Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:25][CH:24]=1>ClCCl.C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:27][CH:28]=1)=[O:6]
Reactant: CCOC(=O)CCc1ccc(N)cc1
Reactant: O=C(O)c1cccnc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)CCc1ccc(NC(=O)c2cccnc2Cl)cc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 99.4 %

Procedure:
2-Chloronicotinic acid (1 g, 6.35 mmol) was dissolved in dichloromethane and added with oxalylchloride and a catalytic amount of N,N-dimethylformamide at 0° C. The resulting mixture was refluxed for 3 hours and concentrated under reduced pressure. And then, the obtained acid chloride was dissolved in dichloromethane and cooled to 0° C. Ethyl 3-(4-nitrophenyl)acrylate (1.35 g, 7 mmol) prepared in step 1 and triethylamine were added, and the reaction mixture was stirred at room temperature for 12 hours. The mixture was extracted with chloroform, dried over anhydrous magnesium sulfate, and concentrated to dryness. The residue then was purified by flash column chromatography (chloroform:methanol=10:1) to obtain the title compound (2.1 g, yield: 92%, colorless liquid).
Reaction SMILES: II.[Mg].[C:4]([O:7][C:8]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=1[CH:15](Br)[CH2:16][CH2:17]Br)(=[O:6])[CH3:5].Cl>C1COCC1>[C:4]([O:7][C:8]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=1[CH:15]1[CH2:17][CH2:16]1)(=[O:6])[CH3:5]
Reactant: CC(=O)Oc1c(F)cccc1C(Br)CCBr
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(=O)Oc1c(F)cccc1C1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.6 %

Procedure:
Iodine (catalytic amount) was added to a mixture of magnesium (95.2 mg, 3.96 mmol) and anhydrous THF (2 ml) under a nitrogen atmosphere and the mixture was stirred at room temperature for 30 minutes. Subsequently, a solution of 2-(1,3-dibromopropyl)-6-fluorophenyl acetate (1.17 g, 3.30 mmol) in anhydrous THF (6 ml) was added to the mixture over 10 minutes at 80° C. After the mixture was stirred at 80° C. for 1 hour, the mixture was further stirred at room temperature for 1 hour. The reaction mixture was ice-cooled and 1M hydrochloric acid (15 ml) was added thereto. The mixture was stirred at room temperature for 1 hour and extracted with a 10% ethyl acetate-90% hexane (V/V) solvent mixture (2×20 ml). The organic layer was combined and successively washed with water (3×20 ml) and a saturated aqueous NaCl solution (20 ml), followed by drying with anhydrous sodium sulfate. After the solid was removed by filtration, the filtrate was concentrated to obtain 645 mg of 2-cyclopropyl-6-fluorophenyl acetate as a brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5](Br)[S:4][C:3]=1[O:8][CH3:9].C(=O)=O.CO.B(OCCCC)(OCCCC)OCCCC.C([O-])([O-])=O.[Na+].[Na+].I[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>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.CCCCCC.C1COCC1>[Br:1][C:2]1[CH:6]=[C:5]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[S:4][C:3]=1[O:8][CH3:9]
Reactant: Ic1ccccc1
Reactant: COc1sc(Br)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCCOB(OCCCC)OCCCC
Agent: O=C([O-])[O-]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CO
Product: COc1sc(-c2ccccc2)cc1Br
Temperature: 70 °C
Reaction time: 1 h

Procedure:
250 ml of anhydrous THF was added into 24 g (88 mmol) of 3,5-dibromo-2-methoxythiophene and was cooled to be −78° C. with dry ice-methanol. Then, 56 ml (92 mmol) of a solution containing 15% n-butylithium hexane was slowly dripped into it. After being stirred for 1 hour, 32 ml (123 mmol) of tri-n-butyl borate was slowly dripped into it and stirred for 2 hours. After being returned to a room temperature, 90 ml of 20 wt % Na2CO3, 18 g (88 mmol) of iodobenzene, and 4.4 g (0.36 mmol) of Pd(Ph3P)4 were added to the solution and refluxed for 5 hours at 70° C. The reaction solution was extracted with ether, washed with a salt solution, and dried with addition of magnesium sulfate. The dried extract was condensed after removing magnesium sulfate by filtration. By developing the product with hexane on a silica gel column, a colorless solid 3-bromo-2-methoxy-5-phenylthiophene was obtained (Rf=0.35). The yield was 15 g in weight and 63% in percentage.
Reaction SMILES: C([O:5][C:6](=[O:37])[C@@H:7]1[CH2:11][C@H:10]([N:12](C(OC(C)(C)C)=O)[C:13]([NH2:22])=[N:14]C(OC(C)(C)C)=O)[CH2:9][N:8]1C(OC(C)(C)C)=O)(C)(C)C.[ClH:38]>O1CCOCC1>[ClH:38].[ClH:38].[NH:12]([C@@H:10]1[CH2:9][NH:8][C@H:7]([C:6]([OH:37])=[O:5])[CH2:11]1)[C:13]([NH2:22])=[NH:14]
Reactant: CC(C)(C)OC(=O)N=C(N)N(C(=O)OC(C)(C)C)[C@H]1C[C@@H](C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: N=C(N)N[C@@H]1CN[C@H](C(=O)O)C1

Procedure:
(4S)-1-(tert-Butyloxycarbonyl)-4-[N,N'-bis(tert-butyloxycarbonyl)guanidino]-L-proline tert-butyl ester (55 mg, 0.104 mmol) was treated with 4N HCl in dioxane (2 mL) for 48 hours at room temperature. The reaction mixture was evaporated under diminished pressure, coevaporated several times with diethyl ether and several times with methanol. The product was dried under high vacuum; yield 17.5 mg (98%). Mass spectrum: m/z 173 (M+1); 400 MHz 1H NMR (CD3OD): δ2.20 (m, 1H); 2.89 (m, 1H); 3.38 (dd, 1H); 3.73 (dd, 1H); 4.43 (m, 1H); 4.51 (t, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([NH:9][CH2:10][C:11]([NH:14][C:15](=[O:17])[CH3:16])([CH3:13])[CH3:12])[C:5]([N+:18]([O-])=O)=[C:4]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:3]=1>C1(C)C=CC=CC=1>[NH2:18][C:5]1[C:4]([O:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[N:3][C:2]([CH3:1])=[C:7]([CH3:8])[C:6]=1[NH:9][CH2:10][C:11]([NH:14][C:15](=[O:17])[CH3:16])([CH3:12])[CH3:13]
Reactant: CC(=O)NC(C)(C)CNc1c(C)c(C)nc(Oc2ccccc2)c1[N+](=O)[O-]
Solvent: Cc1ccccc1
Product: CC(=O)NC(C)(C)CNc1c(C)c(C)nc(Oc2ccccc2)c1N
Reaction time: 24 h
Yield: 81.5 %

Procedure:
N-{2-[(2,3-dimethyl-5-nitro-6-phenoxypyridin-4-yl)amino]-1,1-dimethylethyl}acetamide (2.40 g, 6.45 mmol) was dissolved in 20 mL of toluene and treated with 0.2 g of Pt (5% on carbon). The reaction mixture was then shaken under H2 (3 atm) for 24 h. Then reaction mixture was then treated with an additional 1.5 g of Pt (5% on carbon) and shaken an additional 8 h. The reaction mixture was then filtered through Celite, rinsing with toluene, and concentrated to give N-{2-[(3-amino-5,6-dimethyl-2-phenoxypyridin-4-yl)amino]-1,1-dimethylethyl}acetamide (1.80 g) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][NH:17][CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl:30][CH:31]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:32](Cl)=[O:33]>ClCCl>[Cl:30][CH:31]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:32]([N:17]1[CH2:16][C:15]2[CH:14]=[N:13][C:12]3[N:8]([CH2:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:22][CH:21]=4)[N:9]=[CH:10][C:11]=3[C:20]=2[CH2:19][CH2:18]1)=[O:33]
Reactant: O=C(Cl)C(Cl)c1ccccc1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CNCC4)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(Cn2ncc3c4c(cnc32)CN(C(=O)C(Cl)c2ccccc2)CC4)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.3 %

Procedure:
To a solution of 3-(4-methoxybenzyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridine (1.536 g, 5.22 mmol) in anhydrous dichloromethane (20 mL) was added triethylamine (2.18 mL, 15.66 mmol) followed by 2-chloro-2-phenylacetyl chloride (90%, 1.05 mL, 6.52 mmol). The mixture was stirred at room temperature for 1 hour. The reaction was quenched by the addition of water (10 mL). The reaction mixture was extracted with dichloromethane (10 mL) and the organic layer washed with brine (2×10 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by flash column chromatography (SiO2, gradient from 40% EtOAc in hexanes to 50% EtOAc in hexanes) to give the desired product, 2-chloro-1-(3-(4-methoxybenzyl)-8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridin-7(6H)-yl)-2-phenylethanone as an off-white solid (1.99 g, 85%). 1H NMR (400 MHz, DMSO-d6) δ 8.43/8.24 (s, 1H, rotamers), 8.15/8.12 (s, 1H, rotamers), 7.52 (m, 2H), 7.40 (m, 3H), 7.17 (m, 2H), 6.83 (m, 2H), 6.53/6.48 (s, 1H, rotamers), 5.56 (s, 2H), 5.02-4.70 (m, 2H), 3.84 (m, 2H), 3.68 (s, 3H), 3.11/2.67 (m, 2H, rotamers); LCMS [M+H]: 447.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:32]3[C:27](=[CH:28][C:29]([F:34])=[C:30](F)[CH:31]=3)[C:26](=[O:35])[N:25]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:24]2=[O:44])=[CH:19][CH:18]=1>>[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[C:32]3[C:27](=[CH:28][C:29]([F:34])=[C:30]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)[CH:31]=3)[C:26](=[O:35])[N:25]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:24]2=[O:44])=[CH:21][CH:22]=1
Reactant: COc1ccc(-n2c(=O)n(OCc3ccccc3)c(=O)c3cc(F)c(F)cc32)cc1
Reactant: CN1CCNCC1
Solvent: CCN(CC)CC
Product: COc1ccc(-n2c(=O)n(OCc3ccccc3)c(=O)c3cc(F)c(N4CCN(C)CC4)cc32)cc1
Yield: 77.5 %

Procedure:
Using General Method 4, the reaction of N-methylpiperazine (0.17 mL, 1.5 mmol), triethylamine (0.2 mL, 1.5 mmol), and 1-(4-methoxyphenyl)-3-benzyloxy-6,7-difluoro-1H-quinazoline-2,4-dione (Example C-1, 0.20 g, 0.5 mmol) provided 0.19 g of the title compound as a solid.
Reaction SMILES: C1(C2CCCCCCCC2)BCCCCCCC1.[Cl:19][CH2:20][CH2:21][CH2:22][C:23]#[CH:24].NO.[CH2:27]([Zn:29]CC)[CH3:28].CCCCCC>C1COCC1>[CH2:27]([Zn:29][CH:24]=[CH:23][CH2:22][CH2:21][CH2:20][Cl:19])[CH3:28]
Reactant: C#CCCCCl
Reactant: CC[Zn]CC
Agent: B1CCCCCCCC1C1CCCCCCCC1
Agent: NO
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC[Zn]C=CCCCCl
Reaction time: 1 h

Procedure:
A solution of 9-borabicyclononane (0.24 g, 2.0 mmol) in THF (5 mL) was added dropwise to a solution of 5-chloro-1-pentyne (0.21 g, 2.0 mmol) in THF (5 mL). After 1 h, the solvent was removed at reduced pressure. The resultant vinyl boron derivative was dissolved in toluene (5 mL) and aminoalcohol 1 (0.05 g, 0.17 mmol) prepared as in Example 1 was added. Then 1 M diethylzinc in hexane (3 mL, 3 mmol) was added via syringe at −78° C., forming ethyl-(5-chloro-1-pentenyl)zinc in situ. The dry ice bath was replaced with a wet ice bath and immediately a solution of isobutyraldehyde (0.17 g, 2.4 mmol) in hexane (5 mL) was added dropwise. After 1 hour the wet ice bath was removed and the mixture was stirred at room temperature for 8 h. Acetic anhydride (500 μL) was added and the mixture was allowed to stand overnight. GC analysis at 130° C. on Cyclodex B revealed that trans-3-acetoxy-2-methyl-8-chlorooct-4-ene had been formed in 92% enantiomeric excess.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[CH:20][CH:19]=2)[CH2:14][CH2:13]1)=O)C.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[OH:9][CH2:10][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[CH:20][CH:19]=2)[CH2:14][CH2:13]1
Reactant: CCOC(=O)C1CCN(c2ccnc3ccccc23)CC1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCC1CCN(c2ccnc3ccccc23)CC1
Reaction time: 2 h
Yield: 88 %

Procedure:
To a solution of lithium aluminum hydride (267 mg) in tetrahydrofuran (10 ml) was added dropwise 1-(quinolin4-yl)piperidine-4-carboxylic acid ethyl ester (1 g) in tetrahydrofuran (10 ml) under nitrogen atmosphere and with ice-cooling, and the mixture was stirred at the same temperature for 2 hours. After completion of the reaction, aqueous sodium sulfate was added with ice-cooling and the mixture was filtered through celite. The solvent was evaporated and the obtained solid was washed with diisopropyl ether and dried under reduced pressure to give the title compound (750 mg).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH2:8])=[S:7].Cl[CH:15]([C:21]([CH3:23])=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(O)C>[CH2:19]([O:18][C:16]([C:15]1[S:7][C:6]([C:5]2[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:1])([F:12])[F:13])[CH:4]=2)=[N:8][C:21]=1[CH3:23])=[O:17])[CH3:20]
Reactant: NC(=S)c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: CCO
Product: CCOC(=O)c1sc(-c2cccc(C(F)(F)F)c2)nc1C
Yield: 69.8 %

Procedure:
A solution of 3-trifluoromethyl-thiobenzamide (5 g, 23.2 mmol) and ethyl 2-chloro-acetoacetate (3.2 ml, 23.2 mmol) in ethanol (300 ml) was heated at reflux temperature for 14 hours. The solvent was removed under reduced pressure and the residue partitioned between ice water and ethyl acetate. The layers were separated and the aqueous phase extracted two times with ethyl acetate. The combined extracts were washed two times with ice water/brine 1/1 and dried over sodium sulfate. The solvent was removed under reduced pressure to give a yellow oil which was purified by column chromatography (silica gel, cyclohexane/dichloromethane) to yield 5.1 g (16.2 mmol, 70%) of the title compound as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:9]3([CH2:18][O:19][C:5]=2[CH:4]=1)[CH2:14][CH2:13][CH2:12][N:11]1[CH:15]=[N:16][CH2:17][CH:10]31>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:9]3([CH2:18][O:19][C:5]=2[CH:4]=1)[CH2:14][CH2:13][CH2:12][N:11]1[CH:15]=[N:16][CH:17]=[C:10]31
Reactant: COc1ccc2c(c1)OCC21CCCN2C=NCC21
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)OCC21CCCn2cncc21
Temperature: 25 °C

Procedure:
A mixture of 1.9 mmol of 6-methoxy-1′,6′,7′,8a′-tetrahydro-5′H-spiro[1-benzofuran-3,8′-imidazo[1,5-a]pyridine] and 3 g of manganese-dioxide in 50 ml of toluene is heated to reflux for 1.5 hours. The reaction mixture is cooled to room temperature, the solid is removed by filtration over Hyflo and the filtrate is evaporated. From the residue the title compound is identified by means of flash chromatography (SiO2 60F) on the basis of the Rf value.
Reaction SMILES: [ClH:1].[CH:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]1[N:14]3[CH2:15][CH2:16][CH2:17][N:18](C(OC(C)(C)C)=O)[CH2:19][C:13]3=[N:12][C:5]=1[CH:6]=[N:7]2>O1CCOCC1.CO.C(OCC)C>[ClH:1].[CH:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]1[N:14]3[CH2:15][CH2:16][CH2:17][NH:18][CH2:19][C:13]3=[N:12][C:5]=1[CH:6]=[N:7]2
Reactant: CC(C)(C)OC(=O)N1CCCn2c(nc3cnc4ccccc4c32)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: CO
Product: c1ccc2c(c1)ncc1nc3n(c12)CCCNC3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Hydrogen chloride (100 mL of a 4 N solution in 1,4-dioxane) was added to a solution of tert-butyl 11,12-dihydro-8H-[1,4]diazepino[1′,2′:1,2]imidazo[4,5-c]quinoline-9(10H)-carboxylate (9.1 g, 27 mmol) in methanol (60 mL). The reaction was stirred overnight at ambient temperature and then diluted with diethyl ether. A precipitate was present and was isolated by filtration, washed sequentially with dichloromethane and diethyl ether, and dried under vacuum to provide 7.47 g of 9,10,11,12-tetrahydro-8H-[1,4]diazepino[1′,2′:1,2]imidazo[4,5-c]quinoline hydrochloride as a white solid.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[CH2:7]([O:9][CH:10](OCC)[CH2:11][NH2:12])[CH3:8].C(S(O)(=O)=O)(F)(F)F.[OH-].[K+]>O1CCOCC1>[Br:1][C:2]1[S:3][CH:4]=[C:5]2[C:6]=1[CH2:8][CH2:7][O:9][CH:10]2[CH2:11][NH2:12]
Reactant: Brc1cccs1
Reactant: CCOC(CN)OCC
Agent: O=S(=O)(O)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: NCC1OCCc2c1csc2Br
Temperature: 22 °C
Reaction time: 2 h

Procedure:
Bromothiophene (0.31 g, 1.5 mmol) and aminoacetaldehyde diethyl acetal (0.3 g, 2.25 mmol) were combined with 1,4-dioxane (2 mL). CF3SO3H (0.45 g, 3.0 mmol) was added and the reaction mixture was stirred at 22° C. for 2 hr at which time the mixture was made basic with 10% KOH (aq.) and the aqueous layer was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent removed in vacuo to afford the crude amine product.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][CH:5]1[CH2:11][N:10]([CH3:12])[C:9](=[S:13])[C:8]2[CH:14]=[C:15]([N+:18]([O-])=O)[CH:16]=[CH:17][C:7]=2[O:6]1.[NH4+]=S.C(O)C.Cl>O>[NH2:18][C:15]1[CH:16]=[CH:17][C:7]2[O:6][CH:5]([CH2:4][CH2:3][N:2]([CH3:1])[CH3:21])[CH2:11][N:10]([CH3:12])[C:9](=[S:13])[C:8]=2[CH:14]=1
Reactant: CN(C)CCC1CN(C)C(=S)c2cc([N+](=O)[O-])ccc2O1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CN(C)CCC1CN(C)C(=S)c2cc(N)ccc2O1

Procedure:
To 7.0 g (0.023 mole) of 2-[2-(dimethylamino)ethyl]-2,3-dihydro-4-methyl-7-nitro-1,4-benzoxazepine-5(4H)-thione was added 250 ml of 23% ammonium sulfide in water. Ethyl alcohol was added in amount sufficient to dissolve the starting compound (~50-60 ml). The reaction mixture was heated to reflux for 5 hr. After cooling, the reaction mixture was acidified with concentrated aqueous hydrochloric acid. The ethanol was removed by rotary evaporation at 70° C. The remaining aqueous solution was washed with 3×100 ml of chloroform, filtered, cooled with ice and made slightly basic with sodium hydroxide. The aqueous was then extracted with 3×100 ml of chloroform, dried over sodium sulfate, filtered and concentrated by rotary evaporation. The residue was crystallized from isopropyl alcohol to give 3.5 g (55%) of yellow analytically pure crystals.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=2[CH:19]=1.[CH:20]1([C:26]2[CH:31]=[CH:30][C:29]([SH:32])=[CH:28][CH:27]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([C:26]2[CH:27]=[CH:28][C:29]([S:32][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]3[CH:8]=[CH:9][C:10]4[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=4[CH:19]=3)=[CH:30][CH:31]=2)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: Sc1ccc(C2CCCCC2)cc1
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCCl)cc21
Product: CC1(C)OC(=O)Nc2ccc(OCCCCSc3ccc(C4CCCCC4)cc3)cc21

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-cyclohexyl-thiophenol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([S:15](CC3(CN4C(=O)C(C)(C)N(C)C4=O)NC(=O)NC3=O)(=[O:17])=[O:16])[CH2:11][CH2:10]2)=[N:6][CH:7]=1.Cl.ClC1C=CC(OC2CCNCC2)=NC=1.[O:52]=[C:53]1[NH:57][C:56]([CH2:68]S(Cl)(=O)=O)([CH2:58][CH2:59][O:60][CH2:61][C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[C:55](=[O:73])[NH:54]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([S:15]([CH2:68][C:56]3([CH2:58][CH2:59][O:60][CH2:61][C:62]4[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=4)[NH:57][C:53](=[O:52])[NH:54][C:55]3=[O:73])(=[O:17])=[O:16])[CH2:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: O=C1NC(=O)C(CCOCc2ccccc2)(CS(=O)(=O)Cl)N1
Reactant: CN1C(=O)N(CC2(CS(=O)(=O)N3CCC(Oc4ccc(Cl)cn4)CC3)NC(=O)NC2=O)C(=O)C1(C)C
Agent: Cl
Agent: Clc1ccc(OC2CCNCC2)nc1
Product: O=C1NC(=O)C(CCOCc2ccccc2)(CS(=O)(=O)N2CCC(Oc3ccc(Cl)cn3)CC2)N1

Procedure:
The title compound was prepared as described in the synthesis of 5-[({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)methyl]-5-[(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)methyl]imidazolidine-2,4-dione starting from 5-Chloro-2-(piperidine-4-yloxy)-pyridine hydrochloride and (2,5-dioxo-4-{2-[(phenylmethyl)oxy]ethyl}imidazolidin-4-yl)methanesulfonyl chloride.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[N:11][CH:12]=1.[CH2:13]1[O:23][C:16]2([CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]2)[O:15][CH2:14]1.O>C1COCC1>[N:9]1[CH:8]=[C:7]([C:19]2([OH:22])[CH2:20][CH2:21][C:16]3([O:23][CH2:13][CH2:14][O:15]3)[CH2:17][CH2:18]2)[CH:12]=[N:11][CH:10]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Brc1cncnc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: OC1(c2cncnc2)CCC2(CC1)OCCO2
Temperature: 25 °C
Yield: 12.1 %

Procedure:
A solution of n-butyllithium (4.32 mL of 1.6 M solution in hexane, 6.92 mmol) was added to 5-bromopyrimidine (1.0 g, 6.29 mmol) in THF (10 mL) at −78° C. with stirring under N2. After being stirred at −78° C. for 1 h, a solution of 1,4-cyclohexanedione mono-ethylene ketal (0.982 g, 6.29 mmol) in THF (10 mL) was added to the lithiated compound solution via syringe and stirred for 4 h at −78° C. Water (5 mL) was added, and the reaction mixture was warmed to room temperature and extracted using EtOAc (3×). The combined organic layers were dried (MgSO4), filtered, concentrated in vacuo and chromatographed to yield 0.18 g of 8-pyrimidin-5-yl-1,4 dioxaspiro[4,5]decan-8-ol in 12% yield. MS (E) calcd: (M+H)+=237.1; found: 237.2.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[NH:30]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:31][CH2:32][C:33]([OH:35])=O.[C:43]([NH:46][NH2:47])(=[O:45])[CH3:44]>C(Cl)Cl.O>[C:39]([O:38][C:36](=[O:37])[NH:30][CH2:31][CH2:32][C:33]([NH:47][NH:46][C:43](=[O:45])[CH3:44])=[O:35])([CH3:42])([CH3:41])[CH3:40]
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: CC(=O)NN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NNC(=O)CCNC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
EDCI.HCl (3.05 g, 15.95 mmol), HOBt (1.66 g, 12.27 mmol) and triethylamine (2.22 ml, 15.95 mmol) are added to a stirred solution of BOC-β-Ala-OH (2.32 g, 12.27 mmol) in DCM (60 ml). After stirring for 30 min at 0° C. acetic acid hydrazide (1.0 g, 13.5 mmol) is added in one portion. The reaction mixture is stirred at 0° C. for 1 hour. The reaction is diluted with water and extracted several times with DCM. The organic extract is dried (MgSO4) and the solvent is removed to give an oil. Purification by chromatography on silica, eluting with EtOAc increasing to EtOAc:EtOH 10:1, affords the titled compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([O:16][CH3:17])=[CH:11][C:10]=1[NH:18][C:19]1[C:24]([C:25]#[N:26])=[CH:23][N:22]=[C:21]2[CH:27]=[C:28]([C:30]3[CH:35]=[CH:34][C:33]([CH:36]=O)=[CH:32][CH:31]=3)[S:29][C:20]=12.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CN(C)C=O.C(O)(=O)C>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([O:16][CH3:17])=[CH:11][C:10]=1[NH:18][C:19]1[C:24]([C:25]#[N:26])=[CH:23][N:22]=[C:21]2[CH:27]=[C:28]([C:30]3[CH:35]=[CH:34][C:33]([CH2:36][N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[CH:32][CH:31]=3)[S:29][C:20]=12
Reactant: CN1CCNCC1
Reactant: COc1cc(Nc2c(C#N)cnc3cc(-c4ccc(C=O)cc4)sc23)c(Cl)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(Nc2c(C#N)cnc3cc(-c4ccc(CN5CCN(C)CC5)cc4)sc23)c(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 32.5 %

Procedure:
N-methylpiperazine (177 μL, 1.6 mmol) is added to a suspension of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(4-formylphenyl)thieno[3,2-b]pyridine-6-carbonitrile (560 mg, 1.23 mmol) in 12 mL of dichloromethane and 3 mL of N,N-dimethylformamide. The reaction mixture is cooled to 0° C. and sodium triacetoxyborohydride (1.3 g, 6.13 mmol) is added. After stirring at 0° C. for 10 minutes, 3 drops of acetic acid are added and the reaction mixture is allowed to warm to room temperature and stirred for 5.5 hours. The reaction is quenched by the addition of water and then partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The organic layer is washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with 5% methanol in dichloromethane. The fractions containing product are combined and concentrated in vacuo. The residue is washed with diethyl ether to provide 215 mg of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[4-(4-methylpiperazin-1-ylmethyl)phenyl]thieno[3,2-b]pyridine-6-carbonitrile as white crystals, mp 226-228° C.; 1H NMR (DMSO-d6) δ 2.17 (s, 3H), 2.37 (br s, 8H), 3.49 (s, 2H), 3.85 (s, 3H), 7.37 (s, 1H), 7.40 (d, J=8 Hz, 2H), 7.67 (d, J=8 Hz, 2H), 7.76 (s, 1H), 7.89 (s, 1H), 8.60 (s, 1H), 9.73 (s, 1H); MS 538.2 (M+H)+.