Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH3:27])[C:9](=O)[CH2:10][N:11]1[C:24]2[CH:23]=[C:22]([Cl:25])[CH:21]=[CH:20][C:19]=2[S:18][C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.Cl.CO>[CH2:1]([N:8]([CH2:9][CH2:10][N:11]1[C:24]2[CH:23]=[C:22]([Cl:25])[CH:21]=[CH:20][C:19]=2[S:18][C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH3:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(Cc1ccccc1)C(=O)CN1c2ccccc2Sc2ccc(Cl)cc21
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CN(CCN1c2ccccc2Sc2ccc(Cl)cc21)Cc1ccccc1
Reaction time: 0.5 h
Yield: 118.3 %

Procedure:
N-Benzyl-2-(2-chlorophenothiazin-10-yl)-N-methylacetamide (140 mg, 0.355 mmol) was dissolved in THF (5 mL). A solution of borane• THF complex in THF (1.0 M, 5 mL, 5 mmol) was added, and the solution heated to reflux for 4 h. The mixture was carefully diluted with saturated HCl in methanol and stirred for 30 min. The solvent was removed under vacuum, and the residue dissolved in ethyl acetate and aqueous sodium hydroxide (1 N). The layers were separated and the aqueous layer extracted with ethyl acetate. The organic layers were combined, dried (Na2SO4), filtered, and concentrated to provide benzyl-[2-(2-chlorophenothiazin-10-yl)-ethyl]methyl amine as a white solid (160 mg). The crude product was purified by SiO2 chromatography to provide pure product (50 mg, 34%) and 100 mg of impure product. The pure product was dissolved in acetone and a solution of fumaric acid (0.8 mL, 0.02 g/mL in methanol) was added. The solvents were removed under vacuum, and the residue slurried in chloroform and filtered to provide the sub-titled compound (47 mg) as an off-white solid.
Reaction SMILES: CC1(C)[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]#[C:15][C:16]([O:18][CH2:19]C)=[O:17])[CH:5]=[CH:4][C:3]1=2.CC1(C)C2C(=CC=C(C#C)C=2)[S:26]CC1.COC(Cl)=O.C([Li])CCC>>[CH3:12][C:9]1([CH3:13])[C:8]2[C:3](=[CH:4][CH:5]=[C:6]([C:14]#[C:15][C:16]([O:18][CH3:19])=[O:17])[CH:7]=2)[S:26][CH2:11][CH2:10]1
Reactant: C#Cc1ccc2c(c1)C(C)(C)CCS2
Reactant: CCOC(=O)C#Cc1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: COC(=O)Cl
Agent: [Li]CCCC
Product: COC(=O)C#Cc1ccc2c(c1)C(C)(C)CCS2

Procedure:
Employing the same general procedure as used for the preparation of ethyl 3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)propiolate (Compound A), but instead using 2.0 g (10 mmols) of (4,4-dimethyl-thiochroman-6-yl)ethyne, 2 g (21.3 mmols) of methylchloroformate and 11 mmols of n-butyl lithium the title compound was obtained as a yellow solid.
Reaction SMILES: [N:1]1[N:2]([C:10]2[N:33]=[CH:32][CH:31]=[CH:30][C:11]=2[C:12]([NH:14][CH:15]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:16]([OH:22])[C:17]([O:19]CC)=[O:18])=[O:13])[CH:3]=[C:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[CH:5]2.[OH-].[Li+]>C1COCC1.O>[N:1]1[N:2]([C:10]2[N:33]=[CH:32][CH:31]=[CH:30][C:11]=2[C:12]([NH:14][CH:15]([CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:16]([OH:22])[C:17]([OH:19])=[O:18])=[O:13])[CH:3]=[C:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[CH:5]2
Reactant: CCOC(=O)C(O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1cc2ccccc2n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(NC(Cc1ccccc1)C(O)C(=O)O)c1cccnc1-n1cc2ccccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a suspension of ethyl 3-[2-(2H-indazol-2-yl)nicotinamido]-2-hydroxy-4-phenylbutanoate (1.05 g, 2.362 mmol) in THF (50 ml) a solution of lithium hydroxide (100 mg) in water (5 ml) was added, and the mixture was stirred overnight at room temperature. The mixture was then concentrated in vacuo and, after addition of water (100 ml), acidified using 2 N HCl. The precipitate formed was filtered off and dried to give 895 mg of the title compound as an off-white solid.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[Cl:44][C:45]1[CH:46]=[C:47]([CH:51]=[C:52]([Cl:54])[N:53]=1)[C:48]([OH:50])=O.[N:55]1([CH2:61][CH2:62][NH2:63])[CH2:60][CH2:59][O:58][CH2:57][CH2:56]1>CC(N(C)C)=O>[Cl:54][C:52]1[CH:51]=[C:47]([CH:46]=[C:45]([Cl:44])[N:53]=1)[C:48]([NH:63][CH2:62][CH2:61][N:55]1[CH2:60][CH2:59][O:58][CH2:57][CH2:56]1)=[O:50]
Reactant: NCCN1CCOCC1
Reactant: O=C(O)c1cc(Cl)nc(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCN1CCOCC1)c1cc(Cl)nc(Cl)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 105 %

Procedure:
HATU (989 mg, 2.6 mmol), HOAT (354 mg, 2.6 mmol) and DIEA (907 μl, 5.21 mmol) were added to a stirred solution of 2,6-dichloroisonicotinic acid (500 mg, 2.60 mmol) in anhydrous DMA (4 ml). The mixture was stirred for 10 minutes after which 2-morpholin-4-yl-ethylamine (420 μl, 2.86 mmol) was added. The mixture was stirred at room temperature for 12 h and the mixture was partitioned between EtOAc and water. The EtOAc layer was washed well with water, dried over sodium sulphate and concentrated in vacuo to give the title compound as an oil (830 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH:20]1[CH:21]=[CH:22][N:23]2[CH2:29][C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[NH:26][CH2:25][C:24]=12.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:19]=[CH:18][C:14]([C:15]([N:26]3[C:27]4[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=4[CH2:29][N:23]4[CH:22]=[CH:21][CH:20]=[C:24]4[CH2:25]3)=[O:16])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: Cc1ccc(S(=O)(=O)c2ccc(C(=O)Cl)cc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2)cc1
Reaction time: 16 h
Yield: 54.1 %

Procedure:
A mixture of 2.13 g of 4-[(4-methylphenyl)sulfonyl]benzoyl chloride (Reference Example 42) and 1.0 g of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine in 30 ml of methylene chloride containing 7 ml of triethylamine is stirred under nitrogen atmosphere for 16 hours. The reaction mixture is diluted with ? ml of chloroform and washed with 2N HCl, water, saturated NaHCO3 and water. The organic layer is dried (Na2SO4) and columned on silica gel by elution with 7:1 to 3:1 ethyl acetate:hexane to give 1.3 g of the desired product as a solid. M+H 443.2; M+Na 465.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[C:9]([C:12]2[N:13]=[N:14][N:15]([CH2:17][CH3:18])[N:16]=2)[CH:10]=O)=[CH:4][CH:3]=1.C1(P(=[CH:45][CH:46]=[O:47])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)=[C:9]([C:12]2[N:13]=[N:14][N:15]([CH2:17][CH3:18])[N:16]=2)[CH:10]=[CH:45][CH:46]=[O:47])=[CH:6][CH:7]=1
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCn1nnc(C(C=O)=C(c2ccc(F)cc2)c2ccc(F)cc2)n1
Product: CCn1nnc(C(C=CC=O)=C(c2ccc(F)cc2)c2ccc(F)cc2)n1
Yield: 94.8 %

Procedure:
The procedure of Example 50 was repeated using 3.25 g (9.5 mmoles) of 3,3-bis(4-fluorophenyl)-2-(2-ethyl-2H-tetrazol-5-yl)-2-propenal and 3.05 g (10.0 mmoles) of triphenylphosphoranylidene acetaldehyde and there was thereby produced 3.3 g (95%) of the title compound; m.p.=117°-120° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][Br:7].[C:8]1([CH2:14][CH2:15][CH2:16][OH:17])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[Br:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:17][CH2:16][CH2:15][CH2:14][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OCCCc1ccccc1
Reactant: BrCCCCCBr
Product: BrCCCCCOCCCc1ccccc1

Procedure:
(2.8 g), T.l.c. [K] Rf 0.44 from 1,5-dibromopentane (10.2 g) and benzenepropanol (2 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:15]([C:19]1[S:20][CH:21]=[CH:22][C:23]=1[S:24](Cl)(=[O:26])=[O:25])([O:17][CH3:18])=[O:16]>C1COCC1>[CH3:18][O:17][C:15]([C:19]1[S:20][CH:21]=[CH:22][C:23]=1[S:24](=[O:26])(=[O:25])[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:16]
Reactant: COC(=O)c1sccc1S(=O)(=O)Cl
Reactant: Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1sccc1S(=O)(=O)Nc1ccccc1
Temperature: 25 °C
Yield: 88.3 %

Procedure:
To a solution of an aniline (1.02 g, 10.9 mmol, 11.1 equivalents) dissolved in dry THF (35 mL) and triethylamine (1.53 mL, 1.1 equivalents) at room temperature, sealed with a septum and a nitrogen inlet, was added 2-carbomethoxythiophene-3-sulfonyl chloride (2.5 g, 9.9 mmol, 95% purity). The reaction mixture was stirred at room temperature over night. Upon completion, the reaction will be extracted by diluting with ethyl acetate and washing with aqueous HCl (2N), water and saturated, aqueous sodium chloride solution. The organic layer was dried over sodium sulfate. The solution will be decanted and evaporated under reduced pressure to give the desired 3-phenylsulfamoylthiophene-2-carboxylic acid methyl ester (2.6 g, 88%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([CH2:15][CH2:16][CH3:17])[C:13]=1[OH:14])[N:10]=[C:9]([C:18]([O:20]C)=[O:19])[CH:8]=[C:7]2Cl)(=[O:3])[CH3:2].[CH3:23][NH:24][CH3:25].O>CO.S(=O)(=O)(O)O>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([CH2:15][CH2:16][CH3:17])[C:13]=1[OH:14])[N:10]=[C:9]([C:18]([OH:20])=[O:19])[CH:8]=[C:7]2[N:24]([CH3:25])[CH3:23])(=[O:3])[CH3:2]
Reactant: CCCc1c(O)c(C(C)=O)cc2c(Cl)cc(C(=O)OC)nc12
Reactant: CNC
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: CCCc1c(O)c(C(C)=O)cc2c(N(C)C)cc(C(=O)O)nc12

Procedure:
Methyl 6-acetyl-4-chloro-7-hydroxy-8-propyl-quinoline-2-carboxylate (6 g; 18.6474 mmole) in 33% w/w dimethylamine in methanol (50 ml) was heated at 100° C. under pressure (autoclaved) for 24 hours. The mixture was cooled, and treated with water, concentrated, and extracted with chloroform. The extract was washed with water, dried and evaporated to give a brown solid. The solid was heated in 70% sulphuric acid (150 ml) on a steambath for 6 hours. The mixture was cooled and the pH adjusted to about 7 before extraction into chloroform. The extract was dried and evaporated to give a yellow solid (1.25 g). NMR and mass spectra were consistent with the required structure.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])[C:9]([C:11]1[CH:33]=[CH:32][C:14]2[N:15]([CH3:31])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][C:21]=3[O:29][CH3:30])=[N:17][C:13]=2[CH:12]=1)=[O:10].[OH-].[Na+]>ClCCl.C(O)C>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:34][CH2:35][C:36]([OH:38])=[O:37])[C:9]([C:11]1[CH:33]=[CH:32][C:14]2[N:15]([CH3:31])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH2:28])=[CH:22][C:21]=3[O:29][CH3:30])=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1OC)n2C)c1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: COc1cc(C(=N)N)ccc1NCc1nc2cc(C(=O)N(CCC(=O)O)c3ccccn3)ccc2n1C
Yield: 78 %

Procedure:
Prepared analogously to Example 26 from 1-methyl-2-[N-(4-amidino-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution. Yield: 78% of theory, C26H27N7O4 (501.6) Rf value: 0.12 (silica gel; dichloromethane/ethanol=4:1) EKA mass spectrum: (M+H)+ =502
Reaction SMILES: [N+]([O-])([O:3][CH2:4][C:5](=[O:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([I:13])=[CH:9][CH:8]=1)=O.O.O.O.C([O-])(=O)C.[Na+].O>CS(C)=O>[I:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C:5](=[O:14])[CH:4]=[O:3])=[CH:12][CH:11]=1
Reactant: O=C(CO[N+](=O)[O-])Cc1ccc(I)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=CC(=O)Cc1ccc(I)cc1
Temperature: 25 °C
Yield: 90.1 %

Procedure:
3-(4-Iodophenyl)-2-oxopropyl nitrate (17) (450 mg) was dissolved in dimethylsulfoxide (20 mL) and to this was added sodium acetate trihydrate (211 mg, 1.55 mmol), and stirred for an hour at room temperature. To this was added water and the product was extracted with diethyl ether (×3). The organic layer was washed sequentially with water (×1), saturated aqueous solution of sodium bicarbonate (×1) and saturated brine (×1), and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give 3-(4-iodophenyl)-2-oxopropanal (18) as an orange solid (346 mg, <1.26 mmol, <90.1%), which was used in the next reaction without further purification.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C@@:13]1([CH2:17][N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)[C@H:15]([CH3:16])[O:14]1.C(=O)([O-])[O-].[Li+].[Li+].CN(C)C=O>C(OCC)(=O)C>[N:18]1([CH2:17][C@@:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[F:6])([OH:14])[C@H:15]([N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)[CH3:16])[CH:22]=[N:21][CH:20]=[N:19]1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccccc1F
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H](n1cncn1)[C@](O)(Cn1cncn1)c1ccccc1F
Temperature: 110 °C
Reaction time: 24 h
Yield: 50.9 %

Procedure:
A mixture of 1H-1,2,4-triazole (1.17 g), (2R,3S)-2-(2-fluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl] oxirane (2 g), lithium carbonate (6.32 g) and dimethylformamide (40 ml) was stirred for 24 hours at 110° C. After cooling, to the mixture was added ethyl acetate (50 ml). The mixture was filtered to remove insoluble substances. The filtrate was distilled under reduced pressure. The residue was dissolved in ethyl acetate (100 ml). The mixture was washed with saturated saline (30 ml ×2). The ethyl acetate layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure. The residue was purified by silica gel chromatography (silica gel 50 g, eluent: ethyl acetate/acetone=4.1) to give (2R,3R)-1,3-bis(1H-1,2,4-triazol-1-yl)-2-(2-fluorophenyl)-2-butanol (1.32 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20]#[CH:21])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.Br[C:23]1[CH:24]=[CH:25][C:26]([O:38][CH3:39])=[C:27]([S:29]([NH:32][C:33]([CH3:37])([CH3:36])[CH2:34][OH:35])(=[O:31])=[O:30])[CH:28]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20]#[C:21][C:23]4[CH:24]=[CH:25][C:26]([O:38][CH3:39])=[C:27]([S:29]([NH:32][C:33]([CH3:36])([CH3:37])[CH2:34][OH:35])(=[O:31])=[O:30])[CH:28]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(Br)cc1S(=O)(=O)NC(C)(C)CO
Reactant: C#Cc1cnn2c(C3CC3)cc(-c3ccc(Cl)cc3)nc12
Product: COc1ccc(C#Cc2cnn3c(C4CC4)cc(-c4ccc(Cl)cc4)nc23)cc1S(=O)(=O)NC(C)(C)CO

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-cyclopropyl-3-ethynyl-pyrazolo[1,5-a]pyrimidine (example C.5) (73 mg, 0.25 mmol) and 5-bromo-N-(2-hydroxy-1,1-dimethyl-ethyl)-2-methoxy-benzenesulfonamide (85 mg, 0.25 mmol) (Example B.7) according to general procedure II. Obtained as a yellow solid (38 mg, 28%). MS (ISP) 551.3[(M+H)+]; mp 253-256° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([O:17]C)=[O:16])[C:10](=[O:19])[CH:9]1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:23][CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([OH:17])=[O:16])[C:10](=[O:19])[CH:9]1[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:25][CH:26]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CN1CCN(C(=O)OC(C)(C)C)C(Cc2ccc(OCc3ccccc3)cc2)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(CC(=O)O)C(=O)C1Cc1ccc(OCc2ccccc2)cc1

Procedure:
t-Boc-piperazinoneacetate 4a (0.251 g, 5.37×10-4 mole), 1 M aqueous LiOH (0.59 ml, 5.9×10-4 mole), and methanol (2 ml) are stirred at room temperature for 2 hours. The solvent is then evaporated and the resulting yellow oil is dissolved in CH2Cl2 and transferred to a separatory funnel where it is washed with 0.5 M aqueous HCl. The CH2Cl2 layer is separated and the acidic aqueous phase is extracted with CH2Cl2 (3 times). The CH2Cl2 extracts are combined and washed with saturated aqueous NaCl before being dried over Na2SO4. Filtration of the drying agent and evaporation of the filtrate gives 5a as a colorless foam, which was shown to be homogeneous by TLC on silica gel plates. The structure of 5a was corroborated by NMR. NMR (CDCl3) δ 1.27 (S, 9, t-boc), 3.09-4.07 (m, 8, methylenes), 4.68 (t, 1, C3 -H), 4.97 (S, 2, benzyloxy methylene), 6.89 (q, 4, aromatic), 7.30 (S, 5, aromatic), 9.99 (broad S, 1, acid).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[NH:7][C:8](=O)[C:9]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:13][S:12][C:10]=2[N:11]=1)[CH3:2].P(Cl)(Cl)([Cl:25])=O.CN(C)C1C=CC=CC=1>ClCCl>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[N:7]=[C:8]([Cl:25])[C:9]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:13][S:12][C:10]=2[N:11]=1)[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)Cc1nc2scc(-c3ccccc3)c2c(=O)[nH]1
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Product: CCOC(=O)Cc1nc(Cl)c2c(-c3ccccc3)csc2n1
Reaction time: 18 h

Procedure:
A stirred solution of (4-oxo-5-phenyl-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)acetic acid ethyl ester (1.0 g, 3.185 mmol), phosphoryl chloride (15 ml) and N,N-dimethylaniline (4.8 ml) was heated under reflux for 6 hours and then left to stand at ambient temperature for 18 hours. The excess phosphoryl chloride was removed in vacuo to give a dark residue, which was dissolved in dichloromethane (100 ml) and then washed with water (2×50 ml) followed by saturated sodium hydrogen carbonate solution (50 ml). The organic layer was dried (MgSO4) and the solvent was removed in vacuo to give the crude product. Purification by flash chromatography (silica) eluting with dichloromethane and 40°-60° petroleum ether (3:1) gave (4-chloro-5-phenylthieno[2,3-d]pyrimidin-2-yl)acetic acid ethyl ester as a pale-yellow solid (0.86 g).
Reaction SMILES: [OH-].[K+].[C:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]=[N:13][C:14](=[C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21][C:20]([CH3:29])([CH3:28])[NH:19]2)[C:15](N)=[O:16])=[CH:8][CH:7]=1)(=[O:5])[CH3:4].C([OH:32])C.Cl>O>[C:3]([C:6]1[CH:7]=[CH:8][C:9]([N:12]=[N:13][C:14](=[C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21][C:20]([CH3:28])([CH3:29])[NH:19]2)[C:15]([OH:32])=[O:16])=[CH:10][CH:11]=1)(=[O:5])[CH3:4]
Reactant: CCO
Reactant: CC(=O)c1ccc(N=NC(C(N)=O)=C2NC(C)(C)Cc3ccccc32)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(=O)c1ccc(N=NC(C(=O)O)=C2NC(C)(C)Cc3ccccc32)cc1
Temperature: 25 °C

Procedure:
Potassium hydroxide and 2-(4-acetyl-phenylazo)-2-(3,3-dimethyl-3,4-dihydro-2H-isoquinoline-1-ylidene)-acetamide (Asinex Corp., Russia) are added to ethanol, and the mixture is refluxed under heating. The refluxed product is cooled to room temperature and, then, added with distilled water, and further added with hydrochloric acid to make the pH neutral, followed by extracting the reaction product with diethylether. The reaction product is dried by using anhydrous sodium sulfate and filtered and, then, the solvent is removed by reducing the pressure. The residue containing the reaction product is purified by column chromatography to obtain the title compound.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].[H-].[Na+].Br[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([B:17]([OH:19])[OH:18])=[CH:13][CH:12]=1.Cl>CN(C=O)C>[O:6]=[C:2]1[N:3]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([B:17]([OH:19])[OH:18])=[CH:13][CH:12]=2)[CH2:4][CH2:5][O:1]1
Reactant: OB(O)c1ccc(CBr)cc1
Reactant: O=C1NCCO1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1OCCN1Cc1ccc(B(O)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.1 %

Procedure:
To a solution of oxazolidin-2-one (243 mg) in anhydrous DMF (10 mL) was added sodium hydride (60% dispersion in mineral oil, 140 mg) in small portions under ice-cooling. The reaction mixture was stirred at room temperature for 2 hr, to the reaction mixture was added (4-(bromomethyl)phenyl)boronic acid (500 mg), and the mixture was stirred for 60 hr. To the reaction mixture was added ice water, and the aqueous layer was neutralized with 1N hydrochloric acid under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was washed with diisopropyl ether and ethyl acetate to give the title compound (273 mg).
Reaction SMILES: [CH2:1](N)C.Cl[C:5]1[C:14]([C:15]([C:17](=[CH:23][N:24](C)[CH3:25])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:16])=[CH:13][C:12]2[C:7](=[C:8]([F:29])[C:9]([F:28])=[C:10]([F:27])[CH:11]=2)[N:6]=1>C(O)C>[CH2:21]([O:20][C:18]([C:17]1[C:15](=[O:16])[C:14]2[CH:13]=[C:12]3[CH:11]=[C:10]([F:27])[C:9]([F:28])=[C:8]([F:29])[C:7]3=[N:6][C:5]=2[N:24]([CH2:25][CH3:1])[CH:23]=1)=[O:19])[CH3:22]
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc2cc(F)c(F)c(F)c2nc1Cl
Reactant: CCN
Solvent: CCO
Product: CCOC(=O)c1cn(CC)c2nc3c(F)c(F)c(F)cc3cc2c1=O
Reaction time: 1 h
Yield: 62.2 %

Procedure:
4.5 g of ethylamine are added in the course of 10 minutes, at between 5° and 10° C., to a stirred suspension of 7.1 g of ethyl 2-(2-chloro-6,7,8-trifluoroquinoline-3-carbonyl)-3-dimethylaminoacrylate in 100 cm3 of ethanol kept at a temperature close to 5° C., the mixture is stirred for 1 hour at between 5° and 10° C. and the temperature is allowed to rise to about 20° C. 4 g of 1,8-diazobicyclo[5.4.0]undec-7-ene (DBU) are added to the solution obtained and the mixture is heated at a temperature close to 75° C. for 1 hour and a half. After cooling to a temperature close to 20° C., the product is drained and washed with twice 30 cm3 of ethanol and twice 50 cm3 of diisopropyl ether. 4 g of 3-ethoxycarbonyl-1-ethyl-7,8,9-trifluoro-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine are obtained in the form of a cream solid melting at 284° C., which is used for the subsequent steps without further purification.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:4][C@H:5]([CH2:9][OH:10])[CH2:6][CH:7]=[CH2:8].B(F)(F)F.CCOCC.CO[C:30](OC)([CH3:32])[CH3:31]>CC(C)=O>[OH:10][CH2:9][C@H:5]([CH2:6][CH:7]=[CH2:8])[CH2:4][C@H:3]1[CH2:2][O:1][C:30]([CH3:32])([CH3:31])[N:11]1[C:12]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:18]
Reactant: C=CC[C@@H](CO)C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: COC(C)(C)OC
Agent: FB(F)F
Solvent: CC(C)=O
Solvent: CCOCC
Product: C=CC[C@@H](CO)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
tert-butyl (2S,4R)-1-hydroxy-4-(hydroxymethyl)hept-6-en-2-ylcarbamate (6.8 g, 26.2 mmol) was dissolved in acetone (150 mL) followed by the addition of BF3.Et2O (2.62 mmol). The reaction mixture was cooled to 0° C. and 2,2-dimethoxypropane (4.1 g, 39.4 mmol) was added. The resulting mixture was stirred at rt for 1 h, TEA (0.5 mL) was added and stirred for another 5 min before evaporating under reduced pressure. The residue was dissolved in Et2O (300 mL), washed with 1 N HCl (80 mL), sat. aq. NaHCO3 (80 mL), brine (80 mL) successively, and dried, filtered, and concentrated under vacuum to give crude (S)-tert-butyl 4-((R)-2-(hydroxymethyl)pent-4-enyl)-2,2-dimethyloxazolidine-3-carboxylate (7.5 g, 96%). It was used for the next step without further purification. 1H NMR (CD3OD) δ 1.4-1.5 (m, 13H), 1.5-1.6 (d, 6H), 1.6-1.9 (m, 2H), 2.0-2.1 (m, 1H), 3.3-3.5 (m, 2H), 3.6-3.8 (m, 2H), 3.8-3.9 (m, 2H), 4.1-4.2 (m, 1H), 5.0-5.1 (m, 2H), 5.7-5.8 (m, 1H).