Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[CH2:10][N:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][C:6]=2[N:7]=1.[CH2:21]([NH:23][C:24]([NH:26][C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[C:29]([F:42])[CH:28]=1)=[O:25])[CH3:22]>>[CH2:21]([NH:23][C:24](=[O:25])[NH:26][C:27]1[CH:32]=[CH:31][C:30]([C:2]2[N:3]=[C:4]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[C:5]3[CH2:10][N:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][C:6]=3[N:7]=2)=[C:29]([F:42])[CH:28]=1)[CH3:22]
Reactant: CCNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)c(F)c1
Reactant: COC(=O)N1Cc2nc(Cl)nc(N3CCOCC3)c2C1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CN(C(=O)OC)C3)c(F)c1
Yield: 16 %

Procedure:
Method as described for example 147 using methyl 2-chloro-4-morpholino-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (intermediate 25) and 1-ethyl-3-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl) (intermediate 28) as starting materials. The crude reaction mixture was purified by SCX-2 cartridge (loaded in MeOH eluted with 2M methanolic ammonia). Ammonia eluant was concentrated in vacuo. Residue was then purified by prep. HPLC at high pH to afford an off white solid (34.6 mg, 0.08 mmol, 16%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([OH:14])[C:11]([C:15]([OH:17])=[O:16])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[Si](C)(C)C.[C:30]([CH2:32][C:33](Cl)=[O:34])#[N:31]>ClCCl>[C:30]([CH2:32][C:33]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([OH:14])[C:11]([C:15]([OH:17])=[O:16])=[CH:10][N:9]=2)=[CH:6][CH:7]=1)=[O:34])#[N:31]
Reactant: N#CCC(=O)Cl
Reactant: Nc1ccc(-c2ncc(C(=O)O)c(O)n2)cc1
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#CCC(=O)Nc1ccc(-c2ncc(C(=O)O)c(O)n2)cc1

Procedure:
Using the method for the preparation of the side chain acid in Example 1, 9.2 g (40 mmol) of 2-(4-aminophenyl)-4-hydroxy-5-pyrimidine carboxylic acid, 16.8 ml (120 mmol) of triethylamine, 16 ml (126 mmol) of chlorotrimethylsilane, 400 ml of dichloromethane, and 5.0 (45 mmol) of cyanoacetyl chloride [Org. Syn. Col. Vol. V, p. 171] gives 12.3 g of 2-[4-(cyanoacetylamino)phenyl]-4-hydroxy-5-pyrimidine carboxylic acid as the monohydrate; mp>280°.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[O:9]([C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:16]([O:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:17]=2)[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Nc1cccc(Oc2ccccc2)c1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Clc1cc(Nc2cccc(Oc3ccccc3)c2)ncn1
Yield: 57 %

Procedure:
A solution of 4,6-dichloropyrimidine (0.5 g, 3.3 mmol), 3-phenoxyaniline (0.75 g, 4 mmol) and DIPEA (0.65 g, 5 mmol) in n-butanol (5 mL) was subjected to microwave irradiation (110° C., 30 min). The reaction mixture was cooled, concentrated under reduced pressure and the residue was dissolved in EtOAc (10 mL). This solution was washed with water (5 mL) and brine (5 mL), and was dried over Na2SO4. Concentrated under reduced pressure gave a residue that was purified by column chromatography (SiO2, 60-120, hexane/ethylacetate, 8/2) to give 6-chloro-N-(3-phenoxyphenyl)pyrimidine-4-amine (0.56 g, 56%) as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[C:5]2[N:9]=[CH:10][N:11]([C@@H:12]3[O:32][C@H:31]([CH2:33][O:34]CC4C=CC=CC=4)[C@@H:22]([O:23]CC4C=CC=CC=4)[C@@H:13]3[O:14]CC3C=CC=CC=3)[C:4]=2[CH:3]=1.COC(O)C.[H][H]>[Pd].C(O)(=O)C>[NH2:1][C:2]1[NH:7][C:6](=[O:8])[C:5]2[N:9]=[CH:10][N:11]([C@@H:12]3[O:32][C@H:31]([CH2:33][OH:34])[C@@H:22]([OH:23])[C@@H:13]3[OH:14])[C:4]=2[CH:3]=1
Reactant: Nc1cc2c(ncn2[C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)c(=O)[nH]1
Reactant: [H][H]
Agent: [Pd]
Agent: COC(C)O
Solvent: CC(=O)O
Product: Nc1cc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)[nH]1
Yield: 83.5 %

Procedure:
A mixture of 7.5 g of 6-amino-1-(2,3,5-tri-O-benzyl-β-D-arabinofuranosyl)-1,5-dihydro-4H-imidazo[4,5-c]-pyridin-4-one, 1.5 g of 20% palladium on carbon, 6.4 ml of acetic acid, and 150 ml of methoxy-ethanol is hydrogenated at 50° C. and ca 3 atmospheres until uptake of hydrogen ceases. The mixture is filtered, evaporated in vacuo, dissolved in water, and treated with 50 ml of wet IR-45 ion exchange resin. The filtrate is concentrated to dryness in vacuo and recrystallized from ethanol-water to provide 3.2 g of 6-amino-1-β-D-arabinofuranosyl-1,5-dihydro-4H-imidazo[4,5-c]pyridin-4-one.
Reaction SMILES: CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].I[CH2:13][CH2:14][CH3:15].[F:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([N+:24]([O-:26])=[O:25])[CH:18]=1>O>[F:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:13][CH2:14][CH3:15])=[C:19]([N+:24]([O-:26])=[O:25])[CH:18]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1O
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1ccc(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 96.3 %

Procedure:
A N,N-dimethylformamide (DMF) solution (3 ml) of potassium carbonate (3.48 g, 25.2 mmol) and 1-iodopropane (3.95 g, 23.2 mmol) was added to a DMF solution (7 ml) of 4-fluoro-2-nitrophenol (3.3 g, 21.0 mmol). The mixture was stirred at room temperature for 48 hours. Water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution twice, and concentrated under reduced pressure. The residue was purified using silica gel column chromatography (n-hexane:ethyl acetate=9:1). The purified product was concentrated under reduced pressure to thereby obtain 4.03 g of oily yellow 4-fluoro-2-nitro-1-propoxybenzene (yield: 96%).
Reaction SMILES: [S:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C:4](=[O:12])[NH:3]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:27].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CCO>[Cl:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH2:20][S:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([OH:12])[N:3]=1
Reactant: O=C1Cc2ccccc2C(=S)N1
Reactant: Clc1ccccc1CBr
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Oc1cc2ccccc2c(SCc2ccccc2Cl)n1
Reaction time: 18 h
Yield: 84.8 %

Procedure:
To a 50 mL round bottom flask was added 1-thioxo-1,4-dihydro-2H-isoquinolin-3-one (0.8 g, 4.51 mmol), K2CO3 (1.9 g, 13.5 mmol), and absolute EtOH (15 mL) followed by 1-(bromomethyl)-2-chlorobenzene (0.88 g, 4.29 mmol). Upon completion of addition, the reaction mixture was stirred for 18 h. At the conclusion of this period, the reaction mixture was acidified with a solution of citric acid (100 mL, 10% w/v), extracted with EtOAc (100 mL), washed with brine (75 mL) and then dried over Na2SO4. The solvent was removed under vacuum to yield a residue. The residue was purified via silica gel chromatography (20% EtOAc:Hex) to yield the title compound as a pale yellow solid (1.1 g, 3.64 mmol, 81%). 1H NMR (400 MHz, DMSO-d6): δ ppm 8.05 (d, J=8.35 Hz, 1H), 7.59-7.64 (m, 1H), 7.50-7.57 (m, 2H), 7.37-7.42 (m, 1H), 7.31 (ddd, J=8.46, 6.92, 1.32 Hz, 1H), 7.16-7.23 (m, 2H), 6.71 (s, 1H), 5.92 (br. s., 1H), 4.67 (s, 2H). LC/MS m/z 302 [M+H].
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Cl[CH2:11][C:12]([O-:14])=[O:13].[Na+].C(=O)(O)[O-].[Na+]>O>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:1][CH2:11][C:12]([OH:14])=[O:13])=[CH:3][CH:4]=1)#[N:7]
Reactant: O=C([O-])CCl
Reactant: N#Cc1ccc(N)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: N#Cc1ccc(NCC(=O)O)cc1
Temperature: 25 °C
Yield: 70.5 %

Procedure:
54.0 g (0.46 mol) of 4-aminobenzonitrile and 107.2 g (0.92 mol) of sodium chloroacetate were suspended in 730 mL of water, and the resulting mixture was stirred at reflux temperature for 4 hours. After cooling to room temperature, pH was adjusted to 8-9 with sodium bicarbonate. The resulting solution was washed with 2×200 mL of ethyl acetate, and 5M hydrochloric acid was added to the aqueous phase until pH=3. The precipitated solid was isolated by filtration, washed with 100 mL of water and dried to yield 57.1 g of 2-(4-cyanophenylamino)acetic acid as an off-white solid. Yield: 70.9%. Purity (HPLC, method 3): 92.9%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=3)[C:12](F)=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.ClC1N=C(Cl)C([C:32]([F:35])([F:34])[F:33])=CN=1.NC1C=C(O)C=CC=1>>[OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=3)[C:12]([C:32]([F:35])([F:34])[F:33])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)c1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Agent: Nc1cccc(O)c1
Product: Oc1cccc(Nc2ncc(C(F)(F)F)c(Nc3cccc(O)c3)n2)c1

Procedure:
In a manner similar to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-trifluoromethylpyrimidine and 3-aminophenol were reacted to yield N2,N4-bis(3-hydroxyphenyl)-5-trifluoromethyl-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.82 (bs, 1H), 8.88 (bs, 1H), 8.36 (s, 1H), 7.18-7.11 (m, 2H), 6.96 (m, 4H), 6.63 (dd, 1H, J=2.4 and 8.1 Hz), 6.38 (d, 1H, J=8.1 Hz); 19F NMR (DMSO-d6): −16979; LCMS: ret. time: 19.04 min.; purity: 95%; MS (m/e): 363 (MH+).
Reaction SMILES: [CH3:1][CH2:2][N:3](C(C)C)[CH:4](C)[CH3:5].[N+:10]([C:13]1[CH:21]=[CH:20][CH:19]=[C:15]([C:16]([OH:18])=O)[C:14]=1[OH:22])([O-:12])=[O:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(NCC)C.Cl>CN(C=O)C>[CH2:2]([N:3]([CH2:4][CH3:5])[C:16](=[O:18])[C:15]1[CH:19]=[CH:20][CH:21]=[C:13]([N+:10]([O-:12])=[O:11])[C:14]=1[OH:22])[CH3:1]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1O
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CCN(CC)C(=O)c1cccc([N+](=O)[O-])c1O
Reaction time: 0.02 h

Procedure:
1.19 ml of DIPEA are added to a stirring dispersion of 0.5 g 3-nitrosalicyclic acid and 1.14 g of HATU in 4 ml of DMF at rt under an inert atmosphere of nitrogen. After stirring at it for 1 minute, 0.31 ml of diethylamine in 1 ml of dry DMF are added. After stirring at it for 1 hour, a reaction mixture obtained is added to 50 ml of 1M HCl and extracted with 50 ml EtOAc. Solvent is evaporated and a residue obtained is purified by chromatography on silca eluting with 2:1 iso-hexane/EtOAc. The title compound is obtained. MH+ 239.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([OH:8])[CH:7]=1.O.CC(C)([O-])C.[K+].Br[CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>CN(C=O)C>[CH:19]1([CH2:18][O:8][C:6]2[CH:5]=[C:4]([OH:9])[CH:3]=[C:2]([CH3:1])[CH:7]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: BrCC1CCCCC1
Reactant: Cc1cc(O)cc(O)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(O)cc(OCC2CCCCC2)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of 5-methylbenzene-1,3-diol.H2O (1.0 g, 7.0 mmol) in DMF (15 ml) was added potassium tert-butoxide (0.86 g, 77 mmol). The mixture was stirred at 60° C. for 1 h. To the mixture was added (bromomethyl)cyclohexane (1.2 g, 7.0 mmol). The reaction mixture was stirred at 60° C. for 18 h, concentrated under vacuum, partitioned between water (40 ml) and ethyl acetate (60 ml). Ethyl acetate portion was dried over Na2SO4. Purification by chromatography (10 to 30% EtOAc-hexanes gradient) gave 3-(cyclohexylmethoxy)-5-methylphenol (133) as a light yellow solid. Yield (0.40 g, 26%): 1H NMR (400 MHz, CDCl3) δ 6.31 (s, 1H), 6.20-6.22 (m, 2H), 4.62 (bs, 1H), 3.69 (d, J=6.4 Hz, 2H), 2.50 (s, 3H), 1.64-1.88 (m, 6H), 1.16-1.34 (m, 3H), 0.98-1.08 (m, 2H).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C1([C:19]2=[CH:20][C:21]([O:23][C:24]2=[O:25])=[O:22])C2C(=CC=CC=2)C=C1>CCCCCC>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:21]1(=[O:22])[O:23][C:24](=[O:25])[CH:19]=[CH:20]1
Reactant: O=C1C=C(C2C=Cc3ccccc32)C(=O)O1
Agent: C1=Cc2ccccc2C1
Solvent: CCCCCC
Product: O=C1C=CC(=O)O1
Reaction time: 1 h

Procedure:
Under agitation with the stirrer, the charge was held at the reflux temperature by heating with an external heater. Thereafter, a solution containing 27 g (0.25 mol) of indene and 410 mg of azoisobutyronitrile (AIBN) as a radical polymerization initiator was charged into the overhead dropping funnel and this solution was dripped slowly into the polymerizer over 1 h. After completion of the dripping, the reaction solution was left under reflux for 2h until the reaction was completed. The reaction solution was thereafter returned to room temperature and gradually added to 200 ml of n-hexane in a precipitating tank (beaker with an inner capacity of 500 ml), whereupon a white precipitate of indene-maleic anhydride copolymer formed. The precipitate was separated by filtration under suction and vacuum-dried to obtain a copolymer of indene and maleic anhydride in a yield of 95 wt % as calculated from equation (1) given hereinabove.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[C:5]([NH:7][C:8]1([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]1=[O:17])=[O:6].[C:29]1([CH2:35][CH2:36][CH2:37]Br)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[C:5]([NH:7][C:8]1([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:37][CH2:36][CH2:35][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:9]1=[O:17])=[O:6]
Reactant: CCOC(=O)CCC1(NC(=O)c2ccc(Cl)c(Cl)c2)C(=O)Nc2ccccc21
Reactant: BrCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CCC1(NC(=O)c2ccc(Cl)c(Cl)c2)C(=O)N(CCCc2ccccc2)c2ccccc21
Yield: 92.1 %

Procedure:
A mixture of 1.06 g of ethyl 3-[3-(3,4-dichlorobenzoylamino)-2,3-dihydro-2-oxo-1H-indol-3-yl]propionate, 1.0 g of 3-phenylpropyl bromide, 1.10 g of potassium carbonate and 16 ml of acetone was refluxed overnight. The solvent was removed by evaporation. The residue was extracted with ethyl acetate, washed with water and dried. After removal of solvent, the residual solid was crystallized from isopropyl ether-hexane to afford 1.25 g of ethyl 3-[3-(3,4-dichlorobenzoylamino)-2,3-dihydro-2-oxo-1-(3-phenylpropyl)-1H-indol-3-yl]propionate as a colorless solid. Melting point: 119.5° to 121.5° C., IR (Nujol) (cm-1): 3320, 1730, 1700, 1660, 1615, FAB-MS (m/z): 541 & 539 (MH+).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:19]=[CH:20][C:21]=3[CH3:22])[C:15]([O:17][CH3:18])=[O:16])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.P(Cl)(Cl)([Cl:25])=O>C(#N)C>[Cl:25][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:19]=[CH:20][C:21]=3[CH3:22])[C:15]([O:17][CH3:18])=[O:16])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1ccc(C)c(-c2ccc3c(O)nncc3c2)c1
Solvent: CC#N
Product: COC(=O)c1ccc(C)c(-c2ccc3c(Cl)nncc3c2)c1
Temperature: 80 °C

Procedure:
Methyl 3-(1-hydroxyphthalazin-6-yl)-4-methylbenzoate (2.85 g, 9.68 mmol) was suspended in acetonitrile (19.4 mL), cooled to 0° C. to which phosphorus oxychloride (1.81 mL, 19.4 mmol) was added dropwise. The reaction mixture was warmed to 80° C. for 2.5 h, then concentrated, diluted with 150 mL of ethyl acetate, added to a separatory funnel and partitioned with water. The organics were washed 2×50 mL with water, separated, dried over sodium sulfate, and concentrated in vacuo to give the title compound. MS (ES+): 313(M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](Cl)=[O:6].[CH3:12][NH:13][CH2:14][C:15]1([N:21]2[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([N:13]([CH3:12])[CH2:14][C:15]1([N:21]2[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:6]
Reactant: CNCC1(N2CCN(C)CC2)CCCCC1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Solvent: c1ccccc1
Product: CN1CCN(C2(CN(C)C(=O)c3ccc(Cl)c(Cl)c3)CCCCC2)CC1
Yield: 23.5 %

Procedure:
A solution of 3,4-dichlorobenzoylchloride (0.61 g.,) in benzene (10 ml) was added dropwise over 25 mins. to a stirred solution of 1-[1-(methylaminomethyl)cyclohexyl]-4-methyl piperazine (1) (0.65 g.,). The mixture was then heated on a steambath for 1 hr. and the mixture was evaporated to dryness. The residue was dissolved in hot light petroleum (60°-80°) and decolourised with charcoal. The solid which separated was crystallised from light petroleum (60°-80°) to give 3,4-Dichloro-N-methyl-N-[[1-(4-methyl-1-piperazinyl)cyclohexyl]methyl]benzamide (0.27 g., 23%) m.p. 126°-129°.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])[C:14]2=[O:21]>>[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])[C:14]2([C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH3:9])[OH:21]
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Reactant: Cc1ccc(C)c(Br)c1
Product: Cc1ccc(C)c(C2(O)C(=O)Nc3ccc(Cl)cc32)c1
Yield: 88.8 %

Procedure:
With 8.00 g of 1-bromo-2,5-dimethyl benzene and 5.79 g of 5-chloroisatin as starting materials, 8.15 g of the title compound (colorless amorphous) was obtained by a similar method to Step 21-1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([O-:14])(=O)=[O:12].[Na+].S1(CCCC1)(=O)=O.P(Cl)(Cl)([Cl:25])=O>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([Cl:25])(=[O:14])=[O:12]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)[O-])c1
Agent: [Na+]
Solvent: CC#N
Solvent: O=S1(=O)CCCC1
Product: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1
Temperature: 25 °C

Procedure:
To a mixture of 104 g of commercially available sodium 2-chloro-5-nitrobenzenesulfonate, 200 ml of acetonitrile and 200 ml of sulfolane stirred at 25° C., was added 153 ml of phosphorus oxychloride over a period of 30 minutes. The temperature was not allowed to exceed 40° C. After completion of the addition, the reaction mixture was heated to 70° C. for 1.5 hours. On cooling to 0° C., the reaction mixture was poured over ice. The resulting solid product was washed with cold water, filtered and air-dried to give 77.6 g of the title compound with a melting point of 87°-89° C.
Reaction SMILES: [Br-].Br[CH2:3][C:4]1[CH:5]=[NH+:6][CH:7]=[CH:8][CH:9]=1.[CH3:10][C:11]1[N:16]=[C:15]([SH:17])[N:14]=[C:13]([OH:18])[CH:12]=1.C(N(CC)CC)C>C(O)C>[CH3:10][C:11]1[N:16]=[C:15]([S:17][CH2:3][C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[N:14]=[C:13]([OH:18])[CH:12]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: BrCc1ccc[nH+]c1
Agent: [Br-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(O)nc(SCc2cccnc2)n1
Yield: 38.8 %

Procedure:
A mixture 3-(bromomethyl)pyridin-1-ium bromide (550 mg, 2.5 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (285 mg, 2.0 mmol), and triethylamine (1.1 mL, 8.0 mmol) in absolute ethanol (10 mL) was stirred at room temperature overnight. The solid residue was removed by filtration. The filtrate was recovered and evaporated under reduced pressure. The solid product was suspended in acetone (50 mL). The solid material was removed by filtration. The filtrate was recovered and evaporated to dryness. The residue was suspended in water (50 mL). The product was recovered by filtration, washed with diethyl ether (2×20 mL), and dried in vacuo, affording 6-methyl-2-[(pyridin-3-ylmethyl)sulfanyl]pyrimidin-4-ol (181 mg, 39% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.19 (s, 3H), 4.36 (s, 2H), 6.00 (s (br), 1H), 7.32 (td, 1H, J=0.8 Hz, 7.8 Hz), 7.82 (dd, 1H, J=0.8 Hz, 7.8 Hz), 8.42 (dd, 1H, J=0.8 Hz, 4.7 Hz), 8.61 (d, 1H, J=1.8 Hz); M+234; HPLC purity: 98.1%.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])O1.Br[C:18]1[N:23]=[C:22]([N:24]2[CH2:29][CH2:28][N:27]([C:30](=[O:37])[C@H:31]([OH:36])[CH2:32][CH:33]([CH3:35])[CH3:34])[CH2:26][CH2:25]2)[CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.CC#N.CC#N.O>[OH:36][C@H:31]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:30]([N:27]1[CH2:26][CH2:25][N:24]([C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[OH:15])[N:23]=2)[CH2:29][CH2:28]1)=[O:37]
Reactant: CC(C)C[C@@H](O)C(=O)N1CCN(c2cccc(Br)n2)CC1
Reactant: CC1(C)OB(c2ccccc2O)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)C[C@@H](O)C(=O)N1CCN(c2cccc(-c3ccccc3O)n2)CC1
Temperature: 120 °C

Procedure:
2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-phenol (25 μL, 120/μmol), 1a (36 mg, 100 μmol), Pd(Ph3P)4 (12 mg, 10 μmol), K2CO3 (28 mg, 200 μmol), CH3CN (900 μL), and H2O(100 μL) were sealed in a microwave vessel and heated by microwave irradiation at 120° C. for 15 minutes. The reaction was filtered and purified by reverse phase HPLC to give 4. (10%-99% CH3CN/H2O), (10%-99% CH3CN (0.035% TFA)/H2O(0.05% TFA). LCMS: m/z 370.1 (M+H)+ at 2.89 minutes (10%-99% CH3CN/H2O), (10%-99% CH3CN (0.035% TFA)/H2O(0.05% TFA).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9]C(O)=O)[C:7]2[CH:13]=[CH:14][CH:15]=[CH:16][C:6]=2[N:5]([C:17](=[O:21])[CH2:18][O:19][CH3:20])[CH2:4][C@@H:3]1[NH:22][C:23](=[O:33])[C:24]1[CH:29]=[C:28]([CH3:30])[C:27]([OH:31])=[C:26]([CH3:32])[CH:25]=1.O=C1N(C[C:43]([NH:45][C@H:46]2[CH2:50][C:49](=[O:51])[O:48][CH:47]2[O:52][CH2:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)=[O:44])C2C=CC=CC=2N(C(=O)COC)C[C@@H]1NC(=O)C1C=C(Cl)C(O)=C(Cl)C=1.O=C1N(CC(O)=O)C2C=CC=CC=2N(C(=O)COC)C[C@@H]1NC(=O)C1C=C(Cl)C(O)=C(Cl)C=1>>[O:1]=[C:2]1[N:8]([CH2:9][C:43]([NH:45][C@H:46]2[CH2:50][C:49](=[O:51])[O:48][CH:47]2[O:52][CH2:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)=[O:44])[C:7]2[CH:13]=[CH:14][CH:15]=[CH:16][C:6]=2[N:5]([C:17](=[O:21])[CH2:18][O:19][CH3:20])[CH2:4][C@@H:3]1[NH:22][C:23](=[O:33])[C:24]1[CH:25]=[C:26]([CH3:32])[C:27]([OH:31])=[C:28]([CH3:30])[CH:29]=1
Reactant: COCC(=O)N1C[C@H](NC(=O)c2cc(Cl)c(O)c(Cl)c2)C(=O)N(CC(=O)N[C@H]2CC(=O)OC2OCc2ccccc2)c2ccccc21
Reactant: COCC(=O)N1C[C@H](NC(=O)c2cc(C)c(O)c(C)c2)C(=O)N(CC(=O)O)c2ccccc21
Agent: COCC(=O)N1C[C@H](NC(=O)c2cc(Cl)c(O)c(Cl)c2)C(=O)N(CC(=O)O)c2ccccc21
Product: COCC(=O)N1C[C@H](NC(=O)c2cc(C)c(O)c(C)c2)C(=O)N(CC(=O)N[C@H]2CC(=O)OC2OCc2ccccc2)c2ccccc21

Procedure:
was synthesized from 687b by the method used to prepare 688a from 687a to afford 960 mg of 688b as an off-white solid, 1H NMR (CD3OD) δ2.6(dd, 1H), 2.7(dd, 1H), 3.0(dd, 1H), 3.2(s, 3H), 3.7(m, 3H), 3.9(m, 2H), 4.4-4.5(m, 2H), 4.6(m, 3H), 5.35(s, 1H), 5.55(d, 1H), 7.25(m, 2H), 7.4-7.5 (m, 4H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]2[CH2:13][CH2:12][CH2:11]2)[N:4]=1.C[O:15][C:16]([CH:18]1[CH2:20][CH:19]1[C:21]1[CH:26]=[C:25]([F:27])[C:24]([OH:28])=[C:23]([F:29])[CH:22]=1)=[O:17]>>[CH:10]1([S:9][C:5]2[N:4]=[C:3]([CH2:2][O:28][C:24]3[C:23]([F:29])=[CH:22][C:21]([CH:19]4[CH2:20][CH:18]4[C:16]([OH:17])=[O:15])=[CH:26][C:25]=3[F:27])[CH:8]=[CH:7][CH:6]=2)[CH2:13][CH2:12][CH2:11]1
Reactant: COC(=O)C1CC1c1cc(F)c(O)c(F)c1
Reactant: ClCc1cccc(SC2CCC2)n1
Product: O=C(O)C1CC1c1cc(F)c(OCc2cccc(SC3CCC3)n2)c(F)c1
Yield: 88 %

Procedure:
2-Chloromethyl-6-cyclobutylsulfanyl-pyridine (0.018 g, 0.08 mmol) obtained in Step C of Preparation Example 37 and 2-(3,5-difluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid methyl ester (more polar) (0.020 g, 0.08 mmol) obtained in Step C of Preparation Example 60 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.030 g, 88%).