Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([F:9])[C:3]=1[C:10]([F:13])([F:12])[F:11].[OH-].[K+].[CH2:16]([OH:18])[CH3:17]>>[F:9][C:4]1[CH:5]=[C:6]([Br:8])[CH:7]=[C:2]([O:18][CH2:16][CH3:17])[C:3]=1[C:10]([F:13])([F:12])[F:11]
Reactant: Fc1cc(Br)cc(F)c1C(F)(F)F
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Product: CCOc1cc(Br)cc(F)c1C(F)(F)F
Reaction time: 4 h

Procedure:
To a 500 ml three neck flask provided with a stirrer, thermometer, and cooling tube were added 20.0 g (76.7 mmol) of 2,6-difluoro-4-bromobenzotrifluoride, 12.9 g (222.9 mmol) of potassium hydroxide, and 100 ml of ethanol, and heated to reflux while being stirred for 4 hours. After unreacted ethanol was distilled off under a reduced pressure from the reaction mixture, 200 ml of water was added thereto and extracted with 200 ml of diethyl ether. The extract was washed with water (150 ml) thrice and then dried over anhydrous magnesium sulfate. The colorless oily product in an amount of 20.5 g which was obtained by distilling off the solvent was purified by silica gel column chromatography (eluent: heptane) to obtain 18.7 g of colorless oily 2-fluoro-4-bromo-6-ethoxybenzotrifluoride.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].[CH3:18][C:19]([C:23]1[CH:28]=[CH:27][C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][CH:24]=1)([CH3:22])[C:20]#[N:21]>>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:8]2[NH:7][C:6](=[O:14])[C:5]3[S:15][CH:16]=[CH:17][C:4]=3[C:3]=2[C:2]=1[C:26]1[CH:27]=[CH:28][C:23]([C:19]([CH3:22])([CH3:18])[C:20]#[N:21])=[CH:24][CH:25]=1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Reactant: CC(C)(C#N)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)(C)C#N)cc1
Yield: 57.9 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (380 mg, 1.2 mmol) was reacted with 2-methyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanenitrile (500 mg, 1.9 mmol) to afford the desired product (260 mg, 56%) as a brown solid: ESI MS m/z 375 [C22H18N2O2S+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][CH:9]=[O:10])=[C:6]([Cl:11])[N:5]=[C:4]([NH:12][CH:13]=[O:14])[N:3]=1.[CH2:15]([O:22][CH2:23][CH:24]([CH2:28][O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:25][O:26][NH2:27])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>O1CCOCC1>[CH2:30]([O:29][CH2:28][CH:24]([CH2:23][O:22][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:25][O:26][NH:27][C:2]1[N:3]=[C:4]([NH:12][CH:13]=[O:14])[N:5]=[C:6]([Cl:11])[C:7]=1[NH:8][CH:9]=[O:10])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: NOCC(COCc1ccccc1)COCc1ccccc1
Reactant: O=CNc1nc(Cl)c(NC=O)c(Cl)n1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=CNc1nc(Cl)c(NC=O)c(NOCC(COCc2ccccc2)COCc2ccccc2)n1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 70 %

Procedure:
A mixture of 4,6-dichloro-2,5-diformamidopyrimidine (from Description 1a) (3.3 g, 14.0 mmol), 3-benzyloxy-2-benzyloxymethylprop-1-oxyamine (4.2 g, 14.0 mmol), triethylamine (5.8 ml, 41.6 mmol) and dioxan (100 ml) was stirred at 100° C. for 2.5 hours. The cooled reaction mixture was filtered and the precipitate collected and washed with dioxan (2×25 ml). The filtrate and washings were combined and evaporated to a syrup. Column chromatography on silica gel (eluted with chloroform-ethanol, 50:1) afforded the title compound (4.9 g, 70%). IR: υmax (KBr) 3240, 2910, 2860, 1690, 1585, 1565, 1475, 1420 cm-1. 1H NMR: δH [(CD3)2SO] 2.29 (1H, quintet, J=6.0, 5.6 Hz, CH), 3.56 (4H, d, J=5.6 Hz, 2×CH2OCH2Ph), 3.94 (2H, d, J=6.0 Hz, CH2ON) 4.46 (4H, s, 2×CH2Ph), 7.30 (10H, m, 2 ×Ph), 9.28 (1H, br.s, NCHO), 9.42 (1H, br.s, NCHO), 10.86 (2H, br.s, D2O exchangeable, 2×NHCHO).
Reaction SMILES: COC1C=C2C(=CC=1)C=C([C@@H](C)C([O:16][C@H:17]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=1)[CH2:18][C:19]1[C:24]([Cl:25])=[CH:23][N:22]=[CH:21][C:20]=1[Cl:26])=O)C=C2.C1(C)C=CC=CC=1.CC(C)([O-])C.[K+]>CO.O>[Cl:25][C:24]1[CH:23]=[N:22][CH:21]=[C:20]([Cl:26])[C:19]=1[CH2:18][C@@H:17]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=1)[OH:16]
Reactant: COc1ccc2cc([C@@H](C)C(=O)O[C@@H](Cc3c(Cl)cncc3Cl)c3ccc(OC)c(OC)c3)ccc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1ccc([C@@H](O)Cc2c(Cl)cncc2Cl)cc1OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(R)—((S)-2-(3,5-dichloropyridin-4-yl)-1-(3,4-dimethoxyphenyl)ethyl) 2-(6-methoxynaphthalen-2-yl)propanoate (30 g, 56 mmol) was dissolved in MeOH, and toluene was slowly added. Potassium terbutoxide was slowly added to the suspension. The mixture was stirred for 24 hours at RT. The reaction was diluted with water (500 ml), and the aqueous mixture was extracted with CHCl3 (500 ml). The organic layer was dried over Na2SO4 and the solvent was evaporated under vacuum. The residue was crystallized from CHCl3 (100 ml) and hexane (20 ml). The mother liquor was concentrated and recrystallized with an analogous procedure giving a second crop of desired compound. In total, 16 g of the title compound (87% yield) were obtained. Chiral HPLC analysis Rt=58.03 min; eluent:hexane:isopropanol=95:5; [α]D20=+10.21 (c=0.506, Methanol); 1H NMR (400 MHz, acetone) δ ppm 8.47 (s, 2H), 6.96-7.15 (m, 1H), 6.87 (m, 2H), 4.93-5.21 (m, 1H), 4.50 (d, J=3.97 Hz, 1H), 3.78 (s, 6H), 3.44 (dd, J=12.79, 8.38 Hz, 1H), 3.22 (dd, J=13.01, 5.51 Hz, 1H). MS/ESI+ [MH]+: 328.19
Reaction SMILES: [C:1]1([CH2:7][C:8](=[N:10][OH:11])[NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:12][C:13]([F:25])([F:24])[C:14]([F:23])([F:22])[C:15](OC(C)(C)C)=O>>[F:22][C:14]([F:23])([C:15]1[O:11][N:10]=[C:8]([NH2:9])[C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:13]([F:25])([F:24])[F:12]
Reactant: NC(Cc1ccccc1)=NO
Reactant: CC(C)(C)OC(=O)C(F)(F)C(F)(F)F
Product: Nc1noc(C(F)(F)C(F)(F)F)c1-c1ccccc1

Procedure:
The title compouhd was obtained according to the same procedure as described in Example 32 except that phenylacetoamide oxime (1.50 g, 0.0100 mole) and t-butyl pentafluoropropionate (6.66 g, 0.0300 mole) were used.
Reaction SMILES: [F:1][CH:2]([F:18])[O:3][C:4]1[C:13]2[N:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:7]([C:14]([O:16]C)=[O:15])=[CH:6][CH:5]=1.[OH-].[Na+]>O>[F:18][CH:2]([F:1])[O:3][C:4]1[C:13]2[N:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:7]([C:14]([OH:16])=[O:15])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(OC(F)F)c2ncccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1ccc(OC(F)F)c2ncccc12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
0.7 g (2.8 mmol) of methyl 8-difluoromethoxy-5-quinolinecarboxylate was suspended in 15 ml of water and 0.4 g (10 mmol) of sodium hydroxide was added. The mixture was stirred at 25° C. for 20 hours and then filtered off, and the filtrate was washed with methyl tert-butyl ether. The aqueous phase was adjusted to pH 3 using concentrated hydrochloric acid and filtered off, and the residue was dried. This gave 0.45 g of a colorless powder;
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.[I-].C[N+]1C=CN([C:26]([N:28]2[CH2:33][CH2:32][CH:31]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:30][CH2:29]2)=[O:27])C=1>>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:26]([N:28]3[CH2:29][CH2:30][CH:31]([CH2:34][C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[CH2:32][CH2:33]3)=[O:27])=[CH:14][CH:15]=2)=[N:7][CH:8]=1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: C[n+]1ccn(C(=O)N2CCC(Cc3ccccc3)CC2)c1
Agent: [I-]
Product: O=C(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)N1CCC(Cc2ccccc2)CC1

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenol and 1-methyl-3-(4-benzyl-piperidine-1-carbonyl)-3H-imidazol-1-ium iodide. The crude product was purified by flash chromatography using a Quad flash 25 (ethyl acetate/heptane (1:6), (72%, white crystals). HPLC-MS m/z=457.2 (M+1), Rt: 6.0 min.
Reaction SMILES: C(OC([N:8]1[CH:12]=[CH:11][C:10]([N:13]([C:16]([C:18]2[C:23]([NH:24][S:25]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([C:35]([F:38])([F:37])[F:36])[CH:29]=3)(=[O:27])=[O:26])=[CH:22][C:21]([Cl:39])=[CH:20][N:19]=2)=[O:17])[CH2:14][CH3:15])=[N:9]1)=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH2:14]([N:13]([C:10]1[CH:11]=[CH:12][NH:8][N:9]=1)[C:16]([C:18]1[C:23]([NH:24][S:25]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([C:35]([F:38])([F:36])[F:37])[CH:29]=2)(=[O:27])=[O:26])=[CH:22][C:21]([Cl:39])=[CH:20][N:19]=1)=[O:17])[CH3:15]
Reactant: CCN(C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)c1ccn(C(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN(C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)c1cc[nH]n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-{[5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine -2-carbonyl]-ethyl-amino}-pyrazole-1-carboxylic acid tert-butyl ester from step 2 was dissolved in a mixture of DCM and TFA (1:1) (5 mL). It was stirred at RT for 1 hour, concentrated, purified with HPLC to give 5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid ethyl-(1H-pyrazol-3-yl)-amide: 1H NMR (400 MHz, CDCl3) δ 8.11 (d, 1 H), 8.0 (d, 1 H), 7.94 (m, 1 H), 7.88 (br, 1 H), 7.6 (d, 1 H), 7.37 (br, 1 H), 5.8 (s, 1 H), 3.8 (m, 2H), 1.1 (m, 3H); MS m/z: 508 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[O:16][CH3:17])=[C:6]([Cl:18])[N:5]=[CH:4][N:3]=1.[F:19][C:20]([F:32])([F:31])[C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1>>[Cl:18][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:30][S:27]([C:24]2[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:32])[F:31])=[CH:26][CH:25]=2)(=[O:28])=[O:29])[C:7]=1[O:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[O:16][CH3:17]
Reactant: NS(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: COc1ccc(F)cc1Oc1c(Cl)ncnc1Cl
Product: COc1ccc(F)cc1Oc1c(Cl)ncnc1NS(=O)(=O)c1ccc(C(F)(F)F)cc1

Procedure:
The N-[6-chloro-5-(5-fluoro-2-methoxy-phenoxy)pyrimidin-4-yl]-4-trifluoromethyl-benzenesulfonamide (m.p. 185°-186° C.) was prepared from 4,6-dichloro-5-(5-fluoro-2-methoxy-phenoxy)-pyrimidine and 4-trifluoromethylbenzenesulfonamide K.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14]([Br:19])[CH:13]=3)[C:10](=[O:20])[O:9][N:8]=2)=[N:4][O:5][N:6]=1.CO[CH:23](OC)[CH2:24][NH:25][S:26]([NH:29][C:30](=[O:37])[O:31][CH2:32][C:33]([Cl:36])([Cl:35])[Cl:34])(=[O:28])=[O:27].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Br:19][C:14]1[CH:13]=[C:12]([N:11]2[C:10](=[O:20])[O:9][N:8]=[C:7]2[C:3]2[C:2]([NH:1][CH2:23][CH2:24][NH:25][S:26]([NH:29][C:30](=[O:37])[O:31][CH2:32][C:33]([Cl:36])([Cl:34])[Cl:35])(=[O:28])=[O:27])=[N:6][O:5][N:4]=2)[CH:17]=[CH:16][C:15]=1[F:18]
Reactant: Nc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Reactant: COC(CNS(=O)(=O)NC(=O)OCC(Cl)(Cl)Cl)OC
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NS(=O)(=O)NCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 90.3 %

Procedure:
A suspension of 3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one (5, 0.680 g, 1.99 mmol) and 2,2,2-trichloroethyl {[(2,2-dimethoxyethyl)amino]sulfonyl}carbamate (17d, 2.22 g, 6.17 mmol, 3.1 equiv.) in dichloromethane (DCM, 6.0 mL) was stirred at room temperature. To this mixture was added triethylsilane (1.27 mL, 7.95 mmol, 4.0 equiv.) and a solution of trifluoroacetic acid (TFA, 3.0 mL, 39.0 mmol) in dichloromethane (DCM, 2.0 mL) while maintaining the reaction temperature below 30° C. The reaction mixture became homogenous after 5 min with agitation at room temperature and was stirred at room temperature for 1 h. HPLC indicated reaction completion. The reaction was filtered and the precipitate was suspended in a mixture of dichloromethane and heptane (ratio of dichloromethane to heptane was 1 to 9 by volume). The suspension was stirred at room temperature overnight. The precipitate was collected by filtration and washed with 10% dichloromethane in heptane and dried in vacuum to give the desired product (1.15 g, 90.4%) as an off-white solid, which was used in the subsequent reaction without further purification. 1H NMR (300 MHz, DMSO-d6) δ 11.85 (s, 1H), 8.07 (m, 2H), 7.70 (m, 1H), 7.57 (t, 1H, J=8.7 Hz), 6.56 (m, 1H), 4.88 (m, 2H), 3.37 (m, 2H), 3.16 (m, 2H); C15H12BrCl3FN7O7S (MW 639.62), LCMS (EI) m/e 638/640/642 (M++H).
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][C:5]1[C:9]2[C:10]([Cl:27])=[CH:11][C:12]([O:14][CH2:15][C:16]3[C:17]([CH3:26])=[N:18][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:21]=3)=[CH:13][C:8]=2[S:7][C:6]=1[CH3:28].C1COCC1.[OH-].[Na+].Cl>CO>[Cl:27][C:10]1[C:9]2[C:5]([CH2:4][C:3]([OH:29])=[O:2])=[C:6]([CH3:28])[S:7][C:8]=2[CH:13]=[C:12]([O:14][CH2:15][C:16]2[C:17]([CH3:26])=[N:18][C:19]([C:22]([F:23])([F:25])[F:24])=[CH:20][CH:21]=2)[CH:11]=1
Reactant: COC(=O)Cc1c(C)sc2cc(OCc3ccc(C(F)(F)F)nc3C)cc(Cl)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc(C(F)(F)F)ccc1COc1cc(Cl)c2c(CC(=O)O)c(C)sc2c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
To a mixture of methyl(4-chloro-2-methyl-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methoxy)-1-benzothiophen-3-yl)acetate (132.1 mg), THF (dry) (1.5 mL) and MeOH (1.5 mL) was added 1N NaOH (0.893 mL) at room temperature. The mixture was stirred at 50° C. for 2 h. The mixture was neutralized with 1N HCl. The resulting precipitate was collected by filtration to give a colorless solid. The solid was crystallized from acetone-hexane to give the title compound (87 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH3:9])=[C:4]([CH2:10]Cl)[C:3]=1[CH2:12][CH3:13].[C-:14]#[N:15].[Na+]>O1CCCC1.CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[C:3]([CH2:12][CH3:13])=[C:4]([CH2:10][C:14]#[N:15])[C:5]([CH2:8][CH3:9])=[CH:6][CH:7]=1
Reactant: [C-]#N
Reactant: CCc1ccc(Br)c(CC)c1CCl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCc1ccc(Br)c(CC)c1CC#N
Temperature: 50 °C

Procedure:
To a solution of 6.28 g (24 mmol) 1-bromo-3-chloromethyl-2,4-diethyl-benzene in 120 ml tetrahydrofurane/N,N-dimethylformamide 1:1 cooled to 0° C. were added 1.76 g (36 mmol) sodium cyanide. The mixture was warmed to 50° C. and stirred at this temperature over night. Then the reaction mixture was diluted with ethyl acetate and extracted several times with water. The organic phase was dried over Na2SO4, filtered and evaporated: 7.2 g (3-bromo-2,6-diethyl-phenyl)-acetonitrile that did not require further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([CH2:9][CH3:10])[CH:3]=1.[Li]CCCC.[B:16](OC)([O:19]C)[O:17]C>C1COCC1>[CH2:9]([C:4]1[CH:3]=[C:2]([B:16]([OH:19])[OH:17])[CH:7]=[CH:6][C:5]=1[F:8])[CH3:10]
Reactant: CCc1cc(Br)ccc1F
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1cc(B(O)O)ccc1F
Reaction time: 3 h
Yield: 70.8 %

Procedure:
To a solution of 95A (290 mg, 1.43 mmol) in THF (5 mL) at −78° C. was added n-BuLi (2.5 M in hexanes, 0.86 mL, 2.15 mmol). The mixture was stirred at −78° C. for 30 min before trimethyl borate (0.32 mL, 2.86 mmol) was added. The reaction was left stirring from −78° C. to rt over 3 h. It was quenched with 1.0 N HCl (2 mL), extracted with EtOAc, washed with Na2S2O3, brine and dried over Na2SO4. After evaporation of the solvent, the crude solid product was purified by silica gel column chromatography eluting with gradient CH2Cl2 in hexanes (0-15%) to give 95B (170 mg, 71% yield). 1H NMR (400 MHz, Methanol-d4) δ ppm 1.09 (t, J=7.47 Hz, 3H) 2.54 (q, J=7.47 Hz, 2H) 6.81-6.88 (m, 1H) 7.42-7.47 (m, 1H) 7.51 (d, J=9.23 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=O)[CH:6]=[CH:5]2.[CH3:15][N:16](C)C=O.S(Cl)(Cl)=O.C(N(CC)CC)C.CO.CN>C(OCC)(=O)C.O.CN(C)C(=O)C.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([NH:16][CH3:15])=[O:14])[CH:6]=[CH:5]2
Reactant: O=C(O)c1ccc2cc(Br)ccc2c1
Reactant: CN(C)C=O
Agent: CN
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: CO
Product: CNC(=O)c1ccc2cc(Br)ccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.8 %

Procedure:
6-Bromo-2-naphthoic acid (10.1 g, 40.1 mmol) and N,N-dimethylformamide (4.75 g, 65.0 mmol) were added to toluene (80 mL). To the reaction mixture was added dropwise thionyl chloride (5.7 g, 48.2 mmol) at 45 to 50° C., and the mixture was stirred for 1 hr, and allowed to cool to room temperature. The reaction mixture was added dropwise at 10 to 25° C. to a solution prepared by adding triethylamine (11.4 g, 112.4 mmol) and 40% methylamine methanol solution (8.1 g, 104.4 mmol) to toluene (80 mL), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added dropwise water (50 mL), and the mixture was stirred at room temperature. The crystals were collected by filtration, and washed with a mixed solvent (25 mL) of methanol/water (2:8) to give wet crystals. The total amount of the wet crystals was added to N,N-dimethylacetamide (70 mL), and dissolved with heating to 60° C. The reaction mixture was allowed to cool to room temperature, and water (140 mL) was added dropwise thereto. The crystals were collected by filtration, and washed with water (80 mL) to give wet crystals. The total amount of the wet crystals was suspended in ethyl acetate (25 mL) with stirring at room temperature. The crystals were collected by filtration, and washed with ethyl acetate (5 mL). The obtained wet crystals were dried under reduced pressure to give 6-bromo-N-methyl-2-naphthamide (9.4 g, 35.6 mmol). yield 89%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:12])=[N:8][NH:9][C:10]=1[CH3:11])=[O:5])[CH3:2].Br[C:14]1[CH:15]=[N:16][CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O.CCOC(C)=O.[Cu](I)I>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:12])=[N:8][N:9]([C:14]2[CH:15]=[N:16][CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: FC(F)(F)c1cncc(Br)c1
Reactant: CCOC(=O)c1c(C)n[nH]c1C
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(C)nn(-c2cncc(C(F)(F)F)c2)c1C
Temperature: 160 °C
Yield: 22.3 %

Procedure:
3,5-Dimethyl-1H-pyrazole-4-carboxylic acid ethyl ester (0.10 g, 1 mmol) (prepared as described in Tett 2002, 58, 18, p 3639), 3-bromo-5-trifluoromethyl-pyridine (0.16 g, 1 mmol), copper iodide (0.02 g, 0.2 mmol) and cesium carbonate (1.0 g, 3 mmol) were suspended in DMA (0.5 ml) and heated to 160° C. for 16 h. The reaction was diluted with EtOAc, washed repeatedly with ammonium hydroxide, brine and dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography (EtOAc:n-heptane 1:9-2:8 gradient affording the title compound (0.07 g, 35%) as a yellow oil. MS: 314.2 (MH+).
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12][N:11]([CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9][N:8]([CH2:21][C:22]([OH:24])=[O:23])[CH2:7][CH2:6]1)([OH:3])=[O:2].[OH-].[Na+].[CH2:27]1[O:30][CH:28]1[CH3:29]>O>[C:1]([CH2:4][N:5]1[CH2:16][CH2:15][N:14]([CH2:27][CH:28]([OH:30])[CH3:29])[CH2:13][CH2:12][N:11]([CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9][N:8]([CH2:21][C:22]([OH:24])=[O:23])[CH2:7][CH2:6]1)([OH:3])=[O:2]
Reactant: CC1CO1
Reactant: O=C(O)CN1CCNCCN(CC(=O)O)CCN(CC(=O)O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(O)CN1CCN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CC1
Yield: 96 %

Procedure:
To a solution of 194.0 g (0.56 mol) of 15 in 450 mL of water is added sufficient NaOH to adjust the pH to 12.0 to 12.5 (the temperature is maintained below 30° C. during the addition). Propylene oxide (65 g, 1.12 mols) is added to the basic solution. After 6 hours at ambient temperature the excess propylene oxide and solvent is removed under reduced pressure. The product is precipitated from a minimal amount of methanol to afford 16 in 96% yield.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[C:3]=1[CH3:21]>CCO.[Pd]>[CH3:21][C:3]1[C:4]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:5][CH:6]=[N:7][CH:2]=1
Reactant: Cc1c(Cl)ncnc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CCO
Product: Cc1cncnc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.6 %

Procedure:
tert-Butyl 4-(6-chloro-5-methylpyrimidin-4-yl)piperazine-1-carboxylate (400 mg) was dissolved in EtOH (8 ml), and 10% Pd/C (40 mg) was added thereto, followed by stirring at room temperature overnight under a hydrogen atmosphere. To the reaction mixture was added TEA (129 mg) and filtered using Celite as a filtration assistant, and the filtrate was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (10% to 80% EtOAc/hexane) to obtain tert-butyl 4-(5-methylpyrimidin-4-yl)piperazine-1-carboxylate (255 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([S:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])[CH:7]=[CH:6][C:5]=1[NH:18][C:19]([NH:21][C:22]([O:24][CH3:25])=[O:23])=[S:20])([O-])=O.CO.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[NH2:1][C:4]1[CH:9]=[C:8]([S:10]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:11])[CH:7]=[CH:6][C:5]=1[NH:18][C:19]([NH:21][C:22]([O:24][CH3:25])=[O:23])=[S:20]
Reactant: COC(=O)NC(=S)Nc1ccc(S(=O)c2ccccc2)cc1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)NC(=S)Nc1ccc(S(=O)c2ccccc2)cc1N
Reaction time: 0.17 h

Procedure:
1.5 G. of 2-nitro-4-phenysulfinyl-1-(3-methoxycarbonyl-2-thioureido)benzene is dissolved in a hot mixture of 450ml. of methanol and 200ml. of water. 15 G. of sodium hydrosulfite is added and, after boiling for 10 minutes, the solution is concentrated. The mixture is diluted with water, extracted thoroughly with chloroform and the product isolated by evaporation of the chloroform. Recrystallizing from methanol-chloroform yields 2-amino-1-(3-methoxycarbonyl-2-thioureido)-4-phenylsulfinylbenzene.
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[C@H:3]([NH:8][C:9]([N:11]1[C:19]2[CH2:18][CH2:17][N:16]([CH3:20])[CH2:15][C:14]=2[C:13]([C:21]2[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:22]=2F)=[N:12]1)=[O:10])[C:4](NC)=[O:5].FC1C=C(C2C3CN(C(OC(C)(C)C)=O)CCC=3NN=2)C=CC=1F.N[C@H](CO)C(C)(C)C>>[F:27][C:25]1[CH:26]=[C:21]([C:13]2[C:14]3[CH2:15][N:16]([CH3:20])[CH2:17][CH2:18][C:19]=3[N:11]([C:9]([NH:8][C@@H:3]([C:2]([CH3:31])([CH3:30])[CH3:1])[CH2:4][OH:5])=[O:10])[N:12]=2)[CH:22]=[CH:23][C:24]=1[F:28]
Reactant: CNC(=O)[C@@H](NC(=O)n1nc(-c2cc(F)c(F)cc2F)c2c1CCN(C)C2)C(C)(C)C
Agent: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(F)c(F)c3)c2C1
Agent: CC(C)(C)[C@H](N)CO
Product: CN1CCc2c(c(-c3ccc(F)c(F)c3)nn2C(=O)N[C@H](CO)C(C)(C)C)C1

Procedure:
Compound 48 was prepared according to the procedure described for the synthesis of compound 37 by replacing intermediate 19 with intermediate 15, and replacing tert-leucine methylamide with tert-leucinol. 1H NMR (CDCl3) δ 7.48-7.53 (m, 1H), 7.33-7.38 (m, 2H), 7.18-7.22 (m, 1H), 3.92-3.95 (m, 1H), 3.78-3.83 (m, 1H), 3.64-3.68 (m, 1H), 3.57 (s, 2H), 3.20 (m, 2H), 2.72-2.79 (m, 2H), 2.53 (s, 3H), 1.02 (s, 9H). LCMS (+ESI) m/z=393.2 [M+H]+.