Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].Br[CH:3]([CH3:7])[CH:4](Br)[CH3:5].C[O:9][C:10]([C:12]1[CH:16]=[C:15]([C:17]2[S:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:23]=3)=[CH:20][CH:21]=2)[N:14]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[Cl:38])[N:13]=1)=O.[NH4+].[Cl-]>C1COCC1>[Cl:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[N:14]1[C:15]([C:17]2[S:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:23]=3)=[CH:20][CH:21]=2)=[CH:16][C:12]([C:10]2([OH:9])[CH2:5][CH2:4][CH2:3][CH2:7]2)=[N:13]1
Reactant: COC(=O)c1cc(-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)n(-c2ccccc2Cl)n1
Reactant: CC(Br)C(C)Br
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CS(=O)(=O)c1cccc(-c2ccc(-c3cc(C4(O)CCCC4)nn3-c3ccccc3Cl)s2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.1 %

Procedure:
Magnesium turnings (300 mg, 12.5 mmol) was introduced into a oven-dried flask under N2, covered with anhydrous THF (150 mL), and a solution of dibromobutane (0.72 mL, 6.08 mmol) in anhydrous THF (20 mL) was added dropwise at ambient temperature at such a rate that the temperature of the reaction mixture did not rise above 40° C. The mixture was stirred at ambient temperature for 1 h, and the magnesium turnings disappeared. 1-(2-chloro-phenyl)-5-[5-(3-methanesulfonyl-phenyl)thiophen-2-yl]-1H-pyrazole-3-carboxylic acid methyl ester (2.37 g, 5 mmol) was added as a solid, and the resulting dark-purple solution was stirred at room temperature under N2 for 1 h, At 0° C. aqueous NH4Cl solution was added, and then extracted with EtOAc, The combined extracts were washed with brine, dried over Na2SO4. and evaporated in vacuo. The crude product was purified by flash chromatography (0-60% EtOc/hexanes) to afford the title compound as a white solid (1.4 g, 56%). 1HNMR (CDCl3): δ 8.04 (d, 1H), 7.83-7.81 (m, 1H), 7.74-7.71 (m, 1H), 7.57-7.52 (m, 3H), 7.48-7.44 (m, 2H), 7.20 (d, 1H), 6.74 (d, 1H), 6.63 (s, 1H), 3.07 (s, 3H), 2.42 (brs, 1H), 2.20-1.83 (m, 8H). MS(ES) 499 [M+H]+, 481 (M-OH).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([C:22]3[C:30]([O:31][CH3:32])=[CH:29][C:28]([CH3:33])=[C:27]4[C:23]=3[CH:24]=[CH:25][N:26]4C([O-])=O)([O:16][CH2:17][C:18]([O:20]C)=[O:19])[C:12]([F:15])([F:14])[F:13])=[N:8][C:7]=2[CH:37]=1)#[N:2].[OH-].[Na+].OS([O-])(=O)=O.[K+].CCOC(C)=O>C1COCC1.CO.[Cl-].[Na+].O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([C:22]3[C:30]([O:31][CH3:32])=[CH:29][C:28]([CH3:33])=[C:27]4[C:23]=3[CH:24]=[CH:25][NH:26]4)([O:16][CH2:17][C:18]([OH:20])=[O:19])[C:12]([F:13])([F:14])[F:15])=[N:8][C:7]=2[CH:37]=1)#[N:2]
Reactant: COC(=O)COC(c1nc2cc(C#N)ccc2o1)(c1c(OC)cc(C)c2c1ccn2C(=O)[O-])C(F)(F)F
Agent: O=S(=O)([O-])O
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc(C)c2[nH]ccc2c1C(OCC(=O)O)(c1nc2cc(C#N)ccc2o1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (±)-4-(1-(5-cyanobenzo[d]oxazol-2-yl)-2,2,2-trifluoro-1-(2-methoxy-2-oxoethoxy)ethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (90 mg, 0.157 mmol) in THF (1.5 mL) and MeOH (0.15 mL) was added 1 M aq. NaOH (0.47 mL, 0.47 mmol) and the reaction left to stir at rt for 1 h and then warmed up to 60° C. At this point, 2 M aq. NaOH (0.47 mL, 0.94 mmol) was added and the reaction mixture was stirred for 2 h. The reaction mixture was cooled to rt and diluted with 1M aq.KHSO4, brine and EtOAc. The organic layer was separated, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by RP-HPLC (HC-A) to give the title compound. 1H NMR (TFA salt, 400 MHz, CD3OD) δ ppm 8.21 (br. t, J=1.07 Hz, 1H), 7.80-7.81 (m, 2H), 7.35 (br. t, 1H), 6.82 (br. d, J=2.65 Hz, 1H), 6.72 (s, 1H), 4.32-4.46 (m, 2H) 3.20 (s, 3H), 2.54 (s, 3H). HRMS calcd. for C22H16F3N3O5 (M+H)+ 460.1120. found 460.1114.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[CH:33]=[CH:32][C:12]2[C:13](=[O:31])[C:14]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][C@H:24]4[CH2:28][O:27]C(C)(C)[O:25]4)=[CH:18][C:15]=3[CH2:16][CH2:17][C:11]=2[CH:10]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.O>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[CH:33]=[CH:32][C:12]2[C:13](=[O:31])[C:14]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][C@H:24]([OH:25])[CH2:28][OH:27])=[CH:18][C:15]=3[CH2:16][CH2:17][C:11]=2[CH:10]=1
Reactant: CC1(C)OC[C@H](COc2ccc3c(c2)CCc2cc(Nc4ccccc4N)ccc2C3=O)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: Nc1ccccc1Nc1ccc2c(c1)CCc1cc(OC[C@H](O)CO)ccc1C2=O

Procedure:
For the synthesis of the title compound, 0.10 g (0.225 mmol) of (S)-2-(2-amino-phenylamino)-8-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-10,11-dihydrodibenzo[a,d]cyclohepten-5-one and 0.0537 g (0.282 mmol) of p-toluenesulfonic acid monohydrate in 6 ml of methanol and 1.5 ml of water are reacted by method N. C24H24N2O4 (Mr=404.47)
Reaction SMILES: C([O:3][C:4](=[O:40])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=3)[CH:17]=[C:16]([C:31]#[C:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:15]=2)=[CH:9][C:8]=1[CH3:39])C.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.C(O)C>[CH3:39][C:8]1[CH:9]=[C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=3)[CH:17]=[C:16]([C:31]#[C:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:15]=2)[CH:11]=[CH:12][C:7]=1[O:6][CH2:5][C:4]([OH:40])=[O:3]
Reactant: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccccc3)cc(Oc3ccc(C(F)(F)F)cn3)c2)cc1C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(Sc2cc(C#Cc3ccccc3)cc(Oc3ccc(C(F)(F)F)cn3)c2)ccc1OCC(=O)O
Reaction time: 0.5 h

Procedure:
{2-Methyl-4-[3-phenylethynyl-5-(5-trifluoromethyl-pyridin-2-yloxy)phenylsulfanyl]-phenoxy}-acetic acid ethyl ester (150 mg; 0.266 mmol) was dissolved in THF (2 mL) and ethanol (4 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for ½ h. acidified with 5% aqueous citric acid and extracted with ethyl acetate, dried and evaporated to dryness. Yield: 100 mg (75%). HPLC-MS: m/z: 535.7 (M)+; Rt: 2.78 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=O)[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.C(N(CC)CC)C.ClC(OCC)=O.[C:27]1([CH2:33][N:34]2[CH2:38][CH2:37][CH2:36][CH:35]2[CH2:39][NH2:40])[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]=1>C(Cl)(Cl)Cl>[C:27]1([CH2:33][N:34]2[CH2:38][CH2:37][CH2:36][CH:35]2[CH2:39][NH:40][C:11]([C:4]2[C:5]3[O:9][CH2:8][CH2:7][C:6]=3[CH:10]=[C:2]([Cl:1])[CH:3]=2)=[O:13])[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]=1
Reactant: O=C(O)c1cc(Cl)cc2c1OCC2
Reactant: NCC1CCCN1CC1=CCCCC1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(NCC1CCCN1CC1=CCCCC1)c1cc(Cl)cc2c1OCC2
Reaction time: 0.5 h

Procedure:
32 g of 5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid, 130 ml of chloroform and 16 g of triethylamine were introduced into a 1-liter round-bottomed flask. The contents were cooled to 0°-5° C. and 17.5 g of ethyl chloroformate were then added dropwise and the mixture was stirred for 1 hour and 30 minutes. A solution of 34 g of 1-cyclohexenylmethyl-2-aminomethylpyrrolidine in 68 ml of chloroform was then poured in dropwise, between 5° and 10° C., and the mixture was then stirred for 1 hour at 5° C. and for 1 hour at ambient temperature.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].CN(P(N(C)C)(N(C)C)=O)C.[CH2:22](I)[CH:23]=[CH2:24]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1([CH2:24][CH:23]=[CH2:22])[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1CCOCC1
Reactant: C=CCI
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C=CCC1(C(=O)OC)CCOCC1
Temperature: -78 °C
Yield: 95 %

Procedure:
To this mixture was added tetrahydro-pyran-4-carboxylic acid methyl ester (7.2 g, 50 mmol) in THF (10 mL). There was almost no color change (light a little bit). This was stirred at −78° C. using dry ice/acetone bath for 45 min. Then, a mixture of 5 g of HMPA and 10.92 g of allyl iodide was added via canula. At the end of about 90% addition of this mixture, white precipitate formed suddenly. This mixture was stirred at −78° C. for 20 min, then the dry ice/acetone bath was removed and the stirring was continued to allow the reaction mixture to warm to r.t. over 30 min. At which time the precipitate dissolved, the reaction mixture was poured into ice-water (100 mL) and ether (50 mL). The two layers were separated, and the aqueous layer was extracted with ether (3×50 mL). The combined organic layers were washed with brine, dried (K2CO3), filtered, and concentrated in vacuo to obtain 8.75 g (95% yield) of the title compound as a yellow liquid.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[N:14][CH:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:32])[NH:6]2.[C:33]([O-])(=O)C.[Na+].C=O.[BH4-].[Na+].C(O)(=O)C.C(O)(=O)C.C(O)(=O)C>C(Cl)Cl.CO.C(O)(=O)C>[F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][CH:26]4[CH2:31][CH2:30][N:29]([CH3:33])[CH2:28][CH2:27]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[N:14][CH:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:32])[NH:6]2
Reactant: CC(=O)[O-]
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)cnnc2cc1OCC1CCNCC1
Agent: C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)cnnc2cc1OCC1CCN(C)CC1
Reaction time: 0.08 h
Yield: 53.7 %

Procedure:
To a solution of 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(piperidin-4-ylmethoxy)cinnoline (170 mg, 0.31 mmol), (prepared as described in Example 6), in methylene chloride (6 ml) and methanol (3 ml) was added a solution of sodium acetate (25 mg, 0.31 mmol). Acetic acid (22 ml) and formaldehyde (37%) (50 ml) were added. The mixture was stirred for 5 minutes and triacetate sodium borohydride (100 mg, 0.46 mmol) was added in portions. The mixture was stirred at ambient temperature for 1 hour. The volatiles were removed under vacuum and the residue was dissolved in water and the pH was adjusted to 10 with 2N aqueous sodium hydroxide. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and evaporated. The residue was triturated under diethyl ether, filtered, washed with ether and dried under vacuum to give 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)cinnoline (75 mg, 43%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH:9]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:11][CH2:12][CH3:13])[CH:5]=[CH:4][C:3]=1[O:30][CH2:31][C:32]([O:34]CC)=[O:33].[OH-].[Na+]>O1CCOCC1.O>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH:9]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:11][CH2:12][CH3:13])[CH:5]=[CH:4][C:3]=1[O:30][CH2:31][C:32]([OH:34])=[O:33]
Reactant: CCCCC(Oc1ccc(OCC(=O)OCC)c(C)c1)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCCCC(Oc1ccc(OCC(=O)O)c(C)c1)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.3 %

Procedure:
To a solution of ethyl {[2-methyl-4-({1-[4′-(trifluoromethyl)-4-biphenylyl]pentyl}oxy)phenyl]oxy}acetate (310 mg, 0.62 mmol) in dioxan (6 mL) and water (3 mL), was added aqueous NaOH (2M, 2.43 mL, 1.22 mmol), and the mixture stirred at rt for 1 hour. The dioxan was removed under vacuum and brine (5 mL) added to the residue. The precipitate was collected by filtration and dried under vacuum to give the title compound as a white solid (250 mg).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][NH:11][C:12]2[CH:31]=[CH:30][C:15]([C:16]([NH:18][C:19]([NH:21][NH:22]C(OC(C)(C)C)=O)=[O:20])=O)=[CH:14][CH:13]=2)[N:9]=1)(=[O:3])[CH3:2].O1CCOCC1.[ClH:38]>ClCCl>[ClH:38].[ClH:38].[C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][NH:11][C:12]2[CH:31]=[CH:30][C:15]([CH2:16][NH:18][C:19]([NH:21][NH2:22])=[O:20])=[CH:14][CH:13]=2)[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(CNc2ccc(C(=O)NC(=O)NNC(=O)OC(C)(C)C)cc2)cs1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(=O)Nc1nc(CNc2ccc(CNC(=O)NN)cc2)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a suspension of tert-butyl 2-{[4-({[2-(acetylamino)-1,3-thiazol-4-yl]methyl}amino)benzoyl]carbamoyl}hydrazinecarboxylate (306.2 mg, 0.705 mmol) in anhydrous dichloromethane (7 ml) was added 4M hydrogen chloride dioxane solution (7.0 ml, 28.0 mmol). The mixture was stirred at room temperature for 2 hr, and concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was concentrated again under reduced pressure. This operation was repeated 3 times to remove hydrogen chloride azeotropically. The residue was suspended in ethyl acetate, and the suspension was filtered, washed twice with ethyl acetate, and dried under reduced pressure. The residue was recrystallized by dissolving in methanol (3.6 ml) and then addition of ethyl acetate (12 ml). The crystals were collected by filtration, and dried under reduced pressure to give the title compound (272.8 mg, 0.670 mmol, yield 95.0%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:24])=[C:7]2[C:11]=1[CH:10]([NH:12][C:13]1[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([NH2:23])[CH:19]=3)[N:14]=1)[CH2:9][CH2:8]2.[CH:25]([N:28]=[C:29]=[O:30])([CH3:27])[CH3:26]>>[CH:25]([NH:28][C:29]([NH:23][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([NH:12][CH:10]1[C:11]3[C:7](=[C:6]([CH3:24])[CH:5]=[CH:4][C:3]=3[O:2][CH3:1])[CH2:8][CH2:9]1)[CH:22]=[CH:21]2)=[O:30])([CH3:27])[CH3:26]
Reactant: CC(C)N=C=O
Reactant: COc1ccc(C)c2c1C(Nc1ccc3cc(N)ccc3n1)CC2
Product: COc1ccc(C)c2c1C(Nc1ccc3cc(NC(=O)NC(C)C)ccc3n1)CC2

Procedure:
Rac-N2-(7-methoxy-4-methyl-indan-1-yl)-quinoline-2,6-diamine was obtained from (7-methoxy-4-methyl-indan-1-yl)-(6-nitro-quinolin-2-yl)-amine according to the general procedure described in step B of example 2; MS: m/e=320.6 (M+H+). Step E: The title compound was prepared in accordance with the general method described in example 3 from rac-N2-(7-methoxy-4-methyl-indan-1-yl)-quinoline-2,6-diamine and isopropyl isocyanate; MS: m/e=405.6 (M+H+).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1.[CH:21]1([Mg]Br)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.S(=O)(=O)(O)O>O1CCCC1.[Li+].[Li+].[Cl-].[Cl-].[Cl-].[Cl-].[Cu+2]>[CH:21]1([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: BrCCCCCCCCCCCCOC1CCCCO1
Reactant: Br[Mg]C1CCCCC1
Agent: [Cu+2]
Agent: O=S(=O)(O)O
Agent: [Cl-]
Solvent: C1CCOC1
Product: C(CCCCCCC1CCCCC1)CCCCCOC1CCCCO1

Procedure:
Into 250 ml of tetrahydrofuran (THF) is dissolved 57.8 g of 2-[(12-bromododecyl)oxy]tetrahydro-2H-pyran, to which a solution of 0.35 g of dilithium tetrachlorocuprate in 16 ml of THF is added dropwise at room temperature with stirring under nitrogen streams. To the resulting solution, a solution of 39.6 g of cyclohexylmagnesium bromide in 200 ml of THF is added dropwise while maintaining the reaction temperature at 10°-15° C. Thereafter, the reaction mixture is stirred for 7 hours at room temperature to complete the reaction. The reaction mixture is then acidified with 2N sulfuric acid under ice cooling. The undissolved substances are removed by filtration and the precipitates are washed with ethyl acetate. The THF layer and the ethyl acetate layer are combined and the resulting solution is washed with water, an aqueous sodium bicarbonate solution and then water and is dried. The solvent is removed by distillation under reduced pressure to leave crude [(12-cyclohexyldodecyl)oxy]-tetrahydro-2H-pyran which in turn is dissolved in 450 ml of methanol. Amberlyst® H-15 (4.5 g) is added to the methanol solution and the mixture is stirred at 45° C. for 2 hours. The resin is then filtered off and the filtrate is concentrated to leave a residue. Purification of the residue by silica gel column chromatography yields 20.6 g of the captioned compound as colorless solids.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2].[F:19][C:20]([F:26])([F:25])[CH2:21][CH2:22][CH2:23][NH2:24]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:24][CH2:23][CH2:22][CH2:21][C:20]([F:26])([F:25])[F:19])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2]
Reactant: NCCCC(F)(F)F
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1Cl
Product: CCOC(=O)c1cnc2c(OC)cccc2c1NCCCC(F)(F)F

Procedure:
4-Chloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (250 mg, 0.94 mmol) was treated with 4,4,4-trifluoro-butylamine following general procedure B to afford 8-methoxy-4-(4,4,4-trifluoro-butylamino)-quinoline-3-carboxylic acid ethyl ester (210 mg). Thus obtained amino-ester was hydrolyzed to the corresponding acid in quantitative yield using general procedure D and then transformed into the corresponding ethylamide (170 mg) following general procedure E. The above ethylamide (0.48 mmol) was subjected to reaction with methyl chloroformate according to general procedure F to furnish 3-ethyl-7-methoxy-1-(4,4,4-trifluoro-butyl)-1H-pyrimido[5,4-c]quinoline-2,4-dione (70 mg). LCMS: m/z 382 [M+1]+.
Reaction SMILES: [ClH:1].[C:2]1([S:8]([N:11]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]4[CH2:20][CH2:21][NH:22][CH2:23][C:13]([C:14]=34)=[CH:12]2)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24](O[BH-](OC(=O)C)OC(=O)C)(=O)[CH3:25].[Na+].C(O)(=O)C.C(=O)C.Cl>C1COCC1>[ClH:1].[CH2:24]([N:22]1[CH2:21][CH2:20][C:15]2[C:14]3[C:13](=[CH:12][N:11]([S:8]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)(=[O:10])=[O:9])[C:19]=3[CH:18]=[CH:17][CH:16]=2)[CH2:23]1)[CH3:25]
Reactant: O=S(=O)(c1ccccc1)n1cc2c3c(cccc31)CCNC2
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCN1CCc2cccc3c2c(cn3S(=O)(=O)c2ccccc2)C1
Temperature: 70 °C

Procedure:
1-(Phenylsulfonyl)-3,4,5,6-tetrahydro-1H-azepino[3,4,5-cd]indole hydrochloride, Example 12 (70 mg, 0.2 mmol) was dissolved in THF (4 mL) before sodium triacetoxyborohydride (142 mg, 0.7 mmol) and acetic acid (134 mg, 2.2 mmol) was added. acetaldehyde (14.7 mg, 0.3 mmol) was added and the reaction mixture was heated in MW at 70° C. for 600 s. The reaction mixture was evaporated and the crude product was purified by preparative HPLC (33-63), using Xterra column. The product was isolated and transformed to the hydrochloride. 12.9 mg of the pure product was isolated as a clear oil. MS m/z 341 [M+H]+.
Reaction SMILES: [NH2:1][C@@H:2]1[C:31](=[O:32])[N:4]2[C:5]([C:28]([OH:30])=[O:29])=[C:6]([CH2:9][O:10][C:11](=[O:27])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[S:18](=[O:26])(=[O:25])[NH:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:7][S:8][C@H:3]12.ClCCl.CN(C)C=O.[N:41]1([CH2:46][C:47](Cl)=[O:48])[CH:45]=[N:44][N:43]=[N:42]1>O1CCCC1>[N:41]1([CH2:46][C:47]([NH:1][C@@H:2]2[C:31](=[O:32])[N:4]3[C:5]([C:28]([OH:30])=[O:29])=[C:6]([CH2:9][O:10][C:11](=[O:27])[C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[S:18](=[O:26])(=[O:25])[NH:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:7][S:8][C@H:3]23)=[O:48])[CH:45]=[N:44][N:43]=[N:42]1
Reactant: CCOC(=O)NS(=O)(=O)c1ccccc1C(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: O=C(Cl)Cn1cnnn1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)NS(=O)(=O)c1ccccc1C(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cn3cnnn3)[C@H]2SC1
Reaction time: 2 h
Yield: 38.5 %

Procedure:
7β-Amino-3-[2-(N-carboethoxysulfamoyl)benzoyloxy]methyl-3-cephem-4-carboxylic acid (457 mg) is suspended in a mixed solution of dichloromethane (5 ml) and N,N-dimethylformamide (1.0 ml) and to the mixture, a solution of (1H-tetrazol-1-yl)acetyl chloride (161 mg) in tetrahydrofuran (2 ml) is added over a period of 20 minutes and stirred for 2 hours. The solvent is distilled off under reduced pressure and to the resultant viscous residue, ethyl acetate (50 ml) and water (20 ml) are added and stirred. After separation, the ethyl acetate layer is washed with water, dried over anhydrous sodium sulfate and concentrated. To the concentrate (5 ml), chloroform (50 ml) is added and the resultant precipitate is filtered off. The filtrate is concentrated and to the concentrate (5 ml), ether (50 ml) is added. The resultant precipitate is collected by filtration and dried over phosphorous pentoxide. The procedure provides 7β-(1H-tetrazol-1-yl)acetamido-3-[2-(N-carboethoxysulfamoyl)benzoyloxy]methyl-3-cephem-4-carboxylic acid (216 mg).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:12]([C:15]1[CH:16]=[C:17]([OH:24])[CH:18]=[C:19]([CH:21]([CH3:23])[CH3:22])[CH:20]=1)([CH3:14])[CH3:13].[H-].[Na+]>C1(C)C(C)=CC=CC=1>[Cl:11][C:8]1[CH:7]=[C:3]([C:2]([O:24][C:17]2[CH:18]=[C:19]([CH:21]([CH3:22])[CH3:23])[CH:20]=[C:15]([CH:12]([CH3:14])[CH3:13])[CH:16]=2)=[CH:10][CH:9]=1)[C:4]([OH:6])=[O:5]
Reactant: CC(C)c1cc(O)cc(C(C)C)c1
Reactant: O=C(O)c1cc(Cl)ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: CC(C)c1cc(Oc2ccc(Cl)cc2C(=O)O)cc(C(C)C)c1
Yield: 49.4 %

Procedure:
2,5-dichlorobenzoic acid (5 g) and 3,5-diisopropylphenol (4.66 g) were dissolved in dry xylene and the solution placed under dry oxygen-free nitrogen. Sodium hydride (1.25 g) was added as a suspension in petroleum ether. Cuprous bromide was added and the solution refluxed for 5 hours and cooled. The xylene was removed by low pressure distillation. The remaining solid was acidified with dilute hydrochloric acid and extracted with diethyl ether. The ethereal layer was separated, dried and distilled under low pressure to give an oil. The oil was dissolved in petroleum ether (30°-40° ). Standing gave a crystalline solid, which was recrystallised from hexane to give the title compound (4.3 g), mp 129°-130° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[CH3:11][OH:12].[H-].[Na+].O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([O:12][CH3:11])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1
Reactant: CSc1nc(Cl)cc(Cl)n1
Reactant: CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(Cl)nc(SC)n1

Procedure:
4,6-dichloro-2-(methylthio)pyrimidine (Compound IV-5) (19.5 g, 0.100 mol) was dissolved in tetrahydrofuran (200 ml) just after distilled, then methyl alcohol (3.2 g, 0.100×1.0 mol) was added thereto. While cooling with ice, 60% sodium hydride (4.4 g, 0.100×1.1 mol) was added thereto while stirring. After stirred for 3 hours, the reaction solution was poured into water and extracted with toluene. The organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and filtered, and thereafter, the solvent was distilled off to obtain the compound (IV-29).