Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:19]=2[F:26])=[C:14]([CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])[N:13]=1)[CH2:3][C:4]1[CH:5]=[C:6]([CH2:10][OH:11])[CH:7]=[CH:8][CH:9]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>CS(C)=O>[F:1][CH:2]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:19]=2[F:26])=[C:14]([CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])[N:13]=1)[CH2:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[CH:10]=[O:11]
Reactant: COc1ccc(F)c(-c2ccc(C(F)Cc3cccc(CO)c3)nc2CC(C)(C)C)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(F)c(-c2ccc(C(F)Cc3cccc(C=O)c3)nc2CC(C)(C)C)c1
Reaction time: 0.33 h

Procedure:
To a solution of (3-(2-fluoro-2-(5-(2-fluoro-5-methoxyphenyl)-6-neopentylpyridin-2-yl)ethyl)phenyl)methanol (126 mg) in DMSO (1.0 mL) was added a Dess-Martin reagent (188 mg) at room temperature, and the mixture was stirred for 20 min. To the reaction mixture was added aqueous sodium thiosulfate solution at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give a crude product of the title compound as a brown oil. This compound was used for the next step without further purification.
Reaction SMILES: O1C(C2C=C(N[C:13]3[N:18]=[C:17]([C:19]4[C:20]([C:28]5[CH:29]=[C:30]([NH:34][C:35](=[O:42])[CH2:36][C:37]6[S:38][CH:39]=[CH:40][CH:41]=6)[CH:31]=[CH:32][CH:33]=5)=[N:21][N:22]5[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=45)[CH:16]=[CH:15][N:14]=3)C=CC=2)=CN=C1.[NH2:43][C:44]1[CH:45]=[C:46]2[C:50](=[CH:51][CH:52]=1)[CH2:49][CH:48]([N:53]([CH3:55])[CH3:54])[CH2:47]2.Cl.C(OCC)C>CC(O)C>[CH3:54][N:53]([CH3:55])[CH:48]1[CH2:47][C:46]2[C:50](=[CH:51][CH:52]=[C:44]([NH:43][C:13]3[N:18]=[C:17]([C:19]4[C:20]([C:28]5[CH:29]=[C:30]([NH:34][C:35](=[O:42])[CH2:36][C:37]6[S:38][CH:39]=[CH:40][CH:41]=6)[CH:31]=[CH:32][CH:33]=5)=[N:21][N:22]5[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=45)[CH:16]=[CH:15][N:14]=3)[CH:45]=2)[CH2:49]1
Reactant: CN(C)C1Cc2ccc(N)cc2C1
Reactant: O=C(Cc1cccs1)Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(-c4cnco4)c3)n2)c1
Agent: Cl
Solvent: CC(C)O
Solvent: CCOCC
Product: CN(C)C1Cc2ccc(Nc3nccc(-c4c(-c5cccc(NC(=O)Cc6cccs6)c5)nn5ccccc45)n3)cc2C1
Temperature: 180 °C

Procedure:
The title compound was synthesized by combining N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2-(2-thienyl)acetamide (147 mg, 0.33 mmol) (see Example 2, step B) and (5-amino-2,3-dihydro-1H-inden-2-yl)dimethylamine (70 mg, 0.40 mmol) in i-PrOH (2 mL) and adding 1M hydrochloric acid in diethyl ether (33 uL, 0.03 mmol). The reaction was heated to 180° C. in the microwave for 20 min. repeatedly until LC/MS analysis of the reaction mixture showed consumption of starting material. The reaction product was concentrated to a residue, partitioned between chloroform and saturated aqueous NaHCO3 and the organic fraction was washed with brine. The crude organic solution was dried with Na2SO4 and concentrated. The crude product was purified by silica gel flash column chromatography (DCM: 0-100% 90:9:1 DCM:MeOH:NH4OH(aq)). Purification yielded 43 mg (22%) of a brown powder. 1H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 9.41 (s, 1H), 8.81 (d, J=6.9 Hz, 1H), 8.46 (m, 1H), 8.21 (dd, J=5.2, 4.1 Hz, 1H), 7.90-7.87 (m, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.64 (d, J=15.4 Hz, 1H), 7.48-7.35 (m, 4H), 7.25 (d, J=7.7 Hz, 1H), 7.11 (t, J=7.0 Hz, 1H), 7.06-7.02 (m, 1H), 6.97-6.94 (m, 1H), 6.45 (dd, J=8.6, 5.4 Hz, 1H), 3.86 (s, 2H), 3.30 (s, 6H), 3.02-2.86 (m, 2H), 2.70-2.63 (m, 1H), 2.17 (s, 2H). ES-LC/MS m/z=586 [M+H]+.
Reaction SMILES: CN(C)C=O.[C:6]([C:10]1[CH:36]=[CH:35][C:13]([NH:14][C:15]2[CH:34]=[CH:33][C:18]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([OH:32])=[C:27]([O:30][CH3:31])[CH:28]=4)[N:23]=[CH:22][CH:21]=3)=[CH:17][CH:16]=2)=[CH:12][CH:11]=1)([CH3:9])([CH3:8])[CH3:7].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:45][CH2:46][N:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1>C(OCC)(=O)C.O>[C:6]([C:10]1[CH:36]=[CH:35][C:13]([NH:14][C:15]2[CH:34]=[CH:33][C:18]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:32][CH2:45][CH2:46][N:47]5[CH2:52][CH2:51][O:50][CH2:49][CH2:48]5)=[C:27]([O:30][CH3:31])[CH:28]=4)[N:23]=[CH:22][CH:21]=3)=[CH:17][CH:16]=2)=[CH:12][CH:11]=1)([CH3:9])([CH3:7])[CH3:8]
Reactant: COc1cc2c(Oc3ccc(Nc4ccc(C(C)(C)C)cc4)cc3)ccnc2cc1O
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(Nc4ccc(C(C)(C)C)cc4)cc3)ccnc2cc1OCCN1CCOCC1
Temperature: 77.5 °C
Reaction time: 6 h
Yield: 80.1 %

Procedure:
N,N-Dimethylformamide (2 ml) was added to 4-{4-[4-(tert-butyl)anilino]phenoxy}-6-methoxy-7-quinolinol (compound 21) (100 mg), potassium carbonate (167 mg), and 4-(2-chloroethyl)morpholine hydrochloride (70 mg), and the mixture was stirred at 75 to 80° C. for 6 hr. Water and ethyl acetate were added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and was dried over sodium sulfate, and the solvent was then removed by evaporation under the reduced pressure. The crude thus obtained was purified by thin-layer chromatography on silica gel using chloroform/methanol for development to give the title compound (102 mg, yield 81%).
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:7]=[C:8]([C:18](=[O:21])[CH2:19]Br)[CH:9]=[C:10]([C:13]([CH3:17])([CH3:16])[CH2:14][CH3:15])[C:11]=1[OH:12])([CH3:5])[CH2:3][CH3:4].[I-:22].[Na+].CCCCCC>COCCOC>[CH3:1][C:2]([C:6]1[CH:7]=[C:8]([C:18](=[O:21])[CH2:19][I:22])[CH:9]=[C:10]([C:13]([CH3:17])([CH3:16])[CH2:14][CH3:15])[C:11]=1[OH:12])([CH3:5])[CH2:3][CH3:4]
Reactant: [I-]
Reactant: CCC(C)(C)c1cc(C(=O)CBr)cc(C(C)(C)CC)c1O
Agent: [Na+]
Solvent: COCCOC
Solvent: CCCCCC
Product: CCC(C)(C)c1cc(C(=O)CI)cc(C(C)(C)CC)c1O
Reaction time: 16 h
Yield: 53.4 %

Procedure:
To a solution of 3.56 g (10 mmol) of 1-(3,5-bis(1,1-dimethylpropyl)-4-hydroxyphenyl)-2-bromo-ethanone in 15 ml of 1,2-dimethoxyethane, a solution of 1.65 g (11 mmol) of sodium iodide in 10 ml of 1,2-dimethoxyethane is added dropwise at room temperature. After the addition, stirring is continued for 16 hours at room temperature. Then 5 ml of hexane is added and, after stirring for additional 15 minutes, the precipitated salts are removed by filtration. The obtained solution is evaporated and the resulting residue is purified by recrystallization from hexane to give 2.15 g (53%) of compound 204, m.p. 76-77° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[CH3:12][O:13][C:14]([C:16]1[CH:17]=[C:18]([CH3:43])[C:19]2[O:25][C:24]3[C:26]([Cl:39])=[CH:27][C:28]([N:30]4[CH2:35][CH2:34][N:33](C5CC5)[CH2:32][CH2:31]4)=[CH:29][C:23]=3[CH2:22][S:21](=[O:41])(=[O:40])[C:20]=2[CH:42]=1)=[O:15].C([BH3-])#N.[Na+].O>CO.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH3:12][O:13][C:14]([C:16]1[CH:17]=[C:18]([CH3:43])[C:19]2[O:25][C:24]3[C:26]([Cl:39])=[CH:27][C:28]([N:30]4[CH2:31][CH2:32][N:33]([CH2:7][C:6]5[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=5)[CH2:34][CH2:35]4)=[CH:29][C:23]=3[CH2:22][S:21](=[O:40])(=[O:41])[C:20]=2[CH:42]=1)=[O:15]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCN(C4CC4)CC3)cc(Cl)c1O2
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH3-]C#N
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCN(Cc4cccc([N+](=O)[O-])c4)CC3)cc(Cl)c1O2

Procedure:
m-Nitrobenzaldehyde (0.456 g, 3.02 mmol) and titanium isopropoxide (1.23 mL, 4.12 mmol) were added to a solution of Example 125k (1.2 g, 2.75 mmol) in methanol (75 mL) and refluxed for 1.5 h. Sodium cyanoborohydride (0.188 g, 2.75 mmol) was then added to the reaction mixture at 30° C. and refluxed for 3 h. It was cooled, treated with water and filtered. The filtrate was extracted with chloroform. The organic layer was washed with water, brine, dried, concentrated and purified using flash chromatography (silica gel, 5% methanol/chloroform) to obtain the title compound. Yield: 0.74 g (48%); 1H NMR (CDCl3): δ 2.6 (t, 4H, 2CH2), 2.63 (s, 3H, CH3), 3.22 (t, 4H, 2CH2), 3.63 (s, 2H, CH2), 3.9 (s, 3H, OCH3), 5.2 (s, 2H, CH2), 6.73 (s, 1H, Ar), 6.9 (s, 1H, Ar), 7.5 (t, 1H, Ar), 7.7 (d, 1H, Ar), 8.1 (s, 1H, Ar), 8.15 (d, 1H, Ar), 8.25 (s, 1H, Ar), 8.45 (s, 1H, Ar); MS: m/e (ES+) 573 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:4][C:3]=1[OH:14].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:22][C:23]1[S:24][CH:25]=[CH:26][N:27]=1>CC(C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:4][C:3]=1[O:14][CH2:22][C:23]1[S:24][CH:25]=[CH:26][N:27]=1
Reactant: BrCc1nccs1
Reactant: Cc1ccc(Nc2nccs2)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: Cc1ccc(Nc2nccs2)cc1OCc1nccs1
Yield: 51 %

Procedure:
Following the general procedure for O-alkylation, Method B, a mixture of 2-methyl-5-(thiazol-2-ylamino)phenol (158 mg, 0.48 mmol) and Cs2CO3 (158 mg, 0.48 mmol) in acetone (4.4 mL) was treated with 2-bromomethylthiazole (86 mg, 0.48 mmol) at RT. Reaction control by TLC showed full conversion after 2.5 h. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 4/6) in 51% yield (75 mg).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[C:5]([O:9][C:10]([NH:12][C:13]1[CH:17]=[CH:16][S:15][C:14]=1[C:18]([NH:20][NH2:21])=[O:19])=[O:11])([CH3:8])([CH3:7])[CH3:6].O>C1COCC1>[O:2]=[C:1]1[O:19][C:18]([C:14]2[S:15][CH:16]=[CH:17][C:13]=2[NH:12][C:10](=[O:11])[O:9][C:5]([CH3:8])([CH3:6])[CH3:7])=[N:20][NH:21]1
Reactant: CC(C)(C)OC(=O)Nc1ccsc1C(=O)NN
Reactant: O=C(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccsc1-c1n[nH]c(=O)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4 ml of a 20% toluenic phosgene solution are added dropwise to a solution of 240 mg of 3-(tert-butoxycarbonylamino)thiophene-2-carboxylic hydrazide in 5 ml of THF and the mixture is stirred at RT. After one hour, the mixture is admixed with 10 ml of water and, after brief digestion, extracted with ethyl acetate. After the ethyl acetate phase has been dried over sodium sulfate, the mixture is concentrated under reduced pressure and the remaining residue is used further without further purification.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[N:7][CH:6]=1)=[O:4].[OH-].[Li+].ClCCl>C1COCC1.CO>[N:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:8]1[S:9][C:5]([C:3]([OH:4])=[O:2])=[CH:6][N:7]=1
Reactant: COC(=O)c1cnc(-c2ccccn2)s1
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cnc(-c2ccccn2)s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
2-Pyridin-2-yl-thiazol-5-carboxylic acid methyl ester (0.34 g, 1.55 mmol) was dissolved in a THF/methanol (5 ml/1 ml) mixture, cooled to 0° C. and treated with lithium hydroxide (4.7 ml, 1N aqueous solution). The reaction mixture was allowed to warm-up to ambient temperature, stirred at that temperature for 30 min and the pH value was subsequently adjusted to ˜5. The resulting suspension was treated with dichloromethane (50 ml) and filtered. The precipitate was washed with water and dichloromethane, the filtrate was extracted with dichloromethane. The combined organic phases were dried, evaporated and combined with the precipitate to yield the product as light brown solid (0.3 g, 92%). MS: M=161.1 (M-CO2—H)−
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:18][N:6]2[C:7](=[O:17])[CH:8]=[C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[N:10]=[C:5]2[NH:4][CH2:3]1.[H-].[Na+].CS(O[CH2:27][CH2:28][O:29][CH:30]([CH3:32])[CH3:31])(=O)=O>CN(C=O)C>[CH:30]([O:29][CH2:28][CH2:27][N:4]1[C:5]2=[N:10][C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:8][C:7](=[O:17])[N:6]2[CH2:18][C:2]([CH3:19])([CH3:1])[CH2:3]1)([CH3:32])[CH3:31]
Reactant: CC1(C)CNc2nc(N3CCOCC3)cc(=O)n2C1
Reactant: CC(C)OCCOS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)OCCN1CC(C)(C)Cn2c1nc(N1CCOCC1)cc2=O
Reaction time: 0.5 h
Yield: 35.5 %

Procedure:
0.17 g of 7,7-dimethyl-2-(morpholin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]-pyrimidin-4-one are solubilized in anhydrous DMF. 0.03 g of 60% NaH are added and stirring is performed for 30 mins. 0.24 g of 2-isopropoxyethyl methanesulfonate are added and the mixture is heated with reflux for 3 h. After returning to RT, the mixture is poured in a water/ice/AcOEt mixture. The organic phase is decanted, washed with a solution saturated with NaCl and then dried with magnesium sulfate. The solvents are evaporated. The crude is purified by flash chromatography on silica gel (CH2Cl2/MeOH, 95/5). 0.08 g (yield=35%) of 9-(2-isopropoxyethyl)-7,7-dimethyl-2-(morpholin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one are obtained as a white powder including the following characteristics:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[NH:11][C:10]([CH2:12][O:13][CH3:14])=[C:9]([C:15]([O:17]CCC#N)=[O:16])[CH:8]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)[C:7]=1[C:29](=[O:46])[NH:30][CH2:31][CH2:32][CH:33]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[OH-].[Na+].Cl>CO>[NH2:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[NH:11][C:10]([CH2:12][O:13][CH3:14])=[C:9]([C:15]([OH:17])=[O:16])[CH:8]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)[C:7]=1[C:29](=[O:46])[NH:30][CH2:31][CH2:32][CH:33]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: COCC1=C(C(=O)OCCC#N)C(c2cccc(Cl)c2)C(C(=O)NCCC(c2ccccc2)c2ccccc2)=C(COCCN)N1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCC1=C(C(=O)O)C(c2cccc(Cl)c2)C(C(=O)NCCC(c2ccccc2)c2ccccc2)=C(COCCN)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.065 g (0.10 mmol) of (2-cyanoethyl) 6-(2-aminoethoxy)methyl-4-(3-chlorophenyl)-5-(3,3-diphenylpropylcarbamoyl)-2-methoxymethyl-1,4-dihydropyridine-3-carboxylate was dissolved in 1 ml of methanol. 0.20 ml of 1 N aqueous sodium hydroxide solution was added to the obtained solution, and they were stirred at room temperature for 8 hours. The reaction mixture was neutralized with 1 N hydrochloric acid. After the extraction with ethyl acetate, the solvent was evaporated and the product was purified by TLC (Silanised Silica gel, methanol/water=6/4) to obtain the title compound.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]([CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]([CH3:29])([OH:28])[CH3:27])[CH2:21][CH2:20]1)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.I[CH3:31]>O1CCCC1.CN(C)C=O>[CH2:3]([N:10]([CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]([O:28][CH3:31])([CH3:29])[CH3:27])[CH2:21][CH2:20]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CI
Reactant: CC(C)(O)CN1CCC(CN(Cc2ccccc2)Cc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(C)(C)CN1CCC(CN(Cc2ccccc2)Cc2ccccc2)CC1
Reaction time: 0.5 h
Yield: 24.4 %

Procedure:
To a suspension of sodium hydride (abt. 60% in mineral oil, 342 mg, 8.6 mmol) in a mixture of tetrahydrofuran (20 mL) and N,N-dimethylformamide (10 mL) was added a solution of 1-{4-[(dibenzylamino)methyl]piperidin-1-yl}-2-methylpropan-2-ol (EXAMPLE 4, Step 4, 3.0 g, 8.2 mmol) in tetrahydrofuran (20 ml) at 0° C. Afer being stirred at the same temperature for 30 min, 0.53 mL (8.6 mmol) of iodomethane was added to the mixture. The mixture was stirred at ambient temperature for 3 days. The mixture was partitioned between ethyl acetate and water. After extraction with ethyl acetate, the combined organic phase was dried over magnesium sulfate, and concentrated. The residue was purified by flash column chromatography on amine gel eluting with hexane/ethyl acetate (100:1) to afford 0.76 g (24%) of the title compound as colorless amorphous.
Reaction SMILES: [Rh:1](I)(I)I.[CH3:5][I:6].[F:7][C:8]([F:13])([F:12])[C:9]([OH:11])=[O:10]>O.C(O)(=O)C>[Rh:1].[CH3:5][I:6].[F:7][C:8]([F:13])([F:12])[C:9]([OH:11])=[O:10]
Reactant: I[Rh](I)I
Solvent: O
Solvent: CI
Solvent: CC(=O)O
Product: [Rh]

Procedure:
The reactor was charged with a solution containing rhodium iodide, methyl iodide, water, acetic acid and trifluoroacetic acid (TFAA) in proportions to provide 400 ppm rhodium, 14.0% methyl iodide, 14.0% water and 20.0% TFAA. The reactor was sealed, pressured to approximately 28.14 Kg/cm2 of carbon monoxide partial pressure which was checked at 25° C. The reactor was then slowly vented of its carbon monoxide and then flushed twice with carbon monoxide (7 Kg/cm2). The reactor was then pressureed to 14 Kg/cm2 with carbon monoxide and heated to 120° C. for 2 hours, after which the agitator was turned on to stir at medium speed (100-200 rpm). The reactor was then further heated to 194° C., stirred at high speed (500-600 rpm) and pressured with carbon monoxide to 29 Kg/cm2. The reactor was maintained at a temperature of 194° C. when methanol was fed into the solution and carbon monoxide was introduced continuously at a rate to maintain the pressure in the reactor at about 29 Kg/cm2. The rate of reaction was determined by monitoring the amount of carbon monoxide consumed over a period of time, assuming that the ideal gas law can be applied to carbon monoxide. The rate of CO consumption approximates to the rate of acetic acid production since the formation of by-products is small as shown by products analysis.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=O)[N:12]([CH3:18])[C:11]2([CH3:20])[CH3:19].[OH-].[Na+]>C1COCC1>[NH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[CH2:13][N:12]([CH3:18])[C:11]2([CH3:20])[CH3:19]
Reactant: CN1C(=O)c2ccc(N)cc2C1(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1Cc2ccc(N)cc2C1(C)C
Temperature: 70 °C
Reaction time: 3 h
Yield: 54.6 %

Procedure:
29 mg of lithiumaluminium hydride was added to 3.8 mL of a THF solution of 89 mg of 5-amino-2,3,3,-trimethylisoindolin-1-one, and the mixture was stirred at 70° C. for 3 hours. 0.05 mL of aqueous 5 M sodium hydroxide solution was added to it, and the solvent was evaporated away under reduced pressure. 10% methanol/chloroform was added to the residue, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified through basic silica gel column chromatography (hexane/ethyl acetate) to obtain 45 mg of the entitled compound as a pale yellow solid.
Reaction SMILES: FC(F)(F)C(O)=O.O[C:9]1([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:18][CH2:17][CH2:16][C:15]2[N:14]=[C:13]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:12]=[CH:11][C:10]1=2.[C:34]1([CH2:40][O:41][NH2:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C1(C)C=CC=CC=1>[C:34]1([CH2:40][O:41][NH:42][C:9]2([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:18][CH2:17][CH2:16][C:15]3[N:14]=[C:13]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:12]=[CH:11][C:10]2=3)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: OC1(Cc2ccccc2)CCCc2nc(OCc3ccccc3)ccc21
Reactant: NOCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: c1ccc(CONC2(Cc3ccccc3)CCCc3nc(OCc4ccccc4)ccc32)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 61 %

Procedure:
Trifluoroacetic acid (16.6 g) was added in one portion to a solution of 5,6,7,8-tetrahydro-5-hydroxy-2-(phenylmethoxy)-5-(phenylmethyl)quinoline (50 g), phenylmethoxyamine (44.8 g), and toluene (600 ml) at room temperature. The solution was stirred at room temperature for 19 hrs, and the reaction mixture was quenched with conc ammonium hydroxide solution. The layers were separated and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over potassium carbonate, filtered, and the filtrate was concentrated. Purification by high performance liquid chromatography (silica gel, elution with ethyl acetate-hexanes) gave 40.0 g (61% of 5,6,7,8-tetrahydro-N,2-bis(phenylmethoxy)-5-(phenylmethyl)-5-quinolinamine
Reaction SMILES: N[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:5]([N+:18]([O-:20])=[O:19])=[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:3]=1.B(F)(F)[F:28].F.N([O-])=O.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.O>[CH2:11]([O:10][C:8]([C:7]1[C:2]([F:28])=[N:3][C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:5]([N+:18]([O-:20])=[O:19])[C:6]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:9])[CH3:12]
Reactant: FB(F)F
Reactant: CCOC(=O)c1c(N)nc(-c2ccccc2)c([N+](=O)[O-])c1C(=O)OCC
Agent: F
Agent: O=C([O-])O
Agent: O=N[O-]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1c(F)nc(-c2ccccc2)c([N+](=O)[O-])c1C(=O)OCC
Temperature: -5 °C

Procedure:
In 2 ml of acetic acid was dissolved 100 mg of 2-amino-3,4-diethoxycarbonyl-5-nitro-6-phenylpyridine, and 1.5 ml of 42% hydrofluoroboric acid was added to the solution. The mixture was cooled to -5° C., followed by adding dropwise a solution of 21 mg (1.1 eq) of sodium nitrite dissolved in 0.5 ml of water. Thirty minutes later, the temperature of the mixture was elevated to room temperature and the mixture was neutralized with sodium hydrogencarbonate, followed by extraction with ethyl acetate. After the organic layer was washed with water and a saturated aqueous solution of sodium chloride, and dried. After the solvent was distilled off, the resulting crystals (2-pyridone compound) were collected by filtration with hexane, and washed. The solvent was distilled off from the obtained filtrate, to give an oily substance.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8](I)=[CH:9][CH:10]=3)[C:5]3([CH2:20][O:19][C:18]([NH2:21])=[N:17]3)[C:4]=2[CH:3]=1.[N:22]1[CH:27]=[C:26](B(O)O)[CH:25]=[N:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([C:26]4[CH:27]=[N:22][CH:23]=[N:24][CH:25]=4)=[CH:9][CH:10]=3)[C:5]3([CH2:20][O:19][C:18]([NH2:21])=[N:17]3)[C:4]=2[CH:3]=1
Reactant: NC1=NC2(CO1)c1cc(Br)ccc1Oc1ccc(I)cc12
Reactant: OB(O)c1cncnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: NC1=NC2(CO1)c1cc(Br)ccc1Oc1ccc(-c3cncnc3)cc12
Temperature: 65 °C
Reaction time: 16 h

Procedure:
50 ml Flask was charged with 2′-bromo-7′-iodo-5H-spiro[oxazole-4,9′-xanthen]-2-amine (1.000 g, 2.188 mmol), pyrimidin-5-ylboronic acid (0.380 g, 3.06 mmol), tetrakis(triphenylphosphine)palladium (0.126 g, 0.109 mmol) and DME (10 mL). Sodium carbonate (3.28 mL, 6.56 mmol) was added and the reaction mixture was stirred at 65° C. for 16 hrs. The brown mixture with precipitate was filtered and the solids were washed with DME (3 ml), water (5 ml) and methanol (5 ml), dried on air. The material was treated with 10 ml of DCM and filtered, filtrate was evaporated to afford to afford 2′-bromo-7′-(pyrimidin-5-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine as white solid