 hours. 100 ml of water and 150 ml of dichloromethane were added to the reaction solution to separate the organic layer. The organic layer was washed with 300 ml of water and then dried over anhydrous magnesium sulfate. The resulting solution was concentrated by a rotary evaporator and purified by a column chromatography (filler: silica gel, eluent: hexane/dichloromethane) to obtain 16 g of 2-(2-dodecyloxyethyl)thiophene.
Reaction SMILES: [NH2:1][C:2]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:3]=1[C:4]([NH:6][CH:7]([CH3:9])[CH3:8])=[O:5].C=O.[C:17]1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH3:14][C:13]1[CH:12]=[CH:11][CH:10]=[C:3]2[C:2]=1[NH:1][CH2:17][N:6]([CH:7]([CH3:9])[CH3:8])[C:4]2=[O:5]
Reactant: Cc1cccc(C(=O)NC(C)C)c1N
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C=O
Solvent: CCO
Product: Cc1cccc2c1NCN(C(C)C)C2=O
Yield: 95 %

Procedure:
To a solution of 2-amino-3-methyl-N-(1-methylethyl)benzamide (0.5 g, 2.6 mmol) in ethanol (10 mL) was added paraformaldehyde (78 mg, 2.6 mmol) and p-toluenesulfonic acid (18 mg, 95 μmol) and the mixture was heated at reflux until it became clear (approximately 4 hours). The solvent was removed under reduced pressure to give the title compound (95% pure) which was used without further purification.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]\[C:5]1[C:10]([N+:11]([O-])=O)=[CH:9][N:8]=[C:7]([NH:14][C:15](=[O:17])[CH3:16])[CH:6]=1.C(O)(=O)C>CO.ClCCl.[Pd]>[NH:11]1[C:10]2=[CH:9][N:8]=[C:7]([NH:14][C:15](=[O:17])[CH3:16])[CH:6]=[C:5]2[CH:4]=[CH:3]1
Reactant: CC(=O)Nc1cc(/C=C\N(C)C)c([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: CC(=O)Nc1cc2cc[nH]c2cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.6 %

Procedure:
To a solution of N-{4-[(Z)-2-(dimethylamino)ethenyl]-5-nitropyridin-2-yl}acetamide (0.7 g, 3 mmol, Step b) in methanol and dichloromethane (5:1, 120 mL), palladium on carbon (0.4 g) was added followed by addition of acetic acid (7 mL). The reaction mixture was then purged with hydrogen gas and stirred overnight at room temperature. The resulting mixture was filtered over celite bed, and the residue was washed with methanol (100 mL). The combined filtrate was concentrated under vacuum and purified by silica gel column chromatography using methanol in dichloromethane (2%) to afford N-(1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide (0.35 g, 71%).
Reaction SMILES: [N:1]1[O:2][C:3]2[CH2:4][CH2:5][CH2:6][CH:7]3[C:16]=2[C:15]=1[C:14]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:8]3.C([O-])([O-])=O.[K+].[K+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[CH2:23]([N:8]1[CH:7]2[C:16]3=[C:3]([O:2][N:1]=[C:15]3[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1=3)[CH2:4][CH2:5][CH2:6]2)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: c1ccc2c(c1)NC1CCCc3onc-2c31
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(CN2c3ccccc3-c3noc4c3C2CCC4)cc1
Temperature: 90 °C

Procedure:
In 50 ml dry DMF were combined 2.10 g 4,5,5a,6-tetrahydro-3H-isoxazolo[5,4,3-kl]acridine, 2.0 g milled anhydrous K2CO3 and 1.3 ml benzylbromide. The mechanically stirred mixture was heated under nitrogen at 90° C. for 18 hours. During the first 4 hours, 1 ml benzyl bromide was added every hour as TLC analysis indicated it was being consumed. For the work-up, the mixture was poured in excess water and extracted with DCM. The DCM layer was concentrated to an oil and the oil was purified on a silica column (flash chromatography) using DCM as an eluent. The product-containing fractions were combined and concentrated to a solid. The solid was recrystallized from EtOAc/hexanes and dried in a vacuum desiccator to yield 2.10 g of product, m.p. 162°-163.5° C.
Reaction SMILES: [CH2:1]([C:3]1[N:7]2[N:8]=[C:9]([CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:10]=[C:11]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15](N)=[O:16])[C:6]2=[CH:5][CH:4]=1)[CH3:2].[OH2:26].[OH-].[K+].Cl>C(O)C>[CH2:1]([C:3]1[N:7]2[N:8]=[C:9]([CH2:21][C:22]([CH3:25])([CH3:23])[CH3:24])[CH:10]=[C:11]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([OH:16])=[O:26])[C:6]2=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc2c(-c3cccc(C(N)=O)c3)cc(CC(C)(C)C)nn12
Reactant: O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCc1ccc2c(-c3cccc(C(=O)O)c3)cc(CC(C)(C)C)nn12
Temperature: 60 °C
Reaction time: 2 h
Yield: 54.1 %

Procedure:
To a solution of 3-(7-ethyl-2-neopentylpyrrolo[1,2-b]pyridazin-4-yl)benzamide (35 mg) in ethanol (1 mL) was added water (0.2 mL) and potassium hydroxide (68.9 mg) at ambient temperature. The reaction mixture was heated at 60° C. After 2 hours, potassium hydroxide (100 mg) was added. After 5 hours, potassium hydroxide (100 mg) was added. After 12 hours, the mixture was acidified with 1N hydrogen chloride. The precipitate was filtered, washed with water and ethyl acetate to give 3-(7-ethyl-2-neopentylpyrrolo-[1,2-b]pyridazin-4-yl)benzoic acid as an yellow solid (19 mg, 54.1%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:12]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:13](=[O:22])[C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3Cl)[CH3:10])[C:5]([C:29]#[N:30])=[CH:4][N:3]=1.[CH3:31][O:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[N:37][CH:38]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:12]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:13](=[O:22])[C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[C:35]2[CH:36]=[N:37][CH:38]=[C:33]([O:32][CH3:31])[CH:34]=2)[CH3:10])[C:5]([C:29]#[N:30])=[CH:4][N:3]=1
Reactant: COc1cncc(B(O)O)c1
Reactant: C[C@H](Nc1nc(N)ncc1C#N)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1cncc(-c2cccc3cc([C@H](C)Nc4nc(N)ncc4C#N)n(-c4ccccc4)c(=O)c23)c1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
To a mixture of (S)-2-amino-4-((1-(8-chloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)amino)pyrimidine-5-carbonitrile 8 (50 mg, 0.12 mmol) and (5-methoxypyridin-3-yl)boronic acid (37 mg, 0.24 mmol) in anhydrous 1,4-dioxane (4 mL), PdCl2(dppf) (9.8 mg, 0.012 mmol) and aqueous Na2CO3 solution (1 M, 0.6 mL, 0.6 mmol) were added and the resulting mixture was stirred at 120° C. for 3 h. The reaction mixture was allowed to cool to RT, quenched with water, and then extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel eluting with 0-10% MeOH-DCM to afford the product, (S)-2-amino-4-((1-(8-(5-methoxypyridin-3-yl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)amino)pyrimidine-5-carbonitrile 9. ESI-MS m/z: 490.2 [M+H]+. Compound 2-amino-4-((S)-1-(8-(5-methoxypyridin-3-yl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethylamino)pyrimidine-5-carboxamide 10 was also formed in the above reaction and it was isolated by column chromatography. ESI-MS m/z: 508.2 [M+H]+.