Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1[C:6]2[C@@H:5]([CH:7]=[CH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:4](=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:3](=[O:25])[C:2]1=2.[ClH:26].C(=O)([O-])O.[Na+]>CC(C)=O>[Cl:26][CH:2]1[CH2:6][C@H:5]([CH:7]=[CH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:4](=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:3]1=[O:25]
Reactant: CCCCCCC=C[C@H]1C(=CCCCCCC(=O)OC)C(=O)C2=C1O2
Reactant: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CCCCCCC=C[C@H]1CC(Cl)C(=O)C1=CCCCCCC(=O)OC
Yield: 4 %

Procedure:
To a solution of 450 mg (1.29 mmol) of (4S)-2,3-epoxy-4-(1-octenyl)-5-(6-methoxycarbonylhexylidene)cyclopentenone in 12 ml of acetone was added 2 ml of concentrated hydrochloric acid at room temperature under stirring. The mixture was stirred for 2 hours. A saturated aqueous solution of sodium hydrogencarbonate was added, and the mixture was concentrated. The product was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The dried product was filtered, concentrated and subjected to silica gel column chromatography (silica gel, 40 g; eluent, hexane:ethyl acetate=10:1→5:1) to give 19 mg (yield 4%) of a less polar isomer (Z-form) of (4R)-2-chloro-4-(1-octenyl)-5-(6-methoxycarbonylhexylidene)cyclopentanone and 177 mg (yield 37%) of a more polar isomer (E-form).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=2)[NH:12][CH:11]=[C:10]3[CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:25][N:26]1[CH:30]=[C:29]([S:31](Cl)(=[O:33])=[O:32])[N:28]=[CH:27]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:25][N:26]1[CH:30]=[C:29]([S:31]([N:22]2[CH2:23][CH2:24][CH:19]([C:10]3[C:9]4[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=[C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[CH:8]=4)[NH:12][CH:11]=3)[CH2:20][CH2:21]2)(=[O:33])=[O:32])[N:28]=[CH:27]1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCNCC3)c[nH]c12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cnc(S(=O)(=O)N2CCC(c3c[nH]c4c(C(N)=O)cc(-c5ccccc5)cc34)CC2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 40.4 %

Procedure:
To 5-phenyl-3-(4-piperidinyl)-1H-indole-7-carboxamide (40 mg, 0.12 mmol) in methylene chloride (5 mL) at 0° C., 1-methyl-1H-imidazole-4-sulfonyl chloride (27.1 mg, 0.14 mmol) and triethylamine (0.07 mL, 0.50 mmol) were added. The reaction mixture was stirred at 0° C. for 30 min. Then the reaction mixture was partitioned between methylene chloride and water, the aqueous layer was extracted with methylene chloride (25 mL×2) and combined organic phase was dried with Mg2SO4 and concentrated by reduce pressure, and purified by Gilson HPLC (reverse phase, eluting with CH3CN/Water, 0.1% TFA, 10/90, v/v, over 15 min) to give the title compound (22.5 mg, 39%).
Reaction SMILES: C[O:2][C:3]([CH2:5][N:6]1[C:15]2[C:10](=[CH:11][C:12]([C:21]([F:24])([F:23])[F:22])=[C:13]([N:16]3[CH:20]=[CH:19][CH:18]=[CH:17]3)[CH:14]=2)[NH:9][C:8](=[O:25])[C:7]1=[O:26])=[O:4].[OH-].[Li+]>O1CCCC1.O>[C:3]([CH2:5][N:6]1[C:15]2[C:10](=[CH:11][C:12]([C:21]([F:24])([F:23])[F:22])=[C:13]([N:16]3[CH:20]=[CH:19][CH:18]=[CH:17]3)[CH:14]=2)[NH:9][C:8](=[O:25])[C:7]1=[O:26])([OH:4])=[O:2]
Reactant: COC(=O)Cn1c(=O)c(=O)[nH]c2cc(C(F)(F)F)c(-n3cccc3)cc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cn1c(=O)c(=O)[nH]c2cc(C(F)(F)F)c(-n3cccc3)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.5 %

Procedure:
2 g (5.45 mmol) of 1-(methoxycarbonylmethyl)-7-(1-pyrrolyl)-6-trifluoromethyl-2,3(1H,4H)-quinoxalinedione (Example 24) were dissolved in 30 ml of tetrahydrofuran, and 0.4 g (16.4 mmol) of lithium hydroxide dissolved in 4 ml of water was added. The mixture was stirred at room temperature for 16 h and then organic solvent was removed under reduced pressure. The aqueous phase was acidified with 1M hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure. The residue was recrystallized from methanol, resulting in 1.3 g (69%) of the product. Melting point 161°-163° C. (decomposition).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][CH:10]=1)[OH:8])[CH3:2].C(=O)(O)[O-].[Na+].Br[CH2:26][CH2:27][CH2:28][CH2:29][C:30]([F:33])([CH3:32])[CH3:31]>C(#N)C>[CH2:1]([N:3]([CH2:26][CH2:27][CH2:28][CH2:29][C:30]([F:33])([CH3:32])[CH3:31])[CH2:4][CH2:5][CH2:6][CH:7]([C:9]1[CH:10]=[CH:11][C:12]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])=[CH:13][CH:14]=1)[OH:8])[CH3:2]
Reactant: CCNCCCC(O)c1ccc(NS(C)(=O)=O)cc1
Reactant: CC(C)(F)CCCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCN(CCCCC(C)(C)F)CCCC(O)c1ccc(NS(C)(=O)=O)cc1

Procedure:
According to Procedure B (Example 17, Step IV), a stirred mixture of N-[4-[4-(ethylamino)-1-hydroxybutyl]phenyl]methanesulfonamide (Example 7, Step II) and sodium bicarbonate in acetonitrile was allowed to react with 1-bromo-5-fluoro-5-methylhexane (Step III) to give the titled product, a compound of Formula I'. The high resolution mass spectrum had M+ at m/z 402. Theory for C20H35FN2O3S: 402.2352; measured: 402.2350.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=O.Cl.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][NH2:16]>CO>[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15]/[N:16]=[CH:2]/[C:1]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C=O
Reactant: NNc1ccccc1Cl
Agent: Cl
Solvent: CO
Product: COC(=O)/C=N/Nc1ccccc1Cl

Procedure:
To a solution of methyl glyoxylate (6.8 g, 77 mmol) in methanol (150 mL) was added 2-chlorophenylhydrazine hydrochloride (12.5 g, 77 mmol) and the mixture was heated at reflux overnight, cooled and concentrated. The residue was re-dissolved in toluene and concentrated to give the title compound of Step A.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9](#[N:13])[CH:10]([CH3:12])[CH3:11].Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1.Cl>O1CCCC1>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][C:10]([CH3:12])([CH3:11])[C:9]#[N:13])=[CH:17][CH:18]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: CC(C)C#N
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C#N)Cc1ccc(Cl)cc1
Reaction time: 0.5 h

Procedure:
To a solution of lithium diisopropylamide (11.0 mL, 21.9 mmol, 2 Min tetrahydrofuran, Aldrich) in tetrahydrofuran (100 mL) was added isobutyronitrile (2.0 mL, 21.9 mmol) at 0-5° C. After 30 minutes of stirring, a solution of 1-(bromomethyl)-4-chlorobenzene (3.0 g, 14.6 mmol) in tetrahydrofuran (10 mL) was added at the same temperature. After stirring at room temperature for 2 hours, the reaction mixture was treated with 10% hydrochloric acid (50 mL), and concentrated under reduced pressure to remove tetrahydrofuran. The concentrate was extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed successively with aqueous NaHCO3 (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was then purified by column chromatography using an Analogix® Intelliflash 280™ (SiO2, 0-30% of ethyl acetate in hexanes) to obtain the titled compound. MS (DCI+) m/z 211 (M+NH4)+.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([CH3:12])([CH3:11])[CH2:5][CH2:6][CH2:7][CH:8]([CH3:10])[CH3:9].CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[CH3:11][C:4]([CH3:12])([CH2:5][CH2:6][CH2:7][CH:8]([CH3:9])[CH3:10])[CH2:3][OH:2]
Reactant: COC(=O)C(C)(C)CCCC(C)C
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: CC(C)CCCC(C)(C)CO
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 52.5 %

Procedure:
2,2,6-Trimethyl-heptanoic acid methyl ester (1.97 g, 10.6 mmol) was taken up in toluene (65 mL) and cooled to −78° C. DiBALH (12.7 mL of a 1 N solution in toluene) was added dropwise. After 45 min, 1.5 mL DiBALH was added. After 2 h, the reaction was quenched by the addition of 15 mL MeOH at −78° C. The mixture was warmed to ambient temperature, and then cooled again to −78° C. for the addition of 10 mL 1 N HCl. The mixture was extracted with EtOAc (3×15 mL). The combined organics were washed with brine, dried (MgSO4), filtered and concentrated. The residual oil was purified via silica gel chromatography (95/5 Hexane/EtOAc) to give 2,2,6-Trimethyl-heptan-1-ol (0.88 g). m/z 159 (M+).
Reaction SMILES: [C:1]([S:4][CH2:5][CH2:6][C:7]([N:9]1[C@H:13]([C:14]([OH:16])=O)[CH2:12][S:11][C@@H:10]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23])=[O:8])(=[O:3])[CH3:2].CN1CCOCC1.C(Cl)(=O)OCC(C)C.Cl.[CH2:40]([O:42][C:43](=[O:46])[CH2:44][NH2:45])[CH3:41]>C1COCC1>[CH2:40]([O:42][C:43](=[O:46])[CH2:44][NH:45][C:14]([C@@H:13]1[CH2:12][S:11][C@H:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[OH:23])[N:9]1[C:7](=[O:8])[CH2:6][CH2:5][S:4][C:1](=[O:3])[CH3:2])=[O:16])[CH3:41]
Reactant: CC(=O)SCCC(=O)N1[C@@H](c2ccccc2O)SC[C@H]1C(=O)O
Reactant: CCOC(=O)CN
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCOC(=O)CNC(=O)[C@@H]1CS[C@H](c2ccccc2O)N1C(=O)CCSC(C)=O
Yield: 81.6 %

Procedure:
The suspension is prepared by using 1.78 g of (2R,4R)-3-(S-acetyl-3-mercaptopropanoyl)-2-(2-hydroxyphenyl)-4-thiazolidinecarboxylic acid, 0.51 g of N-methylmorpholine and 0.68 g of isobutyl chlorocarbonate. To the suspension the solution of 0.7 g of glycine ethyl ester hydrochloride and 0.51 g of N-methylmorpholine dissolved in aqueous THF is added, and treated in the same manner as Example 10 to give 1.8 g (82%) of the titled compound.
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].[C:4]([NH:8][S:9]([C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1Cl)(=[O:11])=[O:10])([CH3:7])([CH3:6])[CH3:5].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:4]([NH:8][S:9]([C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[S:3][CH2:1][CH3:2])(=[O:11])=[O:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)NS(=O)(=O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: CCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCSc1ccc([N+](=O)[O-])cc1S(=O)(=O)NC(C)(C)C
Reaction time: 3 h

Procedure:
5.6 ml of ethylmercaptan are added to a suspension of 20.0 g of N-tert-butyl-2-chloro-5-nitrobenzenesulfonamide, 18.9 g of potassium carbonate and 100 ml of DMF at room temperature. After the mixture has been stirred for 3 hours, it is concentrated under a high vacuum. The residue is taken up in water and acidified with concentrated hydrochloric acid (pH 1 to 2). The aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over magnesium sulfate and then concentrated under reduced pressure. 21.25 g of the desired ethylmercaptan are thus obtained; melting point: 172° to 174° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]2[CH2:12][CH2:13][N:14](C(OC(C)(C)C)=O)[CH2:15][C:10]2=[N:9][N:8]=1.C(O)(C(F)(F)F)=O>ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]2[CH2:12][CH2:13][NH:14][CH2:15][C:10]2=[N:9][N:8]=1
Reactant: CC(C)(C)OC(=O)N1CCn2c(nnc2-c2ccccn2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(-c2nnc3n2CCNC3)nc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1,1-dimethylethyl 3-(2-pyridinyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate (I100)(115 mg, 0.382 mmol) in dichloromethane (DCM) (1 mL), TFA (0.588 mL, 7.63 mmol) was added and mixture was stirred at RT for 3 h. Volatiles removed under reduced pressure and residue purified by SCX cartridge eluting first with MeOH and then with 2.0N NH3 in MeOH. Ammonia fractions were concentrated under reduced pressure yielding desired product as a pale yellow solid.60 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([NH:8][C:9]([NH2:11])=[O:10])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:19]([CH:21]1[O:23][CH2:22]1)Br>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH2:19][CH:21]2[CH2:22][O:23]2)=[C:6]([NH:8][C:9]([NH2:11])=[O:10])[CH:7]=1
Reactant: NC(=O)Nc1cc(Cl)ccc1O
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: NC(=O)Nc1cc(Cl)ccc1OCC1CO1
Temperature: 25 °C
Reaction time: 24 h
Yield: 26.5 %

Procedure:
A suspension of N-(5-chloro-2-hydroxyphenyl)urea (53 mg, 0.28 mmol), cesium carbonate (92 mg, 0.28 mmol) and epibromohydrine (49 mg, 0.36 mmol) in dry DMF (0.6 mL) was stirred at room temperature for 24 hours. The mixture was then partitioned between ethyl acetate and water. The organic phase was washed with water three times, dried and concentrated to a solid residue. This crude product was recrystallized (ethyl ether and heptane to afford the subtitle compound (18 mg, 26.5%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.[H-].[Na+].[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.O>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:26]([C:23]1[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=1)(=[O:28])=[O:27])[CH:6]=[C:5]2[CH2:11][CH2:12][N:13]1[CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: Brc1ccc2[nH]cc(CCN3CCCC3)c2c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(CCN3CCCC3)c3cc(Br)ccc32)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5-bromo-3-(2-pyrrolidinylethyl)-1H-indole (Example 2, 9.10 g, 31 mmol) in tetrahydrofuran (100 mL) cooled to 0° C., were added sodium hydride (12.4 g, 310 mmol) and p-toluenesulfonyl chloride (6.10 g, 32 mmol). The resulting mixture was stirred at room temperature for 3 h, poured into water (200 mL) and extracted into ethyl acetate (200 mL). The organic phase was washed with water (200 mL) and then poured onto a silica gel column which was eluted with ethyl acetate followed by methanol. The title compound was obtained as a yellow syrup (11.7 g, 90%).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[NH2:11][C:12]1[C:21]2[N:22]=[C:23]([CH2:30][CH2:31][CH2:32][CH3:33])[N:24]([CH2:25][CH2:26][CH2:27][CH2:28][NH2:29])[C:20]=2[C:19]2[N:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:13]=1>>[NH2:11][C:12]1[C:21]2[N:22]=[C:23]([CH2:30][CH2:31][CH2:32][CH3:33])[N:24]([CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:2](=[O:3])[O:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:20]=2[C:19]2[N:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:13]=1
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCN
Reactant: O=C(Cl)Oc1ccccc1
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCNC(=O)Oc1ccccc1
Yield: 57.8 %

Procedure:
Using the general method of Example 47, phenyl chloroformate (61 μL, 0.48 mmol) was reacted with 4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine (0.15 g, 0.48 mmole) to provide 0.12 g of phenyl N-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]carbamate as a solid. Analysis: Calculated for C24H28N6O2: % C, 66.65; % H, 6.53; % N, 19.43; Found: % C, 66.49; % H, 6.59; % N, 19.32.
Reaction SMILES: [C:1]([N:4]1[CH:9]([CH2:10][N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][S:12]2(=[O:18])=[O:17])[CH2:8][N:7]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[C:6](=[O:27])[CH2:5]1)(=[O:3])[CH3:2].[C:28](OCC)(=[O:34])[C:29](OCC)=[O:30].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1>CN(C=O)C>[O:17]=[S:12]1(=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][N:11]1[CH2:10][CH:9]1[N:4]2[C:1](=[O:3])[CH:2]=[C:28]([OH:34])[C:29]([OH:30])=[C:5]2[C:6](=[O:27])[N:7]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[CH2:8]1
Reactant: CC(=O)N1CC(=O)N(Cc2ccc(F)cc2)CC1CN1CCCCS1(=O)=O
Reactant: CCOC(=O)C(=O)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C1c2c(O)c(O)cc(=O)n2C(CN2CCCCS2(=O)=O)CN1Cc1ccc(F)cc1
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) solution of 4-acetyl-5-[(1,1-dioxido-1,2-thiazinan-2-yl)methyl]-1-(4-fluorobenzyl)-piperazin-2-one (75 mg, 0.19 mmol) and diethyl oxalate (29 μL, 0.21 mmol) in DMF (3 mL) under an atmosphere of nitrogen, a solution of sodium bis(trimethylsilyl)amide in THF (1M, 0.21 mL, 0.21 mmol) was added over a period of 0.5 h and stirred at the temperature for 30 min. Then additional sodium bis(trimethylsilyl)amide in THF (1M, 0.21 mL, 0.21 mmol) was added over a period of 0.5 h and stirred at the temperature for 1 h. The product mixture was concentrated under vacuum, and the residue partitioned between aqueous HCl and ethyl acetate. The organic extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to HPLC purification on C-18 stationary phase eluted with water/acetonitrile/TFA mobile phase. Collection and lyophilization of appropriate fractions provided the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:15](O)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH2:69]([NH:72][CH:73]1[CH2:77][CH2:76][CH2:75][CH2:74]1)[CH:70]=[CH2:71]>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][O:11][C:12]1[CH:20]=[C:19]([Cl:21])[CH:18]=[C:14]([C:15](=[O:16])[N:72]([CH2:69][CH:70]=[CH2:71])[CH:73]2[CH2:77][CH2:76][CH2:75][CH2:74]2)[CH:13]=1)[C:22]1[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)O)c1)c1ccncc1
Reactant: C=CCNC1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=CCN(C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1)C1CCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a strrred solution of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoic acid (0.039 g), TBTU (0.064 g) and HOBt (0.027 g) in DMF (1 ml) was added DIPEA (0.036 ml) followed by N-allylcyclopentylamine (0.029 ml) after 15 min. The reaction mixture was stirred at room temperature for 18 h and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.030 g) obtained by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: [CH:1]([C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[O:5][CH2:6][C:7]([OH:9])=[O:8])=[O:2].[CH2:14](O)[CH3:15].OS(O)(=O)=O.C1(C)C=CC=CC=1>O>[CH2:14]([O:8][C:7]([CH2:6][O:5][C:4]1[CH:10]=[CH:11][CH:12]=[CH:13][C:3]=1[CH:1]=[O:2])=[O:9])[CH3:15]
Reactant: CCO
Reactant: O=Cc1ccccc1OCC(=O)O
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)COc1ccccc1C=O
Yield: 87.4 %

Procedure:
A mixture of 2-formylphenoxyacetic acid (9.01 g, 0.05 mol), ethanol (4.6 g), concentrated H2SO4 (0.4 ml) and toluene (40 ml) was heated to reflux with azeotropic removal of water for 1 hour. The reaction mixture was poured into 10% KHCO3 (100 ml), the layers were separated and the aqueous layer was extracted with ether (2×75 ml). The organic layers were combined, and concentrated in vacuo to afford 9.1 g (95%) of 2-(ethoxycarbonylmethoxy)benzaldehyde.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[S:11][CH3:12].C([O-])([O-])=O.[K+].[K+].[Br:19][CH2:20][CH2:21][CH2:22]Br>C(#N)C>[Br:19][CH2:20][CH2:21][CH2:22][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[S:11][CH3:12]
Reactant: CSc1cc(C(C)=O)ccc1O
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CSc1cc(C(C)=O)ccc1OCCCBr
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-[4-hydroxy-3-(methylmercapto)phenyl]-ethanone (5.4 g; 30 mmol), K2CO3 (4.2 g), 1,3-dibromopropane (8 g, 39 mmol) in acetonitrile (150 ml) was heated at reflux for 3 hours and stirred at room temperature overnight. Acetonitrile was removed at reduced pressure and the residue was extracted into dichloromethane (250 ml). Insolubles were filtered off. The dichloromethane solution was concentrated. The crude product was purified on a silica gel column (SiO2, 100 g; eluted with 3:2 hexane:dichloromethane, 1.6 1). The compound crystallized upon concentration, and the product (3.5 g, 39%) was recrystallized from ethanol (40 ml) to yield 1-[4-(3-bromopropoxy)-3-(methylmercapto)phenyl]ethanone as white needles, 2.0 g; m.p.=120°-122° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:19])[CH:3]=1.[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:24][NH2:25]>>[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:24][NH:25][C:2]1[C:11]2[C:6](=[C:7]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:19])[CH:3]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: Cc1cc(Cl)c2cccc(Oc3ccccn3)c2n1
Product: Cc1cc(NCc2ccc(Cl)c(Cl)c2)c2cccc(Oc3ccccn3)c2n1

Procedure:
Preparation was made using a similar procedure as described in example 1, method 1.3. Starting materials were 4-chloro-2-methyl-8-(pyridin-2-yloxy)-quinoline and 3,4-dichlorobenzylamine.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2C=CC=CC=2)=[CH:8][CH:7]=1)=[N:4][OH:5].Cl>C(Cl)Cl>[F:1][C:2]([F:19])([F:20])[C:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)=[N:4][OH:5]
Reactant: ON=C(c1ccc(Oc2ccccc2)cc1)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(C(=NO)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 122.9 %

Procedure:
2,2,2-Trifluoro-1-(4-phenoxyphenyl)-ethanone oxime (single isomer) 35 g (124 mmol) of 2,2,2-trifluoro-1-(4-phenoxyphenyl)-ethanone oxime (mixture of E- and Z-isomers) prepared according to the method described in example 80.1 is dissolved in 300 ml of methylene chloride. To the solution is added 1.1 ml of conc. HCl and stirred at room temperature for 4.5 hours. The reaction mixture is washed with water and brine, dried over MgSO4, and concentrated, yielding 33.4 g of 2,2,2-trifluoro-1-(4-methoxyphenyl)-ethanone oxime (single isomer) as a white solid. The structure is confirmed by the 1H-NMR spectrum (CDCl3). δ[ppm]: 7.00-7.12 (m, 4H), 7.19 (t, 1H), 7.39 (t, 2H), 7.57 (d, 2H), 8.95 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:12])[N:4]([CH2:9][O:10][CH3:11])[N:5]=[CH:6][C:7]=1Cl.[CH3:13][O-:14].[Na+]>CO>[Cl:1][C:2]1[C:3](=[O:12])[N:4]([CH2:9][O:10][CH3:11])[N:5]=[CH:6][C:7]=1[O:14][CH3:13]
Reactant: C[O-]
Reactant: COCn1ncc(Cl)c(Cl)c1=O
Agent: [Na+]
Solvent: CO
Product: COCn1ncc(OC)c(Cl)c1=O
Reaction time: 2 h
Yield: 98.2 %

Procedure:
To a stirred solution of 4,5-dichloro-2-methoxymethyl-2H-pyridazin-3one (500 mg, 2.39 mmol) in methanol (12 mL) at room temperature was added sodium methoxide (258 mg, 4.78 mmol). After stirred for 2 h, the reaction was concentrated. To this residue was added water (20 mL), then extracted with CH2Cl2 (2×50 mL). The combined organic layer was dried (Na2SO4) and concentrated to give 480 mg (98%) 4-chloro-5-methoxy-2-methoxymethyl-2H-pyridazin-3-one.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][CH2:3][CH:2]1[CH2:11][N:12](CC1C=CC=CC=1)[CH2:13][CH2:14][CH2:15][NH:16][C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1.CO.[ClH:32].[H][H]>[Pd].CC(O)C>[ClH:32].[ClH:32].[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][CH2:3][CH:2]1[CH2:11][NH:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]1[NH:22][CH2:21][CH2:20][CH2:19][N:18]=1
Reactant: [H][H]
Reactant: c1ccc(CN(CCCNc2ncccn2)CC2CCc3ccccc3O2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CC(C)O
Product: c1ccc2c(c1)CCC(CNCCCNC1=NCCCN1)O2
Yield: 38 %

Procedure:
A mixture of 7.8 g of N-(3,4-dihydro-2H-1-benzopyran-2-yl)methyl-N-phenylmethyl-N'-(2-pyrimidinyl)-1,3-propanediamine, 200 ml methanol and 10 ml of 2-propanol saturated with HCl was hydrogenated in the presence of 2 g of palladium-on-charcoal catalyst (5%). After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was converted into the dihydrochloride salt in 2-propanol by adding 2-propanol saturated with hydrochloric acid. The salt was filtered off and dried, yielding 2.9 g (38.0%) of (±)-N-[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]-N'-(1,4,5,6-tetrahydro-2-pyrimidinyl)-1,3-propanediamine dihydrochloride; mp. 227.0° C. (comp. 95).