Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:6][C:7]1[NH:8][C:9](=[O:31])[C:10]2[N:11]=[CH:12][N:13]([C:29]=2[N:30]=1)[C@@H:14]1[O:28][C@H:18]([CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[C@@H:16]([OH:17])[CH2:15]1)(=[O:5])[CH:2]([CH3:4])[CH3:3].C(O)(=O)C.C(OC(=O)C)(=O)C.C([O-])([O-])=O.[K+].[K+].[CH3:49][S:50]([CH3:52])=O>>[C:1]([NH:6][C:7]1[NH:8][C:9](=[O:31])[C:10]2[N:11]=[CH:12][N:13]([C:29]=2[N:30]=1)[C@@H:14]1[O:28][C@H:18]([CH2:19][O:20][Si:21]([C:24]([CH3:26])([CH3:25])[CH3:27])([CH3:23])[CH3:22])[C@@H:16]([O:17][CH2:49][S:50][CH3:52])[CH2:15]1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)Nc1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](CO[Si](C)(C)C(C)(C)C)O2)c(=O)[nH]1
Reactant: CS(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CSCO[C@H]1C[C@H](n2cnc3c(=O)[nH]c(NC(=O)C(C)C)nc32)O[C@@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 69 %

Procedure:
5 g of N2-isobutyryl-5′-O-(tert-butyldimethylsilyl)-2′-deoxyguanosine (11.0 mmol) dissolved in 21 mL dry DMSO was treated with 10 mL acetic acid and 32 mL acetic anhydride, and stirred for 48 h at room temperature. The crude reaction mixture was then neutralized by adding a K2CO3 solution, and extracted with ethyl acetate (100×3 mL). The combined organic extract was then washed with saturated NaHCO3 solution, dried over Na2SO4 and concentrated under vacuum. Then reaction mixture was purified by a silica gel column chromatography resulting the product 11 as white powder (3.9 g, 69% yield; Rf=0.35, CH2Cl2:MeOH/20:1). HR-MS: Obs. m/z 512.2344 cald. for C22H38O5N5SiS 512.2363 [M+H]+. 1H-NMR (CDCl3): δH 12.0 (s, 1H), 8.95 (brs, 1H), 8.09 (s, 1H), 6.24 (t, J=6.8 Hz, 1H), 4.73 (m, 2H), 4.66 (m, 1H), 4.16 (m, 1H), 3.81 (m, 2H), 2.76 (m, 1H), 2.59 (m, 1H), 2.54 (m, 1H), 2.21 (s, 3H), 1.29 (m, 6H), 0.91 (s, 9H), and 0.10 (s, 6H) ppm.
Reaction SMILES: C(OC([C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][Br:19])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)=O)C.[CH2:20]([O:22][C:23](C1C(C2C=CC(C)=CC=2)=CC=CC=1)=[O:24])[CH3:21].BrN1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[CH2:20]([O:22][C:23]([C:7]1[C:8]([C:12]2[CH:13]=[CH:14][C:15]([CH2:18][Br:19])=[CH:16][CH:17]=2)=[CH:9][CH:10]=[CH:11][CH:6]=1)=[O:24])[CH3:21]
Reactant: CCOC(=O)c1ccccc1-c1ccc(C)cc1
Reactant: CCOC(=O)c1cccc(-c2ccc(CBr)cc2)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccccc1-c1ccc(CBr)cc1
Yield: 99 %

Procedure:
4′-Bromomethyl-biphenyl-2-carboxylic acid ethyl ester was prepared in a similar fashion to 4′-bromomethyl-biphenyl-3-carboxylic acid ethyl ester as described. 4′-Methyl-biphenyl-2-carboxylic acid ethyl ester (5.58 g, 23.22 mmol, 1 eq.) in carbon tetrachloride was treated with N-bromosuccinimide (4.96 g, 27.86 mmol, 1.2 eq.) and 2,2′-azobisisobutyronitrile (0.19 g, 1.16 mmol, 5 mol %). When complete, the reaction was worked up as described to give a yellow oil. The oil was purified by silica gel flash chromatography using 5% EtOAc in hexane as the mobile phase. Fractions containing the product were pooled and the solvent removed in vacuo to give 4′-bromomethyl-biphenyl-2-carboxylic acid ethyl ester (7.32 g, 99% yield) as a yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:27]2[CH:28]=[C:29](OS(C(F)(F)F)(=O)=O)[CH:30]=[CH:31][CH:32]=2)([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:26])[N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:41][N:42](C=O)C>C(OCC)C.[C-]#N.[Zn+2].[C-]#N>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[O:26])=[CH:18][CH:19]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:41]#[N:42])[CH:28]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)C(=O)c1ccc(C2(c3cccc(OS(=O)(=O)C(F)(F)F)c3)CCN(Cc3ccccc3)CC2)cc1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOCC
Product: CCN(CC)C(=O)c1ccc(C2(c3cccc(C#N)c3)CCN(Cc3ccccc3)CC2)cc1
Temperature: 90 °C
Reaction time: 5 h
Yield: 91 %

Procedure:
To a solution of trifluoro-methanesulfonic acid 3-[1-benzyl-4-(4-diethylcarbamoyl-phenyl)-piperidin-4-yl]-phenyl ester (1.82 g, 3.16 mmol) in DMF (14 mL) was added zinc cyanide (0.26 g, 2.21 mmol) and tetrakis triphenylphosphine palladium (0.73 g, 0.63 mmol). The reaction was stirred under a nitrogen atmosphere at 90° C. for 5 hours. The mixture was cooled to room temperatures and it was diluted with diethyl ether (100 mL). The organic layer was washed with brine (5×10 mL), dried (MgSO4) and concentrated. Purification with hexanes/EtOAc (1:1) afforded 1.3 g (91% yield) of 4-[1-Benzyl-4-(3-cyano-phenyl)-piperidin-4-yl]-N,N-diethyl-benzamide. 1HNMR (400 MHz, CDCl3) δ 7.69-7.20 (comp, 13H), 3.55-3.43 (comp, 2H), 3.41 (s, 2H), 3.31-3.19 (comp, 2H), 2.6-2.25 (comp, 8H), 1.28-1.19 (comp, 3H), 1.17-1.08 (comp, 3H); MS (M+1) 452.2.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH2:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:6][CH2:7][CH3:8].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](Cl)=[O:24])=[CH:18][CH:17]=1.Cl>ClCCCl>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([C:12]2[CH:13]=[CH:14][C:9]([CH2:5][CH2:6][CH2:7][CH3:8])=[CH:10][CH:11]=2)=[O:24])=[CH:18][CH:17]=1
Reactant: CCCCc1ccccc1
Reactant: O=C(Cl)Cc1ccc(Br)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCCCc1ccc(C(=O)Cc2ccc(Br)cc2)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 90.9 %

Procedure:
To a 1 L three-necked flask containing AlCl3 (40 g, 0.299 mol) in 1,2-dichloroethane (600 mL) under N2, butylbenzene (IVe) (49.7 mL, 0.299 mol) was added in one portion at −30° C. To this suspension (4-bromo-phenyl)-acetyl chloride (IIIa) (70 g, 0.299 mol) was added slowly over a period of 30min at such a rate that the internal temperature did not rise above −30° C. The reaction mixture was stirred at this temperature for 45 min and poured into an ice-cold solution of 1.5M HCl (1000 ml). The product was extracted into dichloromethane (2×500 ml), washed with 10% sodium bicarbonate solution (500 ml), water, brine and dried over Na2SO4. The solvent was evaporated under reduced pressure to obtain the titled compound as a white powder (m=90 g) in a 90.9% yield.
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][N:10]([C:13]3[CH:18]=[C:17]([CH3:19])[N:16]=[C:15](Cl)[N:14]=3)[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[Br:22][C:23]1[CH:29]=[C:28]([CH:30]([CH3:32])[CH3:31])[CH:27]=[CH:26][C:24]=1[NH2:25].C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>C(O)CO>[Br:22][C:23]1[CH:29]=[C:28]([CH:30]([CH3:31])[CH3:32])[CH:27]=[CH:26][C:24]=1[NH:25][C:15]1[N:14]=[C:13]([N:10]2[CH2:11][CH:12]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8][CH2:9]2)[CH:18]=[C:17]([CH3:19])[N:16]=1
Reactant: Cc1cc(N2CC=C(c3ccccc3)CC2)nc(Cl)n1
Reactant: CC(C)c1ccc(N)c(Br)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: OCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(N2CC=C(c3ccccc3)CC2)nc(Nc2ccc(C(C)C)cc2Br)n1
Yield: 60.7 %

Procedure:
4-(4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)-2-chloro-6-methylpyrimidine (466 mg), 408 mg of 2-bromo-4-isopropylaniline hydrochloride and 232 mg of diisopropylethylamine were heated in 5 ml of ethylene glycol under reflux for 1 hour. The reaction solution was poured into a saturated aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate. The extract was washed successively with water and a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The desiccant was filtered off, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=6/1) to give 458 mg of 2-[N-(2-bromo-4-isopropylphenyl)amino]-4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)-6-methylpyrimidine as an amorphous substance.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:17]1[CH2:21][C:20](=[O:22])[NH:19][C:18]1=[O:23].N1CCCCC1>N1C=CC=CC=1>[C:2]1([CH2:1][O:8][C:9]2[CH:10]=[C:11]([CH:12]=[C:21]3[S:17][C:18](=[O:23])[NH:19][C:20]3=[O:22])[CH:14]=[CH:15][CH:16]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1cccc(OCc2ccccc2)c1
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C1NC(=O)C(=Cc2cccc(OCc3ccccc3)c2)S1
Reaction time: 48 h
Yield: 100 %

Procedure:
A solution of 3-benzyloxybenzaldehyde (42.45 g, 200 mmol), 2,4-thiazolidinedione (23.43 g, 200.0 mmol), and piperidine (2 g) in 150 ml pyridine was refluxed for 16 h. The mixture was concentrated in vacuo, and the residue was triturated with 500 ml hot benzene, filtered, and the filtrate left standing at room temperature for two days. The resulting crystals were collected by filtration, washed with petroleum ether, and dried to give the product in 100% yield; mp 233-235° C.; IR (nujol): 1741, 1688 (CO) cm-1 ; NMR (DMSOd6TMS): δ5.19 (s, 2H, ArCH2), 7.15-7.25 (m, 3H), 7.3-7.5 (m, 6H), 7.73 (s, 1H, C=CH); Anal calcd for C17H13NO3, MW 311.36: C, 65.58; H, 4.21; N, 4.50; S, 10.30. Found: C, 65.53; H, 3.91; N, 4.52; S, 10.30. Mass spec m/e 312(M+1).
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:24][C:25]4[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=4)=[N:18][CH:19]=[C:20]([CH:23]=3)[CH:21]=O)[N:10]=2)=CC=1.[CH3:44][O:45][CH2:46][CH2:47][NH2:48]>>[CH3:44][O:45][CH2:46][CH2:47][NH:48][CH2:21][C:20]1[CH:23]=[C:16]([C:11]2[N:12]=[C:13]([CH3:15])[N:14]=[C:9]([NH2:8])[N:10]=2)[C:17]([NH:24][C:25]2[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)=[N:18][CH:19]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C=O)cnc3Nc3ccc(OC)nc3)n2)cc1
Reactant: COCCN
Product: COCCNCc1cnc(Nc2ccc(OC)nc2)c(-c2nc(C)nc(N)n2)c1

Procedure:
The title compound was synthesized following an analogous procedure to Example 220 using 5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)nicotinaldehyde (0.24 g, 0.415 mmol) and 2-methoxyethanamine (Aldrich, St. Louis, Mo.) (0.054 mL, 0.623 mmol). 1H NMR (400 MHz, CDCl3) δ 11.63 (s, 1H); 8.78 (d, J=2.54 Hz, 1H); 8.35 (d, J=2.54 Hz, 1H); 8.24 (d, J=2.54 Hz, 1H); 8.12 (dd, J=8.80, 2.74 Hz, 1H); 6.77 (d, J=8.80 Hz, 1H); 5.63 (s, 2H); 3.94 (s, 3H); 3.78 (s, 2H); 3.52-3.57 (m, 2H); 3.36 (s, 3H); 2.80-2.86 (m, 2H); 2.55 (s, 3H). m/z (ESI, +ve ion) 397.0 (M+H)+.
Reaction SMILES: C([O:5][C:6](=[O:33])[C@H:7]([CH3:32])[NH:8][C:9](=[O:31])[C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]([CH2:27][CH2:28][Cl:29])[CH2:24][CH2:25][Cl:26])=[C:19]([CH3:30])[CH:18]=2)=[CH:12][CH:11]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:26][CH2:25][CH2:24][N:23]([CH2:27][CH2:28][Cl:29])[C:20]1[CH:21]=[CH:22][C:17]([O:16][C:13]2[CH:12]=[CH:11][C:10]([C:9]([NH:8][C@H:7]([C:6]([OH:33])=[O:5])[CH3:32])=[O:31])=[CH:15][CH:14]=2)=[CH:18][C:19]=1[CH3:30]
Reactant: Cc1cc(Oc2ccc(C(=O)N[C@@H](C)C(=O)OC(C)(C)C)cc2)ccc1N(CCCl)CCCl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Oc2ccc(C(=O)N[C@@H](C)C(=O)O)cc2)ccc1N(CCCl)CCCl
Reaction time: 1 h

Procedure:
N-(4-{4-[bis-(2-chloroethyl)-amino]-3-methyl-phenoxy}-benzoyl)-L-alanine-tert-butyl ester (400 mg; compound 9) was dissolved in dichloromethane (4 ml) and trifluoroacetic acid (8 ml) was added. The mixture was allowed to stand at ambient temperature for 1 hour, evaporated to dryness and azeotroped twice with ethyl acetate to give the titled compound (compound 10; the drug corresponding with the prodrug of Example 21) as an oil (0.43 g, 52% yield).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=O)C=1.O=C1C2C(=CC=CC=2)C(=O)[N:14]1[O:23][CH2:24][C:25]1[N:26]([CH2:38][CH2:39][CH2:40][NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[C:27]2[C:36]3[N:35]=[CH:34][CH:33]=[CH:32][C:31]=3[N:30]=[CH:29][C:28]=2[N:37]=1.[OH-].[NH4+:50].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[NH2:50][C:29]1[C:28]2[N:37]=[C:25]([CH2:24][O:23][NH2:14])[N:26]([CH2:38][CH2:39][CH2:40][NH:41][C:42](=[O:48])[O:43][C:44]([CH3:45])([CH3:47])[CH3:46])[C:27]=2[C:36]2[N:35]=[CH:34][CH:33]=[CH:32][C:31]=2[N:30]=1
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)NCCCn1c(CON2C(=O)c3ccccc3C2=O)nc2cnc3cccnc3c21
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NCCCn1c(CON)nc2c(N)nc3cccnc3c21
Reaction time: 4 h

Procedure:
mCPBA (2.33 g, 13.5 mmol) was added to a suspension of tert-butyl 3-(2-{[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]methyl}-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)propylcarbamate (4.86 g, 9.67 mmol) in chloroform (50 mL). The reaction mixture was allowed to stir for 4 hours, then concentrated ammonium hydroxide (27 mL) and p-toluenesulfonyl chloride (2.03 g, 10.6 mmol) were added. The reaction mixture was allowed to stir overnight at room temperature, then was filtered. The filtrate was diluted with saturated aqueous sodium bicarbonate (50 mL) and extracted with chloroform (2×40 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated to afford a brown solid that was purified by chromatography using a HORIZON HPFC system (silica gel, gradient elution with 0-30% CMA in chloroform) to afford 1.00 g of tert-butyl 3-{4-amino-2-[(aminooxy)methyl]-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl}propylcarbamate as a yellow solid that contained some minor impurities.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1.CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>>[CH3:13][O:12][C:10](=[O:11])[C:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)=[CH:16][N:17]([CH3:19])[CH3:18]
Reactant: COC(OC)N(C)C
Reactant: COC(=O)Cc1ccc(OC)cc1
Product: COC(=O)C(=CN(C)C)c1ccc(OC)cc1
Temperature: 100 °C

Procedure:
Methyl 4-methoxyphenylacetate (3.3 g) was diss olved in N,N-5 dimethylformamide (3 cm3) treated with N,N-dimethylformamide dimethyl acetal (6 cm3) and heated at 100° C. for 18 h. The reaction was then cooled and evaporated under high vacuum to afford crude methyl-3-dimethylamino-2-(4-methoxyphenyl)propenoate (3.6 g) which was used without further purification. δH (250 MHz; CDCl3); 2.68 (6H, s), 3.62 (3H, s), 3.8 (3H, s), 6.82 (2H, d, J8.7 Hz), 71 (2H, d, J8.7 Hz) and 7.54 (1H, s).
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:22]>CO>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][N:14]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:22])[C:11]=2[N:12]=[CH:13]1
Reactant: Clc1nc2ccccc2c2c1ncn2Cc1ccccn1
Reactant: N
Solvent: CO
Product: Nc1nc2ccccc2c2c1ncn2Cc1ccccn1
Temperature: 150 °C

Procedure:
A mixture of 2.4 g of 4-chloro-1-(2-pyridylmethyl)-1H-imidazo[4,5-c]quinoline and 50 mL of 15% ammonia in methanol was placed in a bomb and heated at 150° C. for 6 hours. After cooling, the reaction mixture was filtered. The solid was slurried with aqueous sodium bicarbonate, collected and dried to provide 1.9 g of crude product. The crude product was recrystallized from 350 mL of ethanol to provide 1.25 g of a solid, m.p. 278°-284° C. The mother liquor was concentrated to a volume of 50 mL to provide a second crop of 0.32 g, m.p. 275°-281° C. The two crops were combined for analysis. Analysis: Calculated for C16H13N5 : C, 69.8; %H, 4.8; %N, 25.4; Found %C, 69.7; %H, 4.8; N, 25.2.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.[Cl:19][CH2:20][C:21](Cl)=[O:22]>ClCCl>[Cl:19][CH2:20][C:21]([N:9]([C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:8])[CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=[O:22]
Reactant: O=C(Cl)CCl
Reactant: Cc1cccc(C)c1NCCCc1cccnc1
Solvent: ClCCl
Product: Cc1cccc(C)c1N(CCCc1cccnc1)C(=O)CCl
Temperature: 25 °C

Procedure:
A solution of 10.0 g of N-(2,6-dimethylphenyl)-3-pyridinepropanamine in 75 ml of dichloromethane was added dropwise to a cold (0° C.) solution of 3.5 ml of chloroacetylchloride in 35 ml of dichloromethane. The cooling bath was removed and the reaction was allowed to warm to room temperature over 30 minutes followed by the addition of excess aqueous sodium bicarbonate solution. The layers were separated and the organic layer was washed with brine, dried with sodium sulfate and evaporated to give 13.4 g of product as a dark oil which was used directly in the next steps, that is, in Examples 20 and 21.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH2:10])=[N:5][C:6]([NH2:9])=[CH:7][CH:8]=1)#[CH:2].[C:11]1([S:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26](Cl)=[N:27][OH:28])=[CH:21][CH:20]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>O1CCCC1>[C:11]1([S:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26]3[CH:2]=[C:1]([C:3]4[C:4]([NH2:10])=[N:5][C:6]([NH2:9])=[CH:7][CH:8]=4)[O:28][N:27]=3)=[CH:21][CH:20]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: C#Cc1ccc(N)nc1N
Reactant: ON=C(Cl)Cc1ccc(CSc2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ccc(-c2cc(Cc3ccc(CSc4ccccc4)cc3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.1 %

Procedure:
To a tetrahydrofuran (3 mL) solution of 3-ethynyl-pyridine-2,6-diamine (50 mg, 0.376 mmol) described in Manufacturing Example 13-1-3 and (4-phenylsulfanylmethyl-phenyl)acetohydroximoyl chloride (176 mg, 0.602 mmol) described in Manufacturing Example 206-1-6 was added triethylamine (131 μL, 0.94 mmol), which was stirred for 2 hours at room temperature. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:1, then ethyl acetate) to obtain the title compound (98 mg, 67%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[C:10]([N:17]([CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH:9]=2)[CH2:4][CH2:3]1.[CH2:30]([O:37][C:38]1[CH:39]=[C:40]2[C:44](=[CH:45][CH:46]=1)[NH:43][N:42]=[C:41]2[NH2:47])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>N1C=CC=CC=1>[CH2:30]([O:37][C:38]1[CH:39]=[C:40]2[C:44](=[CH:45][CH:46]=1)[NH:43][N:42]=[C:41]2[NH:47][C:12](=[O:13])[C:11]1[CH:15]=[CH:16][C:8]([N:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)=[CH:9][C:10]=1[N:17]([CH:24]1[CH2:25][CH2:26][O:27][CH2:28][CH2:29]1)[C:18](=[O:23])[C:19]([F:20])([F:22])[F:21])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Nc1n[nH]c2ccc(OCc3ccccc3)cc12
Reactant: CN1CCN(c2ccc(C(=O)Cl)c(N(C(=O)C(F)(F)F)C3CCOCC3)c2)CC1
Solvent: c1ccncc1
Product: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ccc(OCc5ccccc5)cc34)c(N(C(=O)C(F)(F)F)C3CCOCC3)c2)CC1
Reaction time: 3 h
Yield: 75.1 %

Procedure:
4-(4-Methyl-piperazin-1-yl)-2-[(tetrahydro-pyran-4-yl)-(2,2,2-trifluoro-acetyl)-amino]-benzoyl chloride (10.04 mmol), in dry pyridine (100 mL), under a nitrogen atmosphere, cooled to 4° C., was treated with 5-benzyloxy-1H-indazol-3-ylamine (2 g, 8.37 mmol) in pyridine (35 mL) and stirred for 3 hours. The mixture was concentrated in vacuo. The residue was added to iced water (350 mL) and extracted with EtOAc (400 mL and 2×200 mL). The combined organic layers were dried over anhydrous sodium sulfate. After removal of the volatiles a brown solid was obtained that was taken in Et20 (200 mL), stirred 2 hours at room temperature, filtered and dried at 50° C. under vacuum to afford 4 g of title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([CH2:11]Cl)[C:9]=1[Cl:10])=[O:4].[C:13]([O-:16])(=[O:15])[CH3:14].[Na+]>C(O)(=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([CH2:11][O:16][C:13](=[O:15])[CH3:14])[C:9]=1[Cl:10])=[O:4]
Reactant: COC(=O)c1scc(CCl)c1Cl
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1scc(COC(C)=O)c1Cl
Yield: 90 %

Procedure:
To 2-methoxycarbonyl-3-chloro-4-(chloromethyl)thiophene (48 g, 0.21 mol) in glacial acetic acid (500 mL) was added sodium acetate (35 g, 0.42 mol). The reaction was heated at reflux for 24 hours, then cooled and concentrated in vacuo. The residual oil was made basic by addition of saturated aqueous sodium bicarbonate, and the resulting solution extracted with ethyl acetate (4×150 mL). The combined extracts were dried over sodium sulfate and concentrated to afford 47 g (90% yield) of 2-methoxycarbonyl-3-chloro-4-(acetoxymethyl)thiophene as a light brown oil; NMR (CDCl3) 7.6 (s, 1), 5.1 (s, 2), 3.9 (s, 3), 2.1 (s, 3) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=1)[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.CN(C)C=O.CS(O)(=O)=O.[NH2:35][CH2:36][C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][CH:45]=1)[C:42](=[O:46])[N:41]([CH:47]1[CH2:52][CH2:51][C:50](=[O:53])[NH:49][C:48]1=[O:54])[C:40]2=[O:55]>O>[O:54]=[C:48]1[CH:47]([N:41]2[C:40](=[O:55])[C:39]3[C:43](=[CH:44][CH:45]=[C:37]([CH2:36][NH:35][C:8](=[O:10])[C:7]4[CH:11]=[CH:12][C:4]([O:3][CH2:1][CH3:2])=[N:5][CH:6]=4)[CH:38]=3)[C:42]2=[O:46])[CH2:52][CH2:51][C:50](=[O:53])[NH:49]1
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: CCOc1ccc(C(=O)O)cn1
Agent: CS(=O)(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(C(=O)NCc2ccc3c(c2)C(=O)N(C2CCC(=O)NC2=O)C3=O)cn1
Temperature: 40 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
A stirred mixture of 6-ethoxy-nicotinic acid (0.50 g, 3.00 mmol) and CDI (0.54 g, 3.30 mmol) in NAN-dimethylformamide (20 mL) was heated to 40° C. under nitrogen. After 1 h, 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione methane sulfonate (1.15 g, 3.00 mmol) was added and the mixture was heated at 40° C. for 1.5 h. The mixture was cooled to rt and water (40 mL) was added. The solvent was removed in vacuo and the crude product was purified by column chromatography (EtOAc/hexanes). The product fractions were combined, concentrated and the residue was triturated in Et2O (20 mL) for 18 h. The product was isolated by filtration and dried in vacuo to give N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-6-ethoxy-nicotinamide as a white solid (1.11 g, 85% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 3.04 min (98.73%); mp: 243-245° C.; 1H NMR (DMSO-d6) δ 1.33 (t, J=7.1 Hz, 3H, CH3), 1.96-2.16 (m, 1H, CHH), 2.41-2.69 (m, 2H, CHH, CHH), 2.79-3.00 (m, 1H, CHH), 4.37 (q, J=7.1 Hz, 2H, CH2), 4.65 (d, J=5.9 Hz, 2H, CH2), 5.15 (dd, J=5.4, 12.7 Hz, 1H, CH), 6.88 (dd, J=0.7, 8.8 Hz, 1H, Ar), 7.77-7.94 (m, 3H, Ar), 8.16 (dd, J=2.6, 8.7 Hz, 1H, Ar), 8.71 (dd, J=0.8, 2.5 Hz, 1H, Ar), 9.21 (t, J=5.9 Hz, 1H, NH), 11.12 (s, 1H, NH); 13C NMR (DMSO-d6) δ 14.41, 21.99, 30.93, 42.51, 49.01, 61.84, 110.27, 121.99, 123.04, 123.55, 129.82, 131.62, 133.44, 138.18, 147.13, 147.48, 164.79, 165.00, 166.97, 167.12, 169.80, 172.72; LCMS: MH=437; Anal Calcd for C22H20N4O6+0.1H2O: C, 60.30; H, 4.65; N, 12.78. Found: C, 60.08; H, 4.62; N, 12.77.
Reaction SMILES: [I:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:10].[H-].[Na+].Cl[CH2:14][C:15]([CH3:17])=[CH2:16].O>CN(C=O)C>[I:1][C:2]1[C:3]([O:10][CH2:16][C:15]([CH3:17])=[CH2:14])=[CH:4][CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: C=C(C)CCl
Reactant: COc1cccc(O)c1I
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C)COc1cccc(OC)c1I
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
To a solution of 2-iodo-3-(methyloxy)phenol (Intermediate 3, 10.3 g) in DMF (100 ml, SCRC) was added NaH (60%, wt., 1.977 g, 49.4 mmol) portionwise. The reaction mixture was stirred at room temperature for 1 hour and 3-chloro-2-methyl-1-propene (3.73 g, 41.2 mmol, Aldrich) was added. The resulting mixture was stirred at room temperature for 2 hours and water (50 ml) was added. The reaction mixture was extracted with ethyl acetate (3 times 200 ml, SCRC) and the combined organic layer were dried, evaporated and purified by silica gel chromatography with as eluents EtOAc/PE (1/30) to afford the title compound as a yellow liquid (11.6 g)