Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:25][C:11]3[C:12](=[O:24])[N:13]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=4)[N:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.[CH3:26][N:27]1[CH2:32][CH2:31][CH:30]([OH:33])[CH2:29][CH2:28]1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:19]([OH:23])(=[O:33])[CH3:20].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:25][C:11]3[C:12](=[O:24])[N:13]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH:30]5[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]5)[CH:18]=4)[N:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=c1c2sc(-c3ccc(Cl)cc3)cc2cnn1Cc1cccc(O)c1
Reactant: CN1CCC(O)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Product: CC(=O)O
Product: CN1CCC(Oc2cccc(Cn3ncc4cc(-c5ccc(Cl)cc5)sc4c3=O)c2)CC1
Yield: 32.8 %

Procedure:
2-(4-Chlorophenyl)-6-(3-hydroxybenzyl)thieno[2,3-d]pyridazin-7(6H)-one (0.082 g, 0.22 mmol), 1-methylpiperidin-4-ol (0.050 g, 0.43 mmol) and TPP (0.107 g, 0.41 mmol) were stirred in THF (3 mL) at 0° C. DEAD (0.2 mL, 40% in toluene, 0.44 mmol) was added and the resulting mixture was allowed to attain room temperature and the stirring was continued over night. Concentration and purification on C8-HPLC (0.1% HOAc, gradient 30→40% CH3CN) gave 0.019 g (16%) of the title compound. 1H NMR (400 MHz, CDCl3/MeOH-d4 1:1, internal standard: MeOH-d4) δ 8.30 (s, 1H), 7.66 (d, 2H, J=8.5 Hz), 7.59 (s, 1H), 7.43 (d, 2H, J=8.5 Hz), 7.22 (t, 1H, J=7.9 Hz), 7.03 (m, 2H), 6.83 (d, 1H, J=7.7 Hz), 5.39 (s, 2H), 4.53 (br, 1H), 3.07-2.86 (m, 4H), 2.59 (s, 3H), 2.16-1.94 (m, 4H), 1.97 (s, 3H). 13C NMR (100 MHz, CDCl3/MeOH-d4 1:1, internal standard: MeOH-d4) δ 177.1, 157.9, 157.5, 153.2, 141.2, 138.8, 136.5, 136.3, 134.7, 131.6, 130.4, 130.1, 128.6, 122.1, 119.9, 116.8, 115.8, 69.1, 51.1, 44.4, 28.8, 22.3. MS (ESI+) 466.1 (M+1H+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:14].[CH:15](N(C(C)C)CC)(C)C.ClC(OC)=O.NC1C=CC=CC=1.[Cl:36][C:37]1[CH:38]=[CH:39][C:40]2[N:46]([CH3:47])[C:45](=[O:48])[CH:44]([N:49]=[C:50]=[S:51])[N:43]=[C:42]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=3[Cl:58])[C:41]=2[CH:59]=1>C(Cl)Cl>[Cl:36][C:37]1[CH:38]=[CH:39][C:40]2[N:46]([CH3:47])[C:45](=[O:48])[CH:44]([NH:49][C:50](=[S:51])[N:14]([CH3:15])[C:3]3[CH:4]=[CH:5][C:6]([N:8]4[CH2:9][CH2:10][O:11][CH2:12][CH2:13]4)=[CH:7][C:2]=3[CH3:1])[N:43]=[C:42]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=3[Cl:58])[C:41]=2[CH:59]=1
Reactant: CN1C(=O)C(N=C=S)N=C(c2ccccc2Cl)c2cc(Cl)ccc21
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1cc(N2CCOCC2)ccc1N
Agent: COC(=O)Cl
Solvent: Nc1ccccc1
Solvent: ClCCl
Product: Cc1cc(N2CCOCC2)ccc1N(C)C(=S)NC1N=C(c2ccccc2Cl)c2cc(Cl)ccc2N(C)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
A solution of 2-methyl4-(4-morpholinyl)benzenamine (53.3 mg, 0.277 mmol) and diisopropylethylamine (0.063 mL, 0.36 mmol) in CH2Cl2 (1 mL) was cooled to 0° C. Methyl chloroformate (0.024 mL, 0.31 mmol) was added dropwise, and then the reaction was allowed to warm to room temperature and stir overnight. The reaction was diluted with CH2Cl2 (20 mL) and washed with brine (10 mL). The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was then suspended in a 1:2 mixture of Et2O:THF (6 mL). A solution of LiAlH4 in Et2O (0.34 mL of a 1 M solution, 0.34 mmol) was added dropwise, and then the reaction mixture was heated to reflux for 1.5 h. The reaction was cooled, diluted with additional Et2O (8 mL), and quenched with Na2SO45H2O (0.98 g, 4.2 mmol). After stirring for 15 minutes, the mixture was filtered and the reaction was concentrated in vacuo. A portion of this crude aniline (0.0580 g, 0.281 mmol) was dissolved in (CH2Cl)2 (8 mL), and 7-chloro-5-(2-chlorophenyl)-1,3-dihydro-3-isothiocyanato-1-methyl-2H-1,4-benzodiazepin-2-one (0.106 g, 0.281 mmol) was added. The resulting mixture was heated at 70° C. for 14 h. The reaction was cooled and concentrated in vacuo, and the residue was purified by silica gel column chromatography (7:1 CH2Cl2:EtOAc) to provide the title compound (0.1211 g, 74%). Due to hindered rotation about one of the bonds, rotamers were observed in the 1H-NMR spectrum. 1H-NMR (CDCl3): δ 7.77-7.68 (m, 1H), 7.51 (dd, J=2.4 Hz, J=8.8 Hz, 1H), 7.43-7.36 (m, 2H), 7.34-7.28 (m, 2H), 7.16 (t, J=8.4 Hz, 1H), 7.10-7.01 (m, 2H), 6.86-6.76 (m, 2H), 6.14 and 6.10 (2×d, J=8.0 Hz, J=7.6 Hz, 1H), 3.88-3.82 (br m, 4H), 3.60 and 3.59 (2×s, 3H), 3.41 (s, 3H), 3.19 (br s, 4H), 2.24 and 2.23 (2×s, 3H). MS (ESI) (M+H)+=582. HRMS calculated for (C29H29Cl2N5O2S+H) (M+H)+: 582.1497. Found (ESI): 582.1448.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[CH3:8][C:9]([CH3:11])=O.C(=O)([O-])[O-].[K+].[K+]>>[CH3:8][C:9]1([CH3:11])[N:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][O:4]1
Reactant: CC(C)=O
Reactant: OCCNCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC1(C)OCCN1CCO
Temperature: 37 °C
Reaction time: 20 h
Yield: 74.8 %

Procedure:
A mixture of 526 g (5.0 moles) of diethanolamine, 581 g (10 moles) of acetone and 690 g (5.0 moles) of anhydrous potassium carbonate are allowed to stir for 20 hours. During the first two hours the solution temperature gradually increases to a maximum of 37° C. The mixture is filtered and the collected solid is washed with 500 ml of acetone. The filtrate and wash are combined, the solvent distilled off under reduced pressure, and the residue distilled under reduced pressure. There is obtained 543 g (75%) of a colorless liquid, b.p. 89°-92°/8 mm, nD26 1.4614, neutralization equivalent 144.5 (calculated 145.2).
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:18]=[CH:17][S:16][C:5]=3[C:6](=[O:15])[NH:7][C:8]=2[C:9]([CH3:14])=[CH:10][C:11]=1[O:12][CH3:13].[F:19][C:20]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[CH:22][C:21]=1[C:35]([CH3:46])([CH3:45])[CH2:36][NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41]>>[F:19][C:20]1[CH:25]=[C:24]([C:2]2[C:3]3[C:4]4[CH:18]=[CH:17][S:16][C:5]=4[C:6](=[O:15])[NH:7][C:8]=3[C:9]([CH3:14])=[CH:10][C:11]=2[O:12][CH3:13])[CH:23]=[CH:22][C:21]=1[C:35]([CH3:46])([CH3:45])[CH2:36][NH:37][C:38](=[O:44])[O:39][C:40]([CH3:42])([CH3:41])[CH3:43]
Reactant: CC(C)(C)OC(=O)NCC(C)(C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Reactant: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1Br
Product: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)(C)CNC(=O)OC(C)(C)C)c(F)c1
Yield: 55.3 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxy-6-methylthieno[2,3-c]quinolin-4(5H)-one (150 mg, 0.46 mmol) was reacted with tert-butyl 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-methylpropylcarbamate (270 mg, 0.64 mmol) to afford the desired product (130 mg, 56%) as a light brown solid: ESI MS m/z 511 [C28H31FN2O4S+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][CH2:12][C:11](=O)[CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[C:16]1([C@@H:22]([NH2:24])[CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[H][H]>[Ni].C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][CH2:12][CH:11]([NH:24][CH:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:23])[CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C2CCCC(=O)C2)c1
Reactant: [H][H]
Reactant: C[C@H](N)c1ccccc1
Agent: [Ni]
Solvent: CCO
Product: COc1cccc(C2CCCC(NC(C)c3ccccc3)C2)c1
Temperature: 25 °C
Yield: 52.2 %

Procedure:
Raney nickel (0.5 g) was added to a solution of 3-(3-methoxyphenyl)cyclohexanone (2.05 g) and (S)-1-phenylethylamine (1.22 g) in ethanol (20 ml) prior to room temperature stirring and hydrogen addition. After the starting materials were consumed, the catalyst was filtered off, and the filtrate was distilled off under reduced pressure to produce a light yellow oily substance which was then separated and purified by silica gel column chromatography (chloroform:methanol=50:1) to give 1.62 g of N-[3-(3-methoxyphenyl) cyclohexyl]-N-(1-phenylethyl)amine (a mixture of trans-H form and trans-L form) (52.5% yield). The proportion of trans form to cis form with this reaction was about 12 to 1 (confirmed by HPLC) . Repeated column chromatography enabled separation of trans-H and trans-L.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:7])([CH3:6])[CH2:4][OH:5].[Cl:8][C:9]1[CH:10]=[C:11]([CH:15]([OH:36])[CH2:16][NH:17][CH:18]([CH3:35])[CH2:19][C:20]2[CH:34]=[CH:33][C:23]3[O:24][C:25]([C:30](O)=[O:31])([C:27]([OH:29])=[O:28])[O:26][C:22]=3[CH:21]=2)[CH:12]=[CH:13][CH:14]=1.[K+].[Br-].Cl>>[OH:1][CH2:2][C:3]([CH3:7])([CH3:6])[CH2:4][O:5][C:30]([C:25]1([C:27]([O:29][CH2:4][C:3]([CH3:7])([CH3:6])[CH2:2][OH:1])=[O:28])[O:24][C:23]2[CH:33]=[CH:34][C:20]([CH2:19][C@H:18]([NH:17][CH2:16][C@@H:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[CH:10]=3)[OH:36])[CH3:35])=[CH:21][C:22]=2[O:26]1)=[O:31]
Reactant: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)NCC(O)c1cccc(Cl)c1
Reactant: CC(C)(CO)CO
Agent: Cl
Agent: [Br-]
Agent: [K+]
Product: C[C@H](Cc1ccc2c(c1)OC(C(=O)OCC(C)(C)CO)(C(=O)OCC(C)(C)CO)O2)NC[C@H](O)c1cccc(Cl)c1

Procedure:
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid 3-hydroxy-2,2-dimethyl-propanol according to the procedure of Example 1 as an off-white solid; 1H NMR (DMSO-d6,400 MHz) δ0.78 (s, 12H, 4×CH3), 1.09 (d, J=6.4 Hz, 3H, CH3), 2.6 (m, 1H, CH), 3-3.3 (m, 7H, CH, CH2), 3.4 (brs, 1H, CH), 4.04 (s, 4H, OCH2, OCH2),4.65 (m, 2H, OH), 5.05 (m, 1H, CH), 6.34 (d, J=4.17 Hz, 1H, OH), 6.85 (dd, J=7.9, 1.53 Hz, 1H, Ar--H), 7.07 (m, 2H, Ar--H), 7.37-7.42 (m, 3H, Ar--H), 7.48 (s, 1H, Ar--H), 8.78 (brs, 1H, NH), 9.2 (brs, 1H, NH); IR (KBr, cm-1) 3400 (OH), 2900 (NH), 1760 (CO); MS m/e 594 (M+H)+ ; Analysis for: C30H40ClNO9 ×HCl: Calc'd: C, 57.14; H, 6.55; N, 2.22; Found: C, 56.44; H, 6.62; N, 2.38.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[N:12]1[CH:16]=[C:15]([C:17]#[N:18])[N:14]=[CH:13]1.C(O)(=O)C.[OH-].[Na+]>CCO.O.[Fe]>[C:17]([C:15]1[N:14]=[CH:13][N:12]([C:4]2[CH:5]=[CH:6][C:7]([NH2:9])=[CH:8][C:3]=2[O:2][CH3:1])[CH:16]=1)#[N:18]
Reactant: COc1cc([N+](=O)[O-])ccc1-n1cnc(C#N)c1
Agent: [Fe]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: COc1cc(N)ccc1-n1cnc(C#N)c1
Reaction time: 2 h

Procedure:
To a solution of 1-(2-methoxy-4-nitrophenyl)-1H-imidazole-4-carbonitrile (689 mg, 2.82 mmol) in EtOH (Ratio: 2, Volume: 15 mL) was added Acetic Acid (Ratio: 1.000, Volume: 7.50 mL) and Iron (630 mg, 11.29 mmol). The resulting mixture was brought to 100° C. and stirred for 2 h. The reaction was then diluted with water and brought to pH 8 by the addition of 1 N aqueous sodium hydroxide. This mixture was extracted with EtOAc (3×5 mL). The combined extracts were washed with water (5 mL), brine (5 mL), dried over MgSO4, filtered and concentrated in vacuo. LC-MS (M+H)+=215.0.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10](SC)[N:9]=2)[CH:5]=[CH:4][N:3]=1.O[O:17][S:18]([O-:20])=O.[K+].[C:22]([O-])(O)=O.[Na+]>CO>[CH3:22][S:18]([C:10]1[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=2)[CH:13]=[CH:12][N:11]=1)(=[O:20])=[O:17]
Reactant: O=C([O-])O
Reactant: O=S([O-])OO
Reactant: CSc1nccc(-c2ccnc(C)c2)n1
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(-c2ccnc(S(C)(=O)=O)n2)ccn1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 65 %

Procedure:
A solution of 4-(2-methyl-pyridin-4-yl)-2-methylsulfanyl-pyrimidine (990 mg, 4.56 mmol) in MeOH (35 ml) was cooled at 0° C. and then an aqueous solution of oxone (8.41 g, 13.85 mmol in 35 ml of water) was slowly added. After stirring 3.5 hours at room temperature, the mixture was basified with solid NaHCO3 and the product was extracted with ethyl acetate. The organic phase was dried (Na2SO4) and evaporated to give 720 mg of the title compound that was used in the next step without further purification (65% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10](=[O:21])[C:11]3[CH2:12][N:13]([CH2:17][C:18](=O)[CH3:19])[CH2:14][CH2:15][C:16]=3[C:7]=2[CH:6]=[CH:5][C:4]=1[O:22][CH3:23].[CH2:24]([NH2:26])[CH3:25]>>[CH2:24]([NH:26][CH:18]([CH3:19])[CH2:17][N:13]1[CH2:14][CH2:15][C:16]2[C:7]3[CH:6]=[CH:5][C:4]([O:22][CH3:23])=[C:3]([O:2][CH3:1])[C:8]=3[O:9][C:10](=[O:21])[C:11]=2[CH2:12]1)[CH3:25]
Reactant: CCN
Reactant: COc1ccc2c3c(c(=O)oc2c1OC)CN(CC(C)=O)CC3
Product: CCNC(C)CN1CCc2c(c(=O)oc3c(OC)c(OC)ccc23)C1
Yield: 55.4 %

Procedure:
Prepared by the method described in Example 49 from 1,2,3,4-tetrahydro-7,8-dimethoxy-3-(2-oxopropyl)-5H-benzopyrano[3,4-c]-pyridin-5-one (49.6 g, 0.16 moles) and ethylamine (21.2 g, 0.47 moles). Recrystallization from ethyl acetate/hexane yielded the product (30.7 g) as the free base, mp 125°-127° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([CH3:35])=[C:15]([N:17]3[C:26](=[O:27])[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([N:28]5[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]5)[CH:24]=4)[N:19]=[CH:18]3)[CH:16]=2)=[O:9])[CH:5]=[CH:4][N:3]=1.[NH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1>O>[CH3:35][C:14]1[CH:13]=[CH:12][C:11]([NH:10][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[CH:7]=2)=[O:9])=[CH:16][C:15]=1[N:17]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([N:28]3[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]3)[CH:24]=2)[N:19]=[CH:18]1
Reactant: C1CCNC1
Reactant: Cc1ccc(NC(=O)c2ccnc(Cl)c2)cc1-n1cnc2ccc(N3CCN(C)CC3)cc2c1=O
Solvent: O
Product: Cc1ccc(NC(=O)c2ccnc(N3CCCC3)c2)cc1-n1cnc2ccc(N3CCN(C)CC3)cc2c1=O
Temperature: 100 °C

Procedure:
A mixture of 3-[5-(2-chloropyrid-4-ylcarbonylamino)-2-methylphenyl]-6-(4-methylpiperazin-1-yl)-3,4-dihydroquinazolin-4-one (0.18 g) and pyrrolidine (2 ml) was stirred and heated to 100° C. for 16 hours. The mixture was cooled to ambient temperature and poured into water. The resultant solid was isolated, washed with water and dried under vacuum at 40° C. There was thus obtained the title compound (0.11 g); NMR Spectrum: (DMSOd6) 1.94-1.97 (m, 4H), 2.04 (s, 3H), 2.22 (s, 3H), 2.45-2.49 (m, 4H), 3.25-3.28 (m, 4H), 3.4-3.45 (m, 4H), 6.85 (s, 1H), 6.96 (d, 1H), 7.42 (d, 1H), 7.42 (d, 1H), 7.44 (s, 1H), 7.62 (s, 2H), 7.77-7.79 (m, 2H), 8.07 (s, 1H), 8.2 (s, 1H), 10.42 (s, 1H); Mass Spectrum: M+H+ 524.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[C@@H:4]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:5][C:6]1[CH:31]=[CH:30][C:9]2[O:10][C@@H:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=4)=[CH:16][CH:15]=3)[CH2:12][O:13][C:8]=2[CH:7]=1.[CH2:41](Cl)Cl>O1CCOCC1>[CH3:1][O:2][C:3]([C@@H:4]1[CH2:5][C:6]2[CH:7]=[C:8]3[O:13][CH2:12][C@H:11]([C:14]4[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]5[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=5)=[CH:18][CH:19]=4)[O:10][C:9]3=[CH:30][C:31]=2[CH2:41][N:32]1[C:33]([O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:34])=[O:40]
Reactant: ClCCl
Reactant: COC(=O)[C@H](Cc1ccc2c(c1)OC[C@H](c1ccc(OCc3ccc(Cl)c(Cl)c3)cc1)O2)NC(=O)OC(C)(C)C
Solvent: C1COCCO1
Product: COC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Temperature: 0 °C

Procedure:
(S)-2-tert-Butoxycarbonylamino-3-{(S)-2-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxin-6-yl}-propionic acid methyl ester (4.9 g) was dissolved in 200 mL dry DCM and stirred on 0° C. bath. 100 mL 4NHCL in dioxane was added and the mixture stirred to rt over 3 h. The solvents were evaporated and the residue was evaporated from diethyl ether 4 times. 4 g of the residue was dissolved in 250 mL dry dioxane and 462 mg paraformaldehyde was added while stirring. Then 62.5 mL trifluoroacetic acid was added and the mixture was stirred 1.5 h. The solvents were then evaporated and the residue was dissolved in 250 mL EtOAc and 250 mL saturated aqueous NaHCO3, and 4.2 g di-t-butyl dicarbonate was added and stirred 18 h at rt. The layers were then separated and the organic layer was washed with brine, dried with Na2SO4, and evaporated. The residue was purified by silica gel flash chromatography (9:1 to 7:3 hexanes/EtOAc) to give 3.25 g after drying under vacuum. 1H NMR (400 MHz, acetone-d6): 7.72(d, 1H), 7.61(d, 1H), 7.51-7.42(m, 3H), 7.12-7.07(m, 2H), 0.680-6.70(m, 2H), 5.20(s, 2H), 5.13-5.07(m, 1H), 5.02 and 4.76(m, 1H), 4.66-4.52(dd, 1H), 4.42(d, 1H), 4.36-4.30(m, 1H), 4.01(m, 1H), 3.64 and 3.60(s, 3H), 3.18-3.00(m, 2H), 1.49 and 1.43(s, 9H).
Reaction SMILES: [C@@H:1]1([N:10]2[C:14]3[N:15]=[N:16][NH:17][C:18](=[O:19])[C:13]=3[N:12]=[CH:11]2)[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@H:2]1[OH:3]>N1C=CC=CC=1.O>[C:2]([O:3][C@@H:2]1[C@H:4]([O:5][C:4](=[O:5])[CH3:6])[C@@H:6]([CH2:8][O:9][C:18](=[O:19])[CH3:13])[O:7][C@H:1]1[N:10]1[C:14]2[N:15]=[N:16][NH:17][C:18](=[O:19])[C:13]=2[N:12]=[CH:11]1)(=[O:3])[CH3:1]
Reactant: O=c1[nH]nnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(=O)[nH]nnc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 20 °C
Reaction time: 16 h
Yield: 121.6 %

Procedure:
The compound from Step A (1.68 gr, 6.24 mmol) was stirred in pyridine (20 mL). The anhydride acetic (2.3 ml, 25 mmol) was added and the mixture was stirred at 20° C. for 16 hours. The mixture was evaporated to dryness to give a syrup which was dissolved in water. The aqueous layer was extracted by acetyl acetate. The organic layer was evaporated to dryness to give the title compound (1.5 gr) as a brown foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:20])[CH:5]=[C:6]([Cl:19])[C:7]=1[O:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:12]=2[N:13]=1.[N+:21]([C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[S:34](Cl)(=[O:36])=[O:35])([O-:23])=[O:22]>>[Cl:19][C:6]1[CH:5]=[C:4]([NH:20][S:34]([C:25]2[CH:26]=[CH:27][C:28]([C:30]([F:32])([F:33])[F:31])=[CH:29][C:24]=2[N+:21]([O-:23])=[O:22])(=[O:35])=[O:36])[CH:3]=[C:2]([Cl:1])[C:7]=1[O:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1S(=O)(=O)Cl
Reactant: Nc1cc(Cl)c(Oc2nc3ccc(Cl)cc3s2)c(Cl)c1
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1S(=O)(=O)Nc1cc(Cl)c(Oc2nc3ccc(Cl)cc3s2)c(Cl)c1

Procedure:
N-[3,5-Dichloro-4-(6-chloro-benzothiazol-2-yloxy)-phenyl]-2-nitro-4-trifluoromethyl-benzenesulfonamide was synthesized (48%) from 3,5-dichloro-4-(6-chloro-benzothiazol-2-yloxy)-phenylamine (420) and 2-nitro-4-trifluoromethylbenzenesulfonyl chloride (Aldrich) in a similar manner as described in Examples 70-91. 1H NMR (400 MHz, DMSO-d6) δ 11.65 (br s, 1H), 8.61 (s, 1H), 8.32-8.28 (m, 2H), 8.15 (d, J=2.2 Hz, 1H), 7.68 (d, J=8.7 Hz, 1H), 7.46 (dd, J=8.7, 2.2 Hz, 1H), 7.34 (s, 2H). MS (EI): m/z 596 (M−H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[C:4]([O:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:3]=1.C([Li])CCC.CN(C)[CH:23]=[O:24].B(F)(F)F.CCOCC>O1CCCC1.CCCCCC>[CH:11]1([O:10][C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=2[S:8][CH3:9])[CH:23]=[O:24])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CN(C)C=O
Reactant: CSc1ccc(Br)cc1OC1CCCC1
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CSc1ccc(C=O)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-bromo-2-cyclopentyloxy-1-(methylthio)benzene (13.2 g) in dry tetrahydrofuran (100 mL) under nitrogen is treated at -70° C. with a solution of butyllithium in hexane (20.24 mL; 2.5M) and the resulting solution is stirred for 1 hour at this temperature. It is then treated with dimethylformamide (7.12 mL), followed by boron trifluoride diethyl etherate (11.32 mL), keeping the temperature at -65° C. When the addition is complete the reaction mixture is allowed to warm to room temperature and is then poured into ice-water (450 mL) and extracted with dichloromethane (3×400 mL). The combined extracts are dried over magnesium sulfate and concentrated to give an oil, which is subjected to flash chromatography, eluting with a mixture of dichloromethane and cyclohexane (3:7 v/v), to give 3-cyclopentyloxy-4-(methylthio)-benzaldehyde (6.2 g). [NMR (DMSO): 9.91(S,1H),7.53(dd, 1H),7.36(d,1H), 7.33(d,1H),5.01 (m,1H),2.44(s,3H),2.0-1.5(m,8H)].
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[S:4][CH2:3]1.C(#N)C.[CH2:25]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([CH2:41][CH2:42][CH2:43][CH2:44][CH:45](Cl)[C:46]([O:48][CH2:49][CH3:50])=[O:47])[CH2:37][CH2:36]1)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[I-].[K+]>C(N(CC)CC)C>[CH2:25]([O:32][C:33]([N:35]1[CH2:36][CH2:37][CH:38]([CH2:41][CH2:42][CH2:43][CH2:44][C@@H:45]([NH:1][C@@H:2]2[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[C:6]3[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=3[S:4][CH2:3]2)[C:46]([O:48][CH2:49][CH3:50])=[O:47])[CH2:39][CH2:40]1)=[O:34])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1.[CH2:25]([O:32][C:33]([N:35]1[CH2:36][CH2:37][CH:38]([CH2:41][CH2:42][CH2:43][CH2:44][C@H:45]([NH:1][C@@H:2]2[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[C:6]3[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=3[S:4][CH2:3]2)[C:46]([O:48][CH2:49][CH3:50])=[O:47])[CH2:39][CH2:40]1)=[O:34])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCOC(=O)C(Cl)CCCCC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N)CSc2ccccc21
Agent: [I-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)[C@@H](CCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@H]1CSc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Product: CCOC(=O)[C@H](CCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@H]1CSc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Temperature: 80 °C
Reaction time: 72 h

Procedure:
A mixture of tert-butyl 3(R)-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate (3.0 g), acetonitrile (100 ml), ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)-2-chlorohexanoate (4.0 g), triethylamine (1.0 g) and potassium iodide (1.6 g) is stirred for 3 days at 80° C. Ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)-2-chlorohexanoate (2.0 g) and potassium iodide (0.8 g) are added, and the stirring is continued for further 1 day at 80° C. The mixture is concentrated in vacuo, diluted with water (100 ml) and extracted with ethyl acetate (300 ml). The extract is washed with water, dried over anhydrous magnesium sulfate and evaporated in vacuo. Purification of the residual oil by silicagel column chromatography (hexane:ethyl acetate=2:1) gives tert-butyl 3(R)-[5-(1-benzyloxycarbonyl-4-piperidyl)-1(R)-ethoxycarbonylpentyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate (3.1 g) as a colorless oil and tert-butyl 3(R)-[5-(1-benzyloxycarbonyl-4-piperidyl)-1 (S)-ethoxycarbonylpentyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate (2.1 g) as a colorless oil.
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[C:12]([C:15]([F:18])([F:17])[F:16])[NH:11][C:10]=2[C:9](=[O:19])[NH:8][C:7]1=[S:20])[CH2:2][CH2:3][CH2:4][CH3:5].[OH-].[Na+].S(OC)(O[CH3:27])(=O)=O>O>[CH3:27][S:20][C:7]1[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:14]2[N:13]=[C:12]([C:15]([F:18])([F:16])[F:17])[NH:11][C:10]=2[C:9](=[O:19])[N:8]=1
Reactant: CCCCCn1c(=S)[nH]c(=O)c2[nH]c(C(F)(F)F)nc21
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCn1c(SC)nc(=O)c2[nH]c(C(F)(F)F)nc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93.7 %

Procedure:
To the solution of 3-pentyl-2-thioxo-8-(trifluoromethyl)-1,2,3,7-tetrahydro-6H-purin-6-one (600 mg, 2 mmol) in a 2 M solution of sodium hydroxide in water (12.0 mL) was added dimethyl sulfate (0.30 mL, 3.2 mmol). The reaction mixture was stirred at room temperature for 1.5 h and quenched with acetic acid. The resulting solution was extracted with methylene chloride three times. The combined organic layer was dried, filtered and concentrated to give the desired product (0.60 g, 95.6%). LCMS calculated for C12H16F3N4OS: (M+H) 321.1. found 321.1.