Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC([Si](C)(C)[O:6][C:7]1[C:8]([F:17])=[C:9]([CH2:14][C:15]#[N:16])[CH:10]=[C:11]([F:13])[CH:12]=1)(C)C.[F-].[K+].[CH3:22][O:23][CH2:24]Cl>CN(C)C=O>[F:17][C:8]1[C:7]([O:6][CH2:22][O:23][CH3:24])=[CH:12][C:11]([F:13])=[CH:10][C:9]=1[CH2:14][C:15]#[N:16]
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(F)cc(CC#N)c1F
Reactant: COCCl
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCOc1cc(F)cc(CC#N)c1F
Temperature: 25 °C
Reaction time: 0.2 h
Yield: 95.2 %

Procedure:
(3-{[(1,1-Dimethylethyl)(dimethyl)silyl]oxy}-2,5-difluorophenyl) acetonitrile (0.353 g, 1.25 mmol) was dissolved in dimethylformamide (3 mL) and potassium fluoride (0.145 g, 2.50 mmol) was added followed by chloromethyl methyl ether (0.117 mL, 1.54 mmol). The mixture was stirred at room temperature for 0.2 h and then was partitioned between ethyl acetate and water. The aqueous portion was extracted with ethyl acetate. The combined organic portion was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford an oil which was purified by column chromatography (ethyl acetate-hexanes 1:6) to afford (2,5-difluoro-3-{[(methyloxy)methyl]oxy}phenyl)acetonitrile as a light brown solid (0.253 g, 1.19 mmol, 95% yield). 1H NMR (400 MHz, CDCl3): 7.05-6.93 (m, 1H), 6.87-6.77 (m, 1H), 5.22 (s, 2H), 3.76 (s, 2H), 3.51 (s, 3H); GCMS for C10H9NO2: 213 (M+).
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][C:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[C:11]([N:20](S(C2C=CC(C(C)(C)C)=CC=2)(=O)=O)[S:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[N:10]([CH2:47][CH2:48][O:49][Si:50]([C:53]([CH3:56])([CH3:55])[CH3:54])([CH3:52])[CH3:51])[N:9]=1)(=O)C.[OH-].[Na+]>C(O)C>[C:30]([C:27]1[CH:26]=[CH:25][C:24]([S:21]([NH:20][C:11]2[N:10]([CH2:47][CH2:48][O:49][Si:50]([C:53]([CH3:56])([CH3:55])[CH3:54])([CH3:52])[CH3:51])[N:9]=[C:8]([O:7][CH2:6][CH2:5][OH:4])[C:12]=2[C:13]2[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=2)(=[O:22])=[O:23])=[CH:29][CH:28]=1)([CH3:31])([CH3:32])[CH3:33]
Reactant: CC(=O)OCCOc1nn(CCO[Si](C)(C)C(C)(C)C)c(N(S(=O)(=O)c2ccc(C(C)(C)C)cc2)S(=O)(=O)c2ccc(C(C)(C)C)cc2)c1-c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(-c2c(OCCO)nn(CCO[Si](C)(C)C(C)(C)C)c2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.2 %

Procedure:
A mixture of 2-{[5-(bis{[4-(tert-butyl)phenyl]sulfonyl}amino}-1-{2-{[tert-butyl(dimethyl)silyl]oxy}ethyl}-4-{4-methylphenyl}-1H-pyrazol-3-yl]oxy}ethyl acetate (300 mg) (Preparation 29) and 1.0M sodium hydroxide solution (2 ml) in ethanol (20 ml) was stirred at room temperature overnight. The reaction mixture was evaporated in vacuo and the residue was then diluted with 1.0M citric acid (50 ml) and extracted with ethyl acetate (2×50 ml). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a Biotage Flash™ 12i column at 10 psi using 25% ethyl acetate/hexane as eluent to give the title compound as a colourless oil (105 mg).
Reaction SMILES: Cl[C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@H:3]1[NH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C([O-])([O-])=O.[K+].[K+]>C(O)C.O>[CH2:15]([O:14][C:12]1[O:13][C@H:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][C@H:3]2[N:11]=1)[CH3:16]
Reactant: CCOC(=O)N[C@@H]1Cc2ccccc2[C@H]1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCOC1=N[C@@H]2Cc3ccccc3[C@@H]2O1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of (±) trans-1-chloro-2-ethoxycarbonylaminoindane (B. J. Walker and P. J. Wrobel, J. Chem. Soc. Chem. Commun., 1980, 462)(4.0 g, 0.017 mol) in ethanol (125 ml) was treated with K2CO3 (2.4 g, 0.018 mol) and diluted with water (50 ml). After stirring at room temperature for 20 h, the reaction was concentrated under high vacuum to approximately one quarter the original volume, then diluted with water (25 ml) and extracted into diethyl ether (3×50 ml). The combined extracts were washed with brine, dried over Na2SO4 and concentrated in vacuo to give the title compound as a low melting solid (3.3 g), m.p 53°-54° C. (from diethyl ether/n-pentane).
Reaction SMILES: [N+:1]([C:4]1[C:14]([N+:15]([O-])=O)=[CH:13][C:12]2[CH:11]3[CH2:18][CH:7]([CH2:8][N:9]([C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH2:10]3)[C:6]=2[CH:5]=1)([O-])=O>CO.[OH-].[OH-].[Pd+2]>[NH2:1][C:4]1[C:14]([NH2:15])=[CH:13][C:12]2[CH:11]3[CH2:18][CH:7]([CH2:8][N:9]([C:19](=[O:24])[C:20]([F:23])([F:21])[F:22])[CH2:10]3)[C:6]=2[CH:5]=1
Reactant: O=C(N1CC2CC(C1)c1cc([N+](=O)[O-])c([N+](=O)[O-])cc12)C(F)(F)F
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Nc1cc2c(cc1N)C1CC2CN(C(=O)C(F)(F)F)C1

Procedure:
1-(4,5-Dinitro-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone (3.0 g, 8.70 mmol) was hydrogenated in methanol (30 ml) under H2 (45 psi) over Pd(OH)2 (300 mg of 20 wt %/C, 10% wt). After 2.5 hours the reaction was filtered through a Celite pad and rinsed with methanol (30 ml). The solution was concentrated to a light brown oil which crystallized (2.42 g, 96%). (TLC 10% methanol/CH2Cl2 Rf 0.56). APCI MS m/e 286.2 [(M+1)+]. M.p. 129–131° C.
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[C:12]2[CH:13]=[CH:14][C:15]([NH:17][C:18]3[CH:30]=[C:29]([C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=4)[CH:28]=[CH:27][C:19]=3[C:20]([O:22]C(C)(C)C)=[O:21])=[CH:16][C:11]=2[CH:10]=[CH:9]1>>[S:8]1[C:12]2[CH:13]=[CH:14][C:15]([NH:17][C:18]3[CH:30]=[C:29]([C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=4)[CH:28]=[CH:27][C:19]=3[C:20]([OH:22])=[O:21])=[CH:16][C:11]=2[CH:10]=[CH:9]1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2cccc(Cl)c2)cc1Nc1ccc2sccc2c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(-c2cccc(Cl)c2)cc1Nc1ccc2sccc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Trifluoroacetic acid 5.0 mL was added to the obtained tert-butyl 2-((benzothiophen-5-yl)amino)-4-(3-chlorophenyl)benzoate, and it was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure, and the obtained residue was refined by reversed-phase silica gel column chromatography [eluent; 80-100% acetonitrile/0.1% trifluoroacetic acid aqueous solution] to give 2-((benzothiophen-5-yl)amino)-4-(3-chlorophenyl)benzoic acid 10 mg of a yellow solid.
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:31]=[CH:30][C:10]([O:11][C:12]3[CH:13]=[C:14]([CH:19]=[C:20]([O:22][C@H:23]4[CH2:27][CH2:26][N:25]([CH3:28])[C:24]4=[O:29])[CH:21]=3)[C:15]([O:17]C)=[O:16])=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.CO.O>C1COCC1.[OH-].[Li+]>[N:1]1([C:5]([C:7]2[CH:8]=[CH:9][C:10]([O:11][C:12]3[CH:13]=[C:14]([CH:19]=[C:20]([O:22][C@H:23]4[CH2:27][CH2:26][N:25]([CH3:28])[C:24]4=[O:29])[CH:21]=3)[C:15]([OH:17])=[O:16])=[CH:30][CH:31]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1cc(Oc2ccc(C(=O)N3CCC3)cc2)cc(O[C@H]2CCN(C)C2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CN1CC[C@H](Oc2cc(Oc3ccc(C(=O)N4CCC4)cc3)cc(C(=O)O)c2)C1=O
Yield: 99.5 %

Procedure:
Methyl 3-[4-(azetidine-1-carbonyl)phenoxy]-5-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-benzoate (Intermediate 16) (309 mg, 0.73 mmol) was dissolved in THF (6 mL) and methanol (2 mL) and IN lithium hydroxide (0.88 mL) was added followed by water (8 mL). The resultant solution was stirred for 1 hr at room temperature. The majority of the organic solvent was removed by distillation under reduced pressure. The remaining aqueous solution was filtered and acidified with 2N hydrochloric acid and extracted with ethyl acetate (2×40 mL), the combined organics were washed with water (10 mL) and brine (20 mL) and dried (MgSO4) to afford the product (298 mg, 100%). m/z 411 (M+H)+
Reaction SMILES: FC(F)(F)C(O)=O.O[C:9]1([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:18][CH2:17][CH2:16][C:15]2[N:14]=[C:13]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:12]=[CH:11][C:10]1=2.[C:34]1([CH2:40][O:41][NH2:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C1(C)C=CC=CC=1>[C:34]1([CH2:40][O:41][NH:42][C:9]2([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:18][CH2:17][CH2:16][C:15]3[N:14]=[C:13]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:12]=[CH:11][C:10]2=3)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: NOCc1ccccc1
Reactant: OC1(Cc2ccccc2)CCCc2nc(OCc3ccccc3)ccc21
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(CONC2(Cc3ccccc3)CCCc3nc(OCc4ccccc4)ccc32)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 61.3 %

Procedure:
Trifluoroacetic acid (16.6 g) was added in one portion to a solution of 5,6,7,8-tetrahydro-5-hydroxy-2-(phenylmethoxy)-5-(phenylmethyl)quinoline (50 g), phenylmethoxyamine (44.8 g), and toluene (600 ml) at room temperature. The solution was stirred at room temperature for 19 hrs, and the reaction mixture was quenched with conc ammonium hydroxide solution. The layers were separated and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over potassium carbonate, filtered, and the filtrate was concentrated. Purification by high performance liquid chromatography (silica gel, elution with ethyl acetate-hexanes) gave 40.0 g (61%) of 5,6,7,8-tetrahydro-N,2-bis(phenylmethoxy)-5-(phenylmethyl)-5-quinolinamine
Reaction SMILES: [CH:1]1(/[CH:5]=[N:6]/[S@:7]([C:9]([CH3:12])([CH3:11])[CH3:10])=[O:8])[CH2:4][CH2:3][CH2:2]1.[CH3:13][Mg]Br.CCOCC>O1CCCC1>[CH:1]1([C@H:5]([NH:6][S@:7]([C:9]([CH3:12])([CH3:11])[CH3:10])=[O:8])[CH3:13])[CH2:2][CH2:3][CH2:4]1
Reactant: C[Mg]Br
Reactant: CC(C)(C)[S@](=O)/N=C/C1CCC1
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[C@@H](N[S@@](=O)C(C)(C)C)C1CCC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Into a 10-L 4-neck round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of (S)—N-[(1E)-cyclobutylmethylidene]-2-methylpropane-2-sulfinamide (200 g, 1.07 mol) in tetrahydrofuran (3000 mL). This was followed by the addition of methylmagnesium bromide in ether (1070 mL, 3.00 equiv) dropwise with stirring at −78° C. over 1 hr. The resulting solution was stirred for 1 h at −70° C., 1 h at −60° C., 1 h at −50° C. and 2 h at −40° C. The reaction was then quenched by the addition of 10 L of saturated aqueous NH4Cl solution. The resulting solution was extracted with 2×3 L of ether. The organic layers were combined, washed with 2×3 L of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was diluted with 250 mL of n-hexane. The resulting solid was collected and washed with 2×100 mL of cold n-hexane to afford (S)—N-[(1R)-1-cyclobutylethyl]-2-methylpropane-2-sulfinamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[CH:18]=[C:19]([N:23]4[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]4)[CH:20]=[CH:21][CH:22]=3)(=[O:16])=[O:15])[C@H:10]([CH3:36])[CH2:9]2)=[C:4]([C:37]([F:40])([F:39])[F:38])[CH:3]=1.C(O)(C(F)(F)F)=O.N>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[CH:18]=3)(=[O:16])=[O:15])[C@H:10]([CH3:36])[CH2:9]2)=[C:4]([C:37]([F:39])([F:38])[F:40])[CH:3]=1
Reactant: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1cccc(N2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1cccc(N2CCNCC2)c1
Yield: 98.7 %

Procedure:
To a solution of (R)-tert-butyl 4-(3-(4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazin-1-ylsulfonyl)phenyl)piperazine-1-carboxylate (970 mg, 1.655 mmol) in DCM (15 mL) was added TFA (5 mL) at room temperature. The resultant mixture was stirred for 4 h then basified with 5% aq. NH3. The precipitate was collected and washed with water to give the desired product as a light yellow solid (795 mg, 99%). HRMS: calcd for C22H26F4N4O2S+H+, 487.17853. found (ESI-FTMS, [M+H]1+), 487.17747.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24]Cl)=[CH:20][CH:19]=2)=[N:16][CH:15]=[CH:14][N:13]=1)(=[O:10])=[O:9].[F:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH:31]=[CH:30]2>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:17]([C:18]2[CH:19]=[CH:20][C:21]([CH2:24][N:32]3[C:33]4[C:29](=[CH:28][C:27]([F:26])=[CH:35][CH:34]=4)[CH:30]=[CH:31]3)=[CH:22][CH:23]=2)=[N:16][CH:15]=[CH:14][N:13]=1)(=[O:10])=[O:9]
Reactant: Fc1ccc2[nH]ccc2c1
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1Cl
Product: O=S(=O)(Nc1nccnc1-c1ccc(Cn2ccc3cc(F)ccc32)cc1)c1ccccc1Cl
Yield: 72 %

Procedure:
Following the general method as outlined in Example 1 (Method B), starting from 2-chloro-N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}benzenesulfonamide (Intermediate 8), and 5-fluoroindole, the title compound was isolated as a yellow solid in 72% yield (96% purity by HPLC).
Reaction SMILES: [CH:1]1[C:6]([Cl:7])=[CH:5][CH:4]=[C:3](Cl)[CH:2]=1.[CH2:9]([Mg]Cl)[CH2:10][CH2:11][CH3:12]>CCOCC>[CH2:9]([C:3]1[CH:2]=[CH:1][C:6]([Cl:7])=[CH:5][CH:4]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCCC[Mg]Cl
Reactant: Clc1ccc(Cl)cc1
Solvent: CCOCC
Product: CCCCc1ccc(Cl)cc1
Yield: 23.6 %

Procedure:
To 2.00 g (13.61 mmoles) of p-dichlorobenzene, and 0.050 g of [NiCltriphos]PF6 in 20 mL of ether at -78° C. was added 7.0 mL (14 mmoles) of 2M nBuMgCl in ether. After refluxing overnight and workup with NH4Cl solution, the residue (602 mg of 1.698 g) was flash-chromatographed with 5% EtOAc/hexane on silica gel to give 542 mg (67%) of 1-butyl-4-chlorobenzene. 1H NMR (200 MHz, CDCl3): δ7.22 (m,2H), 7.05 (m,2H), 2.59 (t, J=5.5 Hz, 2H), 1.58 (m, 2H), 1.34 (m,2H) 0.95 (t, J=5.2 Hz, 3H). IR(neat): 2958s, 2930s, 2859s, 1492s, 1466m, 1407m, 1901s, 1016s cm-1.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]3[CH3:24])=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:25]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[C:27](F)[CH:26]=2)[N:3]=1.CCO.CCN(C(C)C)C(C)C.[NH2:46][NH2:47]>CO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]3[CH3:24])=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:25]2[CH:26]=[C:27]3[C:28]([C:31]([NH2:32])=[N:46][NH:47]3)=[CH:29][CH:30]=2)[N:3]=1
Reactant: NN
Reactant: CC1CCCCC1NC(=O)[C@H]1CC[C@@H](C)N(c2cc(-c3ccc(C#N)c(F)c3)nc(N)n2)C1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CC1CCCCC1NC(=O)[C@H]1CC[C@@H](C)N(c2cc(-c3ccc4c(N)n[nH]c4c3)nc(N)n2)C1
Temperature: 110 °C
Reaction time: 8 h
Yield: 61.9 %

Procedure:
Into a microwave tube, (3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-6-methyl-N-(2-methylcyclohexyl)-3-piperidinecarboxamide (192 mg, 0.426 mmol), EtOH (5 mL), Hunig's base (0.074 ml, 0.426 mmol), and hydrazine anhydrous (0.08 mL, 2.56 mmol) were added, and the yellow suspension mixture was heated overnight at 110° C. in an oil bath. When the temperature of the reaction reached to 100° C., the solid in the mixture was all dissolved. After overnight, there was a yellow solution as well as a little amount of black colored solid formed. LCMS showed mainly product. CH3OH (5 mL) was added to the solution. The black solid was filtered from the yellow solution. Water (20 mL) was added to the yellow solution, and a solid was formed. The solid was filtered, washed by water, and dried in vacuum. The solid was recrystallized from CH3CN, and the solid was filtered, washed by CH3CN, and dried in vacuum to afford the title compound (122 mg) as a light yellow solid. LC-MS (ES) m/z=463 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.68-0.98 (m, 4H), 1.14 (m, 8H), 1.66 (m, 8H), 2.25 (m, 1H), 3.30 (m, 1H), 3.36 (m, 1H), 5.38 (s, 2H), 6.07 (s, 2H), 6.56 (d, J=3.5 Hz, 1H), 7.51-7.65 (m, 1H), 7.70 (s, 1H), 7.73 (s, H), 7.94 (d, J=2.8 Hz, 1H), 11.50 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([NH:12][C@H:13]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]1)=[N:9][C:8]([C:25]#[N:26])=[CH:7]2.[NH2:27][NH2:28].O>CO>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([NH:12][C@H:13]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:14]1)=[N:9][C:8]([C:25]([NH:27][NH2:28])=[NH:26])=[CH:7]2
Reactant: NN
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(C#N)cc3cccc(Cl)c23)C1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(C(=N)NN)cc3cccc(Cl)c23)C1

Procedure:
To a mixture of (S)-tert-butyl 3-((8-chloro-3-cyanoisoquinolin-1-yl)amino)pyrrolidine-1-carboxylate (450 mg, 1.21 mmol) in MeOH (5 mL) was added NH2NH2—H2O (5 mL). The resulting mixture was heated to reflux for 2 hours and the solvent was subsequently removed to give the title compound as a yellow solid, which was used without further purification (450 mg, 91%). ESI-MS m/z [M+H]+ 405.2.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:22])[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=3[F:21])[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].O>CN(C)C=O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:22])[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=3[F:21])[C:8](=[O:12])[N:9]2[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CBr
Reactant: O=c1[nH]c2cc(Br)ccc2c(=O)n1Cc1ccc(Br)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cn1c(=O)n(Cc2ccc(Br)cc2F)c(=O)c2ccc(Br)cc21
Temperature: 0 °C

Procedure:
To a solution of 7-bromo-3-(4-bromo-2-fluorobenzyl)-1,2,3,4-tetrahydro-2,4-dioxoquinazoline 2.80 g) in N,N-dimethylformamide (56 ml) was added sodium hydride (60% in mineral oil, 334 mg) with stirring at 0° C. under an atmosphere of nitrogen and the mixture was stirred at room temperature for 1 hour. To this mixture was added ethyl bromoacetate (0.85 ml) dropwise and the mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure to give a residue, which was poured into water and extracted with ethyl acetate. The extract was washed with water and dried. Removal of the solvent followed by recrystallization from isopropyl ether gave ethyl 2-[7-bromo-3-(4-bromo-2-fluorobenzyl)-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-1-yl]acetate (3.11 g).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6](SC)=[C:7]([CH:10]=1)[C:8]#[N:9].O[O:14][S:15]([O-:17])=O.[K+].Cl.[CH3:20]O>O>[OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([S:15]([CH3:20])(=[O:17])=[O:14])=[C:7]([CH:10]=1)[C:8]#[N:9]
Reactant: CSc1ccc(CO)cc1C#N
Reactant: O=S([O-])OO
Reactant: CO
Agent: Cl
Agent: [K+]
Solvent: O
Product: CS(=O)(=O)c1ccc(CO)cc1C#N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A flask is charged with 5-hydroxymethyl-2-methylsulfanyl-benzonitrile (0.866 g, 4.86 mmol) in a mixture of MeOH (10 mL) and water (10 mL). Oxone (7.47 g, 12.16 mmol) is added and the mixture is stirred at room temperature for 16 h. The residue is acidified to pH 1 using aqueous 1M HCl and then extracted with dichloromethane twice. The organic layer is dried over sodium sulfate and concentrated in vacuo to afford 5-hydroxymethyl-2-methanesulfonyl-benzonitrile as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 3.28 (s, 3H), 4.89 (s, 2H), 7.80 (d, J=8.1 Hz, 1H), 7.95 (s, 1H), 8.18 (d, J=8.1 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=1.ClC1C=C(C2C(COC3C=CC(C(O)=O)=CN=3)=C(C)ON=2)C=CC=1.[NH2:48][CH:49]([OH:51])[CH3:50]>>[OH:20][CH2:19][CH2:18][C:17]1[N:16]=[C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)=[N:5][O:6][C:2]=2[CH3:1])[CH:23]=[CH:22][C:50]=1[C:49]([NH2:48])=[O:51]
Reactant: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)O)cn1
Reactant: CC(N)O
Agent: Cc1onc(-c2cccc(Cl)c2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccccn2)c1COc1ccc(C(N)=O)c(CCO)n1
Yield: 24 %

Procedure:
As described for example 98b, 6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid (77.8 mg, 0.25 mmol) was converted, instead of 6-[3-(3-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid, using aminoethanol instead of 2,2,2-trifluoroethylamine, to the title compound (21 mg, 24%) which was obtained as a white solid. MS: m/e=355.0 [+H]+.
Reaction SMILES: [N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]([CH3:5])=[CH:3][CH:2]=1.[Br:12][CH2:13][CH2:14][CH2:15][OH:16]>C(#N)C>[Br-:12].[OH:16][CH2:15][CH2:14][CH2:13][N+:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]([CH3:5])=[CH:3][CH:2]=1
Reactant: Cc1ccnc2ccccc12
Reactant: OCCCBr
Solvent: CC#N
Product: Cc1cc[n+](CCCO)c2ccccc12
Product: [Br-]
Temperature: 25 °C
Yield: 84 %

Procedure:
A solution mixture of lepidine (0.5 g, 3.5 mmol) and 3-bromopropanol (1.9 g, 14 mmol) in acetonitrile (15 mL) was heated to reflux overnight. After cooling to room temperature, the solvent was removed. The resulting mixture was precipitate from methanol and ethyl acetate to give the desired product 7 (0.83 g) in 84% yield. 1H NMR (400 MHz, DMSO-d6) δ 9.41 (d, J=6 Hz, 1H), 8.58 (d, J=8.8 Hz, 1H), 8.54 (dd, J=8.8 Hz, J=1.2 Hz, 1H), 8.26 (td, J=8.0 Hz, J=1.2 Hz, 1H), 8.08-8.03 (m, 2H), 5.09 (t, J=6.8 Hz, 2H), 3.52 (t, J=5.6 Hz, 2H), 3.01 (s, 3H), 2.15-2.08 (m, 2H). 13C NMR (400 MHz, DMSO-d6) δ 158.5, 148.8, 136.8, 135.1, 129.5, 128.9, 127.2, 122.6, 119.3, 57.4, 54.8, 32.0, 19.7.
Reaction SMILES: Cl.[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[N:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:25]C1C=CN=C(CN)C=1>>[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11]([NH:17][CH2:18][C:19]3[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][N:20]=3)[N:10]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCCC2)c1C
Reactant: Cc1ccnc(CN)c1
Agent: Cl
Product: Cc1ccnc(CNc2nc(C)c(C)c(NC3CCCCC3)n2)c1

Procedure:
The titled compound was synthesized according to the general procedure described for preparation of N4-cyclohexyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 1) using (4-methylpyridin-2-yl)methanamine instead of (pyridin-2-ylmethyl)amine. The product was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a light-grey solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.92-1.67 (m, 10H), 1.88 (s, 3H), 2.28 (s, 3H), 2.53 (s, 3H), 3.63 (bs, 1H), 4.92 (d, J=4.30 Hz, 2H), 7.60-7.80 (m, 3H), 8.19 (bs, 1H), 8.66 (d, J=5.64 Hz, 1H), 13.34 (s, 1H); MS (ESI) m/z 326.0 (M+1)+.