Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH:24]([OH:31])[CH2:25]OS(C)(=O)=O)=[CH:19][CH:18]=3)[N:13]=2)=[CH:9][C:8]=1[CH3:32])[CH2:4][CH3:5])[CH3:2].[NH3:33]>CO.CC(=O)OCC>[NH2:33][CH2:25][CH:24]([OH:31])[CH2:23][C:20]1[CH:21]=[CH:22][C:17]([C:14]2[N:13]=[C:12]([C:10]3[S:11][C:7]([CH2:6][N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[C:8]([CH3:32])[CH:9]=3)[O:16][N:15]=2)=[CH:18][CH:19]=1
Reactant: CCN(CC)Cc1sc(-c2nc(-c3ccc(CC(O)COS(C)(=O)=O)cc3)no2)cc1C
Reactant: N
Solvent: CCOC(C)=O
Solvent: CO
Product: CCN(CC)Cc1sc(-c2nc(-c3ccc(CC(O)CN)cc3)no2)cc1C

Procedure:
To a cooled (0° C.) solution of rac-3-{4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-propane-1,2-diol (619 mg, 1.54 mmol) in THF (15 mL), DIPEA (399 mg, 3.08 mmol) followed by methansulfonyl chloride (247 mg, 2.16 mmol) is added. The mixture is stirred at 0° C. for 1 h, then at rt for 1 h. The mixture is diluted with DCM, washed with brine (3×50 mL), dried over MgSO4, filtered, concentrated and dried to give crude rac-methanesulfonic acid 3-{4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-2-hydroxy-propyl ester (955 mg) as a light brown oil; LC-MS: tR=0.54 min; [M+1]+=480.10. b) A solution of the above rac-methanesulfonic acid 3-{4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-2-hydroxy-propyl ester (600 mg, 1.33 mmol) in 7 M NH3 in methanol (10 mL) is stirred in a sealed vessel at 80° C. for 16 h. The mixture is diluted with EA and washed with water and brine. The organic extract is dried over MgSO4, filtered and concentrated. The crude product is purified on prep. TLC plates using DCM containing 10% of methanol to give the title compound (242 mg) as a pale yellow resin; LC-MS: tR=0.63 min; [M+1]+=400.93.
Reaction SMILES: [C:1]([N:9]1[C:13](=[O:14])[CH:12]=[CH:11][S:10]1)([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:3])[CH3:2].[Cl:15]N1C(=O)CCC1=O.C1(=O)NC(=O)CC1>C(Cl)(Cl)Cl>[Cl:15][C:12]1[C:13](=[O:14])[N:9]([C:1]([CH2:4][C:5]([CH3:7])([CH3:8])[CH3:6])([CH3:2])[CH3:3])[S:10][CH:11]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)CC(C)(C)n1sccc1=O
Agent: O=C1CCC(=O)N1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)CC(C)(C)n1scc(Cl)c1=O
Reaction time: 2.5 h

Procedure:
To a solution of 10.7 g. (0.05 mole) of 2-t-octyl-3-isothiazolone in 100 ml. of chloroform is added in a single portion 13.3 g. (0.1 mole) of N-chlorosuccinimide. The mixture warms somewhat but does not require cooling. After stirring for 2.5 hours, the mixture is filtered giving 7.5 g. of crude succinimide. The filtrate is evaporated under reduced pressure and the residue dissolved in ether. The ether solution is extracted with water, dried over anhydrous magnesium sulfate, and evaporated to a mixture of solid and oil. The oil is washed from the solid with hexane leaving 1.7 g. (14%) of white 4-chloro-2-t-octyl-3-isothiazolone, m.p. 137°-140°.
Reaction SMILES: [C:1]1([C@H:7]2[O:12][CH2:11][C@H:10](OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:24]([O-:27])(=[S:26])[CH3:25].[K+].C1(C)C=CC=CC=1>CN(C)C(=O)C>[C:24]([S:26][C@H:10]1[CH2:9][O:8][C@@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:12][CH2:11]1)(=[O:27])[CH3:25]
Reactant: CC([O-])=S
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CO[C@H](c3ccccc3)OC2)cc1
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: Cc1ccccc1
Product: CC(=O)S[C@H]1CO[C@@H](c2ccccc2)OC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 46.6 %

Procedure:
A mixture of 30 g (90 mmol) of trans-2-phenyl-5-(p-toluenesulfonyloxy)-1,3-dioxane (prepared as described in Tetrahedron, 48, 5941-5950), 15.3 g (134 mmol) of potassium thioacetate, 240 ml of toluene and 60 ml of N,N-dimethylacetamide was stirred at 100° C. for 3 hours and then at 110-120° C. for 7 hours. After cooling, the reaction mixture was partitioned between toluene and water. The organic layer was then washed with water, dried over anhydrous magnesium sulfate and concentrated. The resulting oily residue was purified by chromatography on a silica el (200 g) column using, a 1:4 mixture of ethyl acetate and hexane as the eluant to afford the crude title compound as a solid. This solid was recrystallized from a mixture of ethyl acetate and hexane to afford 10 g (yield 47%) of the title compound as brown needle-like crystals.
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH:2]=[CH:3][CH2:4][CH2:5][CH3:6].C.[OH-].[NH4+:11]>>[NH2:11][CH:3]([CH2:4][CH2:5][CH3:6])[CH2:2][C:1]([OH:8])=[O:7]
Reactant: [NH4+]
Reactant: CCCC=CC(=O)O
Agent: C
Agent: [OH-]
Product: CCCC(N)CC(=O)O
Temperature: 150 °C

Procedure:
A mixture of 2 hexenoic acid (7.0 g, 0.06 mol) and concentrated aqueous ammonium hydroxide (70 ml) is heated for 24 hours in an autoclave at 150° C. The cooled mixture is treated with carbon black and filtered. After evaporation of the solvent the crude product is recrystallized from ethanol to give the title compound m.p. 203° C. (compound 1.21, Table 2). Following an analogous procedure, the compounds 1.8, 1.9, 1.12 and 1.18-1.20 of Table 1 are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH:18]([N:21]([CH:36]([CH3:38])[CH3:37])[CH2:22][CH2:23][NH:24][C:25]([C:27]1[C:31]([CH3:32])=[C:30]([CH:33]=O)[NH:29][C:28]=1[CH3:35])=[O:26])([CH3:20])[CH3:19]>C(O)C.N1CCCCC1>[CH:36]([N:21]([CH:18]([CH3:20])[CH3:19])[CH2:22][CH2:23][NH:24][C:25]([C:27]1[C:31]([CH3:32])=[C:30]([CH:33]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[NH:12][C:11]2=[O:17])[NH:29][C:28]=1[CH3:35])=[O:26])([CH3:37])[CH3:38]
Reactant: O=C1Cc2c(cccc2-c2cccc(Br)c2)N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN(C(C)C)C(C)C
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(Br)c4)c32)c(C)c1C(=O)NCCN(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 30.5 %

Procedure:
To a solution of 4-(3-bromo-phenyl)-1,3-dihydro-indol-2-one (72 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diisopropylamino-ethyl)-amide (73 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(3-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diisopropylamino-ethyl)-amide as a yellow solid (43 mg, 30%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5][CH2:6][C:7]1[NH:8][C:9](=[O:19])[C:10]([OH:18])=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:12]=1.C([O-])([O-])=O.[K+].[K+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C.CCOCC>[CH2:26]([O:18][C:10]1[C:9](=[O:19])[N:8]2[C:7]([CH2:6][S:5][CH2:4][CH2:3][CH2:2]2)=[N:12][C:11]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1nc(CSCCCCl)[nH]c(=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCCSC2
Reaction time: 1.5 h
Yield: 76.3 %

Procedure:
A mixture of ethyl 2-((3-chloropropylthio)methyl)-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxylate (5 g, 16 mmol) and K2CO3 (4.5 g, 32.5 mmol) in DMF (150 mL) was placed in preheated oil bath and stirred for 1.5 h. After this, benzylbromide (2.4 mL, 20 mmol) was added and continued stirring for additional 3 h. Then, the reaction mixture was cooled, diluted with ether (250 mL0, washed with water (3×50 mL). The combine aq. layers extracted with ether (4×100 mL) and combined with previous organic phase, and washed with brine (50 mL). The organic layer was dried (Na2SO4/activated carbon), filtered and concentrated to give viscous paste. Crystalization of this paste from CH2Cl2/hexanes provided the product as a white solid (4.4 g, 75%). 1H NMR (500 MHz, CDCl3) δ: 7.48-7.46 (2H, m), 7.37-7.30 (3H, m), 5.25 (2H, s), 4.36-4.31 (4H, m), 3.89 (2H, s), 2.94 (2H, t, J=5.6 Hz), 2.16-2.12 (2H, m), 1.30 (3H, t, J=7.0 Hz). HRMS (M+H) calcd for C18H21N2O4S: 361.1222; found: 361.1221.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].N1C=CC=CC=1.[CH2:11]([C:13]([C:20]([F:23])([F:22])[F:21])([C:17](F)=[O:18])[C:14](F)=[O:15])[CH3:12]>C(COC)OC>[CH2:11]([C:13]1([C:20]([F:21])([F:22])[F:23])[C:14](=[O:15])[NH:4][C:2](=[O:3])[NH:1][C:17]1=[O:18])[CH3:12]
Reactant: CCC(C(=O)F)(C(=O)F)C(F)(F)F
Reactant: NC(N)=O
Solvent: c1ccncc1
Solvent: COCCOC
Product: CCC1(C(F)(F)F)C(=O)NC(=O)NC1=O
Reaction time: 8 h
Yield: 60.5 %

Procedure:
A mixture of 1.70 g (0.028 mol) of urea, 4.4 g (0.056 mol) of pyridine and 30 ml of glyme was stirred at 25°C while a solution of 5.7 g (0.028 mol) of ethyltrifluoromethylmalonyl fluoride in 20 ml of glyme was added rapidly. The mixture was stirred overnight, solvent was removed under vacuum, and the residue was stirred with 15 ml of water. Filtration provided a solid which was recrystallized from water to give 3.8 g of 5-ethyl-5-trifluoromethylbarbituric acid, mp 210°-211°C. A second crop, 0.2 g, mp 208°-209°C, raised the total to 4.0 g (64%). A sample was recrystallized twice from water for analysis, mp 211°C; ir (KBr): 3.05 and 3.18 (NH), 3.49 (satd. CH), 5.72 and 5.82 (C=O), and 8-8.5 μ (CF); nmr ((CD3)2CO): 1H at ca. 8.5 (very broad (partly exchanged into acetone-d6), 2, NH), 2.37 (quartet with fine structure, JHH = 7.5 Hz, 2, CH2); and 0.94 ppm (triplet, JHH = 7.5 Hz, 3, CH3); 19F at -69.3 ppm (singlet with fine structure, CF3).
Reaction SMILES: [N:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:10]([O:12][CH2:13][C:14]1[N:15]([CH2:26][CH2:27][CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[C:16]2[C:21]([CH3:22])=[C:20]([CH3:23])[N:19]=[C:18]([NH2:24])[C:17]=2[N:25]=1)[CH3:11]>>[CH2:10]([O:12][CH2:13][C:14]1[N:15]([CH2:26][CH2:27][CH:28]2[CH2:29][CH2:30][N:31]([C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[CH2:32][CH2:33]2)[C:16]2[C:21]([CH3:22])=[C:20]([CH3:23])[N:19]=[C:18]([NH2:24])[C:17]=2[N:25]=1)[CH3:11]
Reactant: CCOCc1nc2c(N)nc(C)c(C)c2n1CCC1CCNCC1
Reactant: O=C(Cl)N1CCOCC1
Product: CCOCc1nc2c(N)nc(C)c(C)c2n1CCC1CCN(C(=O)N2CCOCC2)CC1

Procedure:
Using the method of Examples 54-65, 4-morpholinecarbonyl chloride was reacted with 2-(ethoxymethyl)-6,7-dimethyl-1-(2-piperidin-4-ylethyl)-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired compound. The observed accurate mass was 445.2929.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[F:16][C:17]1[CH:18]=[C:19]([CH2:24][CH2:25][OH:26])[CH:20]=[CH:21][C:22]=1[F:23].Cl.C1C[O:31][CH2:30]C1>C(OCC)(=O)C.CN(C=O)C>[F:23][C:22]1[C:17]([F:16])=[CH:18][C:19]([CH2:24][CH2:25][OH:26])=[CH:20][C:21]=1[CH:30]=[O:31]
Reactant: OCCc1ccc(F)c(F)c1
Reactant: C1CCOC1
Agent: CC1(C)CCCC(C)(C)N1
Agent: Cl
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=Cc1cc(CCO)cc(F)c1F
Temperature: -70 °C
Reaction time: 6 h

Procedure:
2,2,6,6-Tetramethylpiperidine (6.15 mL) was added to a solution of n-butyllithium in hexanes (1.6M, 22.8 mL) at −70° C. A solution of 2-(3,4-difluorophenyl)ethanol (example 32, step a) (1.92 g) in THF (25 mL) was added dropwise. THF (25 mL) was added and the mixture stirred at −70° C. for 6 h. DMF (4.7 mL) was then added and the mixture stirred for 1 h at −70° C. The mixture was then allowed to warm to RT and stirred for 70 h. Aqueous HCl solution (2M, 10 mL) was added followed by ethyl acetate (20 mL) and the layers separated. The aqueous phase was extracted with ethyl acetate (2×20 mL). The combined organic solutions were washed with brine (20 mL), dried over magnesium sulphate, filtered and evaporated in vacuo. Purification was by silica gel chromatography eluting with 4:1 to 2:1 isohexane:diethyl ether gradient. The fractions containing product were combined and evaporated in vacuo to give the subtitled compound as a yellow oil. Yield 1.9 g.
Reaction SMILES: [F:1][C:2]1[C:10]([I:11])=[C:9]([CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[CH3:14]O>>[F:1][C:2]1[C:10]([I:11])=[C:9]([CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:14])=[O:5]
Reactant: CO
Reactant: Cc1ccc(C(=O)O)c(F)c1I
Agent: Cl
Product: COC(=O)c1ccc(C)c(I)c1F
Temperature: 80 °C

Procedure:
To the solution of 2-fluoro-3-iodo-4-methylbenzoic acid (450 mg, 1.6 mmol, 1.0 eq) in methanol (5 ml), catalytic amount of conc.HCl (0.1 ml) was added. The resultant solution was heated to reflux at 80° C. for overnight. Methanol was evaporated. To this residue, water was added and the aqueous layer was extracted thrice with ethyl acetate. The combined ethyl acetate extracts were dried over sodium sulphate, filtered and evaporated to afford methyl 2-fluoro-3-iodo-4-methylbenzoate. Yield: 450 mg (95%). 1H NMR (400 MHz, DMSO): δ 2.49 (s, 3H), 3.85 (s, 3H), 7.30-7.32 (d, 1H, J=7.84 Hz), 7.76-7.80 (t, 1H, J=7.82 Hz). LCMS: (ES+) m/z=295 (M+H).
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][NH2:6])[CH3:2].Cl.[CH2:10]([O:12][C:13](=[O:31])[C:14]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[C:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=O)[CH3:11].C([BH3-])#N.[Na+]>CO>[ClH:22].[CH2:10]([O:12][C:13]([C:14]1[N:6]([CH2:5][CH2:4][N:3]([CH2:7][CH3:8])[CH2:1][CH3:2])[C:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:17]2[C:16]=1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18]2)=[O:31])[CH3:11]
Reactant: CCOC(=O)C(=O)c1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: CCN(CC)CCN
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1CCN(CC)CC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3.5 g. of 2-diethylaminoethylamine in 10 ml. of methanol is treated with 2 ml. of 5-N methanolic hydrochloric acid. Then, there are added successively under argon at 20°-25° C. a solution of 1.6 g. of o-benzoyl-p-chlorophenylglyoxylic acid ethyl ester in 5 ml. of methanol and 0.2 g. of sodium cyanoborohydride and the mixture is stirred for an additional 7 hours at room temperature. While cooling with ice, the mixture is made acidic with concentrated hydrochloric acid, stirred for an additional 0.5 hour at room temperature and evaporated to dryness under reduced pressure. The residue is made alkaline with 1-N sodium hydroxide with addition of ice and extracted with 50 ml. of ether. The ethereal extract is treated with 20 ml. of 0.5-N hydrochloric acid, and the mixture shaken thoroughly. After cooling in an ice-bath, the crystallized hydrochloride is isolated and purified in a manner analogous to that described in Example 1, and there is obtained 5-chloro-2-[ 2-(diethylamino)ethyl]-3-phenylisoindole-1-carboxylic acid ethyl ester hydrochloride; melting point 248°-250° C. (decomposition).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[C:10]([F:19])[C:11](F)=[C:12]([F:17])[CH:13]=2)[N:8]([CH:20]2[CH2:22][CH2:21]2)[CH:7]=1)=[O:5])[CH3:2].[NH2:23][CH:24]1[C:28]2([O:32][CH2:31][CH2:30][O:29]2)[CH2:27][NH:26][CH2:25]1>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[C:10]([F:19])[C:11]([N:26]3[CH2:25][CH:24]([NH2:23])[C:28]4([O:32][CH2:31][CH2:30][O:29]4)[CH2:27]3)=[C:12]([F:17])[CH:13]=2)[N:8]([CH:20]2[CH2:22][CH2:21]2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: NC1CNCC12OCCO2
Solvent: ClCCl
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(N3CC(N)C4(C3)OCCO4)c(F)cc2c1=O
Yield: 44.6 %

Procedure:
Following the procedure of Step 1 Example 80, starting with 0.750 g (2.4 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester and substituting 0.521 g (3.6 mmol) of 9-amino-1,4-dioxa-7-azaspiro[4.4]nonane, from Step 6 Example 208, for the spiro compound of that example, and heating at 40° C. instead of 65° C. for 288 hours instead of 48 hours, the crude product was obtained. The compound was dissolved in methylene chloride which was washed with 2×100 mL of water then dried over anhydrous sodium sulfate, then the solvent was removed by evaporation under vacuum. The product was purified with HPLC, eluting with 60% increasing to 65% methanol/water. The solvent was removed by evaporation under vacuum to afford 0.466 g of the title compound, NMR (CDCl3) d 1.12 (m, 4H), 1.40 (t, 3H, J=7.5 Hz), 3.45 (m, 5H), 3.62 (m, 1H), 3.78 (m, 2H), 3.84 (m, 1H), 3.98 (m, 1H), 4.07 (m, 4H), 4.38 (q, 2H, J=7.5 Hz), 7.83 (dd, 1H, J=15, 1.5 Hz), 8.50 (s, 1H).
Reaction SMILES: Cl.[CH3:2][C:3]1[N:8]=[C:7]([C:9]2[C:10](=[O:16])[NH:11][C:12](=[O:15])[NH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:24]([Cl:28])[CH2:25][CH2:26][CH3:27].CC1N=C(C2C(=O)NC(=O)NC=2)C=CC=1>CN(C=O)C.O>[Cl:28][CH2:24][CH2:25][CH2:26][CH2:27][N:13]1[CH:14]=[C:9]([C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([CH3:2])[N:8]=2)[C:10](=[O:16])[NH:11][C:12]1=[O:15]
Reactant: Cc1cccc(-c2c[nH]c(=O)[nH]c2=O)n1
Reactant: CCCC(Cl)Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc(-c2cn(CCCCCl)c(=O)[nH]c2=O)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 157.1 %

Procedure:
5-(6-Methyl-pyridin-2-yl)-1H-pyrimidine-2,4-dione hydrochloride (Prep 50, 50 mg, 0.208 mmol) and K2CO3 (43 mg, 0.312 mmol) were suspended in dry DMF (2 mL) and stirred for 1 h at room temperature. Then a solution of bromo-chloro-butane (71.3 mg, 0.416 mmol) in dry DMF (0.5 mL) was added dropwise and the mixture stirred for 48 hrs at room temperature. A second run of reaction was performed using 5-(6-Methyl-pyridin-2-yl)-1H-pyrimidine-2,4-dione (135 mg, 0.563 mmol), K2CO3 (116 mg, 0.8445 mmol) and bromo-chloro-butane (193 mg, 1.126 mmol). After stirring the reactions at room temperature for 48 hours, the two mixtures were mixed. Water was added and the mixture was extracted with ethyl acetate. The organic phase was dried (Na2SO4), filtered and evaporated; the crude was purified by flash chromatography with DCM-MeOH—NH4OH (98-2-0.2) to give the title compound as a pale yellow solid (96 mg, 43% yield).
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:7]=[C:6]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[C:3]=1[C:4]#[N:5].[ClH:23].[F:24][C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=1)[O:28][CH2:29][CH2:30][NH2:31].C(=O)([O-])O.[Na+].CS(C)=O>O>[ClH:1].[ClH:23].[F:24][C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=1)[O:28][CH2:29][CH2:30][NH:31][C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:7]=[C:6]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[C:3]=1[C:4]#[N:5]
Reactant: NCCOc1cccc(F)c1
Reactant: Cc1cc(Nc2cc(-c3cccnc3)c(C#N)c(Cl)n2)n[nH]1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(Nc2cc(-c3cccnc3)c(C#N)c(NCCOc3cccc(F)c3)n2)n[nH]1
Temperature: 130 °C
Reaction time: 24 h
Yield: 6.7 %

Procedure:
Compound D (202 mg, 650 μmol), 2-(3-fluorophenoxy)ethylamine hydrochloride (357 mg) and sodium hydrogencarbonate (540 mg) were added to DMSO (3 ml), and the mixture was stirred at 130° C. for 24 hr. After stirring, the reaction mixture was added to cold water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and concentrated, and the residue was purified by silica gel chromatography (90 mg). This was converted to hydrochloride to give the object compound of 2-(2-(3-fluorophenoxy)ethylamino)-6-(5-methyl-1H-pyrazol-3-ylamino)-4-(pyridin-3-yl)nicotinonitrile dihydrochloride (22 mg).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][CH:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[O:7][C:6]=2[CH:5]=[CH:4][C:3]=1[Cl:16].Cl[CH:18](Cl)[O:19]C.C(Cl)Cl>[Ti](Cl)(Cl)(Cl)Cl.C(OCC)(=O)C>[Cl:1][C:2]1[C:10]2[O:9][CH:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[O:7][C:6]=2[CH:5]=[C:4]([CH:18]=[O:19])[C:3]=1[Cl:16]
Reactant: COC(Cl)Cl
Reactant: CCOC(=O)C1Oc2ccc(Cl)c(Cl)c2O1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)C1Oc2cc(C=O)c(Cl)c(Cl)c2O1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
3.52 ml of titanium tetrachloride are added dropwise to a mixture of 4.0 g of ethyl 4,5-dichloro-1,3-benzodioxole-2-carboxylate, 2.12 ml of dichloromethoxymethane and 60 ml of methylene chloride at -60° C. and the mixture is stirred at room temperature for 2 days. 2.1 ml of dichloromethoxymethane and 2.1 ml of titanium tetrachloride are added to the reaction mixture at -60° C. and the mixture is stirred at room temperature for 18 hours. The reaction mixture is poured into a mixture of ethyl acetate and an aqueous sodium bicarbonate solution, and the organic layer is separated. The organic layer is washed with water, dried and evaporated to remove solvent. The residue is purified by silica gel column chromatography to give 3.21 g of ethyl 4,5-dichloro-6-formyl-1,3-benzodioxole-2-carboxylate.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu]>[N+:9]([C:5]1[CH:4]=[CH:3][C:2]([O:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][C:6]=1[CH3:8])([O-:11])=[O:10]
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: Oc1ccccc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cc(Oc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 14.2 %

Procedure:
A mixture of 5-fluoro-2-nitrotoluene (9.8 g), phenol (11.89 g), potassium carbonate (12.22 g) and copper bronze (1.0 g) was boiled for 16 hours. After cooling to room temperature the mixture was extracted with boiling diethyl ether (2×500 ml) and the combined organic phases washed with aqueous 1N sodium hydroxide (6×100 ml) and water (3×100 ml). After drying (MgSO4), solvent was removed at reduced pressure and the residue column chromatographed (silica gel, hexane→5% diethyl ether/hexane eluant) to give 2-nitro-5-phenoxytoluene (2.06 g) as an oil.
Reaction SMILES: [CH3:1][N:2]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[Cl:23])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:6]([OH:8])=O.[CH2:24]([S:29]([NH2:32])(=[O:31])=[O:30])[CH2:25][CH2:26][CH2:27][CH3:28].N12CCCN=C1CCCCC2>CN(C)C=O>[CH2:24]([S:29]([NH:32][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:11]([N+:12]([O-:14])=[O:13])=[C:3]([N:2]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])[CH3:1])[CH:4]=1)(=[O:31])=[O:30])[CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CN(Cc1ccc(Cl)cc1Cl)c1cc(C(=O)O)ccc1[N+](=O)[O-]
Reactant: CCCCCS(N)(=O)=O
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCCS(=O)(=O)NC(=O)c1ccc([N+](=O)[O-])c(N(C)Cc2ccc(Cl)cc2Cl)c1
Reaction time: 1 h
Yield: 51.8 %

Procedure:
N,N′-carbonyldiimidazole (0.776 g) was added to a mixture of 0.85 g of 3-(N-methyl-2,4-dichlorobenzylamino)-4-nitrobenzoic acid and 10 ml N,N-dimethylformamide at room temperature, and the mixture was stirred for 1 hour. 1-Pentanesulfonamide (0.724 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.729 g) were then added thereto, and the resulting mixture was stirred at 100° C. for 21 hours. The mixture was concentrated, and the resulting residue was dissolved in ethyl acetate. The organic layer was washed with water, concentrated, and purified by silica-gel column chromatography (eluent: a mixture of hexane and ethyl acetate at a ratio of 1:1 to 0:1). The desired fractions were collected and concentrated. The concentrate was re-dissolved in ethyl acetate, washed twice with diluted hydrochloric acid and subsequently with a solution of sodium hydrogen carbonate. The organic layer was dried and concentrated to give 0.605 g of N-(n-pentanesulfonyl)-3-(N-methy-2,4-dichlorobenzylamino)-4-nitrobenzamide. This product was used immediately in the next reaction step.