Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH2:33][CH3:34])[C:23]4[N:24]=[C:25](SC)[N:26]=[CH:27][C:22]=4[CH:21]=3)[C:17]([CH3:35])=[CH:16][C:15]=2[F:36])=[O:12])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:37][NH2:38]>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH2:33][CH3:34])[C:23]4[N:24]=[C:25]([NH:38][CH3:37])[N:26]=[CH:27][C:22]=4[CH:21]=3)[C:17]([CH3:35])=[CH:16][C:15]=2[F:36])=[O:12])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN
Reactant: CCn1c(=O)c(-c2cc(NC(=O)Nc3cc(C(C)(C)C)no3)c(F)cc2C)cc2cnc(SC)nc21
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3cc(C(C)(C)C)no3)c(F)cc2C)cc2cnc(NC)nc21
Yield: 20 %

Procedure:
Using a procedure analogous to Example A1, 1-(3-tert-butylisoxazol-5-yl)-3-(5-(8-ethyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2-fluoro-4-methylphenyl)urea (0.16 g, 0.315 mmol) and methylamine were combined to provide 1-(3-tert-butylisoxazol-5-yl)-3-(5-(8-ethyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2-fluoro-4-methylphenyl)urea (62 mg, 20% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.3 (brs, 1H), 8.67 (brs, 1H), 8.61 (brs, 1H), 7.88 (d, J=9 Hz, 1H), 7.80 (brs, 1H), 7.66 (s, 1H), 7.16 (d, J=12 Hz, 1H), 6.00 (s, 1H), 5.73 (s, 1H), 4.34 (br, 2H), 2.89 (d, J=6 Hz, 3H), 2.07 (s, 3H), 1.21 (br, 12H); MS (ESI) m/z: 494.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12]/[CH:13]=[CH:14]/[P:15]([O:21][CH:22]([CH3:24])[CH3:23])([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])=[C:4](Cl)[N:3]=1.[NH3:26]>>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12]/[CH:13]=[CH:14]/[P:15]([O:21][CH:22]([CH3:24])[CH3:23])([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])=[C:4]([NH2:26])[N:3]=1
Reactant: N
Reactant: CC(C)OP(=O)(/C=C/CCn1cnc2c(Cl)nc(N)nc21)OC(C)C
Product: CC(C)OP(=O)(/C=C/CCn1cnc2c(N)nc(N)nc21)OC(C)C
Yield: 50 %

Procedure:
A solution of (E)-2-amino-6-chloro-9-[4-(diisopropoxyphosphoryl)but-3-enyl]purine (370 mg, 954 μmol) in saturated ethanolic ammonia (60 ml) was heated at 100° C. in a stainless steel autoclave for 7 hr. The solution was allowed to cool then the solvent was removed. The residue was purified by column chromatography on silica gel eluting with dichloromethane-methanol (19:1, 9:1) to give (E)-2, 6-diamino-9-[4-(diisopropoxyphosphoryl)but-3-enyl]purine as a white solid (175mg, 50%), m.p. 211°-213° C.; λmax (MeOH) 256 (7,860) and 283 (9,670)nm; υmax (KBr) 3460, 3325, 3174, 1630, 1590, 1470, 1410 and 1250 cm-1 ; δH [(CD3)2SO] 1.11 (6H, d, J 6 Hz, CH(CH3)2), 1.17 (6H, d, J 6 Hz, CH(CH3)2), 2.50 (2H, m, CH2), 4.12 (2H, t, J 7 Hz, CH2N), 4.33 (2H, m, CH(CH3)2), 5.73 (2H, s, D2O exchangeable, NH2), 5.73 (1H, dd, J 17 Hz and 20 Hz, PCH=CH), 6.55 (1H, ddt, J 7 Hz, 17 Hz and 20 Hz, PCH=CH), 6.60 (2H, s, D2O exchangeable, NH2), 7.68 (1H, s, H-8) (Found: MH+ 369. 1803. C15H25N6O3P requires MH+ 369. 1804).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].Cl[C:10]([CH3:18])([CH2:12][CH2:13][C:14](Cl)([CH3:16])[CH3:15])[CH3:11].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl.CCCCCC.Cl>[Br:1][C:2]1[C:3]([CH3:8])=[CH:4][C:5]2[C:14]([CH3:16])([CH3:15])[CH2:13][CH2:12][C:10]([CH3:18])([CH3:11])[C:6]=2[CH:7]=1
Reactant: Cc1ccccc1Br
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCCC
Solvent: ClCCl
Product: Cc1cc2c(cc1Br)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.3 %

Procedure:
To a solution of 20 g (117 mmol) of 2-bromotoluene and 14.4 g (97.4 mmol) of 2,5-dichloro-2,5-dimethylhexane in 100 mL of dichloromethane was added 1.56 g (16.9 mmol) of aluminum chloride and the mixture heated at reflux. After 16 hours, the mixture was cooled to room temperature, diluted with 150 mL of hexane and 100 mL of 1 N HCl was added. The organic layer was separated and the aqueous layer was extracted with hexane. The combined organic layers were washed with saturated NaCl solution, dried over sodium sulfate and concentrated under reduced pressure. The product was purified by filtration through a pad of silica gel with elution with hexane and afforded 23.9 g (87%) of 2-bromo-3-methyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene as a solid. (m.p.: 81.1-85° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([NH:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[C:12]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:11]=1[CH3:23])=[O:8].N1C=CC=CC=1.[C:30]1([S:36](Cl)(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl.Cl>[C:30]1([S:36]([NH:1][C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:7]([NH:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[C:12]([N:18]3[CH2:19][CH2:20][CH2:21][CH2:22]3)[C:11]=2[CH3:23])=[O:8])(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1cc(C)c(N2CCCC2)c(C)c1NC(=O)c1sccc1N
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(C)c(N2CCCC2)c(C)c1NC(=O)c1sccc1NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of the carboxamide (0.304 mmol) of step 1 above in dichloromethane (5 mL) in a 25 ml round bottom flask was added pyridine (0.304 mmol) and benzenesulfonyl chloride (0.304 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was then diluted with hydrochloric acid (2N) and extracted with dichloromethane (2×15 mL). The combined organic extracts were washed with a saturated aqueous solution of sodium bicarbonate (2×10 mL). The organic layers were then dried with magnesium sulfate, filtered, and concentrated under reduced pressure to yield a brown oil. The oil was further purified by silica gel chromatography using 5% ethyl acetate in bexanes as the mobile phase to yield ′3-[(phenylsulfonyl)amino]-N-(2,4,6-trimethyl-3-pyrrolidin-1-ylphenyl)thiophene-2-carboxamide as a white to yellow solid.
Reaction SMILES: [C@@H:1]12[CH2:7][NH:6][C@@H:5]1[CH2:4][CH2:3][N:2]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].Br[C:16]1[S:17][C:18]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:19]([CH3:21])[N:20]=1.C(N(C(C)C)CC)(C)C>>[CH2:25]([O:24][C:22]([C:18]1[S:17][C:16]([N:6]2[CH2:7][C@@H:1]3[C@H:5]2[CH2:4][CH2:3][N:2]3[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[N:20][C:19]=1[CH3:21])=[O:23])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2NC[C@H]21
Reactant: CCOC(=O)c1sc(Br)nc1C
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1sc(N2C[C@@H]3[C@H]2CCN3C(=O)OC(C)(C)C)nc1C
Yield: 99.5 %

Procedure:
The same operation as in Example (217a) was performed using tert-butyl (1R,5R)-2,6-diazabicyclo[3.2.0]heptane-2-carboxylate obtained in Example (236a) (150 mg, 0.76 mmol), ethyl 2-bromo-4-methylthiazole-5-carboxylate (189 mg, 0.76 mmol) and diisopropylethylamine (0.26 mL, 1.51 mmol), to obtain 278 mg of the title compound as a yellow oily substance (100%).
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH3:9])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[CH2:10](O)[CH2:11][OH:12].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:8]([C:2]1([CH2:3][C:4]([O:6][CH3:7])=[O:5])[O:12][CH2:11][CH2:10][O:1]1)[CH3:9]
Reactant: OCCO
Reactant: CCC(=O)CC(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCC1(CC(=O)OC)OCCO1
Temperature: 120 °C
Reaction time: 8 h
Yield: 42.2 %

Procedure:
To a solution of methyl 3-oxopentanoate (3 g, 23.1 mmol) in toluene (30 mL) was added ethane-1,2-diol (3 mL, 70.2 mmol) and p-toluenesulfonic acid (500 mg, 2.91 mmol), the resulting mixture was stirred at 120° C. overnight. Then the mixture was concentrated and partitioned between ethyl acetate and aqueous saturated sodium bicarbonate solution. The phases were separated and the aqueous layer was extracted with ethyl acetate. The combined organic phase was washed with brine and dried over sodium sulfate; then it was filtered and concentrated to give methyl 2-(2-ethyl-1,3-dioxolan-2-yl)acetate (1.7 g, 42.5%) as yellow oil which was used without purification. Product tlc [petroleum ether/ethyl acetate (15:1) developed with iodine, Rf 0.6]
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH3:14])=[CH:10][C:9]([CH2:15][CH2:16][CH:17]=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[CH2:31][CH2:30][N:29]([CH2:17][CH2:16][CH2:15][C:9]3[CH:10]=[C:11]([CH2:12][CH2:13][CH3:14])[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=3)[CH2:28][CH2:27]2)=[CH:24][CH:25]=1
Reactant: CCCc1cc(CCC=O)nn1-c1ccccc1
Reactant: Clc1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(CCCN2CCN(c3ccc(Cl)cc3)CC2)nn1-c1ccccc1

Procedure:
69 mg (45%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-5-propyl-1H-pyrazol-3-yl)propanal (80 mg, 0.330 mmol), 1-(4-chlorophenyl)piperazine (89 mg, 0.330 mmol), DIPEA (0.090 mL, 0.495 mmol) and NaBH(OAc)3 (210 mg, 0.990 mmol).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[C:10]=1[C:17](=[O:23])[C:18](OCC)=[O:19])=O)(C)(C)C>OS(O)(=O)=O>[CH3:16][O:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]2[C:10]=1[C:17](=[O:23])[C:18](=[O:19])[NH:8]2
Reactant: CCOC(=O)C(=O)c1c(NC(=O)OC(C)(C)C)cccc1OC
Agent: O=S(=O)(O)O
Product: COc1cccc2c1C(=O)C(=O)N2
Temperature: 100 °C
Yield: 1.9 %

Procedure:
A mixture of ethyl 2-(2-(tert-butoxycarbonylamino)-6-methoxyphenyl)-2-oxoacetate (3.70 g, 110 mmol) and 10% H2SO4 (100 mL) was heated at 100° C. for 10 hours. After cooling down to ambient temperature, the reaction mixture was extracted with ether (3×100 mL). The combined ether solution was washed with water (2×50.0 mL), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography to give 0.37 g (19%) of the title compound: MS (ES+) m/z 200.1 (M+23).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31](=[O:34])(=[O:33])[NH2:32])=[CH:21][CH:20]=2)[C:7](=[O:17])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[N:9]=1)[CH2:2][CH2:3][CH3:4].[C:35](Cl)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>N1C=CC=CC=1>[C:35]([NH:32][S:31]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:22]1[CH:23]=[CH:24][C:19]([CH2:18][N:6]2[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:9][N:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:16])[C:7]2=[O:17])=[CH:20][CH:21]=1)(=[O:33])=[O:34])(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CCCCc1nn(-c2ccccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: CCCCc1nn(-c2ccccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 59.8 %

Procedure:
To a solution of 41.4 mg (0.0834 mmole) of 5-n-butyl-2-(2-chlorophenyl)-2,4-dihydro-4-[(2'-sulfamoylbiphenyl-4-yl)methyl]-3H-1,2,4-triazol-3-one (from Step B) in 1 ml of dry pyridine stirred at room temperature under argon was added 97 μl (117 mg, 0.836 mmole) of benzoyl chloride. The resulting solution was stirred at room temperature for 12 hours and then treated with saturated NaH2PO4 solution. The mixture was extracted 3× with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), and concentrated in vacuo. The residue was flash chromatographed twice on silica gel (elution with 6-7% MeOH in CH2Cl2 containing 0.2-0.4% concd. NH4OH) to give 30 mg (60%) of the title compound as a white solid; satisfactory purity by TLC in 94:6:0.2 CH2Cl2 --MeOH-concd. NH4OH; mass spectrum (FAB) m/e 601 (M+1)+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[S:25][C:24]([CH3:26])=[C:23]([CH3:27])[N:19]3[C:20](=[O:22])[CH:21]=2)[CH2:3][CH2:2]1.[I:28]N1C(=O)CCC1=O>C(#N)C>[CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[S:25][C:24]([CH3:26])=[C:23]([CH3:27])[N:19]3[C:20](=[O:22])[C:21]=2[I:28])[CH2:3][CH2:2]1
Reactant: COc1cccc(/C=C/c2cc(=O)n3c(C)c(C)sc3n2)c1OCC1CC1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: COc1cccc(/C=C/c2nc3sc(C)c(C)n3c(=O)c2I)c1OCC1CC1

Procedure:
To a solution of Step 3 intermediate (500 mg, 1.568 mmol) in acetonitrile (10 ml) was added N-iodosuccinimide (494 mg, 2.195 mmol) and reacted according to the procedure described in Step 4, Intermediate 2 to afford 600 mg of the desired compound; 1H NMR (300 MHz, CDCl3) δ 0.32-0.34 (m, 2H), 0.54-0.56 (m, 2H), 1.17-1.20 (m, 1H), 2.29 (s, 3H), 2.58 (s, 3H), 3.75-3.77 (m, 2H), 3.80 (s, 3H), 7.04-7.13 (m, 2H), 7.25-7.27 (m, 1H), 7.47 (d, J=15.9 Hz, 1H), 8.12 (d, J=15.6 Hz, 1H); ESI-MS (m/z) 509.01 (M+H)+.
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].Cl.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]([NH2:20])[CH2:16][N+:17]([O-:19])=[O:18]>N1C=CC=CC=1>[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]([NH:20][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH2:16][N+:17]([O-:19])=[O:18]
Reactant: NC(C[N+](=O)[O-])c1ccccc1Cl
Reactant: CCS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCS(=O)(=O)NC(C[N+](=O)[O-])c1ccccc1Cl
Reaction time: 1 h

Procedure:
At RT, 219 μl (2.31 mmol) of ethanesulphonyl chloride were added to a solution of 295 mg (about 93% pure, 1.16 mmol) of the compound of Example 25A in 7.0 ml of pyridine, and the mixture was stirred for 1 h. The pyridine was then removed on a rotary evaporator and the residue was purified by preparative HPLC [Method 20]. This gave 230 mg (about 90% pure according to LC/MS, 61% of theory) of the title compound.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:27]=[CH:28][C:29]=1[Br:30])[O:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[C:16]=2[CH3:24])=[CH:11][CH:10]=1)[CH:2]=[CH2:3].[F:31][C:32]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:33]=1[CH2:34]Br>>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:27]=[CH:28][C:29]=1[Br:30])[O:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][N:14]([CH2:34][C:33]2[CH:36]=[CH:37][C:38]([F:40])=[CH:39][C:32]=2[F:31])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[C:16]=2[CH3:24])=[CH:11][CH:10]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(Oc2ccc(CNc3cccc([N+](=O)[O-])c3C)cc2)ccc1Br
Reactant: Fc1ccc(CBr)c(F)c1
Product: C=CCOc1cc(Oc2ccc(CN(Cc3ccc(F)cc3F)c3cccc([N+](=O)[O-])c3C)cc2)ccc1Br

Procedure:
The product from Example 63D and 2,4-difluorobenzyl bromide were processed as described in Example 6B to provide the title compound. MS (ESI+) m/z 597 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2(O)[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)=[C:12]([OH:23])[CH:11]=1)([CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Cl>>[CH3:9][C:2]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH2:17][NH:18][CH2:19][CH2:20][CH:21]=2)=[C:12]([OH:23])[CH:11]=1)([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC(C)(C)c1ccc(C2(O)CCCNC2)c(O)c1
Agent: Cl
Product: CCCCCCC(C)(C)c1ccc(C2=CCCNC2)c(O)c1
Yield: 58 %

Procedure:
A mixture of 23.6 g. (74.2 mmoles) of 3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-3-piperidinol and 400 ml. of 2 N hydrochloric acid is heated at reflux for 2 hours. The reaction is cooled, evaporated and dissolved in excess saturated sodium bicarbonate and 400 ml. of dichloromethane. The dichloromethane extract is combined with a second 400 ml. dichloromethane extract of the aqueous phase, dried over magnesium sulfate and evaporated to an oil. Crystallization from ether-pentane gave 13.0 g. (58%) of the title compound.
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:19]([CH3:20])[C:13]2=[N:14][CH:15]=[C:16]([SH:18])[CH:17]=[C:12]2[N:11]=1)[CH3:2].I[CH3:22].[OH-].[K+].[Cl-].[NH4+]>C(O)C>[CH2:1]([S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:19]([CH3:20])[C:13]2=[N:14][CH:15]=[C:16]([S:18][CH3:22])[CH:17]=[C:12]2[N:11]=1)[CH3:2]
Reactant: CI
Reactant: CCSc1ccccc1-c1nc2cc(S)cnc2n1C
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CCO
Product: CCSc1ccccc1-c1nc2cc(SC)cnc2n1C
Reaction time: 5 h

Procedure:
To a mixture of 2-(2-ethylsulfanyl-phenyl)-3-methyl-3H-imidazo[4,5-b]pyridin-6-thiol (535 mg), iodomethane (166 μl), and ethanol (5 ml), potassium hydroxide (200 mg) was added at room temperature, and stirred for 5 hours. To the reaction mixture, saturated aqueous ammonium chloride solution was added, and extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 515 mg of 2-(2-ethylsulfanyl-phenyl)-3-methyl-6-methylsulfanyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 253).
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([I:9])[C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16](O)=[O:17])=[C:12]([N+:19]([O-:21])=[O:20])[CH:11]=1.S(Cl)([Cl:24])=O>>[I:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([I:9])[C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([Cl:24])=[O:17])=[C:12]([N+:19]([O-:21])=[O:20])[CH:11]=1
Reactant: O=C(O)c1ccc(-c2c(I)cc(I)cc2I)cc1[N+](=O)[O-]
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc(-c2c(I)cc(I)cc2I)cc1[N+](=O)[O-]

Procedure:
2′,4′,6′-triiodo-3-nitrobiphenyl-4-carboxylic acid (6) is reacted with thionyl chloride to yield 2′,4′,6′-triiodo-3-nitrobiphenyl-4-carbonyl chloride (7).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]([CH3:22])[C:12]2=[O:23])=[C:4]([F:24])[CH:3]=1>C(O)(=O)C.O.[Fe]>[NH2:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([F:24])=[C:5]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]([CH3:22])[C:12]2=[O:23])[CH:6]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc([N+](=O)[O-])c(Cl)cc2F)c1=O
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(N)c(Cl)cc2F)c1=O
Temperature: 55 °C
Reaction time: 1.5 h
Yield: 86 %

Procedure:
A solution of 3-(4-chloro-2-fluoro-5-nitrophenyl)-1-methyl-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (3.00 g, 8.16 mmol) in acetic acid is heated to 50-60° C., treated portionwise with iron powder (2.28 g, 40.8 mmol) over 10 minutes, stirred at 50-60° C. for 90 minutes, cooled to room temperature, and diluted with water. The resultant aqueous mixture is filtered to remove solids and extracted with diethyl ether. The organic extracts are combined, washed sequentially with 1 M sodium hydroxide solution and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the title product as a brown solid (2.37 g, 86% yield, mp 132-135° C.) which is identified by 1H and 13C NMR spectral analyses.
Reaction SMILES: C([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:19][CH3:20])=[C:13]([O:17][CH3:18])[CH:14]=2)[CH2:9]1)C1C=CC=CC=1.[ClH:21]>CO.[C].[Pd]>[ClH:21].[CH3:18][O:17][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][C:12]=1[O:19][CH3:20])[CH2:9][NH:8][CH2:16]2
Reactant: COc1cc2c(cc1OC)CN(Cc1ccccc1)C2
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1cc2c(cc1OC)CNC2
Yield: 94.3 %

Procedure:
1.00 g (3.72 mmol) of 2-benzyl-5,6-dimethoxyisoindoline was dissolved in 50 ml of methanol at 40° C., and then 1.24 g (7.44 mmol) of 6N hydrochloric acid and 70 mg of 10% palladium carbon were added thereto. Under a hydrogen gas stream, catalytic reduction was conducted at the same temperature. The solvent was distilled off under reduced pressure, and the crystalline residue was washed with acetone to obtain 758 mg (yield: 94.3%) of the above identified compound as colorless prism crystals.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([CH2:14][OH:15])[CH:3]=1.C([O-])(O)=[O:17].[Na+].[Na+].[Br-].C1(N(Cl)C(=O)N(Cl)C(=O)N1Cl)=O>CC(C)=O.CC1(C)N([O])C(C)(C)CCC1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([C:14]([OH:17])=[O:15])[CH:3]=1
Reactant: OCc1cc(Cl)nc(-c2ccccc2)n1
Reactant: O=C([O-])O
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Agent: [Br-]
Solvent: CC(C)=O
Product: O=C(O)c1cc(Cl)nc(-c2ccccc2)n1
Temperature: 5 °C
Reaction time: 1.5 h

Procedure:
To a solution of (6-chloro-2-phenyl-pyrimidin-4-yl)-methanol (240 g; prepared using a method analogous to the one described in WO 2006/114774, Example 24, intermediate 24.2) in acetone (2 L) was added an aq. NaHCO3 solution (15%, 961 mL). The mixture was cooled down to 5° C. and NaBr (11.2 g) followed by TEMPO (8.56 g) were added. TCCA (506 g) was then added portionwise over 1.5 h. The resulting mixture was stirred at RT for 1.5 h. The mixture was filtered through a pad of Celite and the solution was evaporated off. The residue was diluted in water/EA. The aq. phase was extracted with EA and the combined org. phases were dried (Na2SO4) and evaporated off. Recrystallization of the residue (EA/Hept) afforded the desired product as a beige solid (162.1 g).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[CH2:7]([NH2:10])[C:8]#[CH:9].CN(C1C=CC=CN=1)C>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:1][N:2]([CH3:6])[C:3]([NH:10][CH2:7][C:8]#[CH:9])=[O:4]
Reactant: C#CCN
Reactant: CN(C)C(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C#CCNC(=O)N(C)C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Dimethyl carbamylchloride (0.84 mL, 9.1 mmol) was added to a stirred solution of propargylamine (0.62 mL, 0.1 mmol) and dimethylaminopyridine (22 mg, 0.18 mmol) in pyridine (5 mL) at room temperature. The resulting suspension was stirred at ambient temperature for approximately 15 h. The reaction mixture was diluted with ethyl acetate and washed successively with 1N HCl and brine. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound (i-3), which was used without further purification.
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[C:12](=[O:13])[N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[C:10]2[CH:22]=[CH:23][S:24][C:9]=2[C:8]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:6])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C.[F:60][C:61]1[S:65][C:64]([C:66](O)=[O:67])=[CH:63][CH:62]=1.C([O-])(O)=O.[Na+]>>[CH:1]([O:4][C:5]([C:7]1[C:12](=[O:13])[N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[C:10]2[CH:22]=[CH:23][S:24][C:9]=2[C:8]=1[N:25]1[CH2:26][CH2:27][N:28]([C:66]([C:64]2[S:65][C:61]([F:60])=[CH:62][CH:63]=2)=[O:67])[CH2:29][CH2:30]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)c1c(N2CCNCC2)c2sccc2n(Cc2cccc(F)c2)c1=O
Reactant: O=C(O)c1ccc(F)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)c1c(N2CCN(C(=O)c3ccc(F)s3)CC2)c2sccc2n(Cc2cccc(F)c2)c1=O
Yield: 83.3 %

Procedure:
A solution of 4-(3-fluoro-benzyl)-5-oxo-7-piperazin-1-yl-4,5-dihydro-thieno[3,2-b]pyrdine-6-carboxylic acid isopropyl ester (20) (2 g, 4.65 mmol), HOBt (0.692 g, 5.12 mmol), EDC.HCl (0.982 g, 5.12), triethylamine (0.971 mL, 6.98 mmol) and 5-fluoro-thiophene-2-carboxylic acid (0.749 g, 5.12 mmol) was stirred overnight at room temperature. The solution was poured into 2.5% NaHCO3 solution and the solids formed were filtered, washed by cold water and air dried. The crude product was purified by flash chromatography eluting with 0-10% methanol in CH2Cl2 gradient to yield 2.16 g (83%) of 4-(3-fluoro-benzyl)-7-[4-(5-fluoro-thiophene-2-carbonyl)-piperazin-1-yl]-5-oxo-4,5-dihydro-thieno[3,2-b]pyrdine-6-carboxylic acid isopropyl ester. 1H-NMR (DMSO-d6) δ 1.29 (d, J=6.0 Hz, 6H), 3.37 (m, 4H), 3.79 (m, 4H), 5.10 (m, 1H), 5.38 (s, 2H), 6.80 (m, 1H), 7.07 (m, 3H), 7.28 (t, J=3.6 Hz, 1H), 7.32 (d, J=5.6 Hz, 1H), 7.37 (m, 1H), 8.02 (d, J=5.6 Hz, 1H); EIMS m/z 558 (M+1).