Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=1)[C:12](OCC)=[O:13])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH2:1]([C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=1)[CH2:12][OH:13])[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1cccc(CCc2ccccc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cccc(CCc2ccccc2)c1
Reaction time: 1 h
Yield: 93.2 %

Procedure:
Ethyl 3-phenethylbenzoate (180 mg) was dissolved in 2 ml of anhydrous tetrahydrofuran, and under ice cooling, 42 mg of lithium aluminum hydride was added by portions over 5 minutes. The mixture was stirred for one hour under ice cooling. Water (10 ml) was added to the reaction mixture to decompose the excess of the reducing agent. The mixture was then extracted with 20 ml of ethyl ether. The extract was separated, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was evaporated to give 140 mg (yield 93%) of 3-phenethylbenzyl alcohol.
Reaction SMILES: C(OC(=O)[C:5]([CH2:24][CH2:25][CH2:26][CH3:27])([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([I:21])[CH:19]=2)[N:14]=[CH:13][C:12]=1[C:22]#[N:23])C(OCC)=O)C.[Cl-].[Li+].O>CS(C)=O>[I:21][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][C:12]([C:22]#[N:23])=[C:11]2[CH2:5][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCC(C(=O)OCC)(C(=O)OCC)c1c(C#N)cnc2ccc(I)cc12
Agent: [Cl-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCCc1c(C#N)cnc2ccc(I)cc12

Procedure:
Similar procedure as described in example 71b was used, starting from 2-butyl-2-(3-cyano-6-iodo-quinolin-4-yl)-malonic acid diethyl ester (example 72a), lithium chloride, water, and dimethylsulfoxide to give 6-iodo-4-pentyl-quinoline-3-carbonitrile. LC-MS m/e 351 (MH+).
Reaction SMILES: Br[CH2:2][CH:3]([C:5]1[CH:18]=[CH:17][C:16]2[O:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8][C:7]=2[CH:6]=1)[CH3:4].[O:19]=O.[NH4+].[Cl-]>CCOCC>[CH:6]1[C:7]2[CH2:8][C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[O:15][C:16]=2[CH:17]=[CH:18][C:5]=1[CH:3]([CH3:4])[CH2:2][OH:19]
Reactant: CC(CBr)c1ccc2c(c1)Cc1ccccc1O2
Reactant: O=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(CO)c1ccc2c(c1)Cc1ccccc1O2

Procedure:
3.03 g. of 2-(1-bromo-2-propyl)-xanthene is reacted with 0.26 g. of Mg filings in 100 ml. of ether. The mixture is cooled to -5°, oxygen is introduced for 4 hours, and the mixture is combined with aqueous NH4Cl solution. The usual working-up step yields 2-(2-xanthenyl)-propanol, m.p. 86°-89°.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[C:8]([NH:14][CH2:15][CH2:16][CH3:17])=[N:9][C:10]([Cl:13])=[N:11][CH:12]=1.[C:18]([N:25]([CH3:31])[C@H:26]([C:28](O)=[O:29])[CH3:27])([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)C(C)C)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.C(OCC)(=O)C>[Cl:13][C:10]1[N:9]=[C:8]([NH:14][CH2:15][CH2:16][CH3:17])[C:7]([C:6]#[C:5][CH2:4][CH2:3][CH2:2][NH:1][C:28](=[O:29])[C@@H:26]([N:25]([CH3:31])[C:18](=[O:19])[O:20][C:21]([CH3:22])([CH3:24])[CH3:23])[CH3:27])=[CH:12][N:11]=1
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: CCCNc1nc(Cl)ncc1C#CCCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCCNc1nc(Cl)ncc1C#CCCCNC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 113.4 %

Procedure:
To a solution of 5-(5-amino-1-pentyn-1-yl)-2-chloro-N-propylpyrimidin-4-amine (K2, 505 mg) and N-Boc-N-methyl-L-alanine (270 mg) in N,N-dimethylformamide (5 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (635 mg) and N,N-diisopropylethylamine (378 μL) were added at room temperature, and the mixture was stirred overnight at the same temperature. To the reaction mixture, saturated aqueous sodium carbonate and ethyl acetate were added. The organic layer was separated, washed with water, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (eluent, 50% hexane/50% ethyl acetate) to obtain (S)-tert-butyl (1-((5-(2-chloro-4-(propylamino)pyrimidin-5-yl)-4-pentyn-1-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate (L1, 660 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:7]=[C:8]=[S:9])=[CH:4][S:5][CH:6]=1.[Cl:10][C:11]1[C:12]([NH2:18])=[C:13]([NH2:17])[CH:14]=[CH:15][CH:16]=1>>[NH2:18][C:12]1[C:11]([Cl:10])=[CH:16][CH:15]=[CH:14][C:13]=1[NH:17][C:8]([NH:7][C:3]1[C:2]([Cl:1])=[CH:6][S:5][CH:4]=1)=[S:9]
Reactant: Nc1cccc(Cl)c1N
Reactant: S=C=Nc1cscc1Cl
Product: Nc1c(Cl)cccc1NC(=S)Nc1cscc1Cl

Procedure:
was obtained as described in example 1 b) by reaction of 4-chloro-3-thienyl-isothiocyanate and 3-chloro-1,2-diaminobenzene. The compound crystallizes after stirring in diisopropylether. Solid crystalline material with 2 melting points: 1st m.p. 152-155° C.; 2nd m.p. (after recrystallization of molten material)>310° C.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10](=[O:21])[C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1[F:20].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[N+:17]([C:15]1[CH:16]=[C:11]([C:10]2[O:21][C:2]3[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=3[N:9]=2)[C:12]([F:20])=[CH:13][CH:14]=1)([O-:19])=[O:18]
Reactant: Cc1ccc(O)c(NC(=O)c2cc([N+](=O)[O-])ccc2F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: Cc1ccc2oc(-c3cc([N+](=O)[O-])ccc3F)nc2c1

Procedure:
Prepared by the method of Example 15b), from N-(2-hydroxy-5-methylphenyl)-2-fluoro-5-nitrobenzamide (667 mg, 2.3 mmol) and p-toluenesulfonic acid monohydrate (961 g, 5.1 mmol) the subtitle compound was obtained (345 mg, 55%). 1H NMR (DMSO) δ 8.92(m, 1H), 8.50(m, 1H), 7.79(t, 1H), 7.67(d, 1H), 7.39(t, 1H), 7.28(d, 1H), 2.60(s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:27]=[C:28]([F:30])[CH:29]=1)[CH2:5][C@H:6]([NH:23][C:24](=[O:26])[CH3:25])[C@H:7]([OH:22])[CH2:8][NH:9][C:10]1([CH3:21])[C:19]2[C:14](=[CH:15][CH:16]=[C:17](I)[CH:18]=2)[O:13][CH2:12][CH2:11]1.[Cl-].[CH2:32]([Zn+])[C:33]([CH3:36])([CH3:35])[CH3:34]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:1][C:2]1[CH:3]=[C:4]([CH:27]=[C:28]([F:30])[CH:29]=1)[CH2:5][C@H:6]([NH:23][C:24](=[O:26])[CH3:25])[C@H:7]([OH:22])[CH2:8][NH:9][C:10]1([CH3:21])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH:18]=2)[O:13][CH2:12][CH2:11]1
Reactant: CC(C)(C)C[Zn+]
Reactant: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNC1(C)CCOc2ccc(I)cc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cl-]
Product: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNC1(C)CCOc2ccc(CC(C)(C)C)cc21
Reaction time: 12 h

Procedure:
To a 20 ml serum capped vial containing N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(6-iodo-4-methyl-3,4-dihydro-2H-chromen-4-yl)amino]propyl}acetamide (0.20 g, 0.37 mmol) and Pd(dppf)Cl2 (0.015 g, 0.018 mmol) under nitrogen was added 3.7 ml of a 0.5 M neopentyl zinc chloride (1.85 mmol) prepared as previously described. The mixture was shaken on an orbital shaker for 12 h at which time LC/MS indicated only a trace of the desired compound. An additional 5 eq. of the zinc reagent and another 5 mol % of catalyst was added and the reaction mixture was warmed to 40° C. After 6 h LC/MS indicated complete consumption of SM. The reaction mixture was quenched with NH4Cl and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacou to yield a light brown solid (150 mg) after flash chromatography (4% MeOH/CHCl3 Biotage 40S). This material was subjected to a final reverse phase preparative column (1% TFA in H2O/0.6% TFA in CH3CN) to yield 50 mg of a light yellow solid. This material was dissolved in 4 ml of CH2Cl2 and treated with 0.5 g of 3-mercaptopropyl functionalized silica gel and stirred at r.t. for 30 min. The mixture was filtered through Celite® to remove the resin and the filtrate concentrated in vacuo to yield a white powder (44 mg, 20%). 1H NMR (400 MHz, DMSO-d6) δ 7.08 (d, J=2.07 Hz, 1H), 6.87 (dd, J=8.29, 2.07 Hz, 1H), 6.78 (m, 3H), 6066 (d, J=8.29 Hz, 1H), 4.27 (m, 1H), 4.12 (m, 1H), 4.04 (m, 1H), 3.54 (m, 1H), 3.06 (dd, J=13.99, 3.63 Hz, 1H), 2.56 (m, 2H), 2.45 (bs, 2H), 2.37 (dd, J=11.82, 7.67 Hz, 1H), 2.25 (m, 1H), 1.81 (s, 3H), 1.78 (m, 1H); 1.49 (s, 3H), 0.91 (s, 9H). MS (ESI+) for C27H36N2O3F2 m/z 475.2772 (M+H)+; found, 475.2774.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:8][C:9]1[O:15]C(C)(C)[O:13][C:11](=O)[CH:10]=1>C1(C)C(C)=CC=CC=1>[C:11]([N:1]1[CH2:7][CH2:6][CH2:5][N:4]([C:11](=[O:13])[CH2:10][C:9]([CH3:8])=[O:15])[CH2:3][CH2:2]1)(=[O:13])[CH2:10][C:9]([CH3:8])=[O:15]
Reactant: C1CNCCNC1
Reactant: CC1=CC(=O)OC(C)(C)O1
Solvent: Cc1ccccc1C
Product: CC(=O)CC(=O)N1CCCN(C(=O)CC(C)=O)CC1
Temperature: 124 °C
Yield: 96.2 %

Procedure:
To 1,4-diazacycloheptane (81.90 g, 0.819 mol) in xylene (525 ml) at 122° C. was added with stirring 2,2,6-trimethyl-1,3-dioxen-4-one (232.49 g, 1.637 mol) in xylene (525 ml) over 10 minutes, during which the temperature decreased to 99° C. After heating to 124° C. over 5 minutes vigorous effervescence commenced, and after heating to 127° C. over 5 minutes distillation of acetone (through a Vigreux column) also commenced. Pot temperature was increased to 140° C. over a further 30 minutes, with collection of acetone distillate. After cooling to 15° C. overnight, supernatant liquid was separated from deposited syrup, which was dissolved in dichloromethane. Removal of solvent from combined solutions and drying (91° C./100 Pa) gave N,N′-bis(acetoacetyl)-1,4-diazacycloheptane (BAADCH) as a viscous syrup (211.16 g, 96%), identified by 1H-NMR, 13C-NMR, FT-IR and Raman spectra.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][C@H:4]([CH3:15])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1)=[O:6].B(O)(O)[C@H:18]1N(C([C@@H](N)C(C)C)=O)CC[CH2:19]1.CS(O)(=O)=O.C([Mg]Br)C.S([O-])(O)(=O)=O.[NH4+]>O1CCCC1>[CH3:16][N:2]([CH3:1])[CH2:3][C@H:4]([CH3:15])[C@:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1)([OH:6])[CH2:18][CH3:19]
Reactant: CC(C)[C@H](N)C(=O)N1CCC[C@H]1B(O)O
Reactant: COc1cccc(C(=O)[C@@H](C)CN(C)C)c1
Agent: CC[Mg]Br
Agent: CS(=O)(=O)O
Agent: O=S(=O)([O-])O
Solvent: C1CCOC1
Product: CC[C@](O)(c1cccc(OC)c1)[C@@H](C)CN(C)C
Temperature: 5 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
(S)-3-(Dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one (774.6 g, 3.5 mol, ee 95%) was dissolved in dry tetrahydrofuran (800 mL) in a 10 L double jacket vessel equipped with an electrical impeller stirrer, a gas transition line, Pt100 temperature measuring equipment and an oil based cooling/heating system and ethyl magnesium bromide (2 L, 2 M in THF) was added at a temperature of 15° C. within 2 hours. The reaction mixture was stirred for two hours at that temperature, cooled to 5° C. and aqueous ammonium hydrogen sulfate solution (10% by weight, 2 L) was added. The phases were separated and the organic phase was concentrated in vacuo at 40° C. until a pressure of 5 mbar was reached. (2S,3R)-1-(Dimethylamino)-3-(3-methoxyphenyl)-2-methylpentan-3-ol (871.1 g, 99%) was obtained as a colorless oil (ee 95%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][NH:12][CH3:13]>CO>[CH3:11][N:12]([CH3:13])[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CNC
Solvent: CO
Product: CN(C)c1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Yield: 94 %

Procedure:
To 0.314 g (1.99 mmol) of 2-chloro-5-nitropyridine in MeOH (1 mL) was added 5 mL of dimethylamine (2M solution in MeOH) at 0° C. and the mixture was warmed to room temperature. The reaction mixture was concentrated and extracted with EtOAc. The organic layer was washed successively with sat. NaHCO3 solution and brine, dried (Na2SO4), and concentrated to give 0.313 g (94% yield) of 2-dimethylamino-5-nitropyridine as an orange powder: 1H NMR (CDCl3) δ9.06 (d, J=2.7 Hz, 1H), 8.20 (dd, J=9.5, 2.7 Hz, 1H), 6.46 (dd, J=9.5, 0.4 Hz, 1H), 3.23 (s, 6H); LCMS (APCI+) m/z: 168 (MH+, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[C:6]2[CH2:13][C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17].[Br:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1.[NH4+].[Cl-]>CN(C=O)C>[Br:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][N:8]2[C:9]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)[C:6]([CH2:13][C:14]3[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=3[C:16]([O:18][CH3:19])=[O:17])=[C:7]2[CH3:12])=[CH:27][CH:26]=1
Reactant: COC(=O)c1ccccc1Cc1c(C)[nH]c2ccc(OC)cc12
Reactant: BrCc1ccc(Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1Cc1c(C)n(Cc2ccc(Br)cc2)c2ccc(OC)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.6 %

Procedure:
To the product of Step 1 (210 mg, 0.68 mmol) in dry DMF (5 mL) at 0° C. was added Nail (30 mg, 0.74 mmol, 60% in oil) followed by 4-bromobenzyl bromide (174 mg, 0.7 mmol). The mixture was stirred at r.t. for 0.5 h. NH4Cl solution was added. The mixture was extracted with EtOAc. Chromatography of the concentrated organic extract gave 272 mg of the title compound.
Reaction SMILES: [C:1](=[O:22])([O:3][C@H:4]([CH:8]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)[C:5]([NH2:7])=O)[NH2:2].C(=O)([O-])O.[Na+].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:29]>C(COC)OC>[C:1](=[O:22])([O:3][C@H:4]([CH:8]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)[C:5]([NH2:7])=[S:29])[NH2:2]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CC(C)(C)C(c1c[nH]c2ccccc12)[C@@H](OC(N)=O)C(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)C(c1c[nH]c2ccccc12)[C@@H](OC(N)=O)C(N)=S
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (R)-tert-butyl-1-amino-3-(1H-indol-3-yl)-1-oxopropan-2-yl carbamate (6.80 g, 22.4 mmol) in anhydrous dimethoxyethane (100 mL) was mixed in portions with sodium hydrogencarbonate (7.14 g, 85.1 mmol) and diphosphorus pentasulphide (10.2 g, 44.8 mmol) and stirred overnight at room temperature. The reaction mixture was concentrated to low volume in a vacuum, the residue taken up in ethyl acetate (100 mL) and washed with water and saturated sodium hydrogencarbonate solution (3×50 mL each). The organic phase was dried with sodium sulphate and concentrated to low volume in a vacuum. The raw product was taken up in diethyl ether/cyclohexane (50 mL each) and concentrated to low volume again. During this, the product separated out as a white solid, which was filtered off.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([F:11])[CH:5]=1.[H-].[Na+].Br[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>C(COC)OC>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[C:6]([F:11])[CH:5]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COC(=O)c1ccc(O)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)c1ccc(OCC(=O)OC(C)(C)C)c(F)c1
Temperature: 70 °C
Yield: 84.5 %

Procedure:
A mixture of 3-fluoro-4-hydroxy-benzoic acid methyl ester (2.5 g, 14.7 mmol), NaH suspension in oil (55%) (641 mg, 14.7 mmol), KI (244 mg, 14.7 mmol, 0.1 eq.) and tert.butyl bromoacetate (3.44 g, 17.6 mmol 1.2 eq.) in dimethoxyethane (20 ml) was heated to 70° C. for 16 hrs. After evaporation of the solvent the residue was chromatographed over 120 g SiO2 (Merck 230-400 mesh) with EtOAc/nHexane 7:93, affording the title compound (3.53 g, 85% yield) as a colorless liquid. MS: m/e=284 (M+).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[C:16](=[O:17])[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]4[CH:25]=[N:26][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][CH:29]=4)[CH:19]=3)[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.NC(N)=[O:36].OO.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:1]1([NH:4][C:5]([C:7]2[C:16](=[O:17])[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]4[CH:25]=[N+:26]([O-:36])[C:27]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:28][CH:29]=4)[CH:19]=3)[CH:8]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: CS(=O)(=O)c1ccc(-c2cccc(-n3cc(C(=O)NC4CC4)c(=O)c4cccnc43)c2)cn1
Reactant: NC(N)=O
Agent: OO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc(-c2cccc(-n3cc(C(=O)NC4CC4)c(=O)c4cccnc43)c2)c[n+]1[O-]
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To a suspension of N-cyclopropyl-1-[3-(6-methylsulfonylpyridin-3-yl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide from Example 51 in methylene chloride (30 ml/mmol) was added urea-hydrogen peroxide (8 eq) and the resulting mixture was cooled to 0° C. Trifluoroacetic acid (4.7 eq) was added and the mixture was warmed to room temperature as a solution was obtained. After 18 hours, more urea-hydrogen peroxide (2.6 eq) and trifluoroacetic acid (2 eq) were added and stirring was continued for 2 hours. The mixture was quenched with saturated aqueous sodium metabisulfite, diluted with methylene chloride and the organic phase was washed with 1N aqueous HCl, then brine and water, dried and evaporated. The crude product was chromatographed on silica gel eluting with 40% toluene in acetone to afford the title compound as a solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:14])=[C:8]([S:10]([O:12][CH3:13])=[O:11])[CH:9]=1)(=[O:3])[CH3:2].[Br:15]Br.O>C(Cl)(Cl)Cl>[Br:15][CH2:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:14])=[C:8]([S:10]([O:12][CH3:13])=[O:11])[CH:9]=1)=[O:3]
Reactant: COS(=O)c1cc(C(C)=O)ccc1C
Reactant: BrBr
Solvent: O
Solvent: ClC(Cl)Cl
Product: COS(=O)c1cc(C(=O)CBr)ccc1C
Temperature: 40 °C
Yield: 89.4 %

Procedure:
In 200 ml of chloroform was dissolved 21.2 g of methyl 5-acetyl-2-methylbenzenesulfinate and then 16.8 g of bromine was added dropwise to the solution with stirring at 40° C. After the reaction was over, the reaction mixture was added to 500 ml of water and the chloroform layer formed was recovered, washed with a saturated aqueous sodium hydrogen-carbonate solution, and dried with anhydrous magnesium sulfate. Then, the solvent was distilled off and the crude crystals formed were recrystallized from ethanol to provide 26 g of methyl 5-bromoacetyl-2-methylbenzenesulfinate having a melting point of 123°-125° C.
Reaction SMILES: [N:1]1([CH2:8][C:9]2[NH:20][C:19]3[C:21]4[C:15]([C:16](=[O:22])[NH:17][N:18]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[N:10]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](Cl)=[O:28]>C(Cl)Cl>[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27]([N:4]1[CH2:5][CH2:6][CH2:7][N:1]([CH2:8][C:9]2[NH:20][C:19]3[C:21]4[C:15]([C:16](=[O:22])[NH:17][N:18]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[N:10]=2)[CH2:2][CH2:3]1)=[O:28]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: O=c1[nH]nc2c3c(cccc13)N=C(CN1CCCNCC1)N2
Solvent: ClCCl
Product: O=C(c1cccc(Cl)c1)N1CCCN(CC2=Nc3cccc4c(=O)[nH]nc(c34)N2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16 %

Procedure:
Synthesized from compound 26. To a solution of compound 26 (0.2 g, 0.6 mmol) in 5 mL of CH2Cl2 was added 1 mmol of TEA and 0.8 mmol of 3-chloro-benzoyl chloride. The reaction was stirred overnight at room temperature. After the solvents were evaporated, the residue was purified with semi-preparative HPLC to afford a solid (16% yield). MP: 147-149° C.; MS (ES−): 436; 1H NMR (400 MHz, CDCl3): 1.88-2.08 (m, 2H), 2.86-3.07 (m, 4H), 3.52-3.71 (m, 4H), 3.81-3.89 (m, 2H), 7.33-7.43 (m, 4H), 7.62 (d, 1H), 7.81 (t, 1H), 7.90 (t, 1H). Anal. Calcd. for C22H21ClN6O2.0.7H2O: C, 54.89; H, 4.39; N, 16.70; Found: C, 54.93; H, 4.43; N, 16.34.
Reaction SMILES: C(Cl)Cl.C(O)(=O)C.[C:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:18]([CH3:32])=[CH:19][C:20]([O:23][CH2:24][C:25]([CH3:31])([CH3:30])[C:26]([O:28][CH3:29])=[O:27])=[N:21][CH:22]=2)=[CH:13][C:12]=1[F:33])(=[NH:10])[NH2:9].Br[CH2:35][C:36](=O)[CH2:37][CH:38]1[CH2:40][CH2:39]1.C(=O)([O-])[O-].[K+].[K+]>[Cl-].[Na+].O>[CH:38]1([CH2:37][C:36]2[NH:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4[C:18]([CH3:32])=[CH:19][C:20]([O:23][CH2:24][C:25]([CH3:30])([CH3:31])[C:26]([O:28][CH3:29])=[O:27])=[N:21][CH:22]=4)=[CH:13][C:12]=3[F:33])=[N:10][CH:35]=2)[CH2:40][CH2:39]1
Reactant: COC(=O)C(C)(C)COc1cc(C)c(-c2ccc(C(=N)N)c(F)c2)cn1
Reactant: O=C(CBr)CC1CC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)C(C)(C)COc1cc(C)c(-c2ccc(-c3ncc(CC4CC4)[nH]3)c(F)c2)cn1
Temperature: 40 °C
Reaction time: 5 h
Yield: 79.3 %

Procedure:
A mixture in which methylene chloride (10 mL) and a saturated brine (10 mL) were added to methyl 3-{[5-(4-carbamimidoyl-3-fluorophenyl)-4-methylpyridin-2-yl]oxy}-2,2-dimethylpropanoate acetic acid salt (300 mg), 1-bromo-3-cyclopropylpropan-2-one (190 mg) and potassium carbonate (346 mg) was stirred at 40° C. for 5 hours. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=100:0 to 97:3) to obtain methyl 3-[(5-{4-[5-(cyclopropylmethyl)-1H-imidazol-2-yl]-3-fluorophenyl}-4-methylpyridin-2-yl)oxy]-2,2-dimethylpropanoate (248 mg).
Reaction SMILES: N#N.CCN=C=NCCCN(C)C.Cl.CCN(CC)CC.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH2:34][C:35]([OH:37])=O)[CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31].[CH2:38]([O:40][C:41]([CH2:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)=[O:42])[CH3:39]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:38]([O:40][C:41](=[O:42])[CH2:43][N:44]1[CH2:49][CH2:48][N:47]([C:35](=[O:37])[CH2:34][C:26]2[CH:27]=[C:28]([O:32][CH3:33])[C:29]([O:30][CH3:31])=[C:24]([O:23][CH3:22])[CH:25]=2)[CH2:46][CH2:45]1)[CH3:39]
Reactant: COc1cc(CC(=O)O)cc(OC)c1OC
Reactant: CCOC(=O)CN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CN1CCN(C(=O)Cc2cc(OC)c(OC)c(OC)c2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 40 %

Procedure:
(The following reaction is done in an anhydrous N2 atmosphere.) Suspend EDC.HCl (188 mg, 0.98 mmol) and Et3N (137 μL, 0.98 mmol) in anhydrous DCM (1.0 mL) and stir the resulting solution for 5 min at rt. Add 2-(3,4,5-Trimethoxy-phenyl)-acetic acid (163 mg, 0.72 mmol) and DMAP (8 mg, 0.07 mmol) and stir the resulting solution for 10 min. Add 1-(Ethoxycarbonylmethyl)piperazine (43) (112 mg, 0.65 mmol) and stir the reaction solution overnight at rt. Quench reaction solution with sat. aqu. NH4Cl and water, separate layers and extract aqu. layer with DCM (3 times). Wash the combined organic layer with water and brine and dry with Na2SO4. Purify the crude product by preparative radial chromatography (silica gel, EtOAc/MeOH 10+1) to obtain {4-[2-(3,4,5-Trimethoxy-phenyl)-acetyl]-piperazin-1-yl}-acetic acid ethyl ester (44) (99 mg, 40%) as a colorless oil. 1H NMR (400 MHz, CDCl3): 1.25 (t, 3H, J=7.1 Hz); 2.48 (br.m, 2H); 2.58 (br.m, 2H); 3.21 (br.s, 2H); 3.53 (br.m, 2H); 3.65 (s, 2H); 3.71 (br.m, 2H); 3.81 (s, 3H); 3.82 (s, 6H); 4.16 (q, 2H, J=7.1 Hz); 6.42 (s, 2H).
Reaction SMILES: [C:1]1([C:7](=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([O:19][CH3:20])[CH:13]=2)C(O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(O)=O.[Na+].N1C=CN=C1>>[OH:18][C:15]1[CH:16]=[CH:17][C:12]([CH:11]=[CH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:13][C:14]=1[O:19][CH3:20]
Reactant: COc1cc(C=C(C(=O)O)c2ccccc2)ccc1O
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Product: COc1cc(C=Cc2ccccc2)ccc1O
Yield: 88 %

Procedure:
A mixture of α-phenyl-4-hydroxy-3-methoxy cinnamic acid (0.0083 mol), NaHCO3 (10%, 5 mL), imidazole (2 mL) and polyethylene glycol (15 mL) were taken in a 250 mL iodine flask fitted with loose funnel at the top. The flask was shaken well and placed inside the microwave oven and irradiated (900 W) for 8 minutes in parts. After completion of reaction, the reaction mixture was worked (yield 88%) as in example I. Spectral data as given in example I.