Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH3:25])[C:9]([CH2:11][CH2:12][C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20](=[O:24])[C:21]([OH:23])=O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26]([N:28](CC)CC)[CH3:27].ClC(OCC(C)C)=O.C(N)C>C1COCC1.O>[CH2:1]([N:8]([CH3:25])[C:9]([CH2:11][CH2:12][C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20](=[O:24])[C:21]([NH:28][CH2:26][CH3:27])=[O:23])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(Cc1ccccc1)C(=O)CCC(=O)N1CCC[C@H]1C(=O)C(=O)O
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Agent: CCN
Solvent: C1CCOC1
Solvent: O
Product: CCNC(=O)C(=O)[C@@H]1CCCN1C(=O)CCC(=O)N(C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 2 [(2S)-1-[3-(N-benzyl-N-methylcarbamoyl)propanoyl]pyrrolidin-2-yl]-2-oxoacetic acid (98 mg) in THF (3 ml) was cooled to -20° C. Triethylamine (188 μl) and isobutyl chloroformate (77 μl) were added dropwise to the solution. The mixture was stirred for 20 mins at the same temperature. An aq. solution of ethylamine (70%; 200 μl) was added dropwise to the solution at the same temperature. The solution was stirred for 1 hr, while the temperature of the solution was raised to room temperature gradually. Water was added to the reaction solution. The mixture was extracted with EtOAc. The extract was washed, dried and evaporated. The residue was purified by column chromatography on silica gel (CH2Cl2 --CH3OH) to give the title compound (62 mg) having the following physical data:
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([C:16]3[C:17](=O)[NH:18][C:19](=[O:33])[N:20]([CH2:22][C:23]4[S:24][CH:25]=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:27]=4)[CH:21]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:44])=CC=1>O1CCOCC1.C(OCC)(=O)C>[CH:3]1[C:4]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([C:16]3[C:17](=[S:44])[NH:18][C:19](=[O:33])[N:20]([CH2:22][C:23]4[S:24][CH:25]=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:27]=4)[CH:21]=3)[C:5]=2[CH:11]=[CH:1][CH:2]=1
Reactant: CCOC(=O)c1csc(Cn2cc(C3c4ccccc4C=Cc4ccccc43)c(=O)[nH]c2=O)n1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)c1csc(Cn2cc(C3c4ccccc4C=Cc4ccccc43)c(=S)[nH]c2=O)n1

Procedure:
A mixture of the product of step (iv) (2.1 g) and Lawesson's reagent (1.78 g) in dry 1,4-dioxane (36 ml) was heated at reflux for 16 hours. After cooling, the reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried MgSO4) and evaporated under reduced pressure. Purification was by chromatography eluting with 50% ethyl acetate in isohexane. Yield 1.5 g.
Reaction SMILES: C1(NC(OCC)=O)C=CC=CC=1.O[C:14]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:15]=1[CH:16]([CH3:20])[C:17]([OH:19])=[O:18].[H][H]>C(O)(=O)C.[Pd]>[CH3:25][C:23]1[CH:22]=[CH:21][C:15]([CH:16]([CH3:20])[C:17]([OH:19])=[O:18])=[CH:14][CH:24]=1
Reactant: [H][H]
Reactant: Cc1ccc(C(C)C(=O)O)c(O)c1
Agent: [Pd]
Agent: CCOC(=O)Nc1ccccc1
Solvent: CC(=O)O
Product: Cc1ccc(C(C)C(=O)O)cc1
Yield: 67 %

Procedure:
3 g. of 2-hydroxy-4-methyl-hydratropic acid phenylurethane are dissolved in acetic acid. To the solution 0.4 g. of a 5% palladium-on-charcoal catalyst are added, and the mixture is hydrogenated at 25° C. until the calculated amount of hydrogen is used up. The catalyst is filtered off and the filtrate is evaporated. The residue is admixed with a 10% aqueous hydrochloric acid solution and the separated oil is extracted with chloroform. The chloroform solution is dried over sodium sulphate and evaporated. 1.1 g. (67%) of 4-methyl-hydratropic acid are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[F:9][C:10]([F:21])([F:20])[O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Cl)=[CH:14][CH:13]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:16][C:15]2[CH:18]=[CH:19][C:12]([O:11][C:10]([F:9])([F:20])[F:21])=[CH:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: FC(F)(F)Oc1ccc(CCl)cc1
Reactant: Cc1ccc(S)cc1
Product: Cc1ccc(SCc2ccc(OC(F)(F)F)cc2)cc1
Yield: 80.1 %

Procedure:
The procedure of Example 87 is repeated using 11.8 g of p-thiocresol and 9.6 g of 4-(trifluoromethoxy)benzyl chloride. This affords 10.9 g of the desired product as white crystals. mp 74°-76° C. MS(CI): m/z 299(MH+). Calcd for C15H13F3OS: C=60.39, H=4.39, F=19.11, S=10.75 Found C=60.33, H=4.26, F=19.34, S=11.01
Reaction SMILES: [N+](C(C)C(OC(=O)C)[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([O-])=O.[N+:19]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])#[C-:20].[CH2:27]1[CH2:37]CN2C(=NCCC2)C[CH2:28]1>O.C(OCC)C>[CH2:25]([O:24][C:22]([C:21]1([CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:28][C:27]([CH3:37])=[CH:20][NH:19]1)=[O:23])[CH3:26]
Reactant: C1CCC2=NCCCN2CC1
Reactant: CC(=O)OC(CCc1ccccc1)C(C)[N+](=O)[O-]
Reactant: [C-]#[N+]CC(=O)OCC
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)C1(CCc2ccccc2)CC(C)=CN1
Temperature: 25 °C
Yield: 709.3 %

Procedure:
Acetic acid 2-nitro-1-phenethylpropyl ester (180) (10.4302 g, 44.2 mmol) and ethyl isocyanoacetate (4.957 g, 44.2 mmol) were weighed out into a 250 mL round bottom flask. The flask was sealed with a septum, purged with nitrogen, then dissolved in a solution of THF and iso-propyl alcohol (1.6:1, 44 mL, 1M). The reaction was cooled in an ice bath, then DBU (13.6 mL, 2.05 mmol) was added. The reaction was allowed to warm to room temperature, and was allowed to stir at room temperature until judged complete by HPLC (2 h, 25 min.). The reaction was diluted with H2O and diethyl ether, and the organic layer was removed, extracted with 2N HCl, H2O, and NaHCO3. The combined organics were dried with Na2SO4, filtered, and concentrated. The crude product was purified by purified by silica gel chromatography (Combiflash column, 95:5 Hexanes:EtOAc). The product crystallized from the combined Combiflash fractions to obtain a batch of 3.3224 g (29%) of pure 181 and 3.7709 g of 181 containing a small amount of impure material. HPLC: 11.27 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[N+:18]([O-])=O)=[CH:8][N:7]1[C:21](=[O:23])[CH3:22])=[O:5])[CH3:2].C(O)C>O1CCCC1.CO.[Pt]>[CH2:1]([O:3][C:4]([C:6]1([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[NH2:18])=[CH:8][N:7]1[C:21](=[O:23])[CH3:22])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(C(=O)OCC)CC(c2ccc(Cl)cc2[N+](=O)[O-])=CN1C(C)=O
Agent: [Pt]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CO
Product: CCOC(=O)C1(C(=O)OCC)CC(c2ccc(Cl)cc2N)=CN1C(C)=O
Reaction time: 22 h

Procedure:
A solution of 82.2 g (0.20 mol) of the compound of Example 10 in 300 ml of tetrahydrofuran and 700 ml of methanol was hydrogenated in the presence of 4 g of 5% sulfided platinum on carbon at room temperature and 1500 psi for 22 hours. The reaction mixture was concentrated and the solid residue (76 g) was recrystallized from ethanol (320 ml) to afford 61.4 g (81%) of light orange crystals, m.p. 151.5-153°. The analytical sample was prepared by a second recrystallization from ethanol: white crystals, m.p, 152-153.5°.
Reaction SMILES: [C:1]([CH2:4][CH:5]1[C:9](=[O:10])OC[N:6]1C=O)([OH:3])=[O:2].C(N(CC)CC)C.[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[CH:28]([OH:31])(C)C>>[CH2:20]([NH:27][C:28](=[O:31])[C@:5]([CH:9]=[O:10])([CH2:4][C:1]([OH:3])=[O:2])[NH2:6])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=CN1COC(=O)C1CC(=O)O
Reactant: NCc1ccccc1
Reactant: CC(C)O
Solvent: CCN(CC)CC
Product: N[C@@](C=O)(CC(=O)O)C(=O)NCc1ccccc1
Reaction time: 1 h

Procedure:
The yellowish oil of example 1, dissolved in 100 ml isopropanol, is compounded with 14 ml (100 mmol) triethylamine and compounded with 10 ml (100 mmol) benzylamine. The mixture is heated for 3 h to 50° C. After removal of the isopropanol in a vacuum the residue is taken up in 100 ml 1 N HCl, agitated 1 h and then extracted several times with ethyl acetate. The saturated organic phases are dried over magnesium sulfate and after filtration the solvent is removed in a vacuum. 20 g (80 mmol) 80% of a slightly yellowish solid is obtained.
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([NH2:10])(=[O:9])=[O:8].C(N=[C:22]=[O:23])CCC.N12CCN(CC1)CC2.C(Cl)(Cl)=O>ClC1C=CC=CC=1>[C:1]1([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([N:10]=[C:22]=[O:23])(=[O:9])=[O:8]
Reactant: CCCCN=C=O
Reactant: NS(=O)(=O)c1ccccc1-c1ccccc1
Agent: C1CN2CCN1CC2
Agent: O=C(Cl)Cl
Solvent: Clc1ccccc1
Product: O=C=NS(=O)(=O)c1ccccc1-c1ccccc1
Reaction time: 2 h

Procedure:
23.3 g of 2-biphenylylsulfonamide, 10.9. g of n-butyl isocyanate, a catalytic amount of 1,4-diazabicyclo[2,2,2]-octane and 180 ml of chlorobenzene were refluxed with stirring for 2 hours. Then, phosgene in a slight excess of the theroretical amount was blown through the reaction mixture over 2 hours while maintaining the internal temperature at 115°-120° C. At this time, any unreacted phosgene escaping from the reaction system was trapped in a dry ice trap and returned to the reactor. After addition of the phosgene, the reaction mixture was further stirred at the reflux temperature for a short time to complete the reaction. The mixture was cooled, and if necessary, it was filtered under reduced pressure to remove the insoluble matter. It was then concentrated under reduced pressure, to obtain 20.0 g of 2-biphenylylsulfonylisocyanate. B.p. 135°-137° C./0.7-0.8 mmHg.
Reaction SMILES: C[Zn]C.[CH2:4]([Mg]Br)[CH:5]([CH3:7])[CH3:6].[F:10][C:11]([F:33])([F:32])[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:23]=[CH:22][C:21](/[CH:24]=[N:25]/[S@:26]([C:28]([CH3:31])([CH3:30])[CH3:29])=[O:27])=[CH:20][N:19]=2)=[CH:14][CH:13]=1>>[CH3:6][CH:5]([CH3:7])[CH2:4][C@H:24]([NH:25][S@:26]([C:28]([CH3:31])([CH3:30])[CH3:29])=[O:27])[C:21]1[CH:22]=[N:23][C:18]([C:15]2[CH:16]=[CH:17][C:12]([C:11]([F:33])([F:32])[F:10])=[CH:13][CH:14]=2)=[N:19][CH:20]=1
Reactant: CC(C)C[Mg]Br
Reactant: CC(C)(C)[S@](=O)/N=C/c1cnc(-c2ccc(C(F)(F)F)cc2)nc1
Agent: C[Zn]C
Product: CC(C)C[C@H](N[S@@](=O)C(C)(C)C)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1
Temperature: -78 °C
Reaction time: 1.25 h
Yield: 68.3 %

Procedure:
Dimethyl zinc (117 mL, 2.0 M in toluene, 234 mmol) was added to an oven-dried and nitrogen-purged 500 mL round bottom flask with stir bar. Isobutylmagnesium bromide (103 mL, 2.0 M in ether, 206 mmol) was added over 5 min with stirring and the solution was allowed to stir at room temperature for 30 minutes. (S)-2-Methyl-propane-2-sulfinic acid 1-[2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-meth-(E)-ylideneamide (48.83 g, 137.4 mmol) was placed in an oven dried nitrogen-purged 2 L 3-necked flask with addition funnel, overhead stirring, and internal temperature. The solid was dissolved in anhydrous THF (690 mL) and cooled to −78° C. where it was a white suspension. The zincate solution was cannulated into the addition funnel and then added dropwise over 75 min to the sulfinyl imine, maintaining an internal temperature of less than −72° C. The reaction was then allowed to stir at −78° C. as a yellow solution. At 75 min, the reaction was quenched with saturated NH4Cl, adding 100 mL over 45 min, keeping the internal temperature below-70° C. A second 400 mL was then added more quickly (˜20 min), keeping the internal temperature below −47° C. Gas evolution was observed at these higher temperatures indicating perhaps a latency period. Upon adding a final 100 mL, no gas evolution was observed indicating the reaction was quenched. The cold bath was removed, another 300 mL of water was added and the reaction allowed to warm to 5° C. at which point the contents were added to an addition funnel, along with ethyl acetate and some additional water. The layers were separated and the aqueous layer extracted with three additional portions of ethyl acetate. The combined organics were dried over MgSO4. Purification was done on half the material in two batches by silica gel flash chromatography (ethyl acetate/heptane) to give (S)-2-methyl-propane-2-sulfinic acid {(S)-3-methyl-1-[2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-butyl}-amide (38.83 g, 68%) as a yellow solid. 1H NMR (400 MHz, CDCl3, δ): 8.82 (s, 2H) 8.57 (d, J=8.2 Hz, 2H) 7.75 (d, J=8.4 Hz, 2H) 4.49 (q, J=7.2 Hz, 1H) 3.44 (d, J=5.7 Hz, 1H) 1.99 (dt, J=13.9, 7.3 Hz, 1H) 1.51-1.77 (m, 2H) 1.24 (s, 9H) 0.99 (d, J=6.6 Hz, 3H) 0.95 (d, J=6.4 Hz, 3H); MS (M+1): 414.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([NH:14][CH2:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)[S:12][CH:13]=2)=[CH:5][CH:4]=1.[H-].[Na+].I[CH2:27][CH2:28][CH2:29][CH3:30].C(OCC)(=O)C>CN(C)C=O>[CH2:27]([N:14]([CH2:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1)[C:11]1[S:12][CH:13]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[N:10]=1)[CH2:28][CH2:29][CH3:30]
Reactant: COc1ccc(-c2csc(NCc3ccc(C#N)cc3)n2)cc1
Reactant: CCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCN(Cc1ccc(C#N)cc1)c1nc(-c2ccc(OC)cc2)cs1
Temperature: 25 °C

Procedure:
1.0 g 4-{[4-(4-Methoxy-phenyl)-thiazol-2-ylamino]-methyl}-benzonitrile was dissolved in 150 ml dimethylformamide. 150 mg sodium hydride (24% in mineral oil) were added and the reaction mixture stirred at room temperature for thirty minutes. Then 0.43 ml 1-Iodobutane were added and the reaction mixture stirred at room temperature for two hours. Then 100 ml ethyl acetate were added and the mixture was washed three times with portions of 50 ml water and then dried over MgSO4. The solvents were removed in vacuo to obtain 1.2 g 4-({Butyl-[4-(4-methoxy-phenyl)-thiazol-2-yl]-amino}-methyl)-benzonitrile.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH2:27]([N:29]([CH2:34][CH3:35])[CH2:30][CH2:31][NH:32][CH3:33])[CH3:28]>C(Cl)Cl>[CH2:27]([N:29]([CH2:34][CH3:35])[CH2:30][CH2:31][N:32]([CH3:33])[S:16]([C:14]1[S:15][C:11]([C:7]2[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=2[CH3:10])=[CH:12][CH:13]=1)(=[O:18])=[O:17])[CH3:28]
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)Cl)s2)s1
Reactant: CCN(CC)CCNC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CC)CCN(C)S(=O)(=O)c1ccc(-c2sc(NC(C)=O)nc2C)s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
5-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]thiophene-2-sulfonyl chloride, prepared as in Step II of Example 1 (500 mg; 1.48 mmol; 1.00 eq) is dissolved in DCM (30 ml). The solution is degassed with N2 and cooled down to 0° C. Triethylamine (1.0 ml; 7.42 mmol; 5.00 eq) followed by N,N-diethyl-N′-methylethylenediamine (1.2 ml; 7.42 mmol; 5.00 eq) are added. After 1 hour at 0° C., the reaction is complete. The reaction mixture is washed with NaHCO3 sat. (twice) and water (twice). The organic phase is dried over MgSO4, filtered and concentrated under vacuum, affording Compound (20) as a beige solid (570 mg; 89%).
Reaction SMILES: [N:1]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[NH:23][C:22](=[O:24])[C:21]4[C:16](=[CH:17][C:18]([O:27][CH3:28])=[CH:19][C:20]=4[O:25][CH3:26])[N:15]=3)=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CI.[CH3:31]CN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[CH3:26][O:25][C:20]1[CH:19]=[C:18]([O:27][CH3:28])[CH:17]=[C:16]2[C:21]=1[C:22](=[O:24])[NH:23][C:14]([C:11]1[CH:12]=[CH:13][C:8]([N:1]3[CH2:7][CH2:6][CH2:5][N:4]([CH3:31])[CH2:3][CH2:2]3)=[CH:9][CH:10]=1)=[N:15]2
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCCNCC4)cc3)nc2c1
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCCN(C)CC4)cc3)nc2c1
Temperature: 50 °C
Yield: 22.8 %

Procedure:
To a solution of 2-(4-(1,4-diazepan-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.150 g, 0.39 mmol) in DMF (20 mL) was added CH3I (0.067 g, 0.47 mmol) and Hünig's Base (0.138 mL, 0.79 mmol). The reaction mixture was heated at 50° C. for 1.5 hours, cooled to room temperature, diluted with ethyl acetate (150 mL), washed with brine (2×100 mL), dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel, eluting with 1:1 CH2Cl2/92:7:1 CHCl3/MeOH/concentrated NH4OH to 100% 92:7:1 CHCl3/MeOH/concentrated NH4OH, to afford the title compound (0.035 g, 23%) as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 11.66 (s, 1H), 8.06 (d, J=9.0 Hz, 2H), 6.78 (d, J=9.0 Hz, 2H), 6.65 (d, J=2.2 Hz, 1H), 6.44 (d, J=2.2 Hz, 1H), 3.87 (s, 3H), 3.83 (s, 3H), 3.57-3.59 (m, 2H), 3.52 (t, J=6.1 Hz, 2H), 2.60-2.64 (m, 2H), 2.45-2.50 (m, 2H), 2.26 (s, 3H), 1.89-1.99 (m, 2H). ESI MS m/z 395 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[N:5]=1)(=[O:3])[CH3:2].[I:11]I>N1C=CC=CC=1>[I-:11].[Br:10][C:6]1[N:5]=[C:4]([C:1](=[O:3])[CH2:2][N+:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:4]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: CC(=O)c1cccc(Br)n1
Reactant: II
Solvent: c1ccncc1
Product: O=C(C[n+]1ccccc1)c1cccc(Br)n1
Product: [I-]
Temperature: 25 °C
Yield: 167.9 %

Procedure:
A mixture of 2-acetyl-6-bromopyridine (0.075 mol), 25 ml of pyridine, and iodine (0.075 mol) was allowed to react at 100° C. for 45 minutes and then cooled to room temperature. The reaction mixture was filtered, the solid product was triturated with CH2Cl2 (200 ml), isolated by filtration, and the residual solvent was removed under vacuum to yield 25.5 g (85%) of the desired salt. Melting point: 176°-178 ° C.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]1[C:4]2[S:31][CH:30]=[CH:29][C:5]=2[N:6]=[C:7]([NH:9][C@H:10]2[CH2:14][CH2:13][N:12]([C:15](=O)[CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:11]2)[N:8]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:42])=CC=1>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH3:32])[C:3]1[C:4]2[S:31][CH:30]=[CH:29][C:5]=2[N:6]=[C:7]([NH:9][C@H:10]2[CH2:14][CH2:13][N:12]([C:15](=[S:42])[CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:11]2)[N:8]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CN(C)c1nc(N[C@H]2CCN(C(=O)Cc3ccc(OC(F)(F)F)cc3)C2)nc2ccsc12
Solvent: Cc1ccccc1
Product: CN(C)c1nc(N[C@H]2CCN(C(=S)Cc3ccc(OC(F)(F)F)cc3)C2)nc2ccsc12
Temperature: 110 °C
Yield: 26.1 %

Procedure:
A mixture of (S)-1-(3-(4-dimethylaminothieno[3,2-d]pyrimidin-2-ylamino)pyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone (0.10 g), Lawesson's reagent (0.087 g), and toluene (10 mL) was heated at 110° C. for 5 h with stirring. After left stand for cooling, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (silica gel, chloroform/methanol=50:1) to obtain light yellow solid (S)-1-(3-(4-dimethylaminothieno[3,2-d]pyrimidin-2-ylamino)pyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanethione (0.027 g).
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([NH2:10])OCC)C.[Cl:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[CH2:16][NH:17][NH2:18]>C(O)C>[NH2:10][C:6]1[NH:18][N:17]([CH2:16][C:15]2[CH:19]=[CH:20][CH:21]=[C:13]([Cl:12])[CH:14]=2)[C:4](=[O:3])[CH:5]=1
Reactant: NNCc1cccc(Cl)c1
Reactant: CCOC(=O)C=C(N)OCC
Solvent: CCO
Product: Nc1cc(=O)n(Cc2cccc(Cl)c2)[nH]1
Yield: 42 %

Procedure:
35 g (10% excess) of β-amino-β-ethoxyacrylic acid ethyl ester are introduced into 100 ml of ethanol. 32 g of 3-chlorobenzylhydrazine in 50 ml of ethanol are added while stirring. The mixture is worked up as above. 18.9 g of the compound identified above, as colorless felted needles of melting point 132°, are obtained. (Yield: 42% of theory)
Reaction SMILES: [Cl-].[NH4+].[Br:3][C:4]1[CH:5]=[C:6]([N+:11]([O-])=O)[CH:7]=[CH:8][C:9]=1[CH3:10]>O.CO.[Fe]>[Br:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[CH3:10])[NH2:11]
Reactant: Cc1ccc([N+](=O)[O-])cc1Br
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: Cc1ccc(N)cc1Br

Procedure:
To a suspension of iron (1.5 g, 27.6 mmol) and ammonium chloride (2.46 g, 46 mmol) in water (50 mL) was slowly added a solution of 3-bromo-4-methyl-1-nitrobenzene (1.0 g, 4.6 mmol) in methanol (25 mL). The resulting mixture was refluxed for 2 hours. The solids formed were filtered through celite while the reaction mixture was still hot, the solvent of the clear filtrate was then removed. The crude residue was redissolved in water, extracted with ethyl acetate and dried over anhydrous sodium sulfate. The crude oil was adsorbed on silica gel and purified by flash chromatography on silica gel (hexanes/EtOAc from 95:5 to 50:50). The product, 3-bromo-4-methylaniline, was isolated as pale red oil (462 mg). HPLC Rt 3.425 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:24](N(OC)C)=[O:25])[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:6](/[N:10]=[N:11]/[N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:7]=1[C:8]#[CH:9].[CH3:30][Mg]Cl.Cl.O.[Cl-].[Na+].O>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([C:8]#[CH:9])=[C:6](/[N:10]=[N:11]/[N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:4]([C:24](=[O:25])[CH3:30])[CH:3]=1
Reactant: C[Mg]Cl
Reactant: C#Cc1c(Cl)cc(C(=O)N(C)OC)c(-c2cccc(F)c2)c1/N=N/N1CCCC1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: C#Cc1c(Cl)cc(C(C)=O)c(-c2cccc(F)c2)c1/N=N/N1CCCC1
Temperature: 25 °C
Reaction time: 1.17 h

Procedure:
A solution of 4-chloro-5-ethynyl-3′-fluoro-N-methoxy-N-methyl-6-[(E)-pyrrolidin-1-yldiazenyl]biphenyl-2-carboxamide (930 g, 2.2 mol) in tetrahydrofuran (4.3 L) at 0° C. under nitrogen was treated with 3.0 M methylmagnesium chloride in tetrahydrofuran (2.2 L, 6.7 mol) dropwise over 45 minutes. Gas formation was observed and the internal temperature ranged from 1-8° C. The ice bath was removed and the reaction mixture was stirred at room temperature for 70 minutes. The reaction mixture was cooled to 0-5° C. and treated with 2.0 M hydrogen chloride in water (4.1 L, 8.3 mol) dropwise with gas formation observed. The solution was diluted with ethyl acetate (2 L) and stirred for 10 min. The aqueous layer was separated and extracted with ethyl acetate (1 L). The combined organic layers were washed with brine (0.7 L, 4 mol), dried over sodium sulfate, filtered, and concentrated to an oil. This material was azeotroped with toluene (1 L) to give the desired product. A small sample was purified by silica gel column for spectroscopic analysis. LCMS for C20H18ClFN3O (M+H)+: m/z=370.1; Found: 370.0; 1H NMR (400 MHz, DMSO-d6): δ 7.54 (s, 1H), 7.37-7.31 (m, 1H),7.14-7.09 (m, 1H), 6.94-6.86 (m, 2H), 4.54 (s, 1H), 3.68-3.59 (m, 2H), 3.22-3.13 (m, 2H), 2.11 (s, 3H), 1.89-1.78 (m, 4H).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)=[CH:14][C:13]=1[N+:31]([O-:33])=[O:32].NN.CCOC(C)=O.O>C1COCC1>[NH2:3][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])[CH2:22][CH2:23]2)=[CH:14][C:13]=1[N+:31]([O-:33])=[O:32]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N3C(=O)c4ccccc4C3=O)c([N+](=O)[O-])c2)CC1
Agent: NN
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)c([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.1 %

Procedure:
To a suspension of tert-butyl 4-(4-(1,3-dioxoisoindolin-2-yl)-3-nitrophenyl)piperazine-1-carboxylate (275.4 g, 0.6 mmol) in THF (5.0 ml) was added 1.0M Hydrazine in THF (1.8 ml, 1.8 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into EtOAc/water and organic layer was washed with brine, dried over MgSO4 and evaporated. The resulting oil was purified by flash chromatography on silica eluting with 20% to 70% EtOAc/Hexane to afford the title compound (182 mg, 93% yield). 1H-NMR (400 MHz, DMSO-d6) δ 1.42 (s, 9H) 2.89-2.99 (m, 4H) 3.44 (d, 4H) 6.98 (d, 1H) 7.22 (s, 2H) 7.26-7.38 (m, 2H)