Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([C:20]([F:23])([F:22])[F:21])=[N:15][C:16]([C:17](O)=[O:18])=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(O[C:41](N(C)C)=[N+:42](C)[CH3:43])C2C=CC=CC=2N=N1.Cl.CNC.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:41][N:42]([CH3:43])[C:17]([C:16]1[N:15]=[C:14]([C:20]([F:21])([F:22])[F:23])[N:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][C:10]=12)=[O:18]
Reactant: CC(C)(C)OC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)OC(C)(C)C)CC2
Reaction time: 12 h
Yield: 99.9 %

Procedure:
7-Tert-butoxycarbonyl-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-1-carboxylic acid 20a (330 mg, 1 mmol) was dissolved in 5 mL of N, N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (756 mg, 2 mmol), dimethylamine hydrochloride (156 mg, 2 mmol) and N,N-diisopropylethylamine (387 mg, 3 mmol). After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure, added with 50 mL of ethyl acetate, and washed successively with saturated ammonium chloride solution (30 mL) and saturated sodium chloride solution (20 mL×3). The organic phase was combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain crude tert-butyl 1-(dimethylcarbamoyl)-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carboxylate 22a (362 mg) as a light yellow solid. The product was used directly in the next reaction without purification.
Reaction SMILES: [CH3:1][C:2]([CH3:10])([C:5](=O)[CH2:6][C:7]#[N:8])[C:3]#[N:4].S(O)(O)(=O)=O.NO.C(C1C=C(N)[O:23][N:22]=1)(C)C>>[NH2:8][C:7]1[O:23][N:22]=[C:5]([C:2]([CH3:10])([CH3:1])[C:3]#[N:4])[CH:6]=1
Reactant: CC(C)c1cc(N)on1
Reactant: CC(C)(C#N)C(=O)CC#N
Agent: NO
Agent: O=S(=O)(O)O
Product: CC(C)(C#N)c1cc(N)on1
Yield: 23 %

Procedure:
Prepared from 2,2-dimethyl-3-oxopentanedinitrile (500 mg, 3.68 mmol) and hydroxylamine sulfate (332 mg, 2.02 mmol) according to the method described for 3-isopropylisoxazol-5-amine in Example 122A Step 2. Purification via silica gel chromatography eluting with 5% to 60% ethyl acetate in hexanes, afforded 2-(5-aminoisoxazol-3-yl)-2-methylpropanenitrile as a colorless solid (130 mg, 23%). 1H NMR (300 MHz, CDCl3) δ 5.22 (s, 1H), 4.58 (brs, 2H), 1.72 (s, 6H); LC-MS (ESI) m/z 152 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:26])([CH3:25])[C@@H:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:12]([OH:14])=[O:13])(=[O:7])=[O:6].C(Cl)(=O)C(Cl)=O.[CH2:33](O)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.N1C=CC=CC=1>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:26])([CH3:25])[C@@H:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:12]([O:14][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:13])(=[O:7])=[O:6]
Reactant: OCc1ccccc1
Reactant: COc1ccc(CO[C@@H](C(=O)O)C(C)(C)COS(=O)(=O)CCCCl)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(CO[C@@H](C(=O)OCc2ccccc2)C(C)(C)COS(=O)(=O)CCCCl)cc1
Yield: 73.5 %

Procedure:
Following the general procedure for the preparation of carboxylic esters from carboxylic acids of Description 15, (2R)-4-[(3-chloropropyl)sulfonyloxy]-2-[(4-methoxyphenyl)methoxy]-3,3-dimethylbutanoic acid (13) (0.50 g, 1.2 mmol) dissolved in 20 mL of anhydrous dichloromethane (DCM) was reacted with 0.7 mL (1.4 mmol) of oxalyl chloride (2.0 M in DCM). After completion of the reaction, a solution of 0.34 mL of benzyl alcohol (0.34 mL, 0.36 g, 3.3 mmol) and 0.28 mL of pyridine (0.26 g, 3.3 mmol) in 10 mL of anhydrous dichloromethane (DCM) was added to the acid chloride. After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) as eluent (EtOAc/Hxn=1:2) to provide 0.44 g (74% yield) of the title compound (31a) as a colorless oil. Rf=0.47 (EtOAc/Hxn=1:2). 1H NMR (400 MHz, CDCl3): δ=1.02 (s, 6H), 2.22-2.29 (m, 2H), 3.18-3.22 (m, 2H), 3.45 (t, J=6.4 Hz, 2H), 3.81 (s, 3H), 3.84 (s, 1H), 3.93 (d, J=9.2 Hz, 1H), 4.17 (d, J=9.2 Hz, 1H), 4.27 (d, J=11.2 Hz, 1H), 4.53 (d, J=10.8 Hz, 1H), 5.20 (s, 2H), 6.85 (d, J=8.8 Hz, 2H), 7.21 (d, J=8.8 Hz, 2H), 7.35-7.40 (m, 5H) ppm. MS (ESI) m/z 521.16 (M+Na)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH2:19][N:20]2[CH2:25][CH2:24][CH:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:22][CH2:21]2)[O:18][C:6]2=[C:7]([CH3:17])[C:8]3[CH2:9][CH2:10][N:11](C=O)[C:12]=3[C:13]([CH3:14])=[C:5]2[CH2:4]1.Cl.[OH-].[Na+]>CO>[CH3:2][C:3]1([CH2:19][N:20]2[CH2:25][CH2:24][CH:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:22][CH2:21]2)[O:18][C:6]2=[C:7]([CH3:17])[C:8]3[CH2:9][CH2:10][NH:11][C:12]=3[C:13]([CH3:14])=[C:5]2[CH2:4]1
Reactant: Cc1c2c(c(C)c3c1OC(C)(CN1CCC(c4ccccc4)CC1)C3)N(C=O)CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c2c(c(C)c3c1NCC3)OC(C)(CN1CCC(c3ccccc3)CC1)C2
Temperature: 60 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
3,5,6,7-Tetrahydro-2,4,8-trimethyl-2-[(4-phenylpiperidino)methyl]-2H-furo[2,3-f]indole-5-carbaldehyde hydrochloride (309 mg, 0.7 mmol) was dissolved in methanol (5 ml). To the solution was added concentrated hydrochloric acid (1 ml) and stirred for 1 hour at 60° C. under argon atmosphere. The reaction mixture was cooled to room temperature, made weakly basic with 12N sodium hydroxide, and extracted with ethyl acetate. The extract was washed with saturated brine and dried over sodium sulfate, and the solvent was removed under reduced pressure. The resultant oil was crystallized from hexane to obtain 203 mg of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15].C(N(CC)CC)C>CN(C=O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[CH3:9][O:8][C:6]1[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=[C:2]([C:18]#[C:17][Si:14]([CH3:16])([CH3:15])[CH3:13])[N:7]=1
Reactant: COc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COc1nc(C#C[Si](C)(C)C)ccc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 50.3 %

Procedure:
Bis(triphenylphosphine)palladiumdichloride (0.082 g, 0.118 mmol) was added to a solution of 6-chloro-2-methoxy-3-nitropyridine (0.554 g, 2.94 mmol), trimethylsilylacetylene (0.623 mL, 4.41 mmol), triethylamine (1.843 mL, 13.22 mmol) and copper iodide (0.022 g, 0.118 mmol) in DMF (10.1 mL). The reaction mixture was heated at 80° C. for 1 hour. The reaction mixture was diluted with water and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by Biotage silica gel column chromatography eluting with cyclohexane/EtOAc (99/1) to afford the title compound as a yellow oil (370 mg, 50%).
Reaction SMILES: F[C:2](F)(F)[C:3](O)=[O:4].[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([N:17]2[CH2:21][CH:20]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:19]3([C:34]4[C:29](=[CH:30][C:31]([Cl:35])=[CH:32][CH:33]=4)[NH:28][C:27]3=[O:36])[CH:18]2[C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[C:38]=2[F:44])=[O:16])[CH2:10][CH2:9]1.C(N(CC)CC)C.C(Cl)(=O)C>O1CCCC1>[C:3]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([N:17]2[CH2:21][CH:20]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:19]3([C:34]4[C:29](=[CH:30][C:31]([Cl:35])=[CH:32][CH:33]=4)[NH:28][C:27]3=[O:36])[CH:18]2[C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[C:38]=2[F:44])=[O:16])[CH2:10][CH2:9]1)(=[O:4])[CH3:2]
Reactant: CC(C)(C)CC1CN(C(=O)NC2CCNCC2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: O=C(O)C(F)(F)F
Solvent: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N1CCC(NC(=O)N2CC(CC(C)(C)C)C3(C(=O)Nc4cc(Cl)ccc43)C2c2cccc(Cl)c2F)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.9 %

Procedure:
To a solution of rac-(2′S,3′S,4′S)-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-4′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-1′-carboxylic acid piperidin-4-ylamide trifluoroacetic acid (80 mg, 0.12 mmol) in tetrahydrofuran (2 mL) at 0° C. was added triethylamine (0.042 mL, 0.3 mmol) and acetyl chloride (10.4 mg, 0.13 mmol). The mixture was stirred at room temperature for 0.5 h. The mixture was concentrated, and the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated. The residue was recrystallized in dichloromethane and hexanes to give as rac-(2′S,3′S,4′S)-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-4′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-1′-carboxylic acid (1-acetyl-piperidin-4-yl)-amide as a white solid (65 mg, 92%)
Reaction SMILES: CC1C=C(C(F)(F)F)C2C(=CC=C(O)C=2)N=1.[Br:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([O:28]C)[CH:26]=2)[N:21]=[C:20]([CH3:30])[CH:19]=1>>[Br:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([OH:28])[CH:26]=2)[N:21]=[C:20]([CH3:30])[CH:19]=1
Reactant: COc1ccc2nc(C)cc(Br)c2c1
Agent: Cc1cc(C(F)(F)F)c2cc(O)ccc2n1
Product: Cc1cc(Br)c2cc(O)ccc2n1

Procedure:
Synthesized as per 2-Methyl-4-trifluoromethyl-quinolin-6-ol using 4-Bromo-6-methoxy-2-methyl-quinoline as starting material. ESI-MS (M+H+): 238.00/240.00.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[CH2:10](I)[CH3:11].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:10]([O:8][C:7]([C:5]1[S:6][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:9])[CH3:11]
Reactant: CCI
Reactant: O=C(O)c1ccc(Cl)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
5-Chloro-2-thiophenecarboxylic acid (6.50 g) was dissolved in N,N-dimethylformamide (30 ml), and ethyl iodide (3.2 ml) and potassium carbonate (5.52 g) were added. The mixture was stirred at room temperature for 15 hours, poured into water and extracted with diethyl ether. The extract was washed with 5% aqueous potassium hydrogen sulfate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5-chloro-2-thiophenecarboxylic acid ethyl ester (5.27 g). 5-Chloro-2-thiophenecarboxylic acid ethyl ester (2.23 g) was dissolved in acetonitrile (30 ml), and sulfuryl chloride (1.4 ml) in acetonitrile (20 ml) was added dropwise. The mixture was stirred at room temperature for 48 hours, and 10% aqueous sodium thiosulfate (100 ml) was added. The mixture was stirred at room temperature for 2 hours and extracted with diethyl ether. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography. The desired fractions were concentrated under reduced pressure to give 4,5-dichloro-2-thiophenecarboxylic acid ethyl ester (6.21 g). 4,5-Dichloro-2-thiophenecarboxylic acid ethyl ester (6.21 g) was dissolved in a mixture of ethanol (25 ml) and tetrahydrofuran (25 ml), and 1N aqueous sodium hydroxide (50 ml) was added. The mixture was stirred at 60° C. for 15 hours and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 4,5-dichloro-2-thiophenecarboxylic acid (2.14 g) as crystals.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([CH3:15])([CH3:14])[CH2:12][OH:13])[N:10]=2)[CH:7]=1.[C:16]1([C:22]#[CH:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:14][C:11]([C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([C:23]#[C:22][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:7][N:6]2[N:8]=1)([CH3:15])[CH2:12][OH:13]
Reactant: C#Cc1ccccc1
Reactant: CC(C)(CO)c1nc2ccc(I)cn2n1
Product: CC(C)(CO)c1nc2ccc(C#Cc3ccccc3)cn2n1

Procedure:
The title compound, a brown solid, MS: m/e=292.0 (M+H+), can be prepared in accordance with the general method of example 1 from 2-(6-iodo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-2-methyl-propan-1-ol (example 40, step 7) and phenylacetylene.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][NH:4][C@H:3]1[CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].[OH-].[Na+].Cl[C:20]([O:22][CH2:23][CH:24]=[CH2:25])=[O:21]>C1COCC1>[C:12]([O:11][C:10]([NH:9][CH2:8][C@H:3]1[C@@H:2]([CH3:1])[CH2:7][CH2:6][CH2:5][N:4]1[C:20]([O:22][CH2:23][CH:24]=[CH2:25])=[O:21])=[O:16])([CH3:15])([CH3:14])[CH3:13]
Reactant: C=CCOC(=O)Cl
Reactant: C[C@H]1CCCN[C@H]1CNC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=CCOC(=O)N1CCC[C@H](C)[C@@H]1CNC(=O)OC(C)(C)C

Procedure:
To the mixture of rac-cis-tert-butyl ((3-methylpiperidin-2-yl)methyl)carbamate (9.48 g, 41.53 mmol) in THF (25 mL) was added NaOH (2 M, 25 mL), followed by allyl chloroformate (6.65 mL, 62.3 mmol).
Reaction SMILES: [NH2:1][C:2]1[C:9]([N+:10]([O-])=O)=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:13].O.O.[Sn](Cl)(Cl)(Cl)Cl>C(O)C>[NH2:10][C:9]1[CH:8]=[C:5]([CH:4]=[C:3]([CH3:13])[C:2]=1[NH2:1])[C:6]#[N:7]
Reactant: Cc1cc(C#N)cc([N+](=O)[O-])c1N
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: CCO
Product: Cc1cc(C#N)cc(N)c1N
Temperature: 25 °C
Yield: 80.6 %

Procedure:
To a solution of 4-amino-3-methyl-5-nitro-benzonitrile (3.24 g, 18.3 mmol) in ethanol (80 mL) was added tin chloride dihydrate (8.67 g, 49.75 mmol). The reaction mixture was heated to reflux for 14 h, then cooled to room temperature, and concentrated in vacuum. The residue was diluted with ethyl acetate (100 mL) and treated with triethylamine (20 mL). The resulting slurry was filtered through a pad of celite and the filtercake was rinsed with three-portion ethyl acetate (50 mL). The filtrate was washed with saturated NaHCO3, water, and brine, then dried over Na2SO4 and filtered. After removal of solvent, the residue was purified by flash chromatography on silica gel (30%-50% EtOAc/hexane) to yield the title compound (2.17 g, 81%) as a light yellow solid. 1H NMR (300 MHz, CDCl3) δ 6.94 (1H, s), 6.85 (1H, s), 2.16 (3H, s). LCMS (M+H)+ m/z 148 (t=0.67 min.). Procedure for the Preparation of 5-bromo-3-methyl-benzene-1,2-diamine
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:14])[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:15]2[S:16][CH:17]=[CH:18][N:19]=2)[CH:3]=1.C(C1N=C(C2C=C(O[CH:39]3[CH2:57][CH:56]4[N:41]([C:42](=[O:62])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH:49]=[CH:50][CH:51]5[C:53]([C:59]([OH:61])=[O:60])([NH:54][C:55]4=[O:58])[CH2:52]5)[CH2:40]3)C3C(=CC(OC)=CC=3)N=2)SC=1)(C)C>>[S:16]1[CH:17]=[CH:18][N:19]=[C:15]1[C:4]1[CH:3]=[C:2]([O:1][CH:39]2[CH2:57][CH:56]3[N:41]([C:42](=[O:62])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH:49]=[CH:50][CH:51]4[C:53]([C:59]([OH:61])=[O:60])([NH:54][C:55]3=[O:58])[CH2:52]4)[CH2:40]2)[C:11]2[C:6](=[C:7]([CH3:14])[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=1
Reactant: COc1ccc2c(O)cc(-c3nccs3)nc2c1C
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCCCC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCCCC(=O)N4C3)cc(-c3nccs3)nc2c1C

Procedure:
The title compound was prepared from quinoline 24 and intermediate 7 following the procedure (Step F-H) reported for 18-[2-[4-(isopropyl)thiazol-2-yl]-7-methoxyquinolin-4-yloxy]-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid 10: m/z=605 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:15]([C:17]2[C:26]3[C:21](=[C:22]([C:27]([F:30])([F:29])[F:28])[CH:23]=[CH:24][CH:25]=3)[N:20]=[C:19]([C:31]([F:34])([F:33])[F:32])[CH:18]=2)[OH:16])[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1>CCO.[Pd]>[F:33][C:31]([F:32])([F:34])[C:19]1[CH:18]=[C:17]([CH:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([OH:8])[CH:10]=2)[OH:16])[C:26]2[C:21](=[C:22]([C:27]([F:30])([F:28])[F:29])[CH:23]=[CH:24][CH:25]=2)[N:20]=1
Reactant: OC(c1cccc(OCc2ccccc2)c1)c1cc(C(F)(F)F)nc2c(C(F)(F)F)cccc12
Agent: [Pd]
Solvent: CCO
Product: Oc1cccc(C(O)c2cc(C(F)(F)F)nc3c(C(F)(F)F)cccc23)c1
Yield: 54.7 %

Procedure:
A solution of α-(3-benzyloxyphenyl)-2,8-bis(trifluoromethyl)-4-quinolinemethanol (80 mg, 0.17 mmol) in EtOH (4 mL) was treated with 10% Pd/C (5 mg), hydrogenated for 2 h, filtered to remove the catalyst, concentrated in vacuo and the resulting oil purified by chromatography [SiO2; heptane-EtOAc (1:1)] to give the title compound (36 mg, 53%) as an oil: NMR δH (400 MHz, CDCl3) 5.35 (1H, br s), 6.45 (1H, s), 6.65-6.80 (2H, m), 6.91 (1H, d, J 10.0 Hz), 7.21 (1H, t, J 7.0 Hz), 7.59 (1H, t, J 9.0 Hz), 8.12 (2H, t, J 9.0 Hz) and 8.22 (1H, s).
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4]([C:7]1[CH:8]=[C:9]([NH:13][C:14]2[N:23]=[CH:22][C:21]3[N:20]([CH3:24])[C:19](=[O:25])[CH2:18][N:17]([CH:26]([CH3:28])[CH3:27])[C:16]=3[N:15]=2)[CH:10]=[CH:11][CH:12]=1)(=[O:6])=[O:5].C(N(C(C)C)C(C)C)C.[S:38](Cl)([CH3:41])(=[O:40])=[O:39].O>ClCCl.CN(C)C1C=CN=CC=1>[CH:26]([N:17]1[C:16]2[N:15]=[C:14]([NH:13][C:9]3[CH:8]=[C:7]([S:4]([CH2:3][CH2:2][O:1][S:38]([CH3:41])(=[O:40])=[O:39])(=[O:5])=[O:6])[CH:12]=[CH:11][CH:10]=3)[N:23]=[CH:22][C:21]=2[N:20]([CH3:24])[C:19](=[O:25])[CH2:18]1)([CH3:28])[CH3:27]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)N1CC(=O)N(C)c2cnc(Nc3cccc(S(=O)(=O)CCO)c3)nc21
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CC(C)N1CC(=O)N(C)c2cnc(Nc3cccc(S(=O)(=O)CCOS(C)(=O)=O)c3)nc21
Temperature: 0 °C
Yield: 63 %

Procedure:
2-(3-(2-Hydroxyethylsulfonyl)phenylamino)-8-isopropyl-5-methyl-7,8-dihydropteridin-6(5H)-one (1.45 g; 3.576 mmol) was dissolved in 35 mL dichloromethane, ethyldiisopropylamine (0.92 mL; 5.360 mmol) and 4-dimethylaminopyridine (cat.) were added. Then the mixture was cooled to 0° C. and mesylchloride (0.332 ml; 4.290 mmol) was added slowly. The reaction mixture was allowed to get to room temperature and after 4 h water was added and the mixture was extracted with dichloromethane. Drying of the organic layer with sodium sulphate and removal of the solvents gave 1.1 g (2.275; 63% yield) of intermediate the desired product as foam.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]2[C:5]([N:6]=[C:7]3[C:12](=[C:13]2[CH:16]([F:18])[F:17])[CH:11]=[CH:10][CH:9]=[N:8]3)=[CH:4][CH:3]=1.[CH2:19]([Li])[CH2:20][CH2:21][CH3:22]>C1COCC1>[CH2:19]([C:13]1([CH:16]([F:18])[F:17])[C:12]2[CH:11]=[CH:10][CH:9]=[N:8][C:7]=2[NH:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:15][C:14]1=2)[CH2:20][CH2:21][CH3:22]
Reactant: FC(F)c1c2cc(Cl)ccc2nc2ncccc12
Reactant: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCC1(C(F)F)c2cc(Cl)ccc2Nc2ncccc21
Temperature: -78 °C
Reaction time: 5 h
Yield: 2.1 %

Procedure:
Method GG: A solution of 7-chloro-9-difluoromethyl-4-azaacridine (396 mg 1.5 mmol) in THF (10 mL) was cooled under N2 to −78° C. n-Butyl lithium was added dropwise over 15 min and the reaction mixture was stirred at −78° C. for 5 h. The reaction was quenched with sat. NH4Cl solution and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine, dried and concentrated. Column chromatography (SiO2, 10% EtOAc-hexane-1% Et3N) afforded the desired material 5-Butyl-7-chloro-5-difluoromethyl-5,10-dihydro-benzo[b][1,8]naphthyridine as a viscous yellow oil (10 mg, 2.1%).
Reaction SMILES: [Cl:1][C:2]1C=CC(SCCl)=CC=1.[OH:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1.CC(C)([O-])C.[K+].C=CC1C=CC=CC=1>CN(C=O)C.C(Cl)Cl>[Cl:1][CH2:2][O:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1
Reactant: Oc1ccc2ccccc2c1
Reactant: ClCSc1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C=Cc1ccccc1
Solvent: ClCCl
Product: ClCOc1ccc2ccccc2c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
4-Chloro-1-(chloromethylthio)benzene (20 mmol) in DMF (10 ml) was added to a mixture of 2-hydroxynaphthalene (20 mmol) and potassium tert-butoxide (20 mmol) in DMF (40 ml). The mixture was stirred at 80° C. for 2 hours before the solvent was distilled off and the residue triturated with water, extracted into ether and washed three times with water. The dried (MgSO4) solution was evaporated and recrystallized from EtOH yield: 3.30 g (57%). m.p. 70° C. The product (10.3 mmol) was dissolved in dry CH2Cl2 (30 ml) and SO2Cl2 (10.3 mmol) in dry CH2Cl2 (10 ml) was added with stirring at room temperature for 5 minutes. The mixture was stirred for 10 minutes before styrene (10.3 mmol) in dry CH2Cl2 (10 ml) was added with stirring at 5° C. for 10 minutes. The mixture was stirred for 20 minutes at room temperature before the solvent was distilled off and the residue distilled under vacuum. Yield: 1.50 g (76%) b.p. 82°-95° C. 0.03 mmHg [see J. Appl. Chem. 3, 266(1953) b.p. 90°-110° C./0.15 mmHg].
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[NH2:13][CH:14]([C:18]([OH:20])=[O:19])[CH:15]([CH3:17])[OH:16].CO>[Ni].[Pd].O>[OH:4][CH:3]([CH:5]([OH:6])[CH:7]([OH:8])[CH:9]([OH:10])[CH2:11][OH:12])[CH2:2][NH:13][CH:14]([C:18]([OH:20])=[O:19])[CH:15]([CH3:17])[OH:16]
Reactant: CC(O)C(N)C(=O)O
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Ni]
Agent: [Pd]
Solvent: O
Solvent: CO
Product: CC(O)C(NCC(O)C(O)C(O)C(O)CO)C(=O)O

Procedure:
The starting materials were D-glucose and DL-threonine. The reductive amination was carried out using Raney nickel or palladium/activated carbon (10%) and yielded a product having a melting point of 219° C. (decomposition) and a RF -value of 0.67 (determined on DC-finished plates of silica gel G (Merck) with a transporting fluid made up of 75 parts by volume of methanol and 25 parts by volume of water).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9](=[O:24])[N:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:11]=[C:12]([C:14]([O:16][CH3:17])=O)[CH:13]=1.Br[C:26]1[C:27](=O)[N:28](C2C=CC=CC=2)[CH:29]=[C:30](C(OC)=O)[CH:31]=1.ClC1C=CC=CC=1B(O)O.C(Cl)(=O)C(Cl)=O.NC1C=CC=CC=1O>ClCCl.CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9](=[O:24])[N:10]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:11]=[C:12]([C:14]2[O:16][C:17]3[CH:29]=[CH:30][CH:31]=[CH:26][C:27]=3[N:28]=2)[CH:13]=1
Reactant: COC(=O)c1cc(-c2ccccc2Cl)c(=O)n(-c2ccccc2)c1
Reactant: COC(=O)c1cc(Br)c(=O)n(-c2ccccc2)c1
Agent: Nc1ccccc1O
Agent: O=C(Cl)C(=O)Cl
Agent: OB(O)c1ccccc1Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=c1c(-c2ccccc2Cl)cc(-c2nc3ccccc3o2)cn1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
19 mg of carboxylate obtained by hydrolyzing the ester group of 3-(2-chlorophenyl)-5-(methoxycarbonyl)-1-phenyl-1,2-dihydropyridin-2-one (synthesized from 3-bromo-5-(methoxycarbonyl)-1-phenyl-1,2-dihydropyridin-2-one and 2-chlorophenylboronic acid in accordance with the method of Referential Example 3) was dissolved in 20 ml of dichloromethane. Under ice-cooling, a solution of 11 mg of oxalyl chloride in dichloromethane was added dropwise thereinto and a catalytic amount of dimethylformamide was added thereto, followed by stirring at room temperature in nitrogen atmosphere for 1 hour. The reaction solution was evaporeted, and the residue was dissolved in dichloromethane. The solution was added dropwise into a solution of 19 mg of 2-aminophenol in dichloromethane under ice-cooling. After heating to room temperature, dichlotomethane was evaporated. To the residue was added 1 ml of polyphosphoric acid, followed by stirring at 180° C. overnight. After cooling to room temperature, the reaction mixture was neutralized with 1N aqueous solution of sodium hydroxide and saturated aqueous solution of sodium hydrogen carbonate under ice-cooling. The mixture was extracted with ethyl acetate, and the resulting organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography (hexane/ethyl acetate system), to give 3 mg of the title compound as white crystals.