Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:37][C:38]1[S:39][CH:40]=[CH:41][N:42]=1.C(N(C(C)C)CC)(C)C>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:37][C:38]2[S:39][CH:40]=[CH:41][N:42]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: Nc1nccs1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(Cl)c(Cl)c1)Nc1nccs1
Reaction time: 16 h
Yield: 69.6 %

Procedure:
To a solution of (3,4-dichloro-phenyl)-acetic acid (500 mg, 2.4 mmol)in N,N-dimethylformamide (15 mL) at 25° C. was added HBTU (1.02 g, 2.7 mmol), 2-aminothiazole (360 mg, 3.6 mmol) and diisopropylethylamine (1.25 mL, 7.2 mmol). The reaction mixture was stirred for 16 h, then was diluted with water (10 mL) and extracted with ethyl acetate (3×15 mL). The combined organic layers were washed in turn with water (1×10 mL), 1N sodium hydroxide (1×10 mL), 1 N hydrochloric acid (1×10 mL) and brine (1×10 mL), then were dried over sodium sulfate, filtered and evaporated under reduced pressure. The residual material was purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 50150 hexanes/ethyl acetate) to furnish rac-2-(3,4-dichloro-phenyl)-N-thiazol-2-yl-acetamide (480 mg, 70% yield) as a light yellow solid, mp 169.8-172.3° C. EI-HRMS m/e calcd for C11H8N2OSCl2 (M+) 285.9734, found 285.9734.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[NH:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:12]1[CH2:20][C:21]([O:23]CC)=O.[NH2:26][C:27]1[S:28][CH:29]=[CH:30][C:31]=1[C:32]#[N:33]>C1COCC1>[NH2:33][C:32]1[C:31]2[CH:30]=[CH:29][S:28][C:27]=2[NH:26][C:21](=[O:23])[C:20]=1[C:12]1[NH:11][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=1
Reactant: CCOC(=O)Cc1nc2ccccc2[nH]1
Reactant: N#Cc1ccsc1N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1c(-c2nc3ccccc3[nH]2)c(=O)[nH]c2sccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
LiHMDS (4.3 eq) was added to ethyl 1H-benzimidazol-2-ylacetate (1.1 eq) and 2-aminothiophene-3-carbonitrile (1.0 eq) in THF at 0° C. After 1 hour, the resulting mixture was warmed to room temperature and then stirred overnight. The mixture was quenched with an aqueous saturated NH4Cl solution and extracted with EtOAc. The organic layer was washed with H2O and brine, dried over Na2SO4, filtered, and concentrated in vacuo to yield a brown solid. LC/MS m/z 283.1 (MH+), Rt 1.88 minutes.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11]([NH:13][CH2:14][C:15]3[C:16]([OH:23])=[N:17][C:18]([CH3:22])=[CH:19][C:20]=3[CH3:21])=[O:12])=[C:9]([CH3:24])[N:8]([C@@H:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH3:26])[C:6]=2[N:7]=1.[CH3:33][O-:34].[Na+]>CO>[OH:23][C:16]1[C:15]([CH2:14][NH:13][C:11]([C:10]2[C:5]3[CH:4]=[N:3][C:2]([O:34][CH3:33])=[N:7][C:6]=3[N:8]([C@@H:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH3:26])[C:9]=2[CH3:24])=[O:12])=[C:20]([CH3:21])[CH:19]=[C:18]([CH3:22])[N:17]=1
Reactant: Cc1cc(C)c(CNC(=O)c2c(C)n([C@H](C)c3ccccc3)c3nc(Cl)ncc23)c(O)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ncc2c(C(=O)NCc3c(C)cc(C)nc3O)c(C)n([C@H](C)c3ccccc3)c2n1
Yield: 55.4 %

Procedure:
A solution of (R)-2-chloro-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-6-methyl-7-(1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (70 mg, 0.15 mmol) in MeOH (1 mL) solution of sodium methanolate (20 mg) was stirred at 100° C. for 60 minutes under microwave (pressure: 15.3 bar, equipment power: 150 W). The mixture was concentrated in vacuo and purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to afford (R)-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-2-methoxy-6-methyl-7-(1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (37 mg, 51.9%). LRMS (M+H+) m/z: calcd 445.21. found 445. HPLC purity (214 nm): 100%. 1H NMR (400 MHz, CD3OD) δ 8.75 (s, 1H), 7.29-7.22 (m, 5H), 6.11-6.07 (m, 2H), 4.46 (s, 2H), 3.90 (s, 3H), 2.48 (s, 3H), 2.36 (s, 3H), 2.21 (s, 3H), 2.05 (d, J=7.2 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]([CH3:28])[C:12]([C:14]1[S:27][C:17]2[C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1)=[O:13])[C:5]([OH:7])=O.[NH2:29][CH2:30][CH2:31][NH:32][C:33](=[O:35])[CH3:34]>>[C:33]([NH:32][CH2:31][CH2:30][NH:29][C:5]([C:4]1[CH:8]=[CH:9][C:10]([N:11]([CH3:28])[C:12]([C:14]2[S:27][C:17]3[C:18]4[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=4[O:20][CH2:21][CH2:22][C:16]=3[CH:15]=2)=[O:13])=[C:2]([Cl:1])[CH:3]=1)=[O:7])(=[O:35])[CH3:34]
Reactant: CC(=O)NCCN
Reactant: CN(C(=O)c1cc2c(s1)-c1ccccc1OCC2)c1ccc(C(=O)O)cc1Cl
Product: CC(=O)NCCNC(=O)c1ccc(N(C)C(=O)c2cc3c(s2)-c2ccccc2OCC3)c(Cl)c1

Procedure:
3-Chloro-4-(N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)benzoic acid and N-(2-aminoethyl)acetamide were reacted by a procedure similar to that to prepare 137 in Example 47 to give 230. MS: (ESI+) 498.1
Reaction SMILES: COC([N:5]1[CH2:9][CH:8]([C:10]2[C:18]3[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[CH:7]2[N:20]([C:23](=[O:39])[CH:24]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:21][CH2:22][CH:6]12)=O.CCN(C(C)C)C(C)C.[CH3:49][S:50](Cl)(=[O:52])=[O:51]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:35]([O:34][C:32](=[O:33])[NH:31][CH:24]([CH:25]1[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1)[C:23]([N:20]1[CH2:21][CH2:22][CH:6]2[N:5]([S:50]([CH3:49])(=[O:52])=[O:51])[CH2:9][CH:8]([C:10]3[C:18]4[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=4)[NH:12][CH:11]=3)[CH:7]12)=[O:39])([CH3:38])([CH3:37])[CH3:36]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)N1CC(c2c[nH]c3cc(F)ccc23)C2C1CCN2C(=O)C(NC(=O)OC(C)(C)C)C1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC(C(=O)N1CCC2C1C(c1c[nH]c3cc(F)ccc13)CN2S(C)(=O)=O)C1CCCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 49.4 %

Procedure:
A solution containing 50 (200 mg, 0.41 mmol) and DIPEA (163 mg, 1.26 mmol) in anhydrous DCM (5 mL) was cooled to 0° C. A solution of MsCl (44 mg, 0.41 mmol) in DCM (0.5 mL) was added followed by the addition of DMAP (5 mg, cat.). After 2 h, the reaction mixture was diluted with DCM and washed successively with 1M HCl and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by flash silica gel chromatography (1:1 hexanes/EtOAc) to afford 114 mg (49%) of 61 as a white solid. Mass spectrum, m/z [563] (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][CH:11]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)[CH:3]=1.C([O-])(=O)C.[Na+]>CO.[Pd].O>[N:7]1[CH:2]=[CH:3][C:4]([N:8]2[CH2:13][CH2:12][CH:11]([CH:14]3[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]3)[CH2:10][CH2:9]2)=[N:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C2CCN(c3cc(Cl)ncn3)CC2)CC1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(C2CCN(c3ccncn3)CC2)CC1
Reaction time: 8 h

Procedure:
The tert-butyl 1′-(6-chloropyrimidin-4-yl)-4,4′-bipiperidine-1-carboxylate (50 mg, 0.13 mmol, prepared as described for Example 13) and sodium acetate (11 mg, 0.13 mmol) were dissolved in methanol (1.3 ml), 10% palladium on carbon (14 mg) added and the solution stirred overnight under a hydrogen atmosphere. The solution was diluted with 4:1 water:saturated sodium bicarbonate (40 ml) and extracted with ethyl acetate (3×25 ml). The combined organic fraction was washed with brine, dried over magnesium sulfate, filtered, and the volatiles removed in vac. The crude material was purified by chromatography on silica gel with 35% acetone:hexanes to yield the titled compound.
Reaction SMILES: [CH2:1]([O:8][CH2:9][O:10][CH2:11][C@H:12]([CH3:15])[CH2:13][OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[S:23](Cl)([C:26]1[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=1)(=[O:25])=[O:24]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([O:8][CH2:9][O:10][CH2:11][C@@H:12]([CH3:15])[CH2:13][O:14][S:23]([C:26]1[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=1)(=[O:25])=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@H](CO)COCOCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC[C@H](C)COCOCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
To a mixture of diol 3 (29.2 mmol, 6.13 g), DMAP (0.82 mmol, 100 mg) and triethylamine (116.7 mmol, 16.2 mL, 11.8 g) in anhydrous CH2Cl2 (60 mL) was added tosyl chloride (37.9 mmol, 7.23 g) at 0° C. The reaction mixture was allowed to warm to room temperature and stirring was continued overnight. The mixture was then diluted with CH2Cl2 (100 mL) and was then washed with a saturated aqueous solution of NaHCO3, dried over Na2SO4, and concentrated under reduced pressure. The residue was chromatographed on a silica gel using hexane/EtOAc (7:3) as an eluent to give the oily tosylate 4 (10.2 g, 97%).
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]3[C:16]([C:25]4[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=4)=[C:17]([CH2:22][C:23]#N)[N:18]([CH3:21])[C:19](=[O:20])[C:8]2=3)=[CH:4][CH:3]=1.[OH-:34].[K+].Cl.[Si](C=[N+]=[N-])(C)(C)C.[CH2:44]([OH:46])C>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]3[C:16]([C:25]4[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=4)=[C:17]([CH2:22][C:23]([O:46][CH3:44])=[O:34])[N:18]([CH3:21])[C:19](=[O:20])[C:8]2=3)=[CH:32][CH:33]=1
Reactant: [OH-]
Reactant: Cc1ccc(-c2c(CC#N)n(C)c(=O)c3c2c2ccccc2n3Cc2ccc(F)cc2)cc1
Reactant: CCO
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: COC(=O)Cc1c(-c2ccc(C)cc2)c2c3ccccc3n(Cc3ccc(F)cc3)c2c(=O)n1C
Temperature: 140 °C
Reaction time: 0.33 h
Yield: 93 %

Procedure:
A suspension of 2-(9-(4-fluorobenzyl)-2-methyl-1-oxo-4-(p-tolyl)-2,9-dihydro-1H-pyrido[3,4-b]indol-3-yl)acetonitrile (45 mg, 0.103 mmol) in Ethanol (3 mL) and Water (1 mL) was treated with KOH (5.80 mg, 0.103 mmol) and heated in a sealed tube at 140° C. for 3 days. The mixture was cooled to 0° C. and then treated with 4N HCl until pH<2. The mixture was partly concentrated and then extracted with ethyl acetate. The combined extracts were washed with brine and then concentrated. The residue was dissolved AcOH and concentrated HCl (37%) and irradiated in microwave at 120° C. for 1 hour. The mixture was concentrated to dryness. The residue was diluted with Ethyl acetate, washed with brine, dried over Na2SO4, filtered and concentrated. The resultant was dissolved in Methanol (3.00 mL), cooled to 0° C., treated with TMS-diazomethane (59.0 mg, 0.517 mmol) and then stirred at 0° C. for 20 minutes. The mixture was concentrated and the residue purified on silica gel (0-100% ethyl acetate/hexanes) to afford methyl 2-(9-(4-fluorobenzyl)-2-methyl-1-oxo-4-(p-tolyl)-2,9-dihydro-1H-pyrido[3,4-b]indol-3-yl)acetate (45 mg, 0.096 mmol, 93% yield) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.31-7.42 (m, 4H) 7.22-7.27 (m, 3H) 6.92-7.00 (m, 3H) 6.87-6.92 (m, 1H) 6.61-6.66 (m, 1H) 6.16 (s, 2H) 3.73 (s, 3H) 3.70 (s, 3H) 2.48 (s, 3H); LCMS (m/z) ES+=469 (M+1).
Reaction SMILES: Br.Br.Br[CH2:4][C:5]1[C:6]([NH2:14])=[N:7][C:8]([CH2:11][CH2:12][CH3:13])=[N:9][CH:10]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH2:28][CH2:27][N:26]([CH2:4][C:5]2[C:6]([NH2:14])=[N:7][C:8]([CH2:11][CH2:12][CH3:13])=[N:9][CH:10]=2)[CH2:25][CH2:24]1
Reactant: CCCc1ncc(CBr)c(N)n1
Reactant: COc1ccccc1N1CCNCC1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1ncc(CN2CCN(c3ccccc3OC)CC2)c(N)n1
Yield: 19 %

Procedure:
A suspension of 7.0 g (0.020 mol) of 5-bromomethyl-2-propyl-pyrimidin-4-ylamine dihydrobromide, 3.85 g (0.020 mol) of (2-methoxy-phenyl)-piperazine and 6 g (0.043 mol) of dry potassium carbonate in 75 ml of dimethylformamide was dissolved at room temperature for 4 hours. The reaction mixture was suction filtered, the filter cake was washed with ethyl acetate and ethanol, the filtrate was completely freed from the solvents and the residue was chromatographed over silica gel with ethyl acetate as the eluent and recrystallized from hot ethyl acetate. 1.3 g (21%) of 5-[4-(2-methoxy-phenyl)-piperazin-1-ylmethyl]-2-propyl-pyrimidin-4-ylamine were obtained as yellowish crystals, m.p. 130°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24](O)=[O:25])=[CH:15][C:13]=2[N:14]=1.S(Cl)(Cl)=O.[F:31][C:32]([F:44])([F:43])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]1([NH2:42])[CH2:41][CH2:40]1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:22])([CH3:23])[O:21][C:17]=3[C:16]([C:24]([NH:42][C:39]3([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=4[C:32]([F:31])([F:43])[F:44])[CH2:41][CH2:40]3)=[O:25])=[CH:15][C:13]=2[N:14]=1
Reactant: CC1(C)Cc2c(c(C(=O)O)cc3nc(Nc4c(F)cccc4Cl)[nH]c23)O1
Reactant: NC1(c2ccccc2C(F)(F)F)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CC1(C)Cc2c(c(C(=O)NC3(c4ccccc4C(F)(F)F)CC3)cc3nc(Nc4c(F)cccc4Cl)[nH]c23)O1
Yield: 8.1 %

Procedure:
The title compound was prepared by following the procedure described for Example-108 using 2-[(2-chloro-6-fluorophenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-15, 0.100 g, 0.266 mmol), thionyl chloride (2.0 mL), 1-[2-(trifluoromethyl)phenyl]cyclopropanamine (Intermediate-38, 0.078 g, 0.388 mmol), THF (5.0 mL) and DIPEA (2 mL). The obtained crude product was purified by column chromatography on basic alumina eluting with 0.7-1.0% MeOH:DCM to afford 0.012 g of the desired product. 1HNMR (CDCl3): δ 1.08-1.33 (m, 4H), 1.47 (s, 6H), 3.02 (s, 2H), 7.32-7.38 (m, 4H), 7.47 (t, J=6.6 Hz, 1H), 7.61-7.69 (m, 2H), 7.97 (d, J=7.8 Hz, 1H), 8.56 (s, 1H), 10.80-11.00 (s, 2H); MS [M+H]+: 559.26.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[CH:3]=1.[Cl:10][C:11]1[N:16]=[C:15](Cl)[C:14]([Cl:18])=[CH:13][N:12]=1.[I-].[K+]>CC(N(C)C)=O>[Cl:10][C:11]1[N:16]=[C:15]([NH:9][C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[N:5]=2)[C:14]([Cl:18])=[CH:13][N:12]=1
Reactant: Cc1cc(C)nc(N)c1
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1cc(C)nc(Nc2nc(Cl)ncc2Cl)c1

Procedure:
The mixture 4,6-dimethylpyridin-2-amine (61 mg, 0.50 mmol), 2,4,5-trichloropyrimidine (57 μL, 0.5 mmol), and potassium iodide (166 mg, 1.0 mmol) in 3 mL of DMA is heated at 90° C. overnight. The mixture is concentrated in vacuo and the resulting crude product is partitioned between EtOAc and brine. The collected organic extracts are dried (Na2SO4) and concentrated in vacuo to afford 2,5-dichloro-N-(4,6-dimethylpyridin-2-yl)pyrimidin-4-amine; ESMS m/z 269.0 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16](OC(C)(C)C)=O)[CH:5]=[N:6][C:7]=1[Cl:8].C=O>C(O)=O>[ClH:8].[Br:1][C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[CH3:16])[CH:5]=[N:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cnc(Cl)c(Br)c1
Agent: C=O
Solvent: O=CO
Product: CN1CCC[C@@H]1COc1cnc(Cl)c(Br)c1
Product: Cl
Temperature: 70 °C
Yield: 119.1 %

Procedure:
To 5-bromo-6-chloro-3-(1-BOC-2-(R)-pyrrolidinylmethoxy)pyridine from step 69a (210 mg, 0.54 mmol) was added formalin (37%, 7 mL) and formic acid (3.5 mL), and the mixture was heated at 70° C. for 2.5 hours. The solvent was concentrated, and solid NaHCO3 was added to the residue. At pH 8 the mixture was extracted with CH2Cl2, which was dried over MgSO4 and concentrated. The residue was chromatographed on a silica gel column, eluting with CH2Cl2 :MeOH 100:5-100:10 to afford to give the free base of the title compound (110 mg, 67% yield). MS (CI/NH3) m/z 305/307 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ1.68 (m, 3H), 2.02 (m, 1H), 2.32 (m, 1H), 2.48 (s, 3H), 2.67 (m, 1H), 3.12 (m, 1H), 3.96 (m, 2H), 7.52 (m, 1H), 8.06 (m, 1H). The base was converted to the salt by treatment with hydrogen chloride in THF to give the title compound. MS (C NH3) m/z 305/307 (M+H)+. 1H NMR (D2O, 300 MHz) δ2.20-2.17 (m, 2H), 2.18-2.31 (m, 1H), 2.32-2.47 (m, 1H), 3.03 (s, 3H), 3.27 (m, 1H), 3.73 (m, 1H), 3.96 (m, 1H), 4.36 (dd, J=6.1, 11.2 Hz, 1H), 4.53 (dd, J=3.1, 11.2 Hz, 1H), 7.91 (d, J=2.7 Hz, 1H), 8.13 (d, J=2.7 Hz, 1H). Anal. Calcd for C11H14N2OBrCl·1.1 HCl: C, 38.22; H, 4.40; N, 8.10. Found: C, 37.95; H, 4.81; N, 7.76. [α]25D=+11.06° (c 0.24, MeOH).
Reaction SMILES: [I:1][C:2]#[C:3][CH2:4][O:5][C:6]1[C:10]([C:11]#[N:12])=[C:9](S(C)(=O)=O)[S:8][N:7]=1.[CH3:17][O-:18].[Na+].O>CO>[I:1][C:2]#[C:3][CH2:4][O:5][C:6]1[C:10]([C:11]#[N:12])=[C:9]([O:18][CH3:17])[S:8][N:7]=1
Reactant: C[O-]
Reactant: CS(=O)(=O)c1snc(OCC#CI)c1C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1snc(OCC#CI)c1C#N
Temperature: 25 °C
Reaction time: 4 h
Yield: 78 %

Procedure:
3.6 Grams of 3-(3-iodo-2-propynyloxy)-4-cyano5-methylsulfonylisothiazole synthesized in Example 2 was dissolved in 30 ml of methanol, 0.6 g of sodium methoxide was added thereto, and then the reaction solution was stirred at room temperature for 4 hours. Water was added to precipitate crystals, which were then collected by filtration, washed with water, dried and recrystallized from ether. Thus, 2.4 g of crystals having a melting point of 159° to 160° C. (yield 78%) was obtained.
Reaction SMILES: [OH:1][CH2:2][CH:3]=[C:4]([CH2:6][CH2:7][CH:8]=[C:9]([CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH3:10])[CH3:5].C(N(CC)CC)C>O>[CH3:5]/[C:4](/[CH2:6][CH2:7]/[CH:8]=[C:9](\[CH3:10])/[CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])=[CH:3]\[CH:2]=[O:1]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCO
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/C=O
Temperature: -65 °C
Reaction time: 0.42 h
Yield: 100 %

Procedure:
A solution of oxalyl chloride (4.68 g, 0.037 mol) in dry CH2Cl2 under argon atmosphere was cooled to -65° C. A solution of dimethyl sulfoxide (DMSO) (5.33 ml) in CH2Cl2 (17 ml) was added rapidly, dropwise, to the cooled oxalyl chloride solution. After stirring for 7 minutes at -65° C., a 10 ml CH2Cl2 solution of (E,E)-farnesol (7.0 g, 0.032 mol) was added over 10 minutes to the reaction solution at -65° C.: a precipitate formed upon the addition of approximately half of the farnesol solution. After the addition of the farnesol solution was completed, the reaction was stirred at -65° C. for 25 minutes, and then 22.4 ml (2 mol) of triethylamine was added over 10 minutes. After stirring for an additional 15 minutes at -65° C., the reaction was warmed to room temperature, and then diluted with water (~200 ml). The resulting aqueous layer was extracted several times with CH2Cl2. The combined organic layers were washed once with saturated aqueous NaCl solution, once with 1% HCl, once with 5% Na2CO3 solution and once with saturated aqueous NaCl solution. The resulting organic layer was dried over MgSO4 to give 7.05 g (100%) of a clear oil after filtration and solvent removal.
Reaction SMILES: C(O[O:5][C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[C:8](CC)[C:7]=1[CH:15]=[O:16])(=O)C.[Li+].[OH-:18].[CH2:19]1[CH2:23][O:22]CC1>O>[Br:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:19][C:23]([OH:18])=[O:22])=[C:7]([CH:15]=[O:16])[CH:8]=1
Reactant: [OH-]
Reactant: CCc1c(Br)ccc(OOC(C)=O)c1C=O
Reactant: C1CCOC1
Agent: [Li+]
Solvent: O
Product: O=Cc1cc(Br)ccc1OCC(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 94 %

Procedure:
A mixture of ethyl-2-formyl-4-bromophenoxy acetate (60 g, 0.209 mol), LiOH (7.5 g, 0.31 mol), THF (250 mL) and water (100 mL) was stirred at RT for 24 h. The reaction mixture was concentrated under reduce pressure and residue acidified with 1.5N HCl to pH=2. The solid precipitate obtained was filtered and dried to give 4-bromo-2-formylphenoxy acetic acid (50 g, 94%).
Reaction SMILES: O[CH2:2][C@@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15]([CH2:2][C@@H:3]2[NH:7][C:6](=[O:8])[CH2:5][CH2:4]2)(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: O=C1CC[C@H](CO)N1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)C[C@H]2CCC(=O)N2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.6 %

Procedure:
To a solution of (5R)-5-hydroxymethyl-2-pyrrolidinone (5.0 g, 43 mmol) in methylene chloride (100 ml) was added 4-dimethylaminopyridine (15.7 g, 129 mmol) and p-toluenesulphonyl chloride (9.0 g, 47 mmol). The reaction was stirred at ambient temperature for 16 hours. The reaction was then washed with 1M hydrochloric acid and the organic layer separated. This was then dried over MgSO4, filtered and evaporated to give (5R)-5-(p-toluenesulphonylmethyl)-2-pyrrolidinone (10.3 g, 89%) as a white solid.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][N:10]=[CH:11]2.[OH-].[Na+].[BrH:18]>O>[Br:18][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][N:10]=[CH:11]2
Reactant: Br
Reactant: Nc1cccc2cnccc12
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Brc1cccc2cnccc12
Temperature: 75 °C
Reaction time: 1 h

Procedure:
Add a solution of sodium nitrite (9.6 g, 139 mmol) in water (50 mL) cautiously to 5-aminoisoquinoline (20 g, 139 mmol) in hydrobromic acid (48%, 100 mL) at 0° C. Transfer this mixture to a vessel containing CuBr (25 g, 174 mmol) in hydrobromic acid (48%, 200 mL) at 75° C. After complete addition, stir the mixture at 75° C. for one hour, cool to room temperature and stir overnight. Place the mixture in an ice bath, add ice to the reaction mixture, and then add sodium hydroxide aqueous solution (20%, 250 mL). Filter the slurry and extract the filtrate with diethyl ether. Combine the solid and the extract sonicate for one hour in chloroform Filter the suspension through a plug of Celite™, and concentrate the filtrate under reduced pressure. Subject the residue to silica gel chromatography, eluting with chloroform.